Amboss Neurology

Neurological examination

Mental status examination Levels of consciousness Types of impaired consciousness Somnolencedrowsiness from which a patient can be easily arousedPatient responds normally except for a slight delay when addressedStuporA state of insensitivity bordering on unconsciousness; patient is not easily awoken except if exposed to strong external stimuli; into which the patient returns in the absence of further stimulipainful stimulus provokes withdrawal responseComa: Patient cannot be aroused and there is no response to stimuli Glasgow Coma Scale (GCS) quantifies the degree of impaired consciousness Mental status examination Full mental status examination components include: AppearanceBehaviorSpeechOrientation to person, place, and timeMood and affectThought contentMemoryperform simple calculationsInsight and judgementHigher cortical functionlevels of consciousness Mini-mental status examination (MMSE) Findings HemineglectInability to respond to unilateral stimuli due to a brain lesionThe lesion is usually contralateral to the stimuli Motor neglectSensory or perceptual neglect Amnesia: loss of memory (e.g., time, content) Retrograde amnesiaAnterograde amnesiaGlobal amnesia Aphasia: Inability to communicate Broca aphasia (motor aphasia, expressive aphasia)Broca area (frontal lobe)Telegraphic and grammatically incorrect nonfluentspeechComprehension is largely spared (difficulty understanding complex language may occur)The patient is typically aware of the deficitsWernicke aphasia (sensory aphasia, receptive aphasia)Wernicke area (temporal lobe)Fluent speech that lacks meaning (paraphasic errors, neologisms, word salad)Comprehension is impairedThe patient is typically unaware of the deficitsGlobal aphasiaBroca area, Wernicke area, and arcuate fasciculusSevere impairment of speech production and comprehensionPatient may be mute or only utter soundsInability to comprehend speechConduction aphasia (associative aphasia)Arcuate fasciculus of the parietal lobeMostly intact comprehension and fluent speech productionImpaired repetition with paraphasia (they substitute or transpose sounds), which patients try to correctAnomic aphasiaUsually, pinpointing the localization of the lesion is not possible.Isolated difficulty finding wordsParaphrasing occurs when patients cannot find the word they seek.Transcortical aphasiaTranscortical motor aphasiaSupplementary motor area (SMA) in the cortex, with Broca areaintact (exception: may occur during recovery phase of Broca aphasia)Difficulty initiating speechDifficulty in expressing a thought processDifficulty producing own phrasesTranscortical sensory aphasiaVarious areas of the temporal lobe, with Wernicke area intactImpaired speech expression and comprehension Intact echolaliaErrors in paraphrasingPoor comprehension Apraxia: difficulty performing targeted, voluntary movements despite intact motor function Agnosia: Impairment of recognition of sensory stimulus (most commonly visual) Anosognosia: inability to recognize one's own neurologic impairment Olfactory nerve IOlfactionTest the patient's ability to detect and identify an aroma in each nostril Optic nerveIIVisual acuityAsk the patient to read from a Snellen chart using one eye at a time, correct for refractive errors with glasses or a pinhole Test color vision with Ishihara platesVisual fieldAssess each eye by confrontation using a finger or red pinMore accurate testing uses perimetryPupillary light reflexThe examiner shines a light into the patient's eye (e.g., a penlight).A prompt, consensual response should normally be observable.Pupillary shape and width: Healthy pupils are isocoric and of medium width; anisocoric and/or narrow/wide are suggestive of a disorder (see pupillary disorders).PapillaFundoscopic examination (e.g., a pale optic disk is indicative of optic nerve atrophy) Oculomotor nerve, trochlear nerve, abducens nerveIII, IV, VIEye movementPatients are asked to follow a finger moving up, down, laterally, and diagonally with their eyes.Observe if there is paresis, alterations in smooth pursuit appear, or nystagmus, Visual accommodationThe physician moves a finger towards the patient, a normal response is constriction of the pupil.Eyelid ptosis (Levator palpebrae superioris muscle dysfunction)The patient is asked to open and close the eyes. Trigeminal nerveVFacial sensationThe examiner lightly touches three distinct facial areas (the forehead, cheek, and jaw ).Normally, light touch should be felt by the patient in all three areas.If this is not the case, tests for abnormalities of other sensory modalities (e.g., pain, temperature) should be performed.Muscle function (muscles of mastication)The patient is asked to open and close his/her mouth; at the same time, the examiner palpates the masseter muscle.ReflexesMasseter reflex (jaw jerk reflex) A finger is placed on the patient's chin, while the patient's mouth remains slightly openTapping with a reflex hammer normally induces jaw closureIf jaw closure is increased, suspect an UMN lesionCorneal reflexThe cornea is lightly touched with a cotton swab (approaching slowly and sideways from the lid edge)Touch normally induces closing of the eyelid. Facial nerveVIIMotor function (muscles of expression)If motor function is intact, the patient should be able to perform the following: Forehead wrinklingClosing the eyes tightlyNose wrinklingInflate the cheeksSmiling (showing teeth)WhistlingSense of tasteIf the sense is intact, the patient should be able to taste sweet, salty, and sour food/drinks. Vestibulocochlear nerveVIIIHearingBasic hearing test: normally, the patient should be able to hear two fingers rubbing together before the external acoustic meatus (ear canal).The Weber test and Rinne test allow sensorineural hearing loss to be differentiated from conductive hearing loss (see ENT diagnostic testing).Glossopharyngeal nerveand vagus nerveIX, XPalatal movementThe physician performs a visual inspection of the uvula and soft palate: asymmetry and uvula deviation indicate impaired innervation Gag reflex (pharyngeal reflex): Normally, evoked by approaching the uvula quickly and carefully with a spatula/long cotton swab on each side. Absence of the gag reflex is indicative of nerve damageIX only: sense of taste The patient is given a bitter substance to taste: no sense of taste indicates impaired innervation.X only (recurrent laryngeal nerve): vocalizationIn case of lesion, the patient would have hoarseness or bovine cough. Accessory nerveXITrapezius muscle and sternocleidomastoid muscle(motor function)Trapezius muscle: the patient's shoulder is elevated against resistanceSternocleidomastoid muscle: the patient's head is rotated against resistanceHypoglossal nerveXIITongue muscles (motor function)The tongue should be pressed against the cheek from the inside, while the examiner tests the strength by pushing from the outside.Hypoglossal nerve paralysis: when the patients stick out the tongue, it moves towards the impaired side Upper motor neuron lesion (UMN damage) Lesion along the descending motor pathways (corticospinal tract or pyramidal tract) Typically before the anterior horn cell of the spinal cord or motor nuclei of the cranial nerves (e.g., along motor cortex, brain stem) Atrophy is absent Central paresis (spastic paresis): pyramidal tract signs↑ Tone, spasticity, and clonus↓ power in muscle groupsHyperreflexia Bladderfunction Detrusor hyperreflexia and detrusor/external urethral sphincter dyssynergia Positive Babinski sign (toes point upward, abnormal) Pronator drift testThe patient is asked to raise both arms horizontally up to shoulder level, palms facing upwards, with the eyes closed (for 30 seconds)Lowering or pronation of one arm is indicative of paresis. Mingazzini testThe patient is asked to lie in the supine position, with eyes closed, and is asked to raise and hold both legs for 30 seconds (90° angle at knee and hip).Lowering of one leg is indicative of paresisCommon etiologiesMultiple sclerosis, tumor, stroke, Vitamin B12 deficiency, ALS (both UMN and LMN signs) Lower motor neuron lesion (LMN damage) Lesion anywhere along the nerve fibers between the ventral horn of the spinal cord and relevant muscle tissue Atrophied Fasciculations Peripheral paresis (flaccid paresis): absent pyramidal tract signs↓ Tone↓ Power in single muscle fibersHyporeflexia/areflexia Overflow incontinence Absent Babinski sign (toes neutral or point downward, normal) Peripheral neuropathies, poliomyelitis (poliovirus), ALS(both UMN and LMN signs) Muscle appearance FindingsFasciculation: involuntary, asynchronous contraction of muscle fascicles within a single motor unitAbnormal movementsAbnormal postureAtrophy Power Muscle power grading0 = no contraction (paresis)1 = flicker or trace of contraction2 = active movement, with gravity eliminated3 = active movement against gravity4 = active movement against gravity and resistance5 = normal power Upper limbsC5-C6Biceps reflexFirst, the examiner places his/her thumb on the patient's biceps tendon, then the examiner strikes his/her thumb with a reflex hammer and observes the patient's forearm movement.Brachioradialis reflexStriking the lower end of the radius with a reflex hammer elicits movement of the forearm.C7-C8Triceps reflexThe examiner holds the patient's arm (forearm hanging loosely at a right angle) and taps the triceps tendon with a reflex hammer to induce an extension in the elbow joint.Finger flexor reflexThis reflex is induced by tapping the terminal phalanx of a relaxed finger on the palmar side, while the examiner holds the patient's hand in level with the proximal phalanges. The test is positive when there is significant flexion in the terminal phalanx of the tapped finger and the thumb, or when the flexion is very asymmetrical comparing both hands. Lower limbsL2-L4Adductor reflexTapping the tendon above the medial condyle of femur elicits the adductor reflex.Knee reflexStriking the tendon just below the patella (leg is slightly bent) induces knee extension.L5Posterior tibial reflexThe tibialis posterior muscle is tapped with a reflex hammer, either just above or below the medial malleolus. The reflex is positive when an inversion of the foot occurs.S1-S2Ankle reflexStriking the Achilles tendon with a reflex hammer elicits a jerking of the foot towards its plantar surface. Alternatively, the reflex is triggered by tapping the ball of a foot from the plantar side.T6-T12 Abdominal reflexAbdominal reflexes are tested with the patient lying down. The anterior abdominal wall is lightly stroked with a spatula from lateralto medial (bilaterally) in following areas: below the costal archaround the umbilicusabove the inguinal ligamentA normal response is a contraction of the abdominal muscles, while the absence of contractions is indicative of nerve root damage.L1-L2Cremasteric reflexThe reflex is elicited by stroking the medial, inner part of the thigh. A normal response is a contraction of the cremaster muscle that pulls up the testis on the same side of the body.S3-S5Anal reflexStroking the skin around the anus with a spatula elicits the anal reflex, which results in a contraction of the anal sphincter muscles.Bulbocavernosus reflexThe reflex is elicited by squeezing the glans penis or clitoris, resulting in contractions of the pelvic floor muscles. Babinski signThe examiner strokes the sole of a patient's foot on the lateral edge using, e.g., the handle of a reflex hammerThe sign is positive (pathological) when the big toe extends (dorsiflexes), while the other toes fan out. The test is inconclusive when only the big toe responds.Gordon signThe examiner compresses the calf muscles Do not confuse clonus with myoclonus! Myoclonus is arrhythmical and defined by sudden jerks of a muscle or group of muscles while clonus is rather rhythmic and defined by repetitive contractions and relaxations of a muscle group! ToneElbow: The examiner flexes and fully extends the patient's elbow.Forearm: (while elbow in 90° position) The examiner supinatesand pronates the patient's hand.Wrist: The examiner flexes and extends and then twist the patient's wrist from side to side.The patient is asked to relax the limbs while lying in the supine position and then roll the legs from side to side.SpasticityVelocity-dependent phenomenonThe clasp-knife phenomenon: initial resistance due to increased muscle tone is followed by a sudden decrease in resistance.The arm of the examiner is placed under the patient's knee and the examiner briskly lifts the patient's limb → increased muscle tone in limbRigidityVelocity-independent phenomenonCogwheel rigidity: A resistance resembling a cogwheel movement is observed when the joint of a patient's extremity is moved by the examiner.Stiffness and/or inflexibility regardless of movementClonusWrist: The examiner hyperextends the patient's wrist.Patellar clonus: The examiner grasps the patient's patella between the index finger and the thumb, quickly pushes it down distally, and then holds it in this position.Foot clonusThe examiner holds the patient's leg, with both knee and ankle resting in a 90° flexion.Then the examiner proceeds to dorsiflex and partially evert the foot forcefully multiple times while sustaining the pressure.Clonus is seen as a set of involuntary contractions.Light touchDorsal columnsTo test for symmetry of touch sensation, the examiner touches the patient's body at different locations bilaterally.In cases of suspected radicular lesions, the particular dermatomeshould be examined individually. .In cases of suspected peripheral nerve lesions, diagnostics should involve checking the areas innervated by the corresponding sensory nerves.Paresthesia: abnormal sensation (e.g., tingling, prickling, or "pins and needles")DysesthesiaAllodynia: painful sensation triggered by a stimulus that is not ordinarily considered painful.HyperesthesiaHypesthesiaPain and temperatureSpinothalamic tractImplements such as a broken spatula can be used to test painsensation bilaterally (e.g., by gently prodding the patient with the object).Temperature sensation is tested using two objects of different temperatures (e.g., two test tubes with cold and warm water).Decreased (hypoalgesia) or increased (hyperalgesia) sensitivity to nociceptive stimuliPallesthesia(vibration sense)Dorsal columnsA tuning fork is hit and placed on a bony projection (e.g., medial malleolus). The vibration amplitude and thus the vibration intensity decrease over time.The patient reports when the vibration stops. Abnormalities of vibration are described as mild, moderate, or severe loss of vibration sense (pallhypesthesia).Loss of vibration sense may also indicate a peripheral neuropathy or myelopathy.Proprioception(joint position)Dorsal columnsTo test proprioception, the most distal joint of the big toe or the distal interphalangeal joint of the thumb are held by its sides and moved up and down.The patient should be able to identify the positional change with eyes closed.Abnormalities of proprioception suggest peripheral polyneuropathy or myelopathy.Coordination AssessmentFinger-to-nose testHeel-knee-shin testRapid alternating movement test FindingsDysmetriaDysdiadochokinesiaSee also cerebellar syndromes.Romberg testTest for assessing ataxia (vestibular, sensory, or cerebellar ataxia)May help to distinguish between sensory and cerebellar ataxia.The patient is asked to stand with both feet together, raise the arms, and close the eyes.Positive Romberg: closing the eyes impairs coordination (patient starts swaying, or swaying increases), which is indicative of sensory ataxia. Negative RombergClosing the eyes does not affect patient's balance (patient's swaying does not increase).Uncontrollable swaying, even with eyes open, is indicative of cerebellar ataxia. An increased tendency to fall sideways after closing the eyes indicates a vestibular disorder. Unterberger testTest for vestibular or cerebellar lesionsThe patient is asked to walk on the spot with their eyes closed for 50 paces.The test is positive when the patient rotates more than 45° around his/her central axis, which is indicative of a cerebellar lesion or vestibular impairment.Trendelenburg signTests for neurological insufficiency of the gluteus medius and gluteus minimus muscles, which are innervated by the superior gluteal nerveThe patient is asked to stand on one legPhysiological: when standing on one leg, the pelvisremains level (no compensatory movements of the upper body) → Negative Trendelenburg signPathological: pelvic drop towards the unimpaired, unsupported side → Positive Trendelenburg signDuchenne sign: torso tilting towards the contralateral side compensates the pelvic drop on the unimpaired side. Duchenne limp: the Duchenne sign (frequently occurs bilaterally) results in a compensatory to‑and‑fro movement of the torso during walkingSigns of meningeal or nerve root irritation Meningism Definition: triad of nuchal rigidity; headache, and photophobia Examination: The examiner passively flexes the neck of the patient lying in the supine position Causes: subarachnoid hemorrhage (SAH), bacterial meningitis Additional signs of meningeal or nerve root irritation Kernig sign: painful passive extension of the knee when the thigh is flexed at the hip Brudzinski signInvoluntary lifting of the legs provoked by passive flexion of the neck in a patient in supine position

Rare neurological diseases

Prion diseases Diseases caused by prion infection. Prion diseases affect both animals and humans. Creutzfeldt-Jakob disease (CJD) and variant CJD are discussed in a separate card. Kuru Etiology: rapidly lethal prion infection; acquired through ritualistic cannibalism → neuronal loss, gliosis, and spongiform degeneration of the brain gray matter Clinical featuresCerebellar ataxiaMuscle tremorsPathological laughter Treatment: supportive Gerstmann-Sträussler-Scheinker syndrome Etiology: rapidly lethal prion infection → deposition of amyloid plaques, mainly in the cerebellum Clinical featuresCerebellar ataxiaDysarthriaNystagmusLate-onset dementia Treatment: supportive Adrenoleukodystrophy Inheritance: X-linked recessive disorder Epidemiology: rare Most often manifests in young males (early childhood) Pathophysiology: mutation of the ABCD1 gene (located on chromosome X), which encodes a peroxisomal ATP-binding cassette (ABC) transporter protein Impaired transport of very long chain fatty acids (VLCFA) into peroxisomesImpaired β-oxidation of VLCFA results in accumulation of VLCFA in the adrenal glands, testes, and white matterNeuron demyelination and destruction of adrenal and Leydig cells. Clinical featuresCognitive impairmentProgressive vision, hearing, and motor deteriorationDementiaAdrenal insufficiencyComaDeath DiagnosticsIncreased concentration of VLCFA in plasmaDecreased adrenal function (↑ ACTH and ↓ cortisol)Brain MRI: occipitoparietal white matter demyelinationMutation analysis Treatment: supportive (diet and "Lorenzo's oil" ) Lance-Adams syndrome Etiology: hypoxic brain damage Clinical features: myoclonus of different forms (possibly in combination with asterixis and cerebellar ataxia) Treatment: antimyoclonic agents Tolosa-Hunt syndrome Etiology: unknown Pathophysiology: granulomatous inflammation in the area of the cavernous sinus or the superior orbital fissure Clinical featuresSevere retro-ocular painEye muscle paresis (ophthalmoplegia) Treatment: prednisone Empty sella syndrome Etiology: idiopathic Pathophysiology: enlargement or malformation of the sella turcica → compression of the pituitary gland Clinical featuresOften asymptomaticSome patients may experience chronic headache. Treatment: symptomatic Vertical gaze palsy Definition: a conjugate, bilateral, limitation of the eye movements in upgaze and/or downgaze Etiology: tumors (e.g., pinealoma), multiple sclerosis, encephalitis, and cerebral infarction → damage of cranial nervesor superior colliculi in the midbrainThe most common pinealoma in children is a germinoma, which often secretes β-hCG Clinical featuresConjugate vertical gaze palsyMydriasisPoor pupillary constriction to light but intact constriction with accommodationHydrocephalus (due to obstruction of cerebrospinal fluid outflow pathways)Ataxia (due to cerebellar involvement)If germinoma in boys: potentially precocious puberty Treatment: treat the underlying conditionIf pinealomas: focal radiation or chemotherapy. HTLV-1 associated myelopathy Epidemiology: seen in tropical regions Etiology: human T-cell lymphotropic virus type I (HTLV-1) → immunologic response in the CNS → chronic CNSinflammation and neurodegeneration Clinical features: similar to multiple sclerosis or amyotrophic lateral sclerosis, with the addition of: ArthritisUveitisAlveolitisPolymyositis Treatment: supportive Kluver Bucy syndrome EtiologyInfection (e.g., HSV-1 encephalitis)Head traumaStrokeMalignancy (e.g., brain metastases)Neurodegenerative disease (e.g., Alzheimer disease) Pathophysiology: bilateral damage to the medial parts of the anterior temporal lobes (amygdala, hippocampus) Clinical featuresDisinhibited behaviorHyperorality: excessive chewing, sucking, lip-smacking, and examination of objects with the mouthHyperphagiaHypersexuality (e.g., increased libido, sexually suggestive speech and gestures)Placidity Hyperdocility (e.g., excessive obedience, loss of the ability to resist commands)Cognitive dysfunction (e.g., memory loss, distractibility, amnesia, aphasia)Visual agnosia Seizures TreatmentSymptomatic and psychotropic medicationsAcyclovir if active HSV infection is suspected

Inborn errors of metabolism

Alpha-1 antitrypsin deficiency (AAT deficiency) PathophysiologyGene mutation induces a conformational change in the structure of AAT protein.Effect on the liver: impaired secretion of AAT by hepatocytes → accumulation of AAT in hepatocellular ER → hepatocyte destruction → hepatitis and liver cirrhosisEffect on the lungs: lack of functional AAT → uninhibited neutrophil elastase activity in the lungs →destruction of the pulmonary architecture → panacinar emphysema Clinical featuresSevere form: prolonged neonatal jaundice, hepatitis, cirrhosis, barrel chest, diminished breath sounds, wheezing, and dyspneaMild form: manifests in adolescence, primarily with pulmonary disease; hepatic symptoms may also be presentIncreased risk of hepatocellular carcinoma (HCC) DiagnosticsSerum: decreased antitrypsin protein levelsElectrophoresis: decreased alpha-1 peakChest x-ray: low and flat diaphragm, widened intercostal spaces, hyperinflation and increased basilar radiolucencyof both lungs with rarification of peripheral pulmonary vesselsChest CT: panacinar emphysema (in contrast to centriacinar emphysema in smoking-related emphysema), bronchiectasis, bullae TreatmentAvoid active and passive exposure to cigarette smoke.Symptomatic treatment: bronchodilatorsAntitrypsin replacement; patients with severe AAT deficiencyLiver transplantation The diagnosis of alpha-1 antitrypsin deficiency should be considered in all patients with emphysema under the age of 50. Mitochondrial myopathies General considerations EpidemiologyPrevalence: 13:100,000 [10] Etiology: caused by defects in mitochondrial DNA, which are maternally inherited All offspring of the affected mother is also affected.Genetic expression is variable due to heteroplasmy. DiagnosticsGenetic studies (including mitochondrial DNA)Muscle biopsy: immunohistochemistry typically shows "ragged red fibers", which are caused by subsarcolemmaland intermyofibrillar accumulation of mitochondria in muscles (mitochondria stain red). Laboratory studiesNormal CK Elevated lactate and alanine in serum, urine and/or CSF [10] Treatment: mainly supportive Subtypes of mitochondrial myopathies [10] MELAS (mitochondrial encephalomyopathy, lactic acidosis, stroke-like episodes)Lactic acidosisMuscle weaknessTonic-clonic seizuresRecurring strokesEncephalopathy MERRF (myoclonic epilepsy with ragged red fibers)Point mutation of the 8344th base pair of mitochondrial DNA (in 80% of cases) → destruction of important proteins involved in oxidative phosphorylation [11]Myoclonic jerksGeneralized seizuresCerebellar ataxiaDementia CPEO (chronic progressive external ophthalmoplegia): progressive extraocular ophthalmoplegia with bilateral ptosis Kearns-Sayre syndromeOphthalmoplegia and retinitis pigmentosaImpaired electrical activity of the heart, especially AV block LHON (Leber hereditary optic neuropathy): Cellular death in optic nerve neuronsPainless acute or subacute bilateral vision loss. Usually irreversibleVision loss most commonly occurs in teenagers and young adults, predominantly in males Leigh syndrome [12]Vomiting, diarrhea, dysphagiaFailure to thriveHypotonia, dystonia, ataxiaRapidly progressive psychomotor regression Ophthalmoparesis, nystagmus, optic atrophy Disorders of amino acid metabolism Alkaptonuria [20][21] Definition: congenital disorder of impairement to degrade tyrosine to fumarate Etiology: mutation in HGD gene Inheritance: autosomal recessive PathophysiologyDeficient activity of homogentisic acid dioxygenase → impaired conversion of homogentisate to 4-maleylacetoacetateAccumulation of homogentisic acid → tissue discoloration and organ damage Clinical featuresUsually a benign conditionOchronosis : bluish-black discoloration of connective tissuesAffects cartilage (i.e., ears), tendons, skin, and/or scleraBody fluids that are exposed to air turn black (e.g., perspiration, urine) CalcificationsCartilage → arthritis (ochronotic osteoarthropathy); May present with disabling pain in joints (arthralgias). Degenerative changes in the vertebral columnKidneys → nephrolithiasisHeart valves → mitral valve stenosisCoronary arteries → coronary artery disease DiagnosticsUrine turns black when left standing for prolonged time or when alkalinized.↑ Homogentisic acid in urine and serum; normal tyrosine levels Treatment: diet low in tyrosine and phenylalanine → reduced formation of homogentisic acid Homocystinuria [22] Definition: a group of congenital disorders characterized by impaired homocysteine metabolism Etiology: mutations in CBS, MTHFR, MTR, MTRR, and MMADHC genesMethionine synthase deficiencyCystathionine synthase deficiency Impaired affinity of cystathionine synthase for pyridoxal phosphateMethylenetetrahydrofolate reductase (MTHFR) deficiency Inheritance: autosomal recessive (all enzyme deficiencies that cause homocystinuria are AR) PathophysiologyMethionine synthase (homocysteine methyltransferase) deficiency → impaired conversion of homocysteine into methionineCystathionine synthase deficiency → impaired conversion of homocysteine into cystathionineAll forms result in accumulation of homocysteine. Clinical features: Disease severity varies greatly. Nonspecific features in infancy: failure to thrive, developmental delayEyes: downward subluxation of the ocular lens (ectopia lentis) after age 3 ; myopia and glaucoma later in life [23]Progressive intellectual disabilityPsychiatric and behavioral disordersFair complexionMarfanoid habitus: tall, thin, elongated limbs, arachnodactyly [23]Osteoporosis, kyphosisVascular system: thromboembolism, premature arteriosclerosis, coronary heart disease Diagnostics↑ Homocysteine in urine and serumUrine sodium nitroprusside test: Urine changes color to an intense red in the presence of homocysteine. [24] TreatmentSome patients respond to large doses of pyridoxine (vitamin B6). [25]Methionine synthase deficiency↑ methionine diet Cystathionine synthase deficiencyDiet with↓ methionine and ↑ cysteine diet; ↑ vitamin B6, ↑ vitamin B12, and folate supplementationImpaired affinity of cystathionine synthase for pyridoxal phosphateDiet with ↑ cysteine, ↑↑ vitamin B6MTHFR deficiencyFolate supplementationMarfan syndrome and homocystinuria both present with marfanoid habitus. Distinguishing features include intellectual disability, which is only seen in homocystinuria, and the direction of lens dislocation (downwards in homocystinuria; upwards in Marfan syndrome). Hartnup disease [22][26] Definition: congenital disorder characterized by a defect in the renal and intestinal transport of neutral amino acids(e.g., tryptophan) Etiology: mutation in the SLC6A19 gene Inheritance: autosomal recessive Pathophysiology: Impaired Na+-dependent neutral amino acid transporter → decreased absorption of tryptophan from the gut and renal proximal tubules → inability to synthesize vitamin B3 (niacin) Clinical features: symptoms of vitamin B3 deficiencyPellagra: dermatitis, diarrhea, dementia, glossitisCerebellar ataxia Diagnostics: ↑ amino acids in urine (neutral aminoaciduria) TreatmentHigh-protein diet Niacin supplementation Phenylketonuria (PKU) [27][28][29][30] Definition: congenital disorder characterized by accumulation of phenylalanine Epidemiology: incidence ∼ 1:10,000 Etiology: mutations in the PAH gene Inheritance: autosomal recessive PathophysiologyAccumulation of phenylalanine due to impaired conversion to tyrosine Defect of the liver enzyme phenylalanine hydroxylase (PAH) → impaired conversion of phenylalanine to tyrosine → tyrosine becomes nutritionally essential (classical PKU)Deficiency in tetrahydrobiopterin (BH4), a cofactor of phenylalanine metabolism (e.g., PAH) → decreased conversion of phenylalanine to tyrosine (malignant PKU)Often due to a deficiency in dihydropteridine reductase: normally reduces dihydrobiopterin (DHB) to tetrahydrobiopterin (THB)Excess of phenylalanine → transformed into phenylketone metabolites (e.g., phenylpyruvate, phenylacetate, and phenyllactate) → excretion of metabolites in the urineTyrosine deficiency → decreased neurotransmitter, melanin, and thyroxine synthesis (see amino acid derivatives) Clinical featuresSymptoms may manifest within the first few months of life.Psychomotor delay (starting as early as 4-6 months of age) Seizures [31]Blue eyes; light, pale hair EczemaMusty odor Maternal PKU: in pregnant women with PKU who do not follow proper diet during pregnancy; infant is at risk of microcephaly, growth restriction, facial dysmorphisms, congenital heart defects, intellectual disability DiagnosticsNewborn screening: direct measurement of serum phenylalanine levels on the 2nd-3rd day after birth If screening test is positive: oral tetrahydrobiopterin loading test Performed to differentiate between PKU and tetrahydrobiopterin deficiency [28][29][30]In the case of BH4 deficiency, phenylalanine levels decrease; in the case of PAH deficiency, they remain unchanged. [32]↑ Phenylketones in urine: phenylacetate, phenyllactate, phenylpyruvate TreatmentLow phenylalanine and high tyrosine diet BH4 deficiency: supplementation of tetrahydrobiopterin Patients with PKU should be advised to avoid aspartame, an artificial sweetener that contains phenylalanine! Cystinuria [33] Definition: congenital disorder characterized by hereditary defect in the amino acid transporter in the proximal convoluted tubule of the kidneys and in the intestines Epidemiology: incidence ∼ 1:7,000 Inheritance: autosomal recessive Pathophysiology: impaired renal resorption of dibasic amino acids (COAL - cystine, ornithine, arginine, lysine) → accumulation of cystine in the urine → precipitation of hexagonal cystine stones Clinical features: recurrent nephrolithiasis, starting as early as childhood (see also cystine stones) Diagnostics: urine microscopy shows hexagonal cystine stones; urinary cyanide nitroprusside test positive Treatment: Adequate hydrationUrinary alkalinization: acetazolamide, potassium citrateChelating agents: penicillamine Maple syrup urine disease [22][34][35][36] Definition: congenital disorder characterized by the impaired break down of branched-chain amino acids Inheritance: autosomal recessive Pathophysiology: absent or deficient branched-chain alpha-ketoacid dehydrogenase → impaired degradation of branched-chain amino acids (valine, leucine, isoleucine) → elevated α-ketoacid formation Clinical featuresSymptom onset: early neonatal periodDystoniaVomiting, lethargy, poor feedingIntellectual disabilitySweet-smelling urine (maple syrup or burnt sugar odor)Death may occur without appropriate treatment. DiagnosticsPart of newborn screeningSerum: increased alpha-ketoacids (especially leucine alpha-ketoacids); increased blood levels of leucine, isoleucine, and valineUrine: presence of abnormal branched-chain hydroxy acids and ketoacidsHypoglycemia TreatmentAvoidance of foods containing branched-chain amino acidsThiamine supplementation Liver transplantation Pyruvate dehydrogenase complex deficiency [22][37] Definition: congenital disorder characterized by impaired pyruvate metabolism Inheritance: X-linked or autosomal recessive Pathophysiology: Absent pyruvate dehydrogenase complex (PDC) → impaired conversion of pyruvate to acetyl-CoA → reduced production of citrate → impaired citric acid cycle leads to energy deficit (especially in the CNS) and neurological dysfunction. Clinical featuresOnset: early neonatal periodPoor feeding, lethargy, tachypneaDevelopmental delayProgressive neurological symptoms Diagnostics↑ Lactate and pyruvate in serum↑ Alanine in serum and urine TreatmentAcute: correction of acidosisLong-term: ketogenic diet (high-fat, low-carbohydrate, high in ketogenic amino acids) , avoidance of glucogenic acids (e.g., valine)Supplementation of thiamine, carnitine, and lipoic acid (cofactors of PDC) Propionic acidemia [38][39] Definition: congenital disorder characterized by impaired metabolism of fats and proteins Epidemiology: incidence ∼ 1:100,000 Etiology: mutations in the PCCA and PCCB genes Inheritance: autosomal recessive Pathophysiology: Propionyl-CoA carboxylase deficiency → impaired conversion of propionyl-CoA to methylmalonyl-CoA → ↑ propionyl-CoA and ↓ methylmalonic acid → conversion into propionic acid, which accumulates in serum and urinePropionyl-CoA is produced during the catabolism of certain amino acids (isoleucine, valine, threonine, and methionine), odd-chain fatty acids, pyrimidines (thymine, uracil), and cholesterol. Clinical featuresManifests in the neonatal periodVomiting, poor feedingFailure to thriveIntellectual disability, developmental delayGeneralized hypotonia, lethargy, seizuresAnion gap metabolic acidosisHepatomegalyDeath may occur without appropriate treatment. Diagnostics: ↑ propionic acid in urine and serum (organic acidosis) TreatmentLow protein diet (e.g., avoidance of methionine, threonine, isoleucine, or valine)Amino acid supplementation Purine salvage deficiencies Lesch-Nyhan syndrome Hyperuricemia, Gout, Pissed off (aggression, self-mutilation), Retardation (ID), DysTonia! Definition: a congenital disorder characterized by impaired purine salvage pathway, resulting in an overproduction of uric acid Inheritance: X-linked recessive Pathophysiology: defect in the enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRT) → impaired conversion of hypoxanthine to IMP and guanine to GMP → excess uric acid and ↑ de novo purine synthesis Clinical featuresUsually asymptomatic for the first 6 months of lifeOrange sand-like sodium urate crystals can be found in the diapers of infants with hyperuricemia.Developmental delay and cognitive impairmentPyramidal and extrapyramidal signs (dystonia, spasticity)Gouty arthritis, urate nephropathy Aggression, self-injurious behavior Renal failure DiagnosticsHyperuricemiaMegaloblastic anemia may occur.Analysis of HGPRT: ↓ enzyme activity TreatmentThere is no treatment for the underlying enzyme defect.Reduce uric acid levels: Allopurinol (first-line)Febuxostat (second-line)Low-purine diet Prognosis: high mortality if the infant is not treated within the first year of life Adenosine deaminase deficiency [44] Definition: a congenital disorder characterized by the impaired metabolism of deoxyadenosine during DNAbreakdown Etiology: mutations in ADA gene Inheritance: autosomal recessive Pathophysiology: Deficiency in adenosine deaminase → ↓ breakdown of adenosine and deoxyadenosine → ↑ deoxyadenosineaccumulation → lymphocyte toxicity → immunodeficiencySee purines and pyrimidines. Clinical featuresSCID (see severe combined immunodeficiency) Severe, recurrent infections Treatment: supportive care, IVIG, bone marrow transplantation Disorders of fatty acid metabolism Medium-chain acyl-CoA dehydrogenase deficiency (MCAD deficiency) [45][46] Inheritance: autosomal recessive PathophysiologyDeficiency of medium-chain acyl-CoA dehydrogenase → defective breakdown of medium-chain fatty acids into acetyl-CoA → accumulation of fatty acyl-CoA in the blood → hypoketotic hypoglycemiaSymptoms usually triggered byProlonged fastingStates of increased metabolic demand (e.g., infection, exercise) Clinical featuresOnset: within the first years of lifeDehydration, poor feedingHypotoniaVomiting and lethargyComa, seizures, cardiopulmonary collapseSudden death in infants and children DiagnosticsPart of newborn screeningLaboratory findings: hypoglycemia, ↓ ketones in blood and urine, hyperuricemia, metabolic acidosis, ↑ AST and ALT, hyperammonemia, prolonged PT and aPTTPlasma acylcarnitine profileGenetic testing for the common A985G mutation TreatmentIV administration of 10% dextrose during acute decompensationAvoid fasting statesDiet high in carbohydrates and low in fat [47] ComplicationsEncephalopathyFatty liver disease and impaired hepatic functionSudden death Primary carnitine deficiency [46][22] Definition: a condition characterized by a defect of the carnitine transporter, which transfers fatty acids across the mitochondrial membrane Inheritance: autosomal recessive PathophysiologyDefective carnitine transporter → impaired entry of long-chain fatty acids into mitochondria via carnitine-dependent shuttle → impaired fatty acid metabolism via beta-oxidation↓ Energy production from fatty acids (↓ gluconeogenesis) and ↓ production of ketones → hypoketotic hypoglycemiaAccumulation of fat in the liver and cardiac and skeletal muscle Clinical featuresOnset: early childhoodFailure to thriveLiver dysfunctionCardiomyopathy → congestive heart failureHypotoniaEncephalopathy, lethargyRhabdomyolysis → renal failure DiagnosticsPart of newborn screening↓ Glucose and ↓ ketones in serum (hypoketotic hypoglycemia), hyperammonemia, ↑ ALT, ↑ ASTVery low plasma carnitine levels TreatmentAcute hypoketotic hypoglycemic encephalopathy: administer IV carnitine and 10% dextrose in waterOral carnitine supplementationAvoid fasting states Carnitine palmitoyltransferase II deficiency (CPT II deficiency) [48][49][50] Definition: a disorder characterized by impaired long-chain fatty acid oxidation in the mitochondria Inheritance: autosomal recessive PathophysiologyCPT II normally removes carnitine from long-chain fatty acids in the mitochondria, which is necessary for fatty acid oxidation to occurDefective carnitine palmitoyltransferase II (CPT II) → carnitine cannot be removed from long-chain fatty acids→ no fatty acid oxidation → no substrate for gluconeogenesis and ketogenesis → hypoketotic hypoglycemiaAccumulation of fatty acids and long-chain acylcarnitines → damage to liver, heart, and muscles [49] Clinical featuresSymptoms may occur as early as the neonatal period.Presentation is variable.Myalgia, hypotonia, failure to thriveHepatomegaly, liver dysfunction → liver failureCardiomyopathy → congestive heart failureEncephalopathy, seizuresRhabdomyolysis → renal failureSudden death DiagnosticsPart of the expanded newborn screeningHypoglycemia, ↓ serum ketones↓ Total and free carnitine levels, ↑ acylcarnitineMyoglobinuria and ↑ serum creatine kinase↑ ALT, ↑ AST, hyperammonemia TreatmentAvoid prolonged strenuous activity and fastingDiet low in long-chain triglyceride, high in medium-chain fatty acids, and high in carbohydrates Urea cycle disorders Ornithine transcarbamylase deficiency (OTC deficiency) [51][52][53] Definition: congenital disorder characterized by the inability to excrete ammonia Epidemiology: most common urea cycle defect Inheritance: X-linked recessive Pathophysiology: Defect in the enzyme ornithine transcarbamylase → impaired conversion of carbamoyl phosphate and ornithine to citrulline (and phosphate) → ammonia cannot be eliminated and accumulatesAccumulation of carbamoyl phosphate → conversion to orotic acid Clinical featuresSymptoms commonly manifest in the first days of life but can develop at any age.Nausea, vomiting, irritability, poor feedingDelayed growth and cognitive impairmentIn severe cases, metabolic encephalopathy with coma and deathDoes not cause megaloblastic anemia (as opposed to orotic aciduria) DiagnosticsHyperammonemia (usually > 100 μmol/L)↑ Orotic acid in urine and blood, ↓ BUN↑ Carbamoyl phosphate and ↓ citrulline in the serumEnzyme analysis of OTC activity TreatmentStrict low-protein dietReduce serum ammoniaNitrogen scavengers such as sodium benzoateFluid managementDialysis (in severe cases)Arginine supplementation → promotes urea formation OTC deficiency is the only urea cycle disorder that is X-linked recesssive. All of the other urea cycle disorders are autosomal recessive. Arginase deficiency [51][54] Definition: congenital disorder characterized by impaired arginase activity, resulting in the accumulation of nitrogen (in the form of ammonia) Inheritance: autosomal recessive Pathophysiology: absent or nonfunctional arginase enzyme → impaired conversion of arginine to ornithine → accumulation of ammonia and arginine in the serum Clinical featuresAcute: episodic hyperammonemiaOften asymptomaticTriggered by metabolic stress (e.g., infections, trauma, surgery)Chronic Delayed growth (usually present by three years of age)Progressive spasticity (especially of lower extremities), dystonia, ataxia, poor cognitive development, and missed developmental milestonesSeizuresBy young adulthood: severe spasticity, inability to ambulate, complete loss of bowel and bladder control, severe intellectual disability Diagnostics↑ Serum arginine Hyperammonemia↓ BUN Genetic testing, arginase activity analysis TreatmentReduce serum ammoniaDialysis (severe cases)Nitrogen scavengers such as sodium phenylacetate and sodium benzoateFluid managementLow-protein diet Orotic aciduria Definition: a rare, hereditary condition that is characterized by an elevation of orotic acid in the serum and urine due to defective UMP synthase Inheritance: autosomal recessive [56] PathophysiologyUMP synthase normally converts orotic acid into uridine monophosphate.Deficiency of UMP synthase → accumulation of orotic acid in serum and urineDefect de novo synthesis of pyrimidine nucleotides. Clinical featuresManifests in early childhoodFailure to thriveDelayed physical and mental developmentMegaloblastic anemia, which does not respond to folate and vitamin B12 supplementationOrotic acid crystalluria Diagnostics [56]Serum: ↓ hemoglobin, ↑ mean corpuscular volume, ↑ orotic acid, normal ammonia levels, normal BUNUrine: ↑ orotic acid Treatment: uridine monophosphate substitution [56] Orotic aciduria can be distinguished from ornithine transcarbamylase deficiency by the presence of megaloblastic anemia and absence of hyperammonemia!

Cranial nerve palsies Cranial nerve palsy is characterized by a decreased or complete loss of function of one or more cranial nerves. The etiology may be congenital or acquired. Multiple cranial neuropathies are common, particularly in lesions arising from tumors, trauma, impaired blood flow, and infections. While a diagnosis can usually be made based on clinical features, further investigation is often warranted to determine the specific etiology, which should determine the course of treatment.

IOlfactory nerveSensorySmellIIOptic nerveSensoryVisionAfferent arm of the pupillary light reflex IIIOculomotor nerveMotor (somatic)Eye movement: superior rectus, inferior rectus, medial rectus, and inferior oblique musclesEyelid opening: levator palpebrae superiorisMotor (parasympathetic)Pupillary constriction: sphincter pupillae (Edinger-Westphal nucleus and muscarinic receptors)Accommodation: ciliary muscleIVTrochlear nerveMotorEye movement (abduction and internal rotation): superior oblique muscle VTrigeminal nerveSensoryFacial sensation: ophthalmic (V1), maxillary (V2), mandibular nerve (V3)Mucous membranes of the oral and nasal cavity; soft and hard palateTeeth; temporomandibular jointMeningesAnterior wall of the external auditory canalSomatosensation of anterior ⅔ of the tongueAfferent arm of the corneal reflexMotorMuscles of mastication: masseter, temporalis, medial pterygoid, lateral pterygoid musclesTensor tympani muscleTensor veli palatini muscleAnterior belly of the digastric muscleMylohyoid muscleVIAbducens nerveMotorEye movement (abduction): lateral rectus VIIFacial nerveSensoryTaste perception: anterior ⅔ of the tongue (chorda tympani) Motor (parasympathetic)Salivation: submandibular and sublingual glandsLacrimation: lacrimal glandMotor (somatic)Muscles of facial expressionEyelid closing: orbicularis oculi muscleJaw opening: posterior belly of the digastric muscleHyoid elevation: stylohyoid muscleEfferent arm of the acoustic reflex (stapedius muscle)VIIIVestibulocochlear nerveSensoryBalance and equilibrium: vestibular nerveHearing: cochlear nerveIXGlossopharyngeal nerveSensoryTaste perception: posterior ⅓ of the tongue (lingual branch)Somatosensation: posterior ⅓ of the tongue; middle ear and eustachian tube (tympanic nerve)Afferent arm of the gag reflexVisceral sensation: carotid sinus (baroreceptors detect blood pressure)Chemoreception: carotid body (chemoreceptors detect partial pressure of O2 and CO2, and pH)Motor (somatic)Swallowing: pharyngeal muscles StylopharyngeusMotor (parasympathetic)Salivation: parotid glandVagus nerveSensory (somatic)Posterior wall of the external auditory canalSupraglottic region; larynx; tracheaSensory (visceral)Taste perception: supraglottic regionVisceral sensation: aortic body (baroreceptors detect blood pressure), lung, stomach, liver, kidneys, intestines up to Cannon pointChemoreception: aortic body (chemoreceptors detect partial pressure of O2 and CO2)Motor (parasympathetic)↓ Heart rate Blood vessel vasodilationVisceral function: promotes the motility of the esophagus, stomach, intestines (up to the splenic flexure), and other abdominal organsMotor (somatic)Swallowing Middle and inferior pharyngeal constrictor muscles (passage of bolus)Palatoglossus muscle (elevates posterior tongue upon swallowing) Speech: laryngeal musclesXIAccessory spinal nerveMotorHead turn: sternocleidomastoid muscleShoulder elevation: trapeziusXIIHypoglossal nerveMotorTongue protrusion: intrinsic and extrinsic muscles of the tongue CranialNerveNerve OriginPathway of the cranial nerveILeft and right olfactory bulbs Olfactory epitheliumof the nasal mucosaExits through the cribriformplate of the ethmoid boneOlfactory receptor cells (first order neurons) → cribriform plate → olfactory bulb → olfactory tract (second order neurons) → (split into two) lateral portion connects directly with the telencephalon (prepyriform area), medial portion connects with the amygdalaIIOptic discRetinal ganglioncells of the retinaGanglion cells (in the retina) → optic nerve → optic canal (sphenoid bone) → left and right side of the optic chiasm (middle cranial fossa) → optic tracts → lateral geniculate nuclei → superior colliculus → calcarine sulcus- lingual and cuneus gyrus (visual cortex on the occipital lobe) Fibers from nasal retina: cross at the optic chiasmFibers from temporal retina: continue ipsilaterally at the optic chiasmIIIMidbrainSomatic: oculomotor nucleusVisceral: Edinger-Westphal nucleus → cavernous sinus (lateral wall) → superior orbital fissure (sphenoid bone) → ciliary ganglion (in the orbit) → sphincter muscle (iris) and ciliary muscleIVMidbrainContralateral trochlear nucleus → decussates in the midbrain → exits dorsally and caudally to the inferior colliculus → encircles the midbrain anteriorly → cavernous sinus (lateral wall, inferior to CN III) → superior orbital fissure (sphenoid bone)VPonsExits the brainstem on the anterior aspect of the pons at the middle cerebellar peduncleTrigeminal ganglion → foramen ovalePrincipal nucleus/chief sensory nucleus, spinal trigeminal, mesencephalic nucleus, trigeminal motor nucleusV1 ophthalmic branch Cavernous sinus (lateral wall)Superior orbital fissure (sphenoid bone)V2 maxillary branch: foramen rotundum (sphenoid bone)V3 mandibular branch: foramen ovale (sphenoid bone)VIAbducens nucleus (caudal pons) → inferior pontine sulcus → cavernous sinus (middle wall) → superior orbital fissure (sphenoid bone)VIIExits the brainstem in the cerebellopontine angle → internal acoustic meatus and the facial canal Geniculate ganglion (temporal bone) Facial canal → stylomastoid foramen → exits the skull → muscles of facial expressionLacrimal pathway: superior salivatory nucleus → intermediate nerve, greater petrosal nerve → pterygopalatine ganglion → zygomatic nerve (branch of V2) → lacrimal nerve (branch of V1) → lacrimal glandSubmandibular pathway: superior salivatory nucleus → chorda tympani and intermediate nerve → submandibular ganglion → submandibular and sublingual glandsVIIIEnters through the internal acoustic meatus → cerebellopontine angle → brain stemCochlear: outer and inner hair cells (from the organ of Corti) → bipolar neurons of the spiral (cochlear) ganglion → ventral and dorsal nuclei (in the medullopontine junction); see auditory pathway for more info. Vestibular pathway: hair cells of the semicircular canals, macule, and saccule (otolith organs) → bipolar neurons of the vestibular ganglion → vestibular nerve → vestibular nuclei: inferior, medial, superior, and lateral (in the pons and medulla) → to cerebellum(flocculonodular lobe), nuclei of CN III, IV, VI (for the vestibulo-ocular reflex), reticular formation (aids in body positioning), spinal cord, and the thalamusIXMedullaPostolivary sulcus (along with CN X and XI) → superior ganglion → jugular foramen (formed by temporal and occipital bones) Innervates part of the external ear: passes through the external auditory meatusInnervates the carotid body: via the inferior petrosal ganglionInnervates taste buds: via the inferior petrosal ganglionStylopharyngeus muscle: from the nucleus ambiguus (in the lateral medulla)Parotid glands: inferior salivary nucleus → otic ganglion → auriculotemporal nerve → parotid glandsXPostolivary sulcus → jugular foramen (formed by temporal and occipital bones) SynapsesSuperior (jugular) ganglionInferior (nodose) ganglionIntramural ganglia of visceral organs (e.g., esophagus, stomach)XIMedullaPostolivary sulcus → jugular foramen (formed by temporal and occipital bones)Ventral horn of cervical segments C1-C6 → foramen magnum → jugular foramen → trapezius and sternocleidomastoid musclesXIIMedullaHypoglossal nucleus → preolivary sulcus → hypoglossal canal (occipital bone) → intrinsic and extrinsic muscles of the tongue Olfactory nerve palsy EtiologyTrauma: especially impact to the lateral and occipital regions (e.g., ethmoid bone fracture)Neurodegenerative diseases (e.g., Alzheimer disease)Congenital (e.g., Kallmann syndrome)Intracranial space-occupying lesion Clinical features: anosmia Optic nerve palsy EtiologyIschemic optic neuropathy (i.e., caused by microvascular disease)Inflammation: multiple sclerosis, sarcoidosis, viral infections (e.g., measles, mumps)TraumaTumors (e.g., optic nerve glioma)Impaired nutrition: vitamin B deficiencyDrugs: sildenafil, amiodarone, ethambutol Clinical features: impaired visionComplete transection → ipsilateral blindness + loss of direct pupillary light reflexIncreased intracranial pressure → papilledemaCompression (e.g., tumor) → optic atrophy Oculomotor nucleiA pair of oculomotor nuclei are located at the level of the midbrainFascicles (efferent fibers) from each oculomotor nucleus pass through the red nuclei and the emerge anteriorly as the oculomotor nerveIschemic strokeinvolving branches of the posterior cerebral arteryBenedikt syndromeWeber syndromeBasilar segment The oculomotor nerve emerges anteriorly from the midbrain into the interpeduncular fossa and passes between the posterior cerebellar artery and the superior cerebellar artery.The oculomotor nerve then courses in the subarachnoid space over the base of the skull alongside the posterior communicating artery.The parasympathetic pupillomotor fibers join the oculomotor nerveand lie superficially on the nerve.Aneurysm of the posterior communicating arteryBasal meningitisRecent history of headacheIsolated oculomotor nerve palsywith a fixed, dilated pupilTentorial herniationFeatures of elevated intracranial pressureAbducens nerve palsy Hutchinson pupilIntracavernous segmentThe oculomotor nerve pierces the dura mater, enters the cavernous sinus, and runs along the lateral wall.In the anterior part of the cavernous sinus, the oculomotor nervedivides into a superior division and an inferior division, which enter the orbital cavity via the superior orbital fissure.Cavernous sinus thrombosisTolosa-Hunt syndromeInternal carotid arteryaneurysmsLarge parasellar tumors (e.g., meningioma)Associated palsies of the trochlear (IV), trigeminal (V1, V2nerve), and/or abducens (VI) nerveIntraorbital segmentThe superior division innervates the levator palpebrae superioris and the superior rectus muscle.The inferior division inferior innervates the inferior rectus, the medial rectus, the inferior oblique muscle.Tumors within the orbital cavityTraumaOrbital cellulitisLoss of visionPainProptosisAssociated palsies of the trochlear (IV) and/or abducens nerve (VI)Isolated oculomotor nerve palsy EtiologyIschemic microangiopathy (more common in patients above the age of 60)Diabetic cranial mononeuropathyHypertensionCompression or transection Posterior communicating artery aneurysmBase of skull fractures Clinical featuresParalytic squintAdduction weaknessThe affected eye looks outwards (exotropia) and downwards (hypotropia) Ptosis Horizontal diplopia that is worse when the head is turned away from the side of the nerve palsy Pupillary involvement Compressive lesions: a non-reactive, dilated pupil Ischemic microangiopathy: typically sparing of the pupil DiagnosticsA dilated pupil → often a compressive lesion (e.g., posterior communicating artery aneurysm)Best initial test: urgent MRI with MR angiography If MRI is normal: perform a lumbar puncturePupillary sparing → often due to ischemic microangiopathyAssess risk factors for atherosclerosis or arteritis (e.g., blood pressure, glucose, ESR, lipid profile)If no recovery at 3 months: perform an MRI TreatmentCompressive lesions: surgeryPosterior communicating artery aneurysm: urgent neurosurgical clipping or endovascular coiling Ischemic microangiopathy or demyelinating lesions: medical management with adequate control of the underlying disease For more details about oculomotor nerve lesions and drugs affecting pupillary size, see the learning card pupillary abnormalities.Compression of the oculomotor nerve can cause isolated pupillary dilation due to injury of the parasympathetic fibers. Microangiopathy (e.g., due to diabetes mellitus) typically affects the deeper somatic fibers first, causing ophthalmoplegiawithout pupillary dilation. Trochlear nerve palsy (IV) EtiologyAcquired Microvascular damage (diabetes, hypertension, arteriosclerosis)Cavernous sinus thrombosisTraumaCongenital: fourth nerve palsy Clinical featuresExtorsion of the eye: inability to depress and adduct the eyeball simultaneously DiplopiaVertical or oblique diplopia Exacerbated on downgaze (e.g., reading) away from side of affected muscle [3]Worsens when patient turns the head towards the paralyzed muscle → head tilt to the opposite side of the lesionMild esotropia [4]Trigeminal nerve lesion (V) EtiologyTumorVascular compression of the nerveOral surgeryInflammation of the nerveCavernous sinus thrombosis Clinical featuresPeripheral trigeminal nerve lesions Ophthalmic nerve (V1) is affected → absent corneal reflex (afferent limb), anesthesia of the foreheadMaxillary nerve (V2) is affected → anesthesia of the midfaceMandibular nerve (V3) is affected → anesthesia of the chin, lower lip, and anterior two-thirds of the tongue; muscles of mastication are paralyzedThe jaw deviates towards the side of the lesion because of unopposed action from the opposite pterygoid muscle.Involvement of any of the three branches can cause trigeminal neuralgia.Lesion of the tensor tympani branch → hearing impairment (particularly difficulty hearing low-pitched sounds)Lesions of the trigeminal nerve nuclei: Depending on which nuclei are affected, the patient may present with ipsilateral weakness of muscles of mastication and/or ipsilateral loss of sensation. Complete trigeminal nerve lesions are rare. Abducens nerve palsy (VI) EtiologyMost common ocular cranial nerve palsyAcquired Trauma (e.g., at the superior orbital fissure)Pseudotumor cerebriCavernous sinus thrombosisSpace-occupying lesion causing downward pressure (e.g., tumor)Diabetic neuropathyCongenital: Duane syndrome (A rare type of strabismus characterized by an impaired abduction and ptosis on adduction.) Clinical featuresHorizontal diplopia that worsens when looking at distant objectsEsotropia: medial deviation of the affected eye at primary gazeInability to abduct the eye (affected individuals will rotate the head to look to the side) Vestibulocochlear nerve lesion (VIII) EtiologyBacterial meningitis (most common cranial nerve palsy)Lyme diseaseTumor (e.g., acoustic neuroma, neurofibromatosis type 2) Clinical featuresSensorineural hearing lossVertigoHorizontal nystagmus: Movement of the head induces saccadic movement of the eye toward the opposite side the side of the lesion. Motion sickness Glossopharyngeal nerve lesion (IX) Etiology: often unknown; may be associated with compression by a blood vessel Clinical featuresLoss of the gag reflex (afferent limb)Loss of the carotid sinus reflexFlaccid paralysis of the soft palate → deviation of the uvula away from the lesion (similar to vagus nerve lesions)Sensory loss over the soft palate, upper pharynx, and posterior third of the tongue (including loss of taste sensation)Mild dysphagia Glossopharyngeal neuralgia: throat and ear painLesions that affect the glossopharyngeal nerve typically also affect the vagus nerve because the glossopharyngeal nerve exits the medulla above the vagus nerve.Vagus nerve lesion (X) EtiologyTraumaDiabetes InflammationAortic aneurysmsTumors Clinical featuresLoss of the gag reflex (efferent limb)Flaccid paralysis of the soft palate → nasal speech and deviation of the uvula away from the lesionEpiglottic paralysis → aspirationDysphagiaFeatures of vocal cord paralysis Dysphonia (hoarseness)The vocal cord assumes a paramedian position. Dysfunction of vagal nerve in the stomach → features of gastroparesis (poor gastric emptying)Accessory nerve lesion (XI) Etiology: surgeries of the lateral cervical region, especially the posterior border of the sternocleidomastoid (e.g., resection of cervical lymph nodes) Clinical featuresParesis of the sternocleidomastoid muscle → weakness turning the head towards the contralateral side (the left SCM turns the head to the right)Paresis of the trapezius muscle → weakness during elevation of the ipsilateral shoulder (→ shoulder drooping) and lateral winging of the scapulaHypoglossal nerve lesion (XII) EtiologyTumorsTrauma Clinical featuresAtrophy and fasciculation of the tongue on the side of the lesionThe tongue deviates to the side of the lesion when protruded Chronic meningitisAny cranial nerveInfection (Lyme disease, tuberculosis, cryptococcus neoformans)InflammationInsidious or subacute headache, fever, and neck stiffnessAdditional symptoms depend on which cranial nerves are involved.Jugular foramensyndromeCN IX, X, and XIGlomus tumors SchwannomaMeningiomasMetastatic tumorsCholesteatomasLoss of taste from the posterior half of the tongue (CN IX)Impaired speech and swallowing: paralysis of vocal cordsand palate (CN X)Impaired head turning and shoulder elevation: weakness of the trapezius muscle and sternocleidomastoid (CN XI) Cavernous sinus syndromeCN III, IV, V1,V2, VINeoplasm or inflammation affecting the cavernous sinus (e.g., Tolosa-Huntsyndrome)Intracavernous aneurysmsCavernous sinus thrombosisImpaired movement of the eye: paralysis of muscle of the eye (CN III, IV, VI)Horner syndrome: Decreased sensation of the upper face (CN V1, CN V2)See skull base syndromes. Cerebellopontine angle syndromeCN V, VI, VII, VIII, IX, XNeoplasms of the cerebellopontine angleVestibular schwannomasMeningiomasMetastasesCholesteatomasProgressive sensorineural hearing lossGait disequilibriumVertigo is uncommon. See skull base syndromes.Guillain-Barré syndrome Any cranial nerve; most commonly III, VII, IX, XAutoimmune inflammation of peripheral cranial nervesFacial droop (CN VII) Dysarthria and dysphagia (CN IX and X)Ophthalmoplegia and diplopia (CN III) Multiple sclerosisCN IIConnection between III, IV, and VIAutoimmune inflammation of the cranial nervesVision loss (CN II)Internuclear ophthalmoplegia (INO)

Trace elements Essential trace elements are dietary elements including iron, copper, zinc, iodine, selenium, and sulfur that the body requires in minute amounts for proper physiological function and development. While most essential trace elements primarily function as cofactors for a variety of reactions, some also function as constituents of essential molecules (e.g., iron in hemoglobin and myoglobin), transcription factors (e.g., zinc finger), and amino acids (e.g., sulfur in methionine and cysteine). Excess and deficiency of essential trace elements can cause symptoms and diseases, the most important of which are discussed below.

Trace elementMain functionDeficiencyExcessIronCofactor for Cytochrome CCytochrome P450Metalloproteases (e.g., NADH dehydrogenaseIntegral part of HemoglobinMyoglobinIron deficiency anemia Hemochromatosis Iron toxicity CopperForms part of ceruloplasmin, superoxide dismutaseCofactor for: Cytochrome c oxidase(electron transport chain)Tyrosinase (melanin synthesis)Lysyl oxidase (cross-linking in collagen synthesis)Factor V (coagulation cascade)Menkes diseaseDepigmentation of the skinAbnormal hair growthMuscle weaknessHepatosplenomegalyOsteoporosisNeurologic manifestations: ataxia, neuropathyDelayed wound healingSideroblastic anemiaWilson disease ZincProtein structure Forms bonds between cysteine and histidineForms zinc fingertranscription factorsCofactor for Alkaline phosphataseCarbonic anhydraseMetallothioneinSuperoxide dismutaseACECollagenasesImpaired wound healingDysgeusia (abnormal sense of taste), anosmia (loss of smell)Impaired growth and developmentImmune dysfunctionHypogonadismDiarrheaDermatitisAlopeciaAbdominal painNausea, vomiting, diarrhea IodineIntegral part of 3-iodotyrosine (T3) and thyroxine (T4)Increased infant mortalityHypothyroidismCretinismGoiterPre-existing hypothyroidism, latent or overt hyperthyroidism→ symptoms of hyperthyroidism SeleniumCofactor for Glutathione peroxidaseIodothyronine deiodinase 2CardiomyopathySkeletal muscle dysfunctionImmune system dysfunctionMacrocytosisNausea, vomiting, diarrheaNail changesPeripheral neuropathyFatigue SulfurPart of amino acidsMethionineCysteineArthritisBrittle nails and hairNausea, vomiting, diarrheaSkin rashCognitive impairment (e.g., memory loss)May contribute to obesity, heartdisease, Alzheimer diseaseNausea, diarrhea, vomitingHeadache Iron General RDA: 10 mg/d (only 10% of iron is absorbed from the intestines) Iron stores in the bodyTotal body iron content is ∼ 3 g in ♀ and ∼ 6 g in ♂.Total iron exists in two forms: Functional iron (80%): hemoglobin (majority), myoglobin, cytochrome enzymesStorage iron (20%): mainly liver (as ferritin/hemosiderin) Dietary ironHeme iron: from meat Non-heme iron: from plants Free iron can lead to reactive oxygen species via the Fenton reaction. H2O2 + Fe2+ → OH- + Fe3+ + •OH (hydroxyl radical)Hydroxyl radicals → oxidative stress → DNA damage Iron absorption and transport Iron absorptionOccurs in the duodenum and upper jejunumThe enzyme hepcidin regulates intestinal absorption of iron.Hepcidin is synthesized in the liverIncreased body stores of iron → ↑ hepcidin → prevention of iron absorptionIron deficiency → ↓ hepcidin → ↑ iron absorptionFerric iron (non-heme iron, Fe3+) is mainly reduced to ferrous iron (Fe2+) and then absorbed. Vitamin C increases absorption (converts Fe3+ → Fe2+).Calcium decreases absorption (due to chelation of iron).A minority of iron is absorbed as ferric iron (Fe3+).Heme iron can be directly absorbed into intestinal cells. Iron transportThe enzyme ferroxidase (also known as ceruloplasmin) oxidizes ferrous iron back to ferric iron (converts Fe2+ → Fe3+).Transferrin binds and transports the ferric iron to the erythroid precursor cells (in bone marrow) for hemoglobin synthesis. Iron storage, recycling, and loss Iron storage: stored mainly in the liver as ferritin and hemosiderin Iron recyclingReticuloendothelial macrophages (in the spleen and liver) phagocytose senescent RBCs and release iron from hemoglobin. Transferrin binds the released iron and transports it to the bone marrow for erythropoiesis. Iron lossShedding of skin and mucosal epithelial cell → daily loss of 1-2 mg of ironAny source of bleeding (e.g., menstruation, occult GI bleed) increases iron loss. References:[1][2][3] Function Cofactor for Cytochrome C, cytochrome P450PeroxidasesMetalloproteases (e.g., NADH dehydrogenase)Phosphoenolpyruvate carboxykinase (gluconeogenesis), aconitase (Krebs cycle)Ribonucleotide reductase (DNA and RNA synthesis). Integral component of hemoglobin and myoglobin Deficiency For more details regarding the clinical features, diagnosis, and etiology of iron deficiency, see the learning card on iron deficiency anemia. CausesDecreased intakeDecreased absorption Increased demand (e.g., lactation, growth spurt, pregnancy)Iron loss (e.g., menorrhagia, gastrointestinal bleeding) SymptomsFatigue, lethargy, pallor Excess CausesHemochromatosisIron toxicity (poisoning) Copper General Source: meat, fish, poultry, vegetables, grains, legumes (e.g., lentils, beans) MetabolismAbsorbed in the stomach and small intestine Absorbed by active transport and passive diffusionExported from enterocytes via Menkes P-type ATPaseBinds albumin and is transported as part of the enterohepatic circulationTransported by ceruloplasmin from the liver to peripheral tissue Stored primarily in the liver and brain. Small amounts are stored in the heart, kidney, and pancreas. Function Cofactor for Cytochrome c oxidase (electron transport chain)Tyrosinase (melanin synthesis)Lysyl oxidase (important for cross-linking during collagen synthesis)Factor V (coagulation cascade) Deficiency Causes: primarily due to genetic mutations Menkes diseaseCauses inability to transport copper from enterocytes to the liver and other cells of the body → ↓ copper levelsDue to a mutation in the Menkes P-type ATPase, a protein encoded by the ATP7A gene Clinical featuresDepigmentation of the skinAbnormal hair growthMuscle weaknessHepatosplenomegalyEdemaOsteoporosisNeurologic manifestations: ataxia, neuropathyDelayed wound healingSideroblastic anemia Excess Causes: Wilson disease, rarely from toxic water or cooking with copper pots Zinc General Source: poultry, oysters, fish, meat, zinc-fortified food products (e.g., cereals), nuts MetabolismAbsorbed primarily in the duodenum and jejunum Absorption is regulated by metallothioneinExcreted primarily via the gastrointestinal tract Function Protein structure Forms bonds between cysteine and histidineForms zinc finger transcription factors Aids in maintenance and stability of the nuclear membrane Essential part of many enzymes (> 70), including alkaline phosphatase, carbonic anhydrase, metallothionein, superoxide dismutase, ACE, and collagenases Deficiency CausesInadequate dietary intakeCrohn disease, liver, and renal diseaseAcrodermatitis enteropathica: congenital deficiency of the zinc/iron-regulated transporter-like protein (ZIP) Total parenteral nutritionChronic liver disease (esp. liver cirrhosis) Clinical featuresImpaired wound healingDysgeusia (abnormal sense of taste), anosmia (loss of smell)Impaired growth and developmentImmune dysfunctionHypogonadismDiarrheaDermatitisAlopeciaIn patients with liver cirrhosis: associated with accelerated progression of cirrhosis and aggravated clinical symptoms (e.g., hepatic encephalopathy). Excess CausesRare, but can develop due to excess zinc intake Clinical featuresAbdominal painNausea, vomiting, diarrhea Iodine General Source: seafood, seaweed, plants grown in iodine-rich soil, water, vegetables, iodized table salt MetabolismAbsorbed in the small intestineMost iodide is taken up and stored by the thyroid gland; excess is excreted by the kidneys. Elemental iodine can be used as a disinfectant. Function Integral part of 3-iodotyrosine (T3) and thyroxine (T4) See also thyroid hormones. Iodine deficiency Causes: decreased intake (e.g., a diet low in iodine ) Clinical features: Iodine deficiency presents with features of decreased thyroid hormone synthesis. Increased infant mortalityHypothyroidismCretinism (due to untreated congenital hypothyroidism)Myxedema comaGoiter Iodine excess Causes: Excess iodine is rare but can be caused by administration of iodine-containing contrast agents or excessive consumption of dietary supplements (seaweed, kelp). Clinical featuresIn patients with normal thyroid function, excess iodine is usually well tolerated.Jod-Basedow phenomenonHyperthyroidism following iodine excessInduced in patients with pre-existing hypothyroidism (e.g., endemic goiter, Hashimoto thyroiditis) and patients with latent or overt hyperthyroidism → symptoms of hyperthyroidism or thyrotoxicosis Wolff-Chaikoff effect [5][6]Hypothyroidism following iodine excess Temporary autoregulatory compensation mechanism for the prevention of a hypermetabolic state in the event of iodine excess Mechanism: excess iodine inhibits thyroid peroxidase → decreases T3/T4 production Selenium General Source: meat, seafood, grains and seeds (e.g., brazil nut) MetabolismPresent in two forms (in animals): seleno-methionine and seleno-cysteineAbsorbed in the small intestineStored as seleno-methionineActive form: seleno-cysteineExcreted in the urine Function Cofactor for enzymes such as glutathione peroxidase , and iodothyronine deiodinase 2 (thyroid hormoneproduction) Selenium plays an important role in neutralizing oxidant stress as part of the glutathione peroxidase. Deficiency CausesMalnutritionTotal parenteral nutrition (TPN) Clinical featuresCardiomyopathySkeletal muscle dysfunctionImmune system dysfunctionMacrocytosis Excess Causes: excess selenium intake (→ selenosis) Clinical featuresNausea, vomiting, diarrheaHair lossNail changesFatiguePeripheral neuropathy Sulfur General Source: meat, eggs, nuts, salmon, leafy green vegetables (e.g., kale, spinach), legumes Function Form disulfide bonds (between cysteine residues) Integral part in the tertiary structure of proteins Present in methionine, cysteine, homocysteine, cystine, and taurine Present in thiamine and biotin Present in coenzyme-A Present in keratin (aids in maintenance of skin, hair, and nails) Essential for collagen synthesis Deficiency CausesDeficiency is very rare.Diet based on products grown in sulfur-depleted soilsLow-protein diets Clinical featuresArthritisBrittle nails and hairNausea, vomiting, diarrheaSkin rashCognitive impairment (e.g., memory loss)May contribute to obesity, heart disease, Alzheimer disease Excess Causes: Excess consumption of sulfur-rich foods Clinical featuresNausea, diarrhea, vomitingHeadache

Ulnar nerve entrapment Ulnar nerve entrapment occurs when the ulnar nerve is compressed, typically at the elbow or the wrist. Compression at the elbow is called cubital tunnel syndrome; compression at the wrist it is referred to as Guyon's canal syndrome or ulnar tunnel syndrome. The compression causes paresthesias, numbness, and/or pain in the ulnar nerve distribution. Depending on the site of compression, the patient may experience weakness in certain hand muscles. Ulnar entrapment neuropathy may be suspected based on clinical symptoms and signs, but it must be confirmed by electromyography(EMG). Conservative treatment involves NSAIDs, behavior modification, and bracing. Severe, persistent, or worsening symptoms require surgical decompression.

Basic anatomy Derived from nerve roots C8-T1 Medial cord of the brachial plexus → ulnar nerve branch → Passes the medial epicondylar groove at the elbow → Enters the palm through Guyon canal Sensory distribution: dorsal and palmar surface of the medial/ulnar one and a half fingers Muscles innervatedThird and fourth lumbricals: flex at MCP joint and extend at proximal interphalangeal (PIP) jointAdductor pollicis: adducts the thumbAbductor digiti minimi: abducts the little fingerFlexor carpi ulnaris: helps flex the wristDorsal and palmar interossei: finger abduction and adduction respectively Etiology The ulnar nerve is most commonly compressed at or near the cubital tunnel of the elbow and Guyon canal of the wrist. Cubital tunnel syndromeLeaning on the elbow or prolonged elbow flexion during occupational activities (e.g., leaning on a desk), athletic activities, or surgical procedures (e.g., during general anesthesia)Blunt traumaMasses (e.g., tumors, hematomas)Metabolic abnormalities (i.e., diabetes) Guyon canal syndromeIdiopathic: may be associated with cycling, probably caused by direct pressure from the handlebarsMasses, with ganglion cyst being the most commonBlunt trauma (e.g., hook of hamate fracture) Clinical features Muscle weakness and atrophy Claw hand deformity: little and ring finger loss of extension at proximal interphalangeal joint and loss of flexion at metacarpal phalangeal joint Wartenberg sign: little finger in persistent abduction due to weak third palmar interosseous muscleFroment sign: The thumb flexes at the interphalangeal joint while pinching a piece of paper to compensate for a weak adductor pollicis muscle. Sensory lossLoss of sensation over the hypothenar eminence, ulnar 1 ½ fingers.Lesion at the elbow: positive Tinel test → Marked paresthesias can be reproduced in the ulnar portion of the hand by tapping on the medial epicondyle of the humerus. Lesion at the wrist: Sensory symptoms may or may not be present. Pain: Elbow lesions typically present with referred pain in the forearm. Proximal as well as distal lesions lead to claw hand deformity! Diagnostics EMG: main confirmatory diagnostic test; it identifies the level of nerve compression. Ultrasound and MRI: used to support the EMG findings and to detect possible causes of compression (e.g., space-occupying lesions) Treatment Conservative therapyAnalgesia (e.g., NSAIDs)Modify behavior (i.e., avoid prolonged resting on or repeated flexion of elbow)Bracing at night Surgical decompression if clinical features are severe, persistent (lasting more than 6-12 weeks), or progressively worsen despite conservative therapy.

Horner syndrome Horner syndrome (HS) is a neurological disorder characterized by a symptom triad of miosis (an abnormally small pupil), partial ptosis (drooping of the upper eyelid), and facial anhidrosis (absence of sweating). This condition results from lesions that interrupt the sympathetic nervous supply to the head, eye, and neck. Most cases of HS are idiopathic, but conditions such as brainstem stroke, carotid dissection, and neoplasm are occasionally identified as the cause of HS. Because of the wide array of possible causes, diagnosis of the underlying disorder frequently poses a challenge and requires a systematic approach. Once the lesion has been identified, treatment should be tailored to the specific cause

Central Hypothalamus (first neuron) → brainstem, cervical, and thoracic spinal cord → ciliospinal center (C8-T2) Brainstem stroke (e.g., Wallenberg syndrome) Cervical spinal cord injury (e.g., Brown-Séquard syndrome, syringomyelia) Brain tumors Brainstem (pontine) hemorrhage Lateral medullary syndrome Demyelinating disease (e.g., multiple sclerosis) Malformations (e.g., Arnold-Chiari) Meningitis Preganglionic Ciliospinal center (second neuron) → pulmonary apex → stellate ganglion →superior cervical ganglion Tumors (e.g., breast or lung cancer compressing stellate ganglion, esp. Pancoast tumor) Iatrogenic (e.g., birth trauma, central venous catheterization) Lymphadenopathy Arterial lesions/dissection: aorta, subclavian, common carotid Cervical rib Postganglionic Superior cervical ganglion (third neuron) → internal carotid artery and ophthalmic nerve → iris dilator muscle Dissection of the internal carotid artery Cluster headache Tumor Herpes zoster infection Triad of Horner syndromeIpsilateral miosis (constriction of the pupil) Partial ptosis (drooping of the upper eyelid)Occurs because the superior tarsal muscle fails to keep the upper eyelid raised.It is milder than ptosis associated with oculomotor nerve or levator palpebrae lesions.Anhidrosis or reduced sweating on the face and arm, depending on the location of the lesion Presents with central and preganglionic lesions.Anhidrosis is usually absent in postganglionic lesions, but anhidrosis of the forehead could be seen in some patients if terminal branches of the internal carotid nerve, which supply sweat glands of this region, are compromised. (Apparent) enophthalmos Atrophy of arm and hand muscles Facial flushing due to vasodilatation

Tension-type headache Tension-type headache (TTH) is a primary headache disorder and the most common type of headache overall. Tension-type headaches are characterized by a dull, nonpulsating, band-like pain that is often bilateral. Autonomic symptoms like photophobia, phonophobia, or nausea are usually not present. Depending on the frequency and duration of episodes, tension-type headaches are classified as episodic or chronic. Infrequent episodic tension-type headaches are treated with NSAIDs, while chronic and frequent episodic forms may benefit from prophylactic amitriptyline. Nonpharmacological treatment options include lifestyle modification (e.g., stress reduction) and cognitive behavioral therapy.

Chronic tension-type headacheEpidemiology Most common type of headache∼ 70% of primary headaches∼ 50% of the population will have had at least one episode in their lifetime. Sex: ♀ > ♂ Peak incidence: 30-40 years Ethnicity: increased prevalence in white populations Etiology The exact pathophysiology of tension headaches remains unknown. Exacerbating factors: fatigue, lack of sleep, poor posture, anxiety, stress, depression Clinical features Episodic nature Headaches last 30 minutes to a couple of days. [8] Holocranial or bifrontal, band-like headache (mild to moderate intensity) Dull, pressing, nonpulsating ("vice-like") quality Headache does not increase with exertion. Maximum of one autonomic symptom (nausea, phonophobia, or photophobia) No vomiting or aura Palpation of muscles of the head may reveal increased pericranial tenderness. Diagnostic criteria for tension-type headaches [8][9] At least two of the following: Dull, pressing, nonpulsating qualityMild to moderate intensityBilateralNo increase in intensity with exertion Not better explained by any other headache disorder Categorized into three entities (which guide treatment); all criteria have to be fulfilled for the diagnosi Infrequent episodic tension-type headache ≥ 10 episodes < 1 day/month or < 12 days/year 30 minutes to 7 days No nausea or vomiting No more than one of photophobia or phonophobia Frequent episodic tension-type headache ≥ 10 episodes on 1-14 days/month For > 3 months (≥ 12 and< 180 days/year)30 minutes to 7 days Chronic tension-type headache ≥ 15 days/month For > 3 months (≥ 180 days/year) Only one of the following: PhotophobiaPhonophobiaMild nausea No moderate or severe nausea; no vomiting Treatment Both pharmacologic and non-pharmacologic strategies can be used for the treatment of tension-type headache. In addition, any underlying conditions (e.g., depression) should be identified and treated. Pharmacological therapyEpisodic tension-type headache: NSAIDs (e.g., ibuprofen, aspirin) or acetaminophenChronic tension-type headache and frequent episodic type: consider prophylactic therapy (e.g., with amitriptyline). Non-pharmacological therapy: Consider if there is a significant decrease in patient's quality of life. Lifestyle and behavioral modification (e.g., exercise, weight reduction)Psychobehavioral treatments (e.g., cognitive-behavioral therapy, relaxation training) Avoid prolonged use (> 15 days/month) of NSAIDs for chronic tension headache, as this may cause medication overuse headaches. [8]

Anticonvulsant drugs Anticonvulsant drugs are classified as either classic or newer anticonvulsants. Newer anticonvulsants are usually better tolerated and have a broader therapeutic range than classic anticonvulsant drugs. The choice of drug is guided by the type of seizure. First-line treatment for focal seizures includes e.g., lamotrigine or levetiracetam, while valproate is used for generalized seizures. All anticonvulsants have dose-dependent side effects on the central nervous system such as somnolence and nausea, but some agents have more specific side effects (e.g., gingival hyperplasia caused by phenytoin). Besides their importance in anti-epileptic therapy, anticonvulsants are also used for pain management (e.g., carbamazepine or gabapentin as coanalgesics) or as mood stabilizers in bipolar disorders (valproate).

Classic anticonvulsants Valproate First-line long-termtreatment for tonic-clonicgeneralized seizures Partial (focal) seizures Absence seizures Myoclonic seizures Bipolar disorder Inhibits GABA transaminase→ ↑ GABA → decreased neuronal excitability Inactivates Na+ channels Gastrointestinal upset (e.g., abdominal discomfort) Hepatotoxicity (rare) Teratogenicity (see pharmacotherapy during pregnancy) Tremor Sedation Ataxia Alopecia Pancreatitis Skin rash Agranulocytosis Weight gain Carbamazepine First-line treatment for tonic-clonic generalized and focal seizures First-line treatment of trigeminal neuralgia Inactives Na+ channels Nausea Skin rash Hyponatremia, hyperhydration, and edema (due to SIADH) Blood count abnormalities (e.g., agranulocytosis, aplastic anemia) Teratogenicity during the first trimester (see pharmacotherapy during pregnancy) Diplopia Ataxia Hepatotoxicity Stevens-Johnson syndrome Induces cytochrome P-450 Ethosuximide First-line for absence seizures Inhibition of voltage-gatedcalcium channels (T-type) in neurons of the thalamus Gastrointestinal symptoms Allergic skin reactions (urticaria, Stevens-Johnson syndrome) Fatigue Headache Phenytoin First-line treatment for tonic-clonic seizures and for status epilepticusprophylaxis Only rarely used for long-term treatment of focal seizures. Inactivation of Na+ channels Zero-order elimination (i.e., constant rate of drug eliminated) Gingival hyperplasia Stevens-Johnson syndrome Hirsutism Drug-induced lupus erythematosus Osteopathies Megaloblastic anemia Nystagmus, diplopia, ataxia Peripheral neuropathy Teratogenic: fetal hydantoin syndrome Induction of cytochrome P-450 enzymes BenzodiazepineFirst-line for status epilepticusIndirect GABAA agonist → ↑ GABA actionSedation and dependence (See benzodiazepinesfor details) Newer anticonvulsantsLamotrigineFirst-line treatment for long-term therapy of focal seizuresSecond-line treatment for generalized seizures and absence seizuresMood stabilizer for bipolar disordertreatmentExanthema, exfoliative dermatitis, Stevens-Johnson syndrome (slow dose increase necessary to prevent skin and mucous membrane reactions)Rarely hepatotoxic or nephrotoxicBlurry visionGastrointestinal symptomsPhenobarbitalFirst-line treatment in neonatesTonic-clonic generalized seizuresFocal seizuresGABAA agonist → ↑ GABAactionSedationTolerance and dependenceCardiorespiratory depressionInduces cytochrome P-450LevetiracetamFirst-line treatment for long-term therapy of focal seizuresGeneralized seizuresSomnolence, nauseaPsychiatric symptoms (e.g., changes in personality)GabapentinSecond-line treatment for focal seizuresPolyneuropathyPost-herpetic neuralgiaInhibition of voltage-gatedcalcium channels (T-type and L-type) in neurons of the thalamusDry mouthSomnolence, nauseaAtaxiaVigabatrinRefractory focal seizuresInhibits GABA transaminase→ ↑ GABAIrreversible vision loss TopiramateFocal and generalized tonic-clonic epilepticseizuresMigraine prophylaxisIdiopathic intracranial hypertensionBlocks voltage-gated Na+channels↑ GABASomnolenceGlaucomaWeight lossKidney stonesTiagabineFocal seizures, with or without impairment of consciousnessInhibits GABA reuptake → ↑ GABAGastrointestinal upset: nausea, vomiting, diarrheaInsomniaDrowsinessWeight changes Effects Anticonvulsant drugs inhibit neural activity (↓ neural excitation, ↑ neural inhibition) and increase the seizure threshold by interacting with specific receptors and ion channels. Special patient groups Pregnancy and breastfeeding Classic anticonvulsants (especially carbamazepine and sodium valproate!) should be avoided if possible → teratogeniceffects Newer anticonvulsants: lack of medical data and trials during pregnancy Choice of treatment depends on type of seizure and which substance enables optimal control of treatment. ApproachOptimize seizure control prior to conception.Avoid multiple therapies.Administer the drug at the lowest dose which controls seizures.Monitor plasma drug levels regularly.

Parkinson-plus syndromes Parkinson-plus syndromes (or atypical parkinsonism) are a group of neurodegenerative diseases that present with parkinsonism and a variety of additional features. Depending on the particular syndrome, a combination of basal ganglia, cerebral cortical, cerebellar, midbrain, and/or brainstem structures are affected. The prognosis is less favorable than in Parkinson disease. Parkinson-plus syndromes should be considered if parkinsonism does not respond to levodopatreatment, if dementia progresses rapidly, or if gait instability occurs early in the course of the disease. In most cases, only symptomatic treatment is possible.

Common characteristics of Parkinson-plus syndromes Parkinson-plus syndromes have a number of features that differentiate them from Parkinson disease (PD): Poor response to levodopa Early involvement of the autonomic nervous system (orthostatic hypotension, impotence, incontinence, anhidrosis) Early onset of postural instability with frequent falls Dementia Visual hallucinations (usually a sign of Lewy-body disease) Signs of cerebellar involvement Pathological reflexes present (e.g., Babinski sign); enhanced proprioceptive reflexes Eating and swallowing disorders; pronounced dysarthria Supranuclear vertical gaze palsy Apraxia Dementia with Lewy bodies Epidemiology♂ > ♀ (up to 4:1)Second most common form of neurodegenerative dementia (10-20% of dementia cases) PathologyCerebral atrophy, particularly of the frontal lobe with relative sparing of the hippocampiLewy bodies (alpha-synuclein-positive cytoplasmic inclusions) in neurons, which cause neuronal degenerationHistology: hyaline eosinophilic globules that are found inside brain neurons. Clinical presentation: The sequence of symptoms is more variable than in most other types of dementia. DementiaExtrapyramidal motor symptomsVisual hallucinations and paranoid episodesEpisodic impairment of vigilanceFrequent fallsRapid eye movement sleep behavior disorder (RBD)Increased sensitivity to neuroleptic medication and metabolic perturbation TherapyNo causal therapy availableSymptomatic treatment Supportive therapy, behavioral therapy, physical therapyPharmacotherapy Parkinsonian symptoms: generally analogous to treatment of Parkinson diseaseDementia symptoms: generally analogous to treatment of major neurocognitive disorder Prognosis: Median survival is approx. 10 years.Patients with Lewy-body dementia have an increased risk of life-threatening akinetic crises under antipsychotic treatment! Multiple system atrophy (MSA) Definition: Multiple system atrophy (MSA) is a rare, adult-onset, neurodegenerative disease characterized by neuronal degeneration in the substantia nigra. Pathology: Lewy bodies Clinical features: Motor abnormalities MSA-P: predominantly parkinsonian featuresMSA-C: predominantly cerebellar features Autonomic dysfunction (e.g., orthostatic hypotension, urinary incontinence, erectile dysfunction)Cerebellar symptoms (e.g., ataxia, tremor, dysarthria)Additional symptoms Neuropsychiatric disorders (dementia, depression, sleep disorders)Ocular motility disordersMyoclonus, dystoniaPyramidal signs Diagnosis: Primarily based on clinical features (especially autonomic dysfunction, including urogenital symptoms)MRI: hot cross bun sign Differential diagnosisParkinson disease: IBZM-SPECT imaging MSA: presynaptic and postsynaptic degeneration (decreased binding)Parkinson disease: presynaptic degeneration and postsynaptic up-regulation (ligand accumulates here) Pure autonomic failure (PAF) Clinical features: orthostatic dysregulation with life-threatening drops in blood pressure Therapy: no causal therapy Progressive supranuclear palsy (Steele-Richardson-Olszewski syndrome) Clinical featuresPostural instability (leading to frequent falls)Frontal lobe abnormalities (e.g., apathy, disinhibition, impaired reasoning)Vertical gaze palsy, especially downward gaze, to complete external ophthalmoparesis RigorBradykinesiaDysarthria, dysphagiaDementia DiagnosisMRI: "hummingbird sign" showing atrophy of midbrain structures with a relatively intact pons region Corticobasal degeneration Clinical featuresDementia (at any stage)Asymmetric motor abnormalities, often initially affecting only one limbAlien limb phenomenon: The patient perceives the affected limb as not belonging to him or her. Diagnosis: asymmetric focal cortical atrophy and bilateral atrophy of the basal ganglia on MRI Differential diagnoses of Parkinson-plus syndromes Multiple system atrophy (MSA) Lewy bodies Autonomic dysfunction with urogenital problems Progressive supranuclear palsy(PSP) Vertical gaze palsy Frontal lobe disturbances Corticobasal degeneration(CBD) Asymmetric motor symptoms Alien limb phenomenon Dementia with Lewy bodies(DLB) Lewy bodies Visual hallucinations

Degenerative disc disease Degenerative disc disease refers to a variety of pathologies with displacement of disc material into the spinal canal, such as protrusion, herniation, and sequestration. Degenerative disc disease results in mechanical compression on either the spinal cord or a nerve root. The most common symptoms of disc disease are radicular pain in the dermatome of the compressed nerve root, muscle weakness, and loss of deep tendon reflexes in the indicator muscles. The location of the lesion can often be determined by the patient's neurological deficits. In most cases of lumbosacral disc disease, L5 nerve compression is present, which leads to reduced sensitivity in the lateral leg, dorsum of the foot, and weakness in extending the big toe. MRI confirms the diagnosis by showing the protruded/herniated disc. Conus medullaris syndromeand cauda equina syndromes are severe forms of disc herniation that may present with paresis, sensory deficits, and urinary and bowel incontinence. They require urgent decompression via surgical intervention. Most spinal disc herniations, however, can be treated conservatively with analgesia and by maintaining physical activity.

Definition Disc protrusion: Pressure on the vertebra causes the gelatinous core, called the nucleus pulposus, to move and pressagainst the annulus fibrosus. This bulge compresses a spinal nerve and thus causes pain. Disc herniation: (= disc extrusion or disc prolapse): A tear in the annulus fibrosus results in extrusion of the nucleus pulposus and potential compression of the spinal nerve Disc sequestration: Extrusion of the nucleus pulposus and separation of a fragment that enters the spinal canal and may cause compression of the spinal nerve. Epidemiology Age: most common at 30-50 years Sex: ♂ > ♀ Approximately 80% of all Americans suffer from significant back pain at some point in their lives About 5% of back pain is a consequence of disc herniationLumbosacral disc herniationL5-S1 (most common site)L4-L5 (second most common site)Cervical and thoracic disc herniations are rare Pathophysiology The intervertebral disc consists of a dense outer ring (annulus fibrosus) and a gelatinous core (nucleus pulposus). Compression, tension, shear, and torque stresses on the spinal disc → degenerative changes (e.g., dehydration, annular tear) → disc protrusion or herniation → adjacent nerve root impingement → sensorimotoric deficits in affected nerve root Clinical features Acute onset of severe back painStabbing or resembling electric shock (most commonly of the lower back, called lumbago) Radiates to the legs (sciatic pain) or the arms Paresthesia of affected dermatome Muscle weakness and atrophy Loss of deep tendon reflexes in the indicator muscles Pain increases with pressure (e.g., from coughing or sneezing) Short walks and changing position reduces the pain A sudden decrease in pain concomitant with an increase in the degree of paralysis can be a warning sign of neuronal death! Sensory deficitsMotor deficitsReduction of reflexesC3/4 radiculopathyShoulder and neck areaScapular wingingC5 radiculopathyAnterior shoulderBiceps and deltoidBiceps reflexC6 radiculopathyFrom upper lateral elbow over radial forearm up to thumb and radial side of index fingerBiceps and wrist extensorsBicepsBrachioradialisreflexC7 radiculopathyPalmar: fingers II-IV (II ulnar half, III entirely, IV radial half)Dorsal: medial forearm up to fingers II-IVTriceps and wrist flexors, finger extensorsTriceps reflexC8 radiculopathyDorsal forearm up to dorsal and palmar area of fingers IV (ulnar half) and V, hypothenar eminenceFinger flexorsNoneL3 radiculopathyAnterior lateral area of the thigh (stretching diagonally from thigh to upper area of the medial knee)Hip flexionAdductor reflexPatellar reflexL4 radiculopathyExtending from distal lateral thigh area over patella up to inner side of lower legKnee extensionTibialis anterior muscle (foot dorsiflexion) → difficulty heel walkingPatellar reflexL5 radiculopathyDorsolateral thigh, lateral side of the knee, anterolateral lower leg, dorsum of foot, big toeExtensor hallucis longus muscle (first toe dorsiflexion) → difficulty heel walking (foot drop)Posterior tibial reflex (medialhamstring)S1 radiculopathyLateral footPeroneus longus and brevis muscle (foot eversion) and gastrocnemius muscle (foot plantarflexion) → difficulty toe walkingAchilles tendon LateralhamstringS2 radiculopathy, S3 radiculopathy, S4 radiculopathyPosterior aspect of thigh and lower leg (S2), perineum (S3-4), perianal (S4)NoneBulbocavernosus reflexPerineal reflex Spinal cord compression Definition: occurs when the spinal cord is compressed by a lesion such as a tumor, fracture, or ruptured disk EtiologyAcute onset (within minutes to hours): vertebral fracture, acute disc herniation, hematomaInsidious onset: abscess, primary tumor, metastasis (days to weeks); slow-growing primary tumors, degenerative spine changes, e.g., spondylosis (months to years) Clinical features: depend on the location of the spinal compression Common features: back pain, radicular pain (follows dermatomal distribution of affected nerve), and neurological deficits below the level of the lesion (first sensory abnormalities, followed by motor and/or bladder/bowel dysfunction)Incomplete spinal cord syndromes: cauda equina syndrome and conus medullaris syndrome Patients may develop symptoms of isolated cauda equina syndrome, isolated conus medullaris syndrome, or a combination of the two.Considered a medical emergency! TreatmentImmediate management IV glucocorticoids: reduce pain, swelling, and inflammation → immediate decompression; bridge time until surgery can be performed Opioids for further pain control if necessarySurgical management: definitive treatment Decompression surgeryStabilization surgery Radiation therapy: indicated if tumor is inoperable and following surgery; controls local tumor growth and significantly reduces pain Conus medullaris syndromeDamage to the spinal cordsegments S3-S5 (conus medullaris), which are situated at the level of L1 vertebraSpinal tumorsTrauma (e.g., vertebral fracture, spondylolisthesis)Sudden bilateral onsetLower back painLess severe radicular painSymmetric, hyperreflexicdistal paresis of lower limbs, possibly fasciculationsAchilles reflex may be absent Symmetric, bilateral perianal numbness Sensory dissociationEarly onset of bladder and fecal incontinence Erectile dysfunction Cauda equina syndromeDamage to or compression of the cauda equina with nerve fibers of L3-S5 (below L2) Large posteromedial disc herniation, trauma, or tumorsGradual unilateral onsetSevere radicular painAsymmetric, areflexic, flaccid paresis of the legs Muscle atrophySaddle anesthesia (may be asymmetric) Asymmetric, unilateral numbness and/or paresthesia in lower limb dermatomesLate onset of urinary retentionChange in bowel habitsDecreased rectal tone or bulbocavernosus reflexErectile dysfunction Conus medullaris syndrome and cauda equina syndrome are medical emergencies requiring immediate surgical intervention! Diagnostics Physical examination (reflexes, motor strength, sensory deficits) Straight leg-raising maneuvers Straight leg raise test (Lasegue's sign): straight leg of patient is raised → ↑ pain in the ipsilateral leg with radiation to the motor or sensory area of the affected nerve root. Bragard sign: straight leg of patient is raised → ↑ pain in the ipsilateral leg → leg is lowered to just below this point → ankle is dorsiflexed → reproduction of painCrossed straight leg raise test: opposite straight leg of patient is raised → increased pain in contralateral leg with radiation into the motor/sensory area of the affected nerve root. Spurling's maneuver (neck compression test) Used for diagnosis of cervical spine radiculopathyForward flexion , tilting, and rotation of the neck towards the affected side and application of downward pressure to the head → reproduction of pain or paresthesia with radiation to the motor/sensory area of the affected nerve root MRITo confirm diagnosisDisc degeneration: sclerosed, dehydrated disc that is hypointense on T2-weighted imagesDisc prolapse/herniation: herniation of disc tissue with surrounding edema CT-myelogramIf MRI is unavailable or cannot be conductedBetter for analysis of bone structure (e.g. prior to surgery) Plain radiographs: to exclude other pathologies (e.g., spine tumors, instabilities); preoperatively Differential diagnoses of low back pain MusculoskeletalMuscle strain (most common cause of lower back pain)Acute back pain and paravertebral stiffness and difficulty bending after physical exertion(e.g., heavy lifting)No loss of sensory or motor functionStraight leg raise testnegativePercussion: tenderness over lumbar spineNegative straight leg-raising maneuversEarly mobilizationNSAIDs and muscle relaxantsPrevention: correct lifting of heavy items Spinal stenosisIn older patientsPain in buttocks and legs (neuropathic claudication; improves with bending forward)X-ray: degenerative spinechangesMRI: confirmatory test(nerve compression)Conservative NSAIDsPhysiotherapyEpidural steroidinjectionsSurgery if conservative therapy fails Spinal disc herniationUnilateral radicular pain, dermatome referred (usually L5/S1 with positive straight-leg raise test)Paresthesia and muscle weaknessMRI: shows disc herniationConservative Activity continuation, no bed restNSAIDsSurgical decompression: in case of severe/progressive neurologic deficits Degenerative spondylolisthesisOlder agePossibly radicular syndromes, spinal claudicationLateral x-ray of the spineConservative PhysiotherapyOrthotic bracesSteroid/anesthetic injections for radicular painSurgery if conservative treatment not efficient Vertebral fusionDecompression of the spine Vertebral fracturesHistory of injuryLocal pain on pressure, percussion, and compressionX-ray,CTMRI for detecting spinal cord lesionsSurgical stabilization of the spine (e.g., kyphoplasty)Cord decompression MalignancyBone metastases (extradural metastaticlesions)Less commonly: intramedullary tumors (e.g., multiple myeloma, ependymomas, astrocytomas, metastases) and intradural-extramedullary (e.g., meningiomas, nerve sheath tumors)History of cancer (e.g., lung cancer, breast cancer, prostate cancer, melanoma)Advanced agePain worse at nightSpinal cord compressionLocal spinal pain, may radiate to the shoulder and neck (common in spinal metastases)Brown-Séquard syndromeis a common initial findingin patients with spinal metastatic lesions.MRI (urgent if spinal compression is suspected)SurgeryRadiation therapyIn case of spinal cord compression: high-dose corticosteroidsas soon as possible followed by definitive management Spinal epidural abscessPoint tendernessFever and chillsSpinal cord compressionRisk factors: IV drug useDiabetesInvasive procedures(e.g., removal of an epidural catheter)Alcohol use disorderImmunosuppressionUrgent MRICulture of blood, CSF, abscess contents (gained through aspiration) to identify the causative pathogen (Staphylococcus aureus (∼ 65% of cases) Empiric antibiotic therapySurgical drainage and decompression InflammatoryAnkylosing spondylitisPain mostly at restImproves with activityHLA-B27 presentPhysical therapyNSAIDsDMARDs in chronic casesIn severe cases surgeryReactive arthritisPsoriatic arthritis OthersAbdominal aortic aneurysmPulsatile abdominal massBruit on auscultationUltrasound (also for follow-up)CT (in case of rupture)Open or endoscopic grafting (tube or Y-prosthesis)Cauda equina syndromeAsymmetric, areflexic, flaccid paresis of the legsBladder, bowel incontinence, saddle anesthesiaMRISurgical decompression Spinal epidural hematoma♂ > ♀ (4:1)Bimodal distribution(peaks during childhood and between age 40-50 years)Spontaneous or traumatic (e.g., following lumbar puncture, pulling epidural catheter) bleeding Risk factors ThrombocytopeniaBleeding diathesisAnticoagulationVascular malformationsAcute spinal cord compressionBack pain, lower extremity weakness and numbness, hyporeflexiaMRI with and without gadolinium : to demonstrate hematoma and underlying pathology Surgical decompression to avoid permanent neurologic dysfunction (laminectomy and evacuation of blood) Acute spinal cord compression is a medical emergency. Conduct an MRI or CT myelography immediately and decompress the cord via IV steroids and/or surgery as soon as possible! Treatment Conservative treatment Physiotherapy with exercises strengthening the back No bed rest, but continuation of daily activities Local heat Analgesics (e.g., NSAIDs) Periradicular therapy (PRT): CT-navigated injection of a local anesthetic (e.g., ropivacaine) and glucocorticoids at the intervertebral foramen to reduce inflammation and edema at the affected nerve root 80% of all disc herniations are self-limiting and usually resolve within 4 weeks! Surgical treatment Emergency indicationsSignificant or progressive neurological deficitsBladder or bowel incontinenceCauda equina syndrome/conus medullaris syndrome Elective indications: massive radicular pain which cannot be relieved by conservative and/or medical treatment Procedure: microsurgical intervention with nerve decompression Access: windowing of the ligamentum flavum as a dorsal limitation of the spinal canalAim: removal of prolapsed disc material and potential sequestration Surgical complications Damage of large prevertebral blood vessels (rare)Post-dissection syndrome/postnucleotomy syndrome: persistent back pain, radicular pain, and paresthesia in approx. 5% of patients after disc surgery due to scarring, vertebral instability, or arachnoid adhesions to nerve roots.

Diabetic neuropathy

Distal symmetric polyneuropathy Pathophysiology: Chronic hyperglycemia causes glycation of axon proteins with subsequent development of progressive sensomotoric neuropathy; typically affects multiple peripheral nerves Epidemiology: Diabetic polyneuropathy is the most common form of polyneuropathy in Western countries. Clinical featuresEarly: progressive symmetric loss of sensation in the distal lower extremities A "stocking-glove" sensory loss pattern with proximal progression is typicalDysesthesia (burning feet) may occurA similar sensory loss pattern may occur in the upper extremities.Late: pain at rest and at night (painful diabetic neuropathy), but also decreased pain perception, motor weakness, and areflexia Special types: Mononeuropathy Cranial mononeuropathy Peripheral mononeuropathy Mononeuropathy multiplex: asymmetric neuropathy, affecting the multiple peripheral and cranial nervesDiabetic truncal neuropathy Diabetic lumbosacral plexopathy Screening Tuning fork: decreased vibration senseMonofilament test: decreased pressure sensePinprick (pain assessment) or temperature assessment: decreased sensation TreatmentOptimal glycemic control Pain managementAnticonvulsants: pregabalin (most effective; usually first-choice), gabapentin, and sodium valproateAntidepressantsTricyclic antidepressants: amitriptylineSNRI: duloxetine, venlafaxineMiscellaneous: lidocaine patch, capsaicin spray, isosorbide dinitrate sprayOpioids: dextromethorphan, morphine sulfate, tramadol, and oxycodone Urogenital systemErectile dysfunction (most common)Bladder dysfunction: urinary retention, incomplete bladder emptying, bladder distention, overflow incontinence, poor urinary streamCardiovascular systemSilent myocardial infarctionDecreased heart variability or fixed rhythmOrthostatic hypotensionPersistent sinus tachycardiaVentricular arrhythmiaGastrointestinal systemGastroparesis (→ delayed gastric emptying, risk of postprandial hypoglycemia): nausea, abdominal bloating, loss of appetite, early satietyDiarrhea, constipation, incontinenceTreatment involves prokinetic agents (e.g., metoclopramide (1st-line), erythromycin, cisapride). Other manifestationsSweat gland dysfunction associated with heat intolerancePupillary dysfunctionRisk of hypoglycemia due to absence of hormonal counterregulation (secretion of cortisol, glucagon, and catecholamines)

Medication for Parkinson disease There are many pharmacologic options available for the treatment of Parkinson disease; regimens are tailored to the patient's age, symptoms, and symptom severity. While only symptomatic treatment is available at this point in time, drugs that may slow or reverse the course of the disease are currently being investigated. Since treatment of Parkinson diseaseat an early stage can significantly improve a patient's subjective well-being (honeymoon period), medical therapy should be initiated as soon as symptoms begin to interfere with the patient's daily life. For most patients, first-line treatment consists of levodopa (L-DOPA) or dopamine receptor agonists, e.g., ropinirole and pramipexole. Other drugs that are used to treat Parkinson disease include amantadine, MAO-B inhibitors, and COMT inhibitors.

DopamineprecursorsL-DOPA(levodopa)L-DOPA is converted to dopamine by DOPA decarboxylase at the presynaptic neuron → direct dopaminergic effect(especially at D2 receptors) Predominantly controls bradykineticsymptomsFirst-line treatment for patients > 65 yearsof age or patients with comorbidities Second-line treatment for patients < 65 yearsof age Mostly given as monotherapy in combination with decarboxylase inhibitorsMost effective drug for reducing symptomsHowever, increased risk of severe motor dysfunctionwith long-term use (see "Side effects" below)Administer between meals (e.g., 30 minutes before a meal) to increase gastrointestinal absorption (→ avoid high-proteindiets) Decarboxylase inhibitorsCarbidopaDecreased peripheral conversion of L-DOPAto dopamine → reduced peripheral side effects of L-DOPA (e.g., orthostatic hypotension, nausea and vomiting) Always administered together with L-DOPA Dopamine agonists Non-ergotRopinirolePramipexoleApomorphineRotigotineAct directly at striatal dopamine receptorsPredominantly control bradykinetic symptomsFirst-line treatment for patients < 65 yearsof ageLess effective than L-DOPA, but fewer side effects Effective in advanced disease stages ErgotBromocriptineSecond-line treatment for patients < 70 yearsof age COMT inhibitorsEntacaponeTolcaponeInhibition of the peripheral (entacapone) or central (tolcapone) catechol-O-methyltransferase (COMT) → ↓ metabolization of dopamine → ↑ dopamine effect → ↓ demandfor L-DOPA and longer therapeutic effect for each doseEntacapone: If L-DOPA loses effect or motor symptoms fluctuate during L-DOPA therapyTolcapone: for refractory Parkinson diseaseMonotherapy with COMT inhibitors is ineffective → shouldalways be combined with L-DOPA and carbidopa NMDA antagonistsAmantadine Acts antagonistically at the glutamateN-methyl-D-aspartate (NMDA) receptor→ dopaminergic effect ↑ Dopamine release and ↓ dopaminereuptake in central neuronsMostly controls bradykinetic symptomsShort-term treatment of mild symptomsDrug of choice during akinetic crisisReduction of L-DOPA-induceddyskinesiaLoss of effect after several months of treatment → cannot be used for long-term therapyMay have cardiac side effects (prolonged QT interval) MAO-B inhibitorsRasagilineSafinamideSelegilineInhibition of MAO-B → decreased dopaminemetabolization in the brain → prolongeddopamine effect → ↓ demand for L-DOPAAlternative to L-DOPAor dopamine agonistsfor short-term therapy in patients with mild symptoms in early disease stages The combination of L-DOPA and selegilinemay reduce motor fluctuations. Anticholinergic drugs(muscarinic antagonists) Benztropine Trihexyphenidyl Biperiden Inhibition of excitatory cholinergic neurons→ ↓ concentration of acetylcholine Useful as monotherapy in patients < 65 years with tremor as the main complaint May be used as an adjunct if tremor is not sufficiently controllable with standard treatment Usually avoided in patients > 65 years because they are more prone to anticholinergic side effects(e.g., urinary retention, delirium, constipation) Patients who do not respond to levodopa therapy will not respond to dopamine agonist therapy! Side effects Carbidopa-levodopa Becomes less effective over time: may require a shorter interval between doses Vegetative symptomsNausea and vomiting Orthostatic hypotensionCarbidopa reduces the risk of orthostatic hypotension, nausea, and vomiting. Psychotic symptomsHallucinations (often visual) , insomnia, anxiety, and aggressive behavior → treat with clozapine Increased risk in elderly patients, women, concurrent dementia or other psychiatric disorders (e.g., depression), long duration of levodopa treatment, and high doses Motor fluctuations HypokinesiaEnd-of-dose akinesia/wearing-off phenomenon Freezing On-off phenomenon Dyskinesia (hyperkinesia)On-period dystonia Off-period dystonia Diphasic dyskinesias Akinetic crisisDefinition: condition caused by severe dopamine deficiency (e.g., after discontinuation of L-DOPA therapy or insufficient L-DOPA absorption)Clinical features: complete inability to move , incomprehensible speech, possibly hyperthermia → increased risk of dehydration, deep-vein thrombosis, and pneumoniaTreatment: intensive medical care, volume substitution, administration of L-DOPA, apomorphine, amantadine Dopamine agonists Side effects common to all dopamine agonistsVegetative: nausea, vomiting, orthostatic hypotension, dizziness, increased daytime drowsiness and sleep attacksMotor function: dyskinesia (rare)Psychiatric: unrest, hallucinations, impulse control disorders (e.g., compulsive gambling, sexual activity, or shopping), psychosisDopamine agonist withdrawal syndromeEtiology: abrupt discontinuation of dopamine agonist therapyClinical features: similar to malignant hyperthermia and neuroleptic malignant syndrome → hyperthermia and rigor; akinesia; reduced vigilance; increased creatine kinase levels, transaminases, and leukocytesTreatment: intensive medical care, volume substitution, administration of L-DOPA, apomorphine, amantadine Side effects of ergotamine-derived agonists (e.g., bromocriptine) Fibrosis: cardiac fibrosis, Raynaud disease, pleural pulmonary fibrosis and retroperitoneal fibrosis Other substances NMDA antagonists (amantadine)Side effects similar to L-DOPA, but much less pronouncedLivedo reticularis, peripheral edema NMDA antagonists can cause prolonged QT intervals! Do not administer NMDA antagonists to patients with a history of cardiac disorders! MAO-B inhibitorsHeadache, dyskinesia, psychological disorders (e.g., hallucinations)Inhibition of MAO-A with higher doses → reduced peripheral degradation of catecholamines → adrenergic side effects (e.g., tachycardia, sweating, nervousness) Muscarinic antagonists (anticholinergics): See antimuscarinic side effects. Administration of antimuscarinic drugs to patients with mental disorders or delirium will likely worsen psychiatric symptoms! COMT inhibitorsGastrointestinal side effectsDyskinesia and psychiatric symptoms (e.g., hallucinations or confusion)

Traumatic brain injuryTraumatic brain injury (TBI), also referred to as head injury, is acute physical damage to the brain caused by an external impact. TBI is most frequently seen in young children, teenagers, and individuals above the age of 65. Motor vehicle accidents are the most common cause. Although the skull is often fractured in the process, acute cerebral damage can occur even if the skullremains intact. Clinical findings depend on the severity, type, and location of injury. Impaired consciousness is common in more severe TBI, whereas patients with mild TBI often only experience transient confusion, headaches, or nausea. Elevated intracranial pressure, hemorrhages, and seizures may occur rapidly after injury in severe cases, or develop as complications over the course of the illness. Skull fractures may cause immediate damage to sensory organs or cranial nerves, while also increasing the risk of infection. A noncontrast head CT is the diagnostic method of choice for detecting common pathologies such as fractures, midline shifts, or hemorrhages. Treatment is usually not required for mild TBI, although patients should be monitored for 24 hours to rule out complications. In most cases of more severe TBI, specific medical (e.g., reduction of intracranial pressure, prevention of seizures or infections) or surgical (e.g., decompressive craniectomy) measures are necessar

Definition Acute physical damage to the brain as a result of an external force Closed head injury → dura mater is intactOpen head injury → dura mater is injured Epidemiology Incidence: ∼ 800/100,000 Age: especially children 0-4 years, teenagers and young adults 15-24 years, and adults > 65 years Sex: ♂ > ♀ Etiology Falls Motor vehicle accidents Contact sports (e.g., football) Gunshot wounds Pathophysiology Primary and secondary injury Primary injury: acute physical injury that is dealt to the brain during the traumatic event Acceleration-deceleration trauma Coup injury: cerebral contusion on the side of an impactContrecoup: additional cerebral contusion on the opposite side of impact Contact trauma: may involve fractures of the skull or superficial wounds (focal injury) Secondary injury: pathologic changes induced by inadequate cerebral perfusion and/or inflammatory processes after primary injury Consequences of injury Skull fractures Hemorrhages and hematomas (epidural, subdural, subarachnoid) Cerebral edema and elevated intracranial pressure (ICP) Diffuse neuronal damage Diffuse axonal injury (DAI) Clinical features Clinical findings vary depending on the location, severity, and type of injury. In addition to the initial presentation, further symptoms may develop as lesions progress (e.g., intracranial hemorrhages). General symptoms Global neurologic symptoms HeadacheAmnesia , confusion, disorientationImpaired consciousness , possibly with lucid intervals (see Differential diagnosis of intracranial hemorrhage)Dizziness, nausea, vomitingSlurred and/or disorganized speech, impaired coordinationChanges in mood and behavior Focal neurologic deficits (see Stroke) Seizures Sensory disturbances (e.g., anosmia, blurred vision) and cranial nerve palsies Cushing triad Postconcussion syndrome (PCS): headache, fatigue, dizziness, cognitive deficits, depression, and sleep disturbances Signs of basilar skull fracture The most common signs include Liquorrhea: leakage of CSF from the subarachnoid space through an external openingDue to a dural tear immediately or within the first few days after the traumaMay show a halo sign: rapidly-expanding clear ring of fluid surrounding bloodSubcutaneous hematomaCranial nerve palsies: usually arise 1-3 days after the trauma Anterior basilar skull fracture CSF rhinorrhea: leakage of CSF from the noseSubcutaneous hematoma around the eyes ("raccoon eyes")Can cause cranial nerve I, V, VI, VII, or VIII palsies Posterior basilar skull fracture CSF otorrhea: leakage of CSF from the external auditory meatusHemotympanumSubcutaneous hematoma behind the ear (Battle sign)Can cause cranial nerve VI, VII, or VIII palsies; in rare cases, causes facial numbness by damaging CN V Possible traumatic brain injury must always be considered in a patient with a reduced level of consciousness (unless another cause is evident)! Skull fractures, (worsening) neurological impairment, repeated vomiting, and seizures are indicative of more severe trauma or intracranial hemorrhage Diagnostics General approach to TBI patients Acute stabilization and measures of life support should always take precedence over diagnostic investigations! Cranial CT (without contrast) if consciousness is impaired Glasgow Coma Scale (GCS) for evaluation of consciousnessAssessment of neurological status and trauma severity in patients with traumatic brain injury (mostly used in acute cases)Maximum score 15 points (full consciousness); minimum score 3 points (coma or death) Eye openingVerbal response Motor response6Obeys commands5Appropriate words and orientedLocalizes pain stimulus 4SpontaneouslyAppropriate words but confusedWithdraws from pain3To verbal commandInappropriate wordsDecorticate posture 2To painIncomprehensible soundsDecerebrate posture 1No responseNo responseNo response Additional investigations: exact description of injury mechanism with evaluation of injuries; full medical and neurological examination Imaging First-line: cranial CT (cCT) without contrast to look for the following : Skull fracturesDura mater rupture (intracranial enclosures of air)Midline shift Hemorrhage and hematomas (see Differential diagnoses of intracranial hemorrhages below)Diffuse axonal injury (DAI): multiple focal hemorrhages, usually along the grey-white matter junction, the corpus callosum, and possibly the brainstem CT angiography: to evaluate/localize vascular injury (e.g., CTA spot sign ) Survey x-ray: orbital region for orbital fractures; trunk and/or the extremities Treatment Mild TBI No specific treatment Monitoring for 24 h Temporary rest and symptomatic pharmacotherapy For athletes: Refrain from contact sports for a week, re-evaluate at that timeObserve for 6 hours in the ED for worseningFollowing discharge → six stages of gradual recovery, each stage requiring at least 24 hoursNo activityLight aerobic exerciseSport-specific exerciseNon-contact workoutsFull-contact practiceReturn to full play More severe TBI Intensive care with general measures (e.g., fluid management, pain relief, blood pressure management) Intubation: if GCS is 8 or lower Monitoring ofICP, risk of elevated pressure (see ICP management)Cerebral perfusion pressure (CPP) Blood glucose (aiming for normoglycemia) Body temperature (aiming for normothermia) Prevention ofInfections in open head injury (e.g., cephalosporin)Seizures (e.g., phenytoin for up to one week post trauma) Secondary bleeding or hemorrhage enlargement (e.g., transfusion of platelets or fresh frozen plasma) Surgical therapySuperficial debridement, closure of the dura (if skull was fractured or penetrated)Removal of hematomas (usually recommended if GCS ≤ 8)Decompressive craniectomy Complications Cerebral edema Coma Irreversible loss of brain function (brain death) Seizures Post-concussion syndrome Prognosis Mild TBI: usually self-limiting Severe TBI: mortality rate as high as 30% Special patient groups When evaluating children and infants with TBI, a number of special issues must be observed. Causes: Falls (most common)The possibility of child abuse must always be considered. Clinical features: esp. bulging anterior fontanelle (↑ ICP) Diagnosis: cranial CT without contrast Identify patients with significant TBI but avoid unnecessary radiographic testing CT recommended for signs of skull fractures, ↑ ICP, major neurologic symptoms (e.g., impaired consciousness, seizures), suspected child abuseConsider CT: if less severe symptoms (e.g., changes in behavior, self-limited vomiting) are present. ManagementInpatient observation indicationsSkull fracture > 3 mm separation or depressedEvidence of traumatic brain injury on imaging (e.g.., intracranial hemorrhage)Signs of ↑ ICP (e.g., headache, altered mental status)Suspected physical abuseCaregivers who are unreliable or unable to return if neurological deficits develop within 24 hours after release.Release and at-home observation for 24 hoursPatients without neurological deficits and non-depressed linear skull fracture < 3 mm separationRequires a caregiver who can reliably recognize new clinical neurological deficits and return the patient to the hospital if such manifestations arise

Acoustic neuroma Acoustic neuromas (also known as vestibular schwannomas) are benign tumors that arise from Schwann cells and primarily originate within the vestibular portion of cranial nerve VIII. The tumor forms within the internal acoustic canal with variable extension into the cerebellopontine angle. Most tumors are unilateral. Bilateral acoustic neuromas strongly suggest the genetic condition neurofibromatosis type II. Symptoms are related to compression of cranialnerves VIII, V, VII, and the cerebellum. The most common symptom is unilateral sensorineural hearing loss. Diagnosis of acoustic neuroma involves audiometry that demonstrates ipsilateral sensorineural hearing loss and MRI with contrast to confirm the tumor. For patients with large tumors or significant hearing loss, the treatment of choice is surgical removal or radiation therapy. However, observation with follow-up may be appropriate for patients with smaller tumors and minimal hearing loss. On average, the prognosis is favorable, as acoustic neuromas are usually benign, slow-growingtumors with low recurrence rates.

Definition Benign tumors that arise from Schwann cells Epidemiology Median age: 50 years Incidence: 1/100,000 person-years Commonly located within the internal acoustic canal and can extend into the cerebellopontine angleMost common tumor of the cerebellopontine angle Unilateral in 90% of cases Bilateral acoustic neuromas are strongly associated with neurofibromatosis type II Clinical features Early symptoms with insidious onset: caused by pressure on the vestibulocochlear nerve (CN VIII) as a result of tumorexpansion into the internal acoustic canal (internal auditory meatus) Cochlear nerve involvement Unilateral sensorineural hearing loss (most common symptom)TinnitusVestibular nerve involvement Dizziness Unsteady gait and disequilibrium Late symptoms: caused by pressure of adjacent structures within the cerebellopontine angleTrigeminal nerve (CN V) involvement: paresthesia (numbness), hypoesthesia (decreased sensation), and/or unilateral facial painFacial nerve (CN VII) involvement: peripheral, unilateral facial weakness that can progress to paralysis Compression of structures in posterior fossaCerebellum: ataxia4th ventricle: hydrocephalus Diagnostics Cranial nerve testingCochlear nerve (CN VIII): sensorineural hearing lossAudiometryHearing loss with greater deficit for higher frequenciesBest initial screening test: > 95% of patients will have some type of hearing loss.Weber test: lateralization to the normal earRinne test: air conduction > bone conduction in both earsBrainstem-evoked audiometry: delay in cochlear nerve conduction time on affected side finding Can be used as additional screening tool in patients with asymmetric audiometry findingsLess commonly used because of the increased sensitivity and availability of MRI screening Contrast MRI (imaging modality of choice) Recommended in patients with abnormal audiometric testing or high clinical suspicion of acoustic neuroma(cerebellopontine angle syndrome)CT with and without contrast is an alternative for those who cannot undergo MRI. Shows an enhancing lesion by the internal auditory canal, with possible extension into the cerebellopontine angle. Treatment For those with large tumors or significant hearing loss, the main treatment options are surgery or radiation therapy. Observation of the tumor can be considered in patients with small tumors or minimal hearing loss, or if they are of advanced age. These patients should undergo MRI surveillance every 6-12 months Prognosis Good prognosis: Neuromas are a WHO grade I brain tumor with a low rate of recurrence.

Cerebral venous thrombosis Cerebral venous thrombosis (CVT) is a thrombotic obstruction of the cerebral venous system that may lead to ischemic lesions (or hemorrhages) in the brain. The condition can occur in all age groups and affects women more than men, who have a higher risk of predisposing factors such as prothrombotic conditions, pregnancy, oral contraceptive use, malignancy, and infection. Headaches are a typical presenting manifestation of CVT, while focal neurological deficits, seizures, and increased intracranial pressure may develop as the disease progresses. Diagnosis is established by visualizing the cerebral veins and dural sinus with neuroimaging methods (CT and MRI with radiocontrast). Management may include treating underlying causes and neurological symptoms as well as administering systemic anticoagulation or thrombolysis. Surgical intervention in the form of direct clot lysis, recanalization or shunt placement for raised ICP, can be indicated if medical management is insufficient.

Definition CVT, also known as cerebral venous sinus thrombosis, is a thrombotic obstruction of the cerebral veins and/or related anatomical structures (dural sinuses) which drain blood from the brain.Epidemiology Sex: ♀ > ♂, 3:1 Age of onset: ≤ 40 years Prevalence: 3-4 cases per million in adults; 7 cases per million in neonates Etiology Noninfectious Oral contraceptives, pregnancy, and postpartum period Hypercoagulable statesBlot clotting disorders (e.g., factor V Leiden, protein C and S deficiencies, antiphospholipid syndrome)Hematologic diseases (e.g., polycythemia, sickle-cell anemia)PregnancyMalignancies Minor head trauma Neurosurgical procedures (e.g., lumbar puncture) Additional associated systemic conditions Inflammatory bowel disease (e.g., Crohn's disease)Collagen vascular diseases and blood vessel disorders (e.g., lupus erythematosus, Granulomatosis with polyangiitis, temporal arteritis)HyperhomocysteinemiaHematologic conditions (e.g., paroxysmal nocturnal hemoglobinuria, thrombotic thrombocytopenic purpura, sickle cell disease)Nephrotic syndromeDehydration Infectious Otogenic (e.g., after acute otitis media) → generally infection of the lateral sinuses (transverse/sigmoid sinuses) or mastoiditis Rhinogenic (e.g., after sinusitis) Through facial infections Meningitis Pathophysiology Thrombogenesis occurs in the cerebral venous system, including the dural sinuses → ↓ cerebral drainage → ↑ intracranial pressure → clinical features (see below) Additionally, thrombus formation → congestion within the venous system of the brain → blood stasis → ↓ oxygenated blood in brain tissue → cerebral edema and/or infarcts/stroke Clinical features Headache (acute, subacute, or chronic) Nausea, vomiting, vision impairment ), bilateral papilledema on ophthalmoscopy Cranial nerve symptoms (e.g., diplopia, tinnitus, unilateral deafness, facial palsy) Focal epileptic seizures Impaired consciousness and awareness Hemispheric symptoms In cases of cavernous sinus thrombosis: patients may develop cavernous sinus syndrome Diagnostics If CVT is suspected, D-dimer levels and imaging studies are first steps of diagnosis D-dimers: > 500 μg/L Imaging: CT/MRI (with or without venography): tests of choice to confirm the diagnosis Plain CT/MRI help detect only edema and/or infarcts, but the thrombus itself can be visualized by means of venography. CT : Hypodense structures indicate ischemic eventThrombus can appear as a hyperdense vein or sinusCT venography shows a filling defect in a vein or sinus MRI Thrombus is isointense on T1 and hypointense on T2 early in the diseaseCerebral edema can be identifiedMR venography demonstrates a lack of flow Evaluation for possible causes↑ ESR and antibody studies CBC, CRP Tests for clotting disorders (e.g., Leiden factor V mutation) EEG: indicated if seizures are present Determines seizure focusMay show focal abnormalities if a unilateral infarct occurs Treatment Initial management consists of treating underlying causes, general stabilization procedures , and antithrombotic therapy, which is the mainstay of treatment for CVT. Only if there is no improvement shown with medical therapy, is surgical intervention considered. Medical therapy Acute phase: heparinization In individual cases: local thrombolysis Antibiotic therapy for infectious CVT Possibly anticonvulsants Surgical therapy IndicationsProgressive neurologic worsening (despite adequate anticoagulation) Acute rise in intracranial pressureImpending herniation Surgical options: Blood clot removalVessel recanalizationShunt placement

Carotid-cavernous fistula A carotid-cavernous fistula is an abnormal communication between a carotid artery and the cavernous sinus. It is most commonly caused by trauma. The fistula leads to a high-pressure inflow of arterial blood into the venous sinuses, resulting in compression and damage to adjacent structures. The main symptom is diplopia, caused by compression injury of the oculomotor nerves. Other common symptoms include pulsatile tinnitus, exophthalmos, and headache. Diagnosis is established based on typical findings on CT/MRI or angiography (e.g., enlarged cavernous sinus). The preferred treatment method is endovascular occlusion of the fistulawith balloons or coils.

Definition Direct ("high-flow") carotid-cavernous fistula (most common) Abnormal communication between the cavernous sinus and the intracavernous internal carotid arteryTypically rapid onset of symptoms Indirect ("low-flow" or "dural") carotid-cavernous fistulaAbnormal communication between the cavernous sinus and branches of the internal and/or external carotid artery within the dura materTypically gradual onset of symptoms Etiology Direct carotid-cavernous fistulaSecondary to head traumaSpontaneous Indirect carotid-cavernous fistulaSecondary to cavernous carotid aneurysm ruptureSecondary to cavernous sinus thrombosisRarely, as a complication of diseases that affect arterial walls Spontaneous Pathophysiology Arteriovenous fistula formation → high-pressure inflow of arterial blood into venous system → venous congestion → Compression of cavernous sinus structuresCranial nerves III, IV, and VI1st and 2nd branch of the trigeminal nerve (ophthalmic and maxillary nerves)→ Impaired venous drainage Clinical features Onset of symptoms may be abrupt or gradual, depending on whether the fistula is direct or indirect: Headache Orbital pain Diplopia, blurred vision Pulsatile tinnitus (fistula bruit) Signs of congestion Unilateral or bilateral, pulsatile exophthalmosChemosisMassive conjunctival congestion and hemorrhage, with potential bleeding in the retina and vitreous humorIncrease in intraocular pressureOptic disc swelling If not treated swiftly, carotid-cavernous fistulas may result in cerebral hemorrhage/infarction, intracranial hypertension, vision loss, or death! Diagnostics Initial studies help confirm the diagnosis. CT/MR (with or without angiography) may show: ProptosisEnlargement of the cavernous sinusExpansion of the superior ophthalmic vein(s)Skull fractures (if fistula is due to trauma) Abnormal cavernous sinus flow Ultrasound with transcranial Doppler: shows increased blood flow Cerebral angiographyGold standard for diagnosis (and treatment)Visualization of feeding vessels and blood flow Treatment Embolization using balloons or coilsDirect fistulas: transarterial approach Indirect fistulas: transvenous approach NeurosurgeryIndicated if endovascular interventions fail or are not possibleOcclusion of the fistula via suturing or packing

Focal seizures and syndromesFocal (or partial) seizures are an abnormal activation of neurons confined to one cerebral hemisphere, and are best described according to whether or not consciousness and/or awareness are impaired. In contrast, generalized seizures are characterized by abnormal neuronal activity that quickly spreads to both hemispheres of the brain. Seizures can be caused by genetic abnormalities, structural abnormalities, metabolic disturbances, tumors, or infection. Symptoms depend on the location of the ictal event within the brain and may include clonic movements, as well as sensory and psychiatric symptoms. Focal seizures may involve altered levels of consciousness (complex partial seizures) or evolve to secondarily generalized seizures. Temporal lobe epilepsy is the most common type of focal seizure. It frequently arises from hippocampal sclerosis, but may also be caused by malignancies or infections. Diagnosis of focal seizures begins with electroencephalography and neuroimaging. If an infectious or a metabolic etiology is suspected, laboratory tests can also be helpful. Focal seizures secondary to underlying non-neurologic pathologies (e.g., infection or metabolic disturbances) are treated by correcting the underlying abnormality. Seizures of unknown etiology or from a neurological defect are managed with anti-epileptic drugs such as lamotrigine (first-line), levetiracetam, or phenytoin.

Focal seizures can be caused by many factors: GeneticStructural and/or metabolic disturbances:Morphologic changes (e.g., hippocampal sclerosis or tumor growth)Electrolyte imbalancesDrug intakeInfectionsUnknown Common causes based on age group:Childhood: perinatal injury to the brainAdolescence: encephalitis and cerebral traumaMiddle-aged adults: cerebral tumorsAdults of advanced age: vascular encephalopathies and vascular dementia Benign epilepsy with centrotemporal spikes Definition: a benign form of epilepsy in children, featuring centrotemporal spikes EpidemiologyMost common form of epilepsy in children (∼ 10-20% of cases)Peak incidence: 7-9 years Clinical featuresUsually occurs during sleepFacial twitching or numbness, hypersalivation, and speech arrest (during and frequently even after the event)Involvement of an arm or an entire side of the body is possible, as is secondary generalization. EEG: centrotemporal spikes or sharp waves Often occurs in burstsOften bilateral, in which case activity in one hemisphere may be independent of the other Prognosis: usually seizures spontaneously resolve by puberty Treatment:Pharmacotherapy is not recommended in all cases.In cases of high seizure frequency or severity, antiseizure drugs (e.g., valproate) may be used. Rare idiopathic forms Benign childhood epilepsy with occipital spikesClassification: early-onset (called Panayiotopoulos type, < 10 years old) or late-onset (Gastaut type)Clinical features:Panayiotopoulos type Vomiting is typical and frequent.Seizures usually occur at night and last for 5 minutes or longer.Gastaut type Visual symptoms are typical.Seizures usually occur during daytime and last for less than 5 minutes. Focal seizures with structural or metabolic cause Temporal lobe epilepsy Epidemiology: most common form of epilepsy (∼ 40% of all epilepsy cases; ∼ 70% of focal epilepsy cases) EtiologyHippocampal sclerosisFound in approx. 70% of patients suffering from temporal lobe epilepsy that is resistant to pharmacotherapyEncephalitis (e.g., herpes simplex encephalitis), developmental disorders, neurodegenerative disorders, tumors Clinical featuresSeizures commonly occur in clusters, last approx. 30 seconds to 2 minutes, and follow this sequence: Aura Focal seizure with impaired awareness (complex partial seizure) Motor symptoms: typically oral alimentary automatisms like lip-smacking; also fidgeting (e.g., with clothing), stretching of the body, or walking in placeAutonomic symptoms: tachycardia, urge to void the bladder, mydriasis, sweating, salivatingAltered mental status: children appear absent-minded (e.g., staring ahead, unresponsive when spoken to), but no loss of consciousness or syncope occurs!Less frequently: loss or change in the sense of taste or smell, aphasiaFocal seizures may progress to generalized seizures.Postictal phase with confusion and tiredness is common; transient epileptic amnesia (rare): transient anterograde or retrograde amnesia immediately preceding or following a seizureThe limbic system may be impaired in recurrent uncontrolled seizures. Diagnosis: temporal lobe spikes on EEG TreatmentPharmacotherapy: e.g., lamotrigine or levetiracetamPossible surgical treatment in cases of medication resistance Prognosis: unfavorable (only 40% of patients on pharmacotherapy remain asymptomatic)Frontal lobe epilepsy Etiology: see "Etiology" above Clinical featuresUsually simple partial seizures featuring various motor symptoms (muscle tension, vocalization, gaze deviation, or head directed towards the unaffected side ) May feature autonomic symptoms (enuresis, salivation), impairment of speech, or attention deficits (staring spells that may appear similar to absence seizures)Jacksonian march: spreading of paresthesia or uncontrolled motor activity from one part of the body to adjacent areas, usually distally to proximally Todd's paralysis: sustained paralysis of the affected limb/area after the seizureUsually a series of short seizures (≤ 30 s) occurring during sleep (which often wake the patient)Secondary generalization is possible.Usually no aura and no postictal period of confusionParietal lobe epilepsy Epidemiology: 5% of cases of focal epilepsy Etiology: See "Etiology" above. Clinical featuresSimple partial seizures featuring sensory symptoms (e.g., paresthesia, pains), dyslexia, and sensory aphasiaPossible Jacksonian marchTransition to temporal or frontal lobe seizures (featuring the respective symptoms) may occur. Occipital lobe epilepsy Epidemiology: rare Etiology: See "Etiology" above. Clinical featuresSimple partial seizures featuring visual hallucinations, gaze deviation, and cortical blindnessTransition to temporal or frontal lobe seizures (featuring the respective symptoms) is possible.In general, patients suffering from partial seizures of structural or metabolic origin should be treated with antiepileptic drugs(e.g., lamotrigine or levetiracetam). Epilepsia partialis continua Epidemiology: rare Etiology: unspecific; current or past damage to the cortex (e.g., scar tissue, encephalitis, tumors) Clinical features: Clonic muscle activity of a particular region of the body ("partialis"), e.g., the mouth or a fingerSymptoms persist for several days ("continua")Might be considered a focal status epilepticus Treatment: treat the underlying condition

Parkinson disease Parkinson disease (PD) is a neurodegenerative disease involving a progressive depletion of dopaminergic neurons in the basal ganglia, particularly the substantia nigra. PD usually manifests at approximately 60 years of age. Although PD is considered an idiopathic disease, genetic factors seem to play a role in about 10-15% of cases and, accordingly, familial clustering has been observed. The typical clinical picture seen in PD is called parkinsonism and features the classical cardinal symptom of bradykinesia along with resting tremor and/or rigidity. Postural instability is another frequent finding. While PD is the main cause, parkinsonism may also result from other factors, e.g., medication (secondary parkinsonism). Atypical parkinsonism may appear similar to PD, but often features additional or atypical symptoms. To date, there is no cure for PD. Symptomatic treatment includes physical therapy and, depending on patient age and individual symptoms, various medications (e.g., levodopa, dopamine agonists). In specific cases, deep brain stimulation(DBS) surgery may be beneficial.

ParkinsonismParkinsonism is a syndrome featuring bradykinesia and either resting tremor or rigidity (or both). However, research suggests that a constellation of resting tremor, asymmetric movement disorders, and responsiveness to levodopa treatment correlates better with PD-specific neuropathological changes than classic parkinsonism. Secondary parkinsonism: parkinsonism with secondary causes such as medication, intoxication, and head traumaAtypical parkinsonism: parkinsonism that occurs as a feature of neurodegenerative diseases other than Parkinson disease, usually due to different or more extensive neuropathological changes and featuring additional or uncommon symptoms (e.g., early-onset postural instability). Disorders featuring atypical parkinsonism are termed Parkinson-plus syndromes. Parkinson disease: parkinsonism for which no cause can be determined (idiopathic) Epidemiology Sex: ♀ ≅ ♂ Prevalence: increases with age Age of onset: ∼ 60 years Risk factorsFamilial history (various genes) → in approximately 10-15% of cases Environmental factors (e.g., exposure to manganese and other substances)Diet/metabolism (e.g., low levels of vitamin D, high iron intake, obesity)Structural damage (e.g., history of traumatic brain injury) Etiology Parkinson disease: PD is commonly considered idiopathic, although several etiologic factors (e.g., genetic predisposition) are being investigated. Secondary parkinsonism (pseudoparkinsonism) Medication (drug-induced parkinsonism or "pseudoparkinsonism") Most frequent cause of secondary parkinsonismFrequently used drugs with considerable anti-dopaminergic effects: typical antipsychotics (e.g., haloperidol), some antiemetics (e.g., metoclopramide), some calcium channel blockers (e.g., flunarizine, amiodarone), valproate, and lithiumMPTP: Illegal drug, metabolized to MPP+, damages substantia nigraMetabolic disorders: e.g., Wilson diseaseToxins: e.g., manganese, carbon monoxide, carbon disulfideCerebrovascular disease (vascular parkinsonism): e.g., subcortical arteriosclerotic encephalopathyCNS infections: Viruses: e.g., herpes simplex virus, human immunodeficiency virusBacteria: e.g., Treponema pallidumProtozoa: e.g., Toxoplasma gondiiPrion agents: e.g., Creutzfeldt-Jakob disease Atypical parkinsonism: depends on the underlying disease (e.g., genetic abnormalities in Huntington disease) Classification Earlier disease onset type: onset < 55 years Tremor dominant type: onset ≥ 55 years with tremor as sole initial (or generally predominating) symptom Non-tremor dominant type: onset ≥ 55 years with predominating bradykinesia/rigidity Rapid disease progression without dementia type: rapid progression of motor symptoms and death within 10 years Older age, rigidity, and/or bradykinesia at onset signify a comparatively worse prognosis; tremor is a good prognostic sign! Pathophysiology Progressive dopaminergic neuron degeneration in the substantia nigra (part of the basal ganglia) and the locus coeruleus → dopamine deficiency at the respective receptors of the striatum with interrupted transmission to the thalamus and motor cortex → motor symptoms of PD. Serotonin and noradrenaline depletion (in the Raphe nuclei): likely cause of depressive symptoms Acetylcholine surplus (in the nucleus basalis of Meynert): likely cause of dyskinesia A further pathological hallmark of PD is the appearance of Lewy bodiesAggregates of misfolded α-synuclein and other proteins (hyaline eosinophilic globules)Seen in Lewy body dementia Clinical features General Clinical course > 10 years; unilateral onset with persistently asymmetrical course (i.e. unilaterally pronounced symptoms) but may progress to the contralateral side Parkinsonism Bradykinesia/akinesiaSlowness of movement in combination with decreased amplitude or speed during a sequence of movementBradydiadochokinesia Resting tremor (4-6 Hz) Pill-rolling tremor that subsides with voluntary movements, but increases with stressTypical in hands; may involve the legs, jaw, lips, and tongueRigidityIncreased and persistent resistance to passive joint movement that is independent of speed of movement Froment maneuver The patient is asked to perform repetitive movements in the contralateral extremity (e.g., opening and closing of the left fist if the right side is examined) → Subclinical rigidity becomes more pronounced and may be detected.Special form: cogwheel rigidity Postural instability Imbalance and tendency to fall Pull test Parkinsonian gait: shuffling gait with quickened and shortened steps Unhabituated glabellar reflex Signs of dystonia Pyramidal signs (but normal tendon reflexes) Good response to levodopa Other clinical features EarlyProdromal PD and/or Lewy body dementia: rapid eye movement sleep behavior disorder (RBD) Sensory Hyposmia or anosmia (potential early symptom )Dysesthesias: muscle and joint pain (often in the shoulder/arm region)Motor: reduced swinging of arms while walkingPersonality changes: e.g., withdrawal, apathy LateMotor Freezing : sudden inability to start or continue movements (e.g., while walking)Propulsion: forward-leaning gait with risk of patient falling forwardMicrographia: size of handwriting is reducedLow degree of facial expression (hypomimia), decreased blinkingAutonomic Depression, dementia Parkinsonism is required for the diagnosis of Parkinson disease! Unilateral onset is characteristic of Parkinson disease! Parkinson disease is a clinical diagnosis! Pharmacological Levodopa challenge test (alternatively apomorphine test): The result is positive if administration of levodopa/apomorphine relieves symptoms. Imaging Imaging is not routinely required for diagnosis, but should be considered in an atypical presentation or to rule out other underlying disorders. MRI: Conventional MRI is usually used to rule out other possible causes of parkinsonism (e.g., strokes, tumors) Advanced MRI techniques (e.g., diffusion-weighted imaging) allow PD to be distinguished from atypical parkinsonian syndromes in some cases. Differential diagnosis of parkinsonism Parkinson disease (PD) Idiopathic Various factors (genetic, environmental, inflammation, immune response, oxidative stress) appear to play a role. Degeneration of dopaminergic neurons chiefly in the substantia nigra → dopamine deficiency in the striatum → reduced excitatory input to the motor cortex → bradykinesia Serotonin, norepinephrine, and acetylcholinemetabolism are also affected → depression, dementia Depigmentation, atrophy, gliosis Lewy bodiesParkinsonism: bradykinesia plus either resting tremor or rigidity (or both) Postural instability Parkinsonian (shuffling) gait Course: Unilateral onsetProgression usually over > 10 years Parkinson disease is a clinical diagnosis (MDS criteria)! Levodopa challenge test: Symptoms usually improve with levodopa administration. Imaging to rule out other causes MRI DaTSCAN IBZM-SPECT Secondary parkinsonism Drug-induced(e.g., haloperidol) Toxin-induced(e.g., exposure to manganese) Metabolic (e.g., Wilson disease) Structural (e.g., vascular disorders) Normal pressure hydrocephalus(NPH) Infections (e.g., HIV) Parkinsonism: bradykinesia plus either resting tremor or rigidity(or both) Course: variable, depends on the cause To confirm specific etiologies: Laboratory: drugs, toxins, infections, metabolic disorders Imaging: NPH, vascular disorders, tumors Parkinson-plus syndromes Multiple system atrophy (MSA) Dementia with Lewy-bodies (DLB) Corticobasal degeneration (CBS) Progressive supranuclear palsy (PSP) MSASecondary neuronal degeneration as a result of Lewy body deposition in glial cells (and subsequent glial and myelin dysfunction)Particularly in the putamen, the pons, and the cerebellum DLBCerebral atrophy due to deposition of Lewy bodies, amyloid plaques, and neurofibrillary tangles in neuronsOccurs in cortical layers throughout the brain; thefrontal and temporal lobes are particularly affected. CBS: asymmetric frontoparietal atrophy and gliosis PSP: neuronal loss and gliosis particularly of the basal ganglia, midline thalamic nuclei and the brainstemAtypical parkinsonism: Generally poor response to levodopaDementia, oculomotor dysfunction, and early onset of autononomic dysfunction and gait instability are common.Particular syndromes show further characteristic symptoms. Course: The progression is usually faster and the prognosis is usually worse than in PD.May be distinguished from PD with the help of theclinical picture or via the levodopa challenge testand/or imaging studies (see the additional diagnostic tests for PD on the left). Distinction from Alzheimer diseaseMSA: dementia is possible, but not commonDLB: frequent visual hallucinationsCBS: cortical atrophy more pronounced in supplementary motor area and superior frontal gyrusPSP: dementia usually only in later stages Treatment To date, there is no cure for PD. Treatment is aimed at relieving symptoms and should generally begin once patients develop significant functional disability (see Parkinson disease medication). General measures Physiotherapy Speech and language therapy Occupational therapy Support groups Medical therapy For details on effects, administration, and side effects, see medication for Parkinson disease. Levodopa is the drug of choice for the symptomatic therapy of Parkinson disease. Dopaminergic therapy should be considered at an early stage if motor symptoms begin to substantially affect a patient's activities of daily living. The age of 65 should be considered a general point of reference rather than a fixed limit for beginning levodopa therapy.In the early phase of levodopa treatment, patients may experience a "honeymoon period" with relief of symptoms."On" (parkinsonism is relieved by the levodopa) and "off" (levodopa effect wears off, parkinsonism returns) episodes are another common phenomenon. Dopamine agonist in patients under the age of 65 Overstimulation of D2-receptors by levodopa or dopamine agonists may induce psychosis and hallucinations, especially in elderly patients with concurrent dementia or other psychiatric disorders! Patients under the age of 65 with no significant comorbidities First-line treatmentNon-ergot dopamine agonists (e.g., pramipexole, ropinirole, apomorphine): as monotherapy or in combination with levodopa/carbidopa MAO-B inhibitors (e.g., selegiline): may be used as a monotherapy or in combination with dopamine agonists or levodopa/carbidopaCOMT inhibitors (e.g., entacapone): in combination with levodopa/carbidopa AlternativesLevodopaNormally combined with a peripheral decarboxylase inhibitor like carbidopaMost effective symptomatic treatment but carries a higher risk of dyskinesias than other medicationsErgot dopamine agonists (e.g., bromocriptine) NMDA antagonists (e.g., amantadine): used to reduce levodopa-induced dyskinesiasAnticholinergics/muscarinic antagonists (biperiden, benztropine, trihexyphenidyl): useful in patients < 65 yearswith tremor as the main complaint Administration of anticholinergics may worsen existing psychiatric symptoms (particularly dementia)! There is also a risk of ischuria! Patients over the age of 65 or multimorbid patients of any age First-line treatment: levodopa + decarboxylase inhibitor (carbidopa) Levodopa is best taken between meals (e.g., 30 minutes before a meal). High protein binding properties are responsible for decreased activity! Patients with severe motor fluctuation DuodopaTM pump Deep brain stimulation (see below) Treatment of associated symptoms Depressive moods: SSRIs (e.g., citalopram) or SNRIs (e.g., venlafaxine) Dementia: cholinesterase inhibitors (e.g., donepezil) Psychotic episodes: atypical neuroleptics (e.g., clozapine) Dyskinesias: anticholinergics with CNS effects (e.g., trihexyphenidyl, benztropine) Detrusor hyperactivity: anticholinergics without significant CNS effects (e.g., trospium chloride) Deep brain stimulation (DBS) Indication: primarily recommended for patients with severe motor symptoms who respond to levodopa treatment but are not sufficiently controlled by it (or if a decrease in dosage is necessary due to side effects) Adverse effects Related to procedure and material: infections, hemorrhages, breakage or displacement of the electrode(s) or the lead(s)

Brain tumors Brain tumors are masses of abnormal cells within the brain. They can be primary or metastatic, benign or malignant. Common tumors in children are pilocytic astrocytomas, meningiomas, medulloblastomas, ependymomas, and craniopharyngiomas. Adults most often develop glioblastoma multiforme, meningiomas, hemangioblastomas, schwannomas, oligodendrogliomas, and pituitary adenomas. Clinical features and radiological findings vary according to the type, location, and onset of the tumor. Magnetic resonance imaging (MRI) is the primary diagnostic method. Removal of the entire tumor is a prerequisite for remission. The histological grade of the tumor, which is determined postoperatively, is an important factor in determining the prognosis. Malignant tumors usually require additional treatment with radiotherapy and/or chemotherapy. Astrocytomas (e.g., pilocytic astrocytoma, glioblastoma multiforme), meningiomas, pituitary adenomas, and schwannomasare discussed in separate learning cards.

Primary brain tumors Primary brain tumors arise within the CNS MetastasisDrop metastases and leptomeningeal metastases can occur. Typically present as nodules along the spine and cauda equina that can cause back pain with neurologic symptoms (e.g., limb weakness).Can be detected by lumbar puncture.Primary CNS tumors do not metastasize to organs outside the CNS. Pediatric primary brain tumors Most pediatric brain tumors are primaryMost common type of benign pediatric primary brain tumor: pilocytic astrocytomaMost common malignant pediatric primary brain tumor: medulloblastoma Brain tumors are the second most common cause of pediatric cancer after leukemia, accounting for approx. 20% of all cases of pediatric cancer. Pilocytic astrocytoma Astrocytes Posterior cranial fossa(infratentorial) Rosenthal fibers: eosinophilic fibers with corkscrew-likeconfiguration GFAP positive Medulloblastoma Primitive, neuroectodermal tissue Cerebellar vermis(infratentorial) Small round blue cells Homer-Wright rosette Ependymoma Ependymal cells 4th ventricle (infratentorial) Perivascular pseudorosettes: tumor cells that are arranged in a papillary structure around a central blood vessel Craniopharyngioma Rathke pouch Suprasellar region (supratentorial) Nests of stratifiedsquamous epitheliumwith internal areas of lamellar keratindeposits Cholesterol crystals Pinealoma Pineal gland Dorsalmidbrain(infratentorial) Large vacuolated cells with round nuclei(fried egg cells) Lymphoid stroma In children, most primary brain tumors arise infratentorially, craniopharyngiomas being an important exception! Adult primary brain tumors Primary brain tumors are less common than brain metastases in adults. Most common benign primary brain tumor in adults: meningiomaMost common malignant primary brain tumor in adults: glioblastoma multiforme Primary brain tumors account for approx. 2% of cancer cases in adults Glioblastoma multiforme Astrocytes Cerebral hemispheres (supratentorial) May cross the midline (butterfly glioma) Pleomorphicanaplastic cells that form pseudopalisadesdue to central necrosis or hemorrhage Microvascularproliferation GFAP positive Meningioma Arachnoid cap cells Extra-parenchymaltumor that can occur in supratentorial or infratentorialregions Spindle cellsarranged in whorls Psammoma bodies Hemangioblastoma Cerebellum(infratentorial) Densely packed thin-walledcapillaries Schwannoma Schwann cells Cerebellopontine angle(infratentorial) Spindle cells in palisades Antoni A tissue) alternating with myxoid areas (Antoni B tissue) S-100 positive Oligodendroglioma Oligodendrocytes Frontal lobes (supratentorial) Large vacuolated cells with round nuclei (fried eggcells) Chicken-wirepattern of capillaryanastomoses Pituitary adenoma Pituitaryadenotrophic cells (typically lactotrophs) Sella turcica(supratentorial) Monomorphic, acidophilic or basophilic, polygonal cells arranged in sheets or cords Medulloblastoma Description: a highly malignant tumor derived from primitive, neuroectodermal tissue EpidemiologyPeak incidence: 1st decadeMost common malignant pediatric brain tumor (approx. 20-25% of all cases) Associated conditionsTurcot syndrome Clinical featuresThe most common location is the cerebellum → cerebellar defects (e.g., broad-based gait)Most tumors arise within the cerebellar vermis (midline)Invasion or compression of the 4th ventricle → non-communicating hydrocephalus → features of raised intracranial pressure (e.g., papilledema, vomiting, headache)Drop metastases are common → paraplegia DiagnosticsImaging Intraparenchymal contrast-enhancing massBiopsy: anaplastic small round blue cells that surround a central neuropil (Homer-Wright rosettes) TreatmentResectionAdjuvant therapyChildren ≥ 3 years: chemotherapy and craniospinal radiotherapyChildren < 3 years: chemotherapy Ependymoma Description: a relatively benign tumor that arises from ependymal cells of the ventricular system EpidemiologyPeak incidence: children and young adults Associated conditionsNeurofibromatosis type II Clinical featuresThe 4th ventricle is the most common location in children → non-communicating hydrocephalus → features of raised intracranial pressure (e.g., papilledema, headache) DiagnosticsImaging Intra-parenchymal tumor with calcifications and cystic components due to necrosis and/or hemorrhageBiopsyPerivascular pseudorosettesRod-shaped bodies (blepharoblasts) near the nucleus TreatmentResectionAdjuvant radiotherapy Craniopharyngioma Description: a relatively benign dysontogenetic tumor arising from a remnant of the Rathke pouch (ectodermal derivative) EpidemiologyBimodal distribution: 5-14 years; second peak at 50-75 years Clinical featuresThe tumor arises in the suprasellar region and can extend into the intrasellar regionCompression of the optic chiasm → bitemporal hemianopsiaCompression of the infundibular stalk → disconnection hyperprolactinemiaCompression of the ventromedial hypothalamic nucleus → hyperphagia and obesityCompression of the pituitary gland due to intrasellar extension → hypopituitarismHypogonadotropic hypogonadismFailure to thriveCentral diabetes insipidus DiagnosticsImaging Suprasellar calcified cyst with a lobulated contourBiopsyCholesterol crystals found in a motor oil-like fluid on gross examinationHistological variants Adamantinomatous (common) Reticular epithelial cellsFrequently associated with calcificationsCysts and keratin nodulesPapillaryMetaplastic squamous cellsCalcifications and cysts are rareNo keratin nodules TreatmentResectionAdjuvant radiotherapyIn the case of hypopituitarism: hormone replacement therapy Glioblastoma multiforme See glioblastoma Meningioma See meningioma Hemangioblastoma Description: a benign, highly vascularized neoplasm EpidemiologyRarePeak incidence: 20-50 years Associated conditionsVon Hippel-Lindau disease Clinical featuresThe cerebellum is the most common location → cerebellar defectsCompression of the 4th ventricle → non-communicating hydrocephalus → features of raised ICP (e.g., papilledema, headache)Polycythemia DiagnosticsImaging Sharply demarcated intra-parenchymal mass 60% are cystic with a non-enhancing wall and an enhancing mural noduleBiopsy: thin-walled capillary vessels, densely packed together with scarce parenchyma TreatmentResection Antiangiogenic therapy Schwannoma See acoustic neuroma Oligodendroglioma Description: a tumor that arises from oligodendrocytes EpidemiologyMedian age: 40-50 years Clinical featuresThe most common location is the cerebral hemisphere (typically the frontal lobe) → seizures, focal neurological deficits, personality changes DiagnosticsImaging Intra-parenchymal tumor with calcificationsBiopsyCells with a clear cytoplasm and round nucleus (fried egg cells)Chicken-wire pattern of capillary anastomoses TreatmentResectionAdjuvant radiotherapy and chemotherapy Pituitary adenoma See pituitary adenoma Brain metastases Epidemiology: most common cause of brain tumors in adults EtiologyLung cancer (most common)Breast cancerMalignant melanomaRenal cell carcinomaColorectal carcinoma Clinical featuresAcute or subacute onset of symptoms due to rapid tumor growthHeadachesCognitive deficitsFocal neurological deficitsSeizures DiagnosticsNeuroimaging findingsWell-circumscribed tumors at the junction of gray and white matter and/or watershed areas of the arterial system Work-up if the primary tumor is unknown Whole body contrast CT and/or PET scanIf no primary tumor is found or if the tumor is not surgically accessible: biopsy of the brain metastasis TreatmentPrimary therapy Limited brain metastases: surgical resection or stereotactic radiosurgery(e.g., Gamma Knife, CyberKnife, proton beam)Extensive brain metastases: stereotactic radiosurgery, whole brain radiation therapy, or chemotherapyGlucocorticoids to reduce tumor edemaPatients with a high primary tumor burden and a poor functional status (Karnofsky score) can be treated palliatively.

Cerebellar syndromes The cerebellum is the region of the brain responsible for controlling stance, gait, and balance, as well as the coordination of complex and goal-directed movements. The acute onset of cerebellar symptoms is considered a medical emergency and is usually due to stroke, hemorrhage, or cerebral edema. Chronic cerebellar syndromes are either acquired (e.g., alcoholism, tumors, paraneoplastic) or genetic. Cerebellar injury is characterized by impaired cerebellar function, resulting in ataxia, imbalance, uncoordinated movements (dysmetria), speech (dysarthria), and oculomotor disorders (nystagmus). Vertigo may also occur if the vestibulocerebellar system is affected. The diagnosis is based on the evaluation of these symptoms and is confirmed by detection of the underlying cause in imaging or laboratory or genetic tests. As treatment of these causes is often not possible, management is focused on supportive measures such as physiotherapy and psychological support groups. NOTES

Acute Infarction, TIAHead trauma, edema, hemorrhageInfections (acute postviral cerebellitis): Adults: VZV, EBV, Lyme disease, tertiary syphilis, malaria, prion diseases (e.g., Creutzfeldt-Jakob disease)Children: VZV , coxsackievirus, parvovirus B19, HHV-6, hepatitis A, enteroviruses, measles, mumps, Lyme disease, etc. Medication, toxins, and poisons: barbiturates, benzodiazepines, heavy metals, and chemotherapy Subacute and chronicAlcoholismIntracranial tumors (e.g., medulloblastoma)Vitamin deficiencies: vitamin B12 deficiency, vitamin B1 deficiency (Wernicke encephalopathy)Paraneoplastic cerebellar degenerationGenetic: spinocerebellar ataxia, Friedrich ataxia, ataxia telangiectasiaMultiple sclerosisWilson disease (rare) Clinical features The clinical features vary depending on the underlying cause and severity of cerebellar injury. Symptoms manifest ipsilaterally to the lesion site. Cerebellar ataxiaGait ataxia: abnormal wide-based and unsteady gait; irregular, uncoordinated activity of the muscles of pelvic girdle and/or lower limbs Romberg test: unable to perform Unterberger test: positive (see "Differential diagnosis" below)Truncal ataxiaInability to sit upright and/or stand without support; most apparent in the sitting positionOccurs due to damage to the cerebellar vermisLimb ataxiaUncoordinated movements of the upper and lower extremitiesOccurs due to damage to the cerebellar hemispheres Dysmetria and tremor (postural, action, intention tremor)Finger-to-nose test: patients with dysmetria are unable to touch the tip of their nose with their index finger ; patients with tremor perform the test with shaking fingers Heel-knee-shin test: inability to slide the heel of one foot down the shin of the opposite leg; the heel will deviate to alternate sides DysdiadochokinesiaInability to perform rapidly alternating agonistic-antagonistic movementsRapid alternating movement test: the patient is unable to rapidly "screw" in an imaginary light bulb simultaneously with both hands (slow, uncoordinated movements) Rebound phenomenon (Stewart-Holmes sign) The patient bends their arm at the elbow, resisting the examiner's pull on the forearm; sudden release of the arm by the examiner results in an overshooting movement. Indicates impaired coordination between muscular agonists and antagonists Pronator drift: Patients stretch supinated arms out in front of them at shoulder level; the arm ipsilateral to the lesion will pronate and drift upwards. Dysarthria (scanning speech): words are broken down into separate syllables and spoken with varying force Oculomotor dysfunction, including nystagmus In acute cerebellar hemorrhage: occipital headache, neck stiffness, vomiting, nystagmus, gait ataxia Muscular hypotonia Vertigo The localization of symptoms offers important diagnostic clues! Unilateral abnormalities in ocular movements, ataxia, and posture indicate a cerebellar lesion on the ipsilateral side! Diagnostics Cerebellar syndromes are primarily a clinical diagnosis, based especially on the evaluation of posture, gait, and movements. Imaging tests and laboratory studies confirm the diagnosis. Neuroimaging (CT/MRI): indicated to rule out infarction, hemorrhage, tumors, edema Laboratory testing: complete blood cell count; electrolytes, vitamin B12 levels, vitamin B1 levels Genetic testing: if other diagnostic tests are negative or inconclusive Differential diagnoses of ataxia Cerebellar ataxia Romberg test (tests proprioception and vestibular function)Unable to perform Unterberger test (tests vestibular and cerebellar function)Positive Sensory (spinal) ataxia Impaired proprioception Ataxia and postural instabilities that worsen in poorly lit surroundings No abnormalities in speech and eye movementRomberg test (tests proprioception and vestibular function) Positive Unterberger test (tests vestibular and cerebellar function) Negative Vestibular ataxia Ataxia, unsteadiness Vertigo Romberg test (tests proprioception and vestibular function) Positive Unterberger test (tests vestibular and cerebellar function) Positive

Headache Headache is a symptom commonly encountered in everyday clinical practice, and, according to the WHO, one of the ten most common causes of functional disability. It may be primary (e.g., tension-type headaches, migraine) or secondary (e.g., following head trauma or infections) in nature. Although most episodes of headache are harmless, potentially life-threatening causes (e.g., subarachnoid hemorrhage, meningitis) should always be considered. Identifying the cause of headaches is often difficult and requires a detailed clinical history as well as a thorough physical examination. Additional diagnostics, e.g., imaging, are only indicated if headaches persist despite treatment or if specific clinical features are present that are signs of an underlying disease. This learning card gives an overview of the most common types of headache and serves as a guide to diagnosing different headache disorders.

Approach Red flags for headache [1] Fever Focal neurological deficits Seizures Meningeal signs Signs of increased ICP (e.g., papilledema) impaired level of consciousness Epidemiology Most common forms of headache [3]Tension-type headache: 40-80% of casesMigraine: 10% of cases Clinical features History of present illness Nature of the headacheLocalizationCharacter Triggers and exacerbating factorsStressoral contraceptives; menstruationLying down or standing up Associated symptomsNauseaAuraPhotopsia Past medical history, social history, and family history hypertension Medications Substance use Alcohol consumption Family history Physical examination Vital signsBlood pressurePresence of fever HEENTPalpation of the temporal artery; jaw movementPalpation of the sinusesDirect fundoscopy NeurologicalNeurological examination for neurologic deficits Skin: rash Low-risk headacheAge < 30 yearsFeatures of primary headachePrior experience of similar headacheAbsence of neurologic deficitsTypical headache pattern No recent history of cancer, HIV, or Lyme diseaseNo red flags for headacheHigh-risk headacheAny red flags for headacheAny features of secondary headacheHorner syndromeAccompanying systemic illness (e.g., fever, myalgias)Triggered by cough, exertion, or sexual intercourseTenderness over the temporal arteryHistory of cancer, HIV, Lyme disease Laboratory studies There are no routine recommended laboratory studies for headaches. Consider the following based on clinical suspicion: CBCTSHESR, CRP Imaging [6] Test of choice The initial test of choice is usually a head CT without contrast Initial test of choiceAlternativesSudden-onset severe headache (i.e., thunderclap headache)CT head without IV contrastCTA with IV contrast New headache with papilledemaMRI head Without contrastWithout and with IV contrastCT head without IV contrast CTV head with IV contrast MRV head Without IV contrastWithout and with IV contrastCT head with IV contrast New or worsening headache related to head trauma or accompanied by red flagsCT head without IV contrast MRI head Without IV contrast Without and with IV contrast N/ANew primary headache suspected to be of trigeminal autonomic origin (e.g., cluster headache) MRI head without and with IV contrast MRI head without IV contrastChronic headache with new features or change in character, severity, or frequencyMRI head Without IV contrastWithout and with IV contrastCT head Without and with IV contrast Without IV contrast Additional diagnostics to consider [6] Lumbar puncture (LP) with CSF analysis Tension headache 30 minutes to a couple of days No autonomic symptoms(vomiting, nausea, phonophobia, or photophobia) Tightness in the posteriorneck muscles Pericranial tenderness Stress Lack of sleep, fatigue Routine activities (e.g., climbing stairs) do not exacerbate symptoms. Migraine headache 4-72 hours 60% are unilateral. Nausea, vomiting Hyperacusis Photophobia Phonophobia Preceding aura Prodrome Stress Fluctuation in hormone levels: oral contraceptives, menstruation Certain types of food (e.g., those containing tyramines or nitrates such as processed meat, chocolate, cheese) Exacerbated by exertion Improved with sleeping/darkness Cluster headache30-180 minutes Short, recurring attacks Localized to the periorbital and/or temporal region Ipsilateral autonomic symptoms: conjunctival injection and/or lacrimation, rhinorrhea and nasal congestion Partial Horner syndrome: ptosis and miosis, but no anhidrosis Alcohol Meningitis [12][13][14]Classic triad: fever, headache, and neck stiffness (nuchal rigidity)Meningism (e.g., photophobia)Dull, diffuse (holocephalic) headache that worsens over hours/daysAltered mental statusNausea, vomitingSeizures↑ WBC, ↑ procalcitonin (if bacterial)CSF analysisBacterial: WBC ≥ 1000 cells/μL (predominantly neutrophils), elevated protein, low glucose, positive gram stainViral: WBC 10-500 cells/μL (predominantly lymphocytes), normal-elevated protein, normal glucoseIntracerebral hemorrhage[15][16]Acute, severe, nonspecific headacheFocal neurologic signs and symptomsNausea and vomitingConfusion and loss of consciousnessSeizuresCT head without contrast: hyperdense lesion with hypodense perifocal edemaSubarachnoid hemorrhage[17]Acute onset of a thunderclap headacheFocal neurologic deficitsMeningismImpaired consciousness, rapidly worsening neurological statusSeizuresCT head without contrast: blood in subarachnoid space(hyperdense)Lumbar puncture : ↑ RBC countSubdural hematoma (SDH)Diffuse headache that is worst on the side of the hematomaImpaired consciousness and confusionFocal neurologic deficits (e.g., hemiparesis , gait, speech, visual impairment, personality changes, dilated pupil , or nonreactive pupil )Signs of increased intracranial pressureChronic subdural hemorrhage : psychomotor impairment, memory lossCT head without contrast: crescent-shaped, concave, hyperdense hemorrhage that crosses suture lines but not the midlineEpidural hematoma [18]Headache localized to the side of the hematomaContralateral focal symptoms/hemiplegiaImpaired mental status, loss of consciousness, seizures, nausea, and vomitingNearly half of patients who lose consciousness will have a lucid interval followed by clinical deterioration due to further expansion.CT head without contrast: biconvex, hyperdense lesionCerebral venous sinus thrombosis [19]Nonspecific headache (acute, subacute, or chronic) Cranial nerve symptoms (e.g., diplopia, tinnitus, unilateral deafness, facial palsy)Cavernous sinus syndromeFocal neurological deficits SeizuresImpairment in consciousness and awarenessSigns of increased intracranial pressure (e.g., nausea, vomiting)Risk factors: pregnancy, prothrombotic states, vasculitis, smoking, use of oral contraceptivesLabs: ↑ WBC , ↑ D-dimerFundoscopy: papilledemaMRI/MRV or CT/CTV: direct or indirect signs of thrombus (see also "Diagnostics" in cerebral venous thrombosis) [20]Cerebral venography: filling defect [19]Giant cell arteritis [21][22][23][24]Unilateral headache over the temporal/occipital areaProminent, tender temporal arteryJaw claudication, scalp tendernessConstitutional symptoms: fever, malaise, fatigueIf temporal arteritis is associated with polymyalgia rheumatica: shoulder/pelvic pain, depression, tiredness, fever, weight lossPartial or complete vision loss (unilateral or bilateral), amaurosis fugax, diplopiaAnemia, ↑ ESR ≥ 40-50 mm/hour , ↑ CRP, ↑ IL-6Temporal artery biopsy (gold standard): segmental vasculitis with predominant mononuclear cells or granulomatous inflammationMRI with contrast: enhancement of the temporal arteryHypertensive crises [25][26]Diffuse (sometimes bifrontal), pulsating headache that is exacerbated by physical activityHypertension > 180/120 mm HgSigns of end-organ damage (e.g., chest pain, dyspnea, oliguria, altered mental status)Clinical diagnosis: elevated BP with or without signs of end-organdamage Labs: anemia, ↑ creatinine, ↑ BNP, proteinuria, hematuriaECG: left ventricular hypertrophy, signs of cardiac ischemia(e.g., ST depressions or elevations)Chest x-ray: cardiomegaly, pulmonary edemaIschemic stroke [27][28]Tension-type headacheFocal neurological deficitsAltered mental statusCT head without contrast: hyperdense occluded vessels, hypodense parenchyma, effacement of the sulci and loss of corticomedullary differentiationCTA head and neck: vessel occlusionDW-MRI: T1 hypointense signal, T2 hyperintense signal in the area of the infarctionIntracranial space-occupying lesions (e.g., brain tumors) [29][30][31]A dull headache that is usually bifrontal and worsens over weeks/months Signs of increased intracranial pressure (e.g., papilledema)Focal neurologic deficits, altered mental status, seizures, nausea and vomitingT1-weighted MRI brain with gadolinium: hypo-, hyper-, or isointense mass lesion with peritumoral edemaCT brain with IV contrast: mass lesion, commonly with contrast enhancementConcussion (e.g., mild traumatic brain injury) [32][33][34]Headache of variable intensityConfusion Retrograde amnesia and/or anterograde amnesiaNausea, vomiting, dizzinessAgeusia , anosmia, tinnitus, photophobia, blurring of visionLoss of consciousness (rare)History of trauma Clinical diagnosisCT head without contrast: usually normal Trigeminal neuralgia [35][36]Paroxysmal , stabbing, unilateral facial painTender trigger pointsNo neurologic deficitsClinical diagnosis [36]MRI brain: vascular compression of the trigeminal rootMedication overuse headacheDull, long-lasting headache with variable characteristicsHistory of analgesic overuseNausea, irritability, difficulty concentratingClinical diagnosis Differential diagnoses Primary headache Migraine Tension-type headache cluster headaches Secondary headache Bleeding Epidural hemorrhageSubdural hemorrhageSubarachnoid hemorrhage Vascular Cerebral venous thrombosis Autoimmune Temporal arteritis Drug/toxin-related Medication overuse headache Infectious Intracranial infections MeningitisEncephalitisBrain abscess Other Increased intracranial pressurepost-lumbar puncture headacheGlaucomaBrain tumorsTrigeminal neuralgiaHypoxia and/or hypercapniaHypertension

Craniovertebral junction anomalies The craniovertebral junction (CVJ) is composed of the occiput, the foramen magnum, and the first two cervical vertebrae, encompassing the medulla oblongata and the upper cervical spinal cord. Anomalies of the CVJ may be congenital or acquired. CVJ anomalies that decrease the volume of the posterior cranial fossa (e.g., platybasia) cause Chiari malformations, while erosion of the cervical vertebrae causes basilar invagination (cranial migration of the odontoid process), and anomalous fusion of the cervical vertebrae causes Klippel-Feil syndrome. Clinical features of CVJ anomalies are due to compression of the brain stem and the spinal cord and may include recurrent occipital headaches, neck aches, bulbar palsy, and upper and lower motor neuron palsy. CVJ anomalies can also obstruct the flow of CSF, resulting in syringomyelia and/or hydrocephalus. Diagnostics include neck x-ray and CT/MRI of the head and neck. Surgery is often indicated to prevent or treat neurological symptoms.

Basic anatomy The CVJ is composed of the occiput, the foramen magnum, and the first two cervical vertebrae (the atlas, and the axis). It encompasses and protects the medulla oblongata and the upper cervical spinal cord. Etiology Congenital anomalies of the CVJOcciput: condylar hypoplasia, fusion of the atlas to the occiput (atlantooccipital assimilation), platybasia (abnormal flattening of the base skull)Atlas: atlantooccipital assimilation, atlantoaxial fusion, aplasia of the archesAxis: hypoplasia of the odontoid process (dens) Acquired anomalies of the CVJTrauma: to the bones or the supporting ligaments of the CVJInflammatory: rheumatoid arthritis, ankylosing spondylitisGenetic syndromes: Down syndrome, achondroplasia, osteogenesis imperfectaMalignancies: chondrosarcoma, multiple myeloma, metastatic deposits Chiari malformations Definition: caudal displacement of the cerebellum with/without the medulla oblongata, through the foramen magnum, due to CVJ anomalies EpidemiologyIncidence: Type I Chiari malformation is the most common anomaly; 1 in 1,000 live births Sex: ♀ > ♂ AssociationsNeural tube defects (esp. meningomyelocele)SyringomyeliaHydrocephalusKlippel-Feil syndromeBasilar invagination Pathophysiology: multiple theories Fluid theory: neural tube defect → cerebrospinal fluid leakage → decreased volume of the posterior cranial fossa → compression and downward displacement of the cerebellum with/without the medulla oblongata through the foramen magnumMolecular genetic theory: congenital defects of the posterior brain and bony structuresGrowth abnormality theory: poorly coordinated cranial and cervical growthCrowding theory: small posterior cranial fossa → crowding of neural tissue at the foramen magnum Type I CM (Chiari I malformation) Ectopic extension of cerebellar tonsilsthrough the foramen magnum Usually symptomatic in adolescence/young adulthood:Occipital headacheNeck painRadicular pain in the shoulders and armsLower cranial nerve disordersCerebellar symptoms (e.g., dysarthria, ataxia) Downbeat nystagmus: the eyes pathologically drift upwards followed by a quick downward saccade Some patients develop syringomyeliaand/or hydrocephalus.CT/MRIof the brain Caudal displacement of cerebellar tonsilsSmall posterior cranial fossa Type II CM (Arnold-Chiari malformation) Protrusion of cerebellar tonsils, vermis, and medulla oblongata into the foramen magnum Usually symptomatic in infancyObstructive hydrocephalus: Displacement of brain tissue into the foramen magnumresults in stenosis of the cerebral aqueductBreathing difficulties, including apneic episodesFeeding difficulties Always associated with myelomeningocele: manifests with motor and/or sensory deficits at and below the level of the lesion Some patients develop syringomyeliaFeatures of type I CM In addition, caudal displacement of a beakeddorsal midbrain, and (possibly) the fourth ventricle Type III CM (Chiari III malformation)Herniation of parts of the cerebellum and brain stem through an abnormal opening in the back of the skull (encephalocele)Mostly fatal in early infancy For those that survive: Upper and lower motor neuron palsiesCranial nerve disordersCerebellar symptomsEpilepsyIntellectual disabilityFeatures of type I CM In addition, caudally displaced cerebellumand/or medulla protrude through an osseous defect in the skull (encephalocele) TreatmentSurgery: indicated in all patients with type II and III CM and in symptomatic type I CMSurveillance: indicated in asymptomatic type I CM; annual MRI of the brain to look for development of syringomyelia and/or hydrocephalus Basilar invagination Definition: abnormal protrusion of the odontoid process (dens) of the axis into the foramen magnum Etiology: CVJ abnormalities (mostly acquired CVJ) Clinical features Recurrent occipital headache, neck painBreathing difficulties, including sleep apneaBulbar palsy Downbeat nystagmusCommonly associated with Chiari malformations, hydrocephalus, and/or syringomyelia DiagnosticsNeck x-ray (lateral view): protrusion of the odontoid process by ≥ 3 mm above of Chamberlain line CT: confirm x-ray findingsMRI: indicated in patients with neurological symptoms; can demonstrate brainstem/spinal cord compression, hydrocephalus or syringomyelia, if present Treatment: surgery Klippel-Feil syndrome (congenital synostosis of the cervical vertebrae) Definition: congenital fusion of ≥ 2 cervical vertebrae EtiologyGenetic mutation (sporadic/inherited)Associated with Chiari malformations, scoliosis, spina bifida occulta Clinical featuresClassic triad: short neck, restricted cervical mobility, and low posterior hair line Hearing loss, genitourinary abnormalities, and cardiovascular abnormalities are also common. DiagnosticsCervical spine x-ray (AP and lateral views): cervical vertebral fusion CT: useful in planning surgery MRI: indicated in patients with neurological symptoms/deficits; can demonstrate cord compression and/or Chiari malformation, if present TreatmentConservative management (cervical collars/braces/traction): in mildly symptomatic patients without cervical spineinstabilitySurgery: indicated in patients with cervical spine instability or neurological symptoms

Incomplete spinal cord syndromes Incomplete spinal cord syndromes are caused by lesions of the ascending or descending spinal tracts that result from trauma, spinal compression, or occlusion of spinal arteries. Central cord syndrome, anterior cord syndrome, posterior cord syndrome, and Brown-Séquard syndrome are the most common types of incomplete spinal cord syndromes. In contrast to a complete spinal cord injury, lesions only affect part of the cord and patients present with a dissociated sensory loss. A spine MRI is the diagnostic modality of choice to determine the etiology, level, and extent of the lesion. Treatment depends on the underlying etiology. In some cases, surgery may be necessary to treat the underlying cause and to improve the patient's outcome. Spinal compression is a medical emergency and requires urgent treatment with steroidsand decompressive surgery.

Basic neuroanatomy and function Pyramidal tracts (lateral corticospinal tract and anterior corticospinal tract)Descending tracts originate in the cerebral cortex and extend to the alpha (α) motor neuron in the ventral horn of the spinal cord.About 90% of pyramidal neurons decussate as they pass through the medulla and descend further as the lateral corticospinal tract.The remaining 10% continue as the anterior corticospinal tract and decussate at the segmental level.Function: controls motor function Posterior column (posterior funiculus consisting of gracile and cuneate fasciculi)Decussation at the medulla oblongataRemains ipsilateral in the spinal cordFunctionConveys epicritic sensation: fine touch, vibration, pressureConveys proprioception: awareness of position in relation to one's body in space Spinothalamic tract (anterior spinothalamic tract and lateral spinothalamic tract)Decussation only at segmental level or shortly aboveFunction: conveys protopathic sensation (contralateral temperature, pain stimuli, and crude touch) Affected spinal tractsEtiologyClinical features Central cord syndrome(most common)Bilateral central corticospinal tracts and lateral spinothalamic tractsHyperextension injury (e.g., car crash) associated with chronic cervical spondylosisSpinal cord compressionBilateral paresis: upper > lower extremities Anterior cord syndromeCorticospinal and spinothalamic tractsTrauma (e.g., penetrating injury, burst fracture of vertebra)Occlusion of anterior spinal arteryBilateral motor paralysis, loss of pain and temperature sensation, and autonomic dysfunction below the level of the lesion Posterior cord syndromePosterior columnsTrauma (e.g., penetrating injury)Occlusion of the posterior spinal arteryMultiple sclerosisIpsilateral loss of proprioception, vibration, and touch sensation below the level of the lesion Brown-Séquard syndrome(hemisection syndrome)Hemisection of the cordTrauma (e.g., penetrating injury)Spinal cord compressionIpsilateralLoss of proprioception, vibration, and tactilediscrimination below the level of the lesionSegmental flaccid paresis at the level of the lesion, spastic paralysis below the level of the lesion , and ipsilateral Babinski signContralateral: loss of pain and temperature sensationone or two levels below lesion Central cord syndrome Definition: injury to the central region of the spinal cord (central corticospinal tracts and decussating fibers of the lateral spinothalamic tract) Epidemiology: Most common type of incomplete cord syndromeCommon in the elderly with preexisting degenerative changes in the cervical spine Etiology: syringomyelia, degenerative spine disease, cervical spondylosis, traumatic disc herniation, various hyperextension injuries (e.g., car crash → whiplash injury) Clinical featuresBilateral motor paresis (upper > lower extremities; distally > proximally) Variable sensory impairmentSometimes burning pain in the arms Sometimes loss of pain and temperature in the arms Diagnostics: CT and/or MRI to determine location, cause, and extent of neurological damage Therapy: see management of spinal cord injuries Prognosis: relatively good prognosis Anterior cord syndrome Definition: damage to the anterior two-thirds of the spinal cord usually as a result of reduced blood flow or occlusion to the anterior spinal artery (ASA) → Anterior spinal artery syndrome (∼ 95% of cases) EtiologyArteriosclerosis, vasculitis (e.g., associated with diabetes or syphillis), thrombosis, embolic occlusionAortic dissection, aneurysmTrauma (e.g., penetrating injury, burst fracture, hyperflexion injury with vertebral instability which is common in young athletes) Iatrogenic (e.g., during aortic surgery, spinal angiography, or spinal anesthesia))Severe hypotension (e.g., following hemorrhage)Pathological compression (e.g., tumors, cervical spondylosis) Clinical featuresAcute (within hours)Back or chest painSpinal shockBilateral loss of temperature and pain sensation , motor function (flaccid paraparesis or quadriparesis) , and autonomic function (bladder, bowel, and sexual dysfunction, orthostatic hypotension) below the level of the lesionAbsent bulbocavernosus reflex: squeezing the glans penis or pulling on a Foley catheter while digitally palpating the contraction of the anal sphincterLate (after days or weeks)Continued sensory and autonomic dysfunctionSpastic paraparesis or quadriparesis (increased muscle tone) Hyperreflexia Special variant: Lesion of the artery of AdamkiewiczEtiology: same etiologies as mentioned above (especially aortic repairs) → reduced blood flow or occlusion of the artery of Adamkiewicz Clinical features: features of ASA syndrome DiagnosticsSpinal MRI (best confirmatory test): excludes soft-tissue lesions (e.g., tumors, hematomas), bone lesions, and detects spinal cord parenchyma abnormalities (e.g., infarction)Consider VDRL or RPR if syphilis is suspected TherapySee Management of spinal cord injuries (i.e., mostly supportive care)Treat the underlying condition (if possible)Consider surgical repairAspirin for thrombotic occlusionPenicillin for syphillisSurgery for vascular abnormalities (e.g., aortic dissection) or tumorsControl chronic comorbidities (e.g. diabetes) Prognosis: 10-15% functional recovery; if no recovery is evident and progressive after 24 hours, prognosis is poor Posterior cord syndrome Definition: injury of the posterior spinal cord affecting the posterior column (fine touch, vibration, pressure, and proprioception) Epidemiology: very rare EtiologyOcclusion of the posterior spinal artery Multiple sclerosisTabes dorsalisSubacute combined degenerationFriedreich ataxia Clinical features: ipsilateral loss of vibration and proprioceptive sensation below the lesion Diagnostics: MRI showing infarction of the dorsal columns in the case of posterior spinal artery occlusion Therapy: see management of spinal cord injuries Prognosis: patients show functional gain with rehabilitation rown-Séquard syndrome Definition: hemisection of the spinal cord; often in the cervical cord EtiologyUnilateral compression commonly through trauma (e.g., often penetrating injuries, or crush injury)Less commonly disc herniation, spinal epidural hematoma, spinal epidural abscess (rare) or tumor; multiple sclerosis, complication of decompression sickness Clinical featuresIpsilateralLoss of proprioception, vibration, and tactile discrimination below the level of the lesion Segmental flaccid paresis at the level of the lesion , spastic paralysis below lesion , and ipsilateral Babinski sign Contralateral: loss of pain and temperature sensation one or two levels below lesion DiagnosticsClinical diagnosisConsider CT if trauma has occurred or an MRI if a tumor is suspected Therapy: see management of spinal cord injuries (e.g., steroid administration to reduce swelling, surgery depending on the underlying condition) Prognosis: poor

HydrocephalusHydrocephalus refers to the abnormal enlargement of cerebral ventricles and/or subarachnoid space as a result of excess cerebrospinal fluid (CSF) accumulation. There are two types of true hydrocephalus: communicating hydrocephalus, which occurs due to decreased CSF absorption or increased CSF production in absence of any CSF-flow obstruction, and noncommunicating hydrocephalus, which occurs due to the obstructed passage of CSF from the ventricles to the subarachnoidal space. Both forms cause elevated intracranial pressure (ICP), which leads to headache, nausea, and/or vomiting. Specific clinical manifestations include changes in vital signs resulting from brainstem compression and, in congenital hydrocephalus, macrocephaly. Normal pressure hydrocephalus (NPH) is a chronic form of communicating hydrocephalus that occurs in older individuals (> 60 years of age). NPH occurs due to decreased CSF absorption and manifests with normal ICP because of effective compensation to the slow CSF accumulation by ventricular dilation. This ventricular distension leads to the classic presentation of urinary incontinence, dementia, and ataxic gait. Hydrocephalus ex vacuo is the enlargement of the ventricles and subarachnoid space due to loss of brain tissue (e.g., cerebral atrophy) and the subsequent filling of the void with CSF. It is not considered a true hydrocephalus since ventricular enlargement does not result from CSF accumulation and, accordingly, does not affect intracranial pressure or flow of cerebrospinal fluid. CT or MRI (and ultrasound for infants) are important diagnostic procedures for all types of hydrocephalus. A CSF tap test confirms the diagnosis of NPH. Treatment involves surgical insertion of a shunt, which drains excess CSF into another area of the body (usually the peritoneum).

Communicating hydrocephalus↑ CSF production↓ CSF absorptionTypical findings of raised ICPHeadache, nausea, and vomitingPapilledema6th nerve palsyAbnormal gaitImpaired consciousnessCushing triad (irregular breathing, widening pulse pressure, bradycardia)Ultrasonography (in infants < 6 months)MRI or CT (older infantsor adults)Noncommunicating hydrocephalusObstructed passage of CSF from the ventricles to the subarachnoidal spaceNormal pressure hydrocephalus (NPH)↓ CSF absorptionClassic triadWet: urinary incontinenceWacky: dementiaWobbly: frequent falls, broad-based gait with short steps (ataxic gait)MRI (initial test)CSF tap test (confirmatory test) Epidemiology Prevalence: communicating hydrocephalus > noncommunicating hydrocephalus AgeCongenital hydrocephalus (∼ 60% of cases): 3/1.000 live births in the US [1]Acquired hydrocephalus (∼ 40% of cases): affects all ages NPH, a common form of acquired hydrocephalus, primarily affects individuals > 60 years. Sex: ♂ = ♀ Etiology and pathogenesis Communicating hydrocephalus Dysfunction of subarachnoid cisterns or arachnoid villi resulting in decreased CSF absorption or increased CSF production. ↓ CSF absorptionInflammatory diseases of the central nervous system (CNS) → inflamed arachnoid villi Subarachnoidal or intraventricular hemorrhage → inflammatory response → fibrosis Congenital absence of arachnoid villi ↑ CSF productionChoroid plexus papilloma: rare benign tumor of the choroid plexus. Typically presents with headache (and other symptoms of intracranial hypertension) due to hydrocephalus secondary to cerebrospinal fluid overproductionChoroid plexus carcinomaInflammation of the choroid plexus [2] Noncommunicating hydrocephalus Obstruction of the cerebral aqueduct of Sylvius, the lateral foramen of Luschka, or the median foramen of Magendi results in obstructed passage of CSF from the ventricles to the subarachnoidal space. CongenitalArnold-Chiari malformationDandy-Walker malformation: A congenital malformation caused by failure of the fourth ventricle to close, which leads to persistence of Blake's pouch (cyst in the 4th ventricle) and cerebellar vermis hypoplasia. Causes a variety of neurologic abnormalities (e.g., ataxic gait) and hydrocephalusAssociated with a variety of extracranial abnormalities (e.g., craniofacial abnormalities, cardiac defects)Intrauterine infections: e.g., congenital toxoplasmosis (see congenital infections) AcquiredBrain tumor (especially medulloblastomas, pinealoma, ependymomas, and astrocytomas)Subarachnoid hemorrhage or intraventricular hemorrhage → inflammatory response → fibrosis Inflammation (e.g., following recovery from bacterial meningitis) Clinical features Features of increased ICPHeadache, nausea, and vomitingPapilledemaAbnormal gaitImpaired consciousnessCushing triad (irregular breathing, widening pulse pressure, bradycardia)6th nerve palsy Additional features in infants Macrocephaly: an enlarged head with a circumference greater than the average for age and sex by two standard deviations(as indicated by a percentile growth chart)Tense fontanelleSetting sun sign: persistent downward deviation of the eyes due to increased ICP in infants and young children Lower extremity spasticity, hyperreflexia Changes in vital signs resulting from brainstem compression due to herniation Because the fontanelles of infants are still open, the accumulation of CSF can lead to macrocephaly; this accommodation offsets the elevation in ICP, meaning that neurological symptoms often develop later than in older patients whose fontanelles are closed! Subtypes and variants Normal pressure hydrocephalus A form of chronic communicating hydrocephalus that primarily affects elderly individuals (> 60 years) and is characterized by a distinct clinical triad (urinary incontinence, dementia, ataxic gait) and normal or episodic increase in ICP. Etiology and pathogenesis Impaired CSF absorption results in CSF accumulation Idiopathic (most common in adults > 60 years) Possible secondary causes that result in obstruction and/or fibrosis of subarachnoid villi Inflammatory diseases of the CNS (e.g., meningitis)Intraventricular hemorrhageSubarachnoidal hemorrhage ↓ CSF absorption Secondary: impaired CSF absorption caused by hemorrhage and/or inflammation and subsequent fibrosis of the subarachnoid villi Clinical features Classic triadUrinary incontinenceInitially, only increased urgency and frequency of micturition , later also urge incontinence. Incontinence worsens as dementia progresses. Gait disturbances can make the way to the toilet more difficult, leading to further incontinence related issuesDementia Frequent falls, broad-based gait with short steps (ataxic gait) Normal pressure hydrocephalus does not manifest with signs of increased ICP (e.g., headache, papilledema). Patients present with the classic triad of wet, wacky, and wobbly. Diagnostics Rule out other causes of symptoms Cognitive assessmentVitamin B12 level and thyroid function tests MRI (initial test), CT Ventriculomegaly without sulcal enlargementPeriventricular hypodensity due to periventricular edema CSF tap test: confirmatory testNote severity of symptoms before the testOpening pressure is normal or slightly elevated Remove a small amount of CSF fluid (30-50 mL)Improvement of symptoms after CSF removal confirms NPHLumbar puncture is both diagnostic and therapeutic Diagnostics UltrasonographyIndication: clinical suspicion during antenatal period or in infants < 6 months of age (through the anterior fontanelle when it is still open)Findings: enlarged lateral ventricles MRI (preferred for children) or CTIndication: older infants (when fontanelle is already closed, typically patients > 6 months of age) or adults Features of acute hydrocephalus: Enlarged ventriclesCommunicating hydrocephalus: all ventricles are dilatedNon-communicating hydrocephalus: ventricles upstream of the obstruction are dilated Differential diagnoses Hydrocephalus ex vacuo Hydrocephalus ex vacuo is often classified as a form of hydrocephalus, however, this is a misnomer as it is not a true hydrocephalus. The ventricles and subarachnoid space appear enlarged secondary to loss of brain tissue; however, intracranial pressure and flow of cerebrospinal fluid are normal. Etiology and pathogenesis Loss of brain tissue results in the expansion of the subarachnoid space filled with CSF. The ventricles appear dilated as well, with an apparent increase in CSF because of reduced brain tissue. However, there is no increase in CSF production, decreased CSFabsorption, or obstruction. Primary cerebral atrophy Cerebral destructive lesions or degeneration e.g., Alzheimer diseaseHuntington diseasePick diseaseAIDS Clinical features Usually asymptomatic Symptoms of the underlying condition (see "Etiology and pathogenesis" above) Diagnostics Resembles hydrocephalus on imaging (i.e., enlarged CSF spaces, especially lateral ventricles) Cortical atrophy may be prominent ICP is normal Treatment Most types of hydrocephalus are progressive and present a risk of neurological damage. Definitive treatment of hydrocephalus involves the drainage of excess CSF via a cerebral shunt, usually into the peritoneum (e.g., ventriculoperitoneal or VP shunt). Cerebral shunt Important componentsInflow catheter Adjustable one-way pressure valves Outflow catheter Reservoir ComplicationsUnderdrainage → ↑ ICPOverdrainage Symptoms: see intracranial hypotension syndromeShunt infection (∼ 5% of cases) Bacterial contamination (e.g., Staphylococcus epidermidis), often associated with biofilm formationTherapy: shunt explantation surgerySlit ventricle syndrome Symptoms: Chronic intermittent headacheNausea/vomitingAltered mental statusCranial neuropathiesPathophysiology: the exact mechanisms underlying this syndrome are still debated. One hypothesis states that the overdrainage of one ventricle results in the collapse of its walls and occlusion of the shunt catheter. This, in turn, leads to underdrainage of the contralateral ventricle. Possible interim therapy Diuretics, fibrinolysis, serial lumbar punctures, (acetazolamide)

Frontotemporal dementiaFrontotemporal dementia (FTD) is a progressive neurodegenerative disease of the frontal and/or temporal lobe generally caused by mutations to proteins in the brain (e.g., Tau, progranulin). Pick's disease, formerly used synonymously with FTD, is actually a specific subtype of FTD that can only be diagnosed pathologically; therefore, the two terms are not synonymous. Onset usually occurs in middle-aged individuals (40-60 years). Early symptoms are characterized by inappropriate social behavior (e.g., disinhibition, apathy), but patients typically continue to exhibit normal intelligence and orientation. As the disease progresses, patients may develop motor deficits and akinetic parkinsonism as an end‑stage syndrome. Diagnosis of FTD is based on a combination of factors, including the clinical criteria of dementia and possible frontotemporal brain atrophy on CT or MRI. Further diagnostic procedures may be considered to rule out other possible causes of dementia. No effective causal treatment for FTD exists and symptomatic treatment is limited to associated symptoms (e.g., depression). The disease usually has a fatal outcome within six years.

Definition FTD is a heterogeneous group of syndromes that involve degeneration of the frontal, insular, and/or temporal cortices and manifest with a number of symptoms of dementia. FTD is sometimes still referred to as Pick's disease, but this term should be avoided. FTD syndromes are often considered special types of Alzheimer's disease (however, initial symptoms are typically not memory‑related).Epidemiology Age of onset: usually 40-60 years (typically younger than DDx Alzheimer's disease!) Prevalence: 3-4/100,000 in patients ≤ 65 yearsEtiology Generally associated with pathological intracellular inclusion bodies (Pick bodies) that are caused by mutations in tau or progranulin proteins Also associated with ubiquitin inclusion bodies hypothesized to be caused by dysfunction of the ubiquitin proteasome system Familial predisposition (autosomal dominant): ∼ 10-25% of FTD caseslinical features General features of FTD Early changes in personality and behavior → failure to observe social etiquetteApathyDisinhibition (e.g., hypersexual behavior)Exaggerated emotional displayIrritabilityBinge eating (particularly of sweet foods) Changes in cognitive functioningIntelligence, orientation, and memory initially intactAphasia (but no apraxia)Lack of attention Motor deficitsParkinsonism (in later stages)Pyramidal signs (e.g., tendon hyperreflexia, Babinski sign) Patients with FTD display changes to personality and social behavior, but their memory generally remains intact!Diagnostics The diagnosis of FTD syndromes is based on a combination of factors: Clinical diagnosis of a dementia syndrome → see diagnostic criteria for major neurocognitive disorder (previously dementia) in accordance with DSM-5 Other tests to rule out or confirm specific abnormalities CT/MRI: atrophy of the frontal and/or temporal lobes Laboratory tests: to rule out other etiologies of dementia (e.g., infections, hypothyroidism)Pathology Pathological changes in FTD are commonly referred to as frontotemporal lobar degeneration (FTLD). MacroscopicAtrophy of the temporal and/or frontal lobesOften beginning on one side and subsequently affecting both hemispheres HistologicalNonspecific gliosis ; formation of microvacuoles and loss of neuronal tissueSwollen neurons (= pick cells)Detection of different types of intracellular inclusions in surviving neurons (tau or TDP-43 in approx. 90% of cases)Pick bodies: cytoplasmic inclusions of aggregated tau proteinsAssociated with Pick's diseaseFound in ∼ 40% of patients with FTLDAlso found in other neurodegenerative diseases Silver stain: classic Pick bodies stain positive, but many patients with tau inclusions stain negativeFTLD‑TDP: inclusions with hyperphosphorylated TDP‑43 (a protein involved in gene transcription)Treatment No curative treatment exists → symptomatic treatment General measuresSupportive therapy (e.g., behavioral therapy, speech therapy)Dietary measuresExercise PharmacotherapyDementia symptoms: Cholinesterase inhibitors and memantine are usually not effective and may, in some cases, even worsen symptoms. Associated symptoms Depression: SSRIs (e.g., citalopram, PO)Agitation, hallucinations, insomnia: atypical antipsychotics (e.g., olanzapine, PO), trazodonePrognosis Patients with FTD survive an average of six years after symptom onset (progression is usually faster than in Alzheimer's disease). A common cause of death is intercurrent infection (e.g., pneumonia).

Febrile seizures Febrile seizures are one of the most common pediatric emergencies and are usually associated with high fever in children between six months and five years of age. The exact pathophysiology is unknown. Simple febrile seizures are the most common type; they are usually generalized, last under 15 minutes, and do not recur within 24 hours. Complex febrile seizures have a focal onset, last longer than 15 minutes, or recur within 24 hours. Diagnostic examination of simple febrile seizures focuses on addressing the cause of fever. Further diagnostics are required for patients with complex febrile seizures, particularly to exclude herpes encephalitis, and include lumbar puncture, CT scan, and/or EEG. Most febrile seizures end spontaneously and do not require any treatment. If seizures persist after five minutes or present as complex febrile seizures, however, IV benzodiazepines are the treatment of choice. Caregivers should be reassured as the prognosis of febrile seizures is good, with the risk of epilepsy being less than 10%.

Definition Febrile seizures are seizures that are associated with fever (mainly temperatures exceeding 38°C (100.4°F)) in the absence of CNS infection, metabolic abnormalities, or a history of afebrile seizures. Epidemiology Peak incidence: 2nd year of life; most commonly occurs between 6 months and 5 years of age Prevalence: Febrile seizures occur in ∼ 4% of all children. Pathophysiology The exact pathophysiological mechanisms of febrile seizures are not known. Risk factors: Genetic predisposition High fever (> 40°C (104°F)) Viral infection (e.g., HHV-6, influenza) Recent immunization (especially MMR and TDap) Simple febrile seizure (∼75%)Generalized, usually tonic-clonic seizures (clonic seizures are also possible) Symmetrical No other apparent neurologic disorders< 15 min Maximum of one seizure within 24 h6 months to 5 years Complex febrile seizure* (∼25%)Focal onset Pronounced on one side of the body Transient hemiparesis and speech impairment> 15 min > 1 seizure within 24 hMore commonly outside the typical range of 6 months to 5 years Typically a quick return to normal Confusion and drowsiness may be present for a short period of time Prolonged drowsiness or deviated eyes may be a sign of other etiology (e.g., meningitis) or of ongoing seizure activity (see status epilepticus) Diagnostics ApproachSimple febrile seizures do not require specific diagnostic workupDiagnostic examination focuses on identifying the cause of feverComplex febrile seizures always require specific investigative tests (e.g., EEG and imaging). Determine the cause of fever Physical examinationUrinalysis and urine culturesConsider blood tests (CBC with differential blood, CRP, electrolytes, blood glucose)Consider imaging to locate the source of infection (ultrasound, X-ray)In suspected cases of intoxication: toxicology screen Additional diagnostic steps: for complex febrile seizures and/or abnormal neurological examinationLumbar puncture → to exclude meningitis and/or (herpes) encephalitisEEGImaging (e.g., CT or MRI) Treatment Uncomplicated seizures usually resolve after a few minutes spontaneously. However, abortive therapy should be administered if seizures ≥ 5 min or complex. Abortive therapyTreatment of choice: IV lorazepam Alternative: IV diazepam , buccal/intranasal midazolam (when IV access is not possible) If necessary, repeat medication after 5 minAdditional measures are needed with status epilepticus Reassure caregivers and provide information After a febrile seizure, initiate antipyretic therapy (NSAIDs and acetaminophen) at an early stage (temperatures from 38°C (100.4°F)) as they restore the central thermoregulatory setpoint back to normal by reducing the synthesis of prostaglandin E2. Prognosis The risk of recurrent, simple febrile seizures is 30%. Risk of developing epilepsy: ∼ 1-2% in children who have had a simple febrile seizure5-10% in children with complex febrile seizures or a family history of epilepsy Recurrence is more likely in atypical presentations and with cerebral palsy (CP), structural brain lesions, febrile status epilepticus, and an abnormal EEG.

Sodium disorders Sodium is the most important extracellular cation and plays an important role in maintaining the body's extracellular fluidvolume. Sodium imbalances typically reflect a dilution or concentration of extracellular fluid rather than an actual loss or gain of sodium. These changes in extracellular fluid volume are mainly due to an increase or decrease in ADH serum levels (which causes the retention and loss of free water respectively). In certain cases, however, sodium imbalances may be the direct result of sodium loss (e.g., following diarrhea, vomiting, or the use of antidiuretics) or excessive sodium intake. Treating sodium imbalances involves careful correction of the sodium deficit/excess and treating the underlying cause. A rapid correction of sodium imbalance can have damaging osmotic effects such as central pontine myelinolysis.

Definition Hyponatremia: serum concentration < 135 mEql/L Hypernatremia: serum concentration > 145 mEql/L Hyponatremia Hypotonic hyponatremia (↓ serum osmolality) Hypovolemic hyponatremiaRenal causes: diuretics, aldosterone deficiency (Addison's disease)Extrarenal causes: pancreatitis, vomiting, diarrhea, burns, bleeding Euvolemic hyponatremiaSyndrome of inappropriate ADH secretion (SIADH)Psychogenic polydipsiaHypothyroidism Rarely alcoholism Hypervolemic hyponatremiaCongestive heart failureLiver cirrhosisNephrotic syndrome Isotonic hyponatremia (↔︎ serum osmolality) Pseudohyponatremia HyperlipidemiaParaproteinemia (e.g., multiple myeloma) Hypertonic hyponatremia (↑ serum osmolality) Hyperglycemia Due to a water shift from intracellular to extracellular, serum sodium levels decrease by 1.6 points for each 100 mg/dL glucose above normal. The actual sodium content does not change. Use of mannitol AldosteroneEffect: Aldosterone causes sodium and water reabsorptionRelease of aldosterone: decreased renal perfusion → RAAS activation → aldosterone release ADHEffect: ADH causes water reabsorption and increases thirst.Release of ADHPrimary stimulus: increase in serum osmolality (very sensitive even to a 1% change in serum osmolality).Non-osmotic stimulus: A change in extracellular fluid volume by more than 10% (which is sensed by carotid baroreceptors) can also stimulate ADH release. Hypernatremia Hypovolemic hypernatremia Dehydration (e.g., due to poor oral fluid intake, diarrhea) Diuretics Osmotic diuretics and loop diuretics cause more hypernatremia than thiazide diuretics. Osmotic diuresis (e.g., hyperglycemia, uremia, high-protein tube feeding) Euvolemic hypernatremia Diabetes insipidus (central or renal) Lack of access to water Hypervolemic hypernatremia Primary hyperaldosteronism Cushing's syndrome Iatrogenic: excessive infusion of NaCl or sodium bicarbonate solutions Drinking sea wate Clinical features Clinical features are primarily neurological and depend on the severity of the sodium imbalance. Mild symptoms AnorexiaNauseaVomitingHeadacheMuscle crampsModerate symptoms Muscle weaknessLethargyConfusionSevere symptoms SeizuresAltered consciousnessComa Symptoms also depend on the onset of sodium imbalance Acute onset (< 48 hours): usually symptomatic event even with mild sodium derangementsSubacute or chronic onset (> 48 hours): usually asymptomatic unless severe derangements are present Blood testsSerum sodium concentrationSerum osmolality to assess volume status is always the first step in evaluation HyponatremiaHypotonic hyponatremia (most common): serum osmolality < 280 mOsmol/kgHypertonic hyponatremia: serum osmolality > 295 mOsmol/kgIsotonic hyponatremia: serum osmolality 280-295 mOsmol/kgHypernatremia: ↑ serum osmolalityHematocrit↓ Hematocrit: possibly fluid overload↑ Hematocrit: hypovolemia, dehydration Urine examination Hyponatremia: urine sodium concentration > 20 mEq/L implies renal sodium loss < 20 mEq/L implies extrarenal sodium loss Hypernatremia: urine osmolality > 800 mOsmol/kg implies extrarenal water loss < 800 mOsmol/kg implies renal water loss The kidneys continue to excrete water despite a water deficit Treatment General principles Treat underlying cause Patients with serum sodium values < 120 mEq/L or >160 mEq/L require intensive care. Careful correction of sodium levels: maximum correction within 24 hours is 10 mEq/L (rate of correction: 0.5-1 mEq/L per hour)Effects of rapid correctionRapid increase in sodium levels → risk of central pontine myelinolysisRapid fall in serum sodium → risk of cerebral edema Hyponatremia Hypovolemic hyponatremiaMild to moderate symptoms: normal saline Severe symptoms: hypertonic saline Euvolemic hyponatremiaMild to moderate symptoms: fluid restrictionSevere symptoms: hypertonic saline Hypervolemic hyponatremia: Mild to moderate symptoms: fluid restriction ± loop diureticSevere symptoms: isotonic saline Hypernatremia Correct free water deficit Mild hypernatremia in non-hospitalized patients: oral rehydration Moderate to severe hypernatremia, or hypernatremia in hospitalized patients: IV routeAcute hypernatremia (< 48 hours): hypotonic saline (e.g., ½ NS ) or 5% dextrose (D5W) orSubacute or chronic hypernatremia (> 48 hours): 5% dextrose in 0.45% NS (D5½NS) Hypovolemic hypernatremiaFluid resuscitationOnce adequately resuscitated: correct free water deficit Euvolemic hypernatremia: correct free water deficit Hypervolemic hypernatremia: loop diuretic + 5% dextrose Complications Osmotic myelinolysis Definition: Damage to the myelin sheath of nerves in the CNS caused by a sudden rise in the osmolarity of blood. Central pontine myelinolysis Most common type of osmotic myelinolysisAffects central region of the ponsExtrapontine myelinolysisAffects cerebellum, lateral geniculate body, thalamus, putamen, cortical, and subcortical white matter CausesRapid correction of chronic hyponatremia Clinical featuresAltered level of consciousness, comaLocked-in syndromeImpaired cranial nerve function: dysarthria, dysphagia , diplopiaWorsening quadriparesis Treatment: supportive care Others Intracranial hemorrhage Cerebral edema Noncardiogenic pulmonary edema Rhabdomyolysis Bone fractures

Retinal vessel occlusion Retinal artery occlusion refers to occlusion of the central retinal artery and/or its branches, usually as a result of thromboembolic phenomena. Central retinal artery occlusion (CRAO) is characterized by sudden, painless loss of vision and a relative afferent pupillary defect. Ophthalmoscopy reveals a pale, edematous retina and a cherry-red spot in the foveal region. Branch retinal artery occlusion (BRAO) presents with specific patterns of visual field defects depending on which branch is involved. Treatment is usually ineffective because of irreversible ischemic damage to the retina. The prognosis is especially poor if the macula is involved. Retinal vein occlusion is more common than retinal artery occlusion and follows a less fulminant course. Branched retinal vein occlusion (BRVO), which is more common than central retinal vein occlusion (CRVO), is usually asymptomatic unless the macula is involved. CRVO may be either non-ischemic or ischemic. Fluorescein angiography is required in order to differentiate between ischemic and non-ischemic retinal vein occlusion. The prognosis of ischemic CRVO is less favorable since it is associated with neovascular glaucoma and retinal detachment. While BRVO and non-ischemic CRVO usually do not require any treatment, ischemic CRVO requires laser therapy.

Definition Retinal vessel occlusion causing retinal ischemia. Based on the site of occlusion, retinal vessel occlusion can be classified into the following entities: Central retinal artery occlusion (CRAO) Branch retinal artery occlusion (BRAO) Central retinal vein occlusion (CRVO), assuming one of two forms: Non-ischemic CRVO (venous stasis retinopathy)Ischemic CRVO (hemorrhagic retinopathy) Branch retinal vein occlusion (BRVO) Epidemiology Retinal artery occlusion Age of onset: > 60 years Sex: ♂ > ♀ Retinal vein occlusion Age of onset: > 80 years Sex: ♂ = ♀ Retinal vein occlusion is much more common than retinal artery occlusion. Retinal vein occlusion is the second most common vascular disease of the retina (after diabetic retinopathy)! Etiology Retinal artery occlusion EmbolismRelease of thrombotic emboli as a result of carotid artery atherosclerosis (most common)Emboli from the atria (usually as a result of atrial fibrillation) Thrombosis of the retinal vessels (usually as a result of atherosclerosis) Rare causes: vasculitis (e.g., temporal arteritis), fibromuscular dysplasia Retinal vein occlusion Systemic diseases: atherosclerosis, hypertension, diabetes mellitus Hypercoagulable/prothrombotic states (e.g., polycythemia vera, sickle cell disease, oral contraceptive use) Ocular diseases: Atherosclerosis of the retinal artery (may cause compression of the adjacent retinal vein)Glaucoma (increased intraocular pressure may cause compression of the retinal vein)Vasculitis of the retinal artery (since the retinal artery and retinal vein share a common adventitia, inflammation of the retinal artery may spread to the retinal vein). CRAO Sudden, painless loss of vision in one eye (often described as a "descending curtain") A past history of amaurosis fugax may be present. Relative afferent pupillary defectPresentGrayish-white (cloudy) discoloration of the entire retina Cherry-red spot at the fovea centralis Retinal plaques/emboliHollenhorst plaque: cholesterol embolus that presents as a refractive, iridescent lesion (∼ 20% of cases) Whitish-gray platelet thrombiWhite calcific plaques BRAO Sudden onset of visual field defects (scotomas) in the affected eye A past history of amaurosis fugax may be present. Grayish-white discoloration of the retinal quadrant supplied by the affected vessel Retinal emboli/plaques (∼ 60-70% of cases) A bruit over the carotid artery is a sign of carotid atherosclerosis. An irregular pulse may indicate atrial fibrillation. Scalp tenderness and/or jaw claudication is a sign of temporal arteritis. Retinal vein occlusion CRVO Non-ischemic CRVO SymptomsSubacute, mild to moderate loss of vision in the affected eye Ophthalmoscopic findingsA few dot-and-blot and/or flame-shaped hemorrhages in all four retinal quadrants Relative afferent pupillary defectAbsent Ischemic CRVO Sudden, severe loss of vision in the affected eye Pupillary defect Present Many dot-and-blot and/or flame-shaped hemorrhages in all four retinal quadrants and venous thickening (blood and thunder appearance) Cotton wool spotsCharacterized by yellow-white deposits on the retinaCaused by swelling of retinal nerve fibers due to ischemia Severe macular edema Severe papilledema BRVOUsually asymptomaticDot-and blot and/or flame-shapedhemorrhages in the retinal quadrant drained by the affected vein Amaurosis fugax Definition: sudden, painless loss of vision that lasts for seconds to minutes and is followed by spontaneous recovery (mostly unilateral) Cause: retinal ischemia following transient occlusion of the central retinal artery by microemboliCardiovascular causes (atherosclerosis, carotid artery stenosis, cardiac thrombi)Vasculitis (e.g., temporal arteritis, lupus erythematosus, polyarteritis nodosa, etc.) TreatmentAlthough amaurosis fugax is self-limiting, it is a harbinger of more serious conditions. Therefore, perimetry and treatment of the underlying cause are essential: Reduction of cardiovascular risk factors (e.g., low-dose aspirin therapy)In the case of temporal arteritis: high-dose glucocorticoid therapy ComplicationsRetinal artery occlusionTransient ischemic attacks (TIA)Stroke Diagnostics Retinal vessel occlusion is primarily a clinical diagnosis (based on the patient's history and fundus examination). Additional investigations are usually performed to identify underlying risk factors, to differentiate between subtypes (e.g., in the case of CRVO). Retinal artery occlusion Evaluation for cardiovascular risk factors: Carotid doppler (to look for atherosclerotic plaques)Echocardiography (to identify potential sources of emboli, e.g. cardiac vegetations, patent foramen ovale) Tests to rule out temporal arteritis:Inflammatory markers (e.g., ↑ ESR)Temporal artery biopsy Retinal vein occlusion Fluorescein angiography: in order to differentiate ischemic from non-ischemic forms of retinal vein occlusion Treatment Retinal artery occlusion Retinal artery occlusion is an ophthalmologic emergency. Eyeball massage Carbogen therapy: inhaling a mixture of 5% CO2 and 95% O2 Decrease intraocular pressure with drugs and/or surgical therapy (e.g., paracentesis of the anterior chamber) Hemodilution Vasodilators (e.g., calcium channel blockers, sublingual nitroglycerine) High-dose glucocorticoid therapy if temporal arteritis is suspected Treatment should be initiated as soon as possible, as permanent retinal damage occurs within 1.5 hours of central retinal artery occlusion. Retinal vein occlusion Ischemic CRVO must be treated with: Laser therapy Panretinal photocoagulation A technique that uses a laser to cause thermal burns to retinal tissue.Corrects ischemic hypoxia and thereby minimizes neovascularization.If macular edema is present: grid photocoagulationIntravitreal injection of VEGF inhibitors and/or steroids BRVO and non-ischemic CRVO usually do not require treatment.Complications Release of vasoproliferative substances (e.g., VEGF) from the ischemic retina causes: Neovascularization of the iris (rubeosis iridis) → neovascular glaucoma Neovascularization of the retina → vitreous hemorrhage → retinal detachmentOf all types of retinal vessel occlusion, ischemic CRVO is most commonly associated with neovascularization!Prognosis Retinal artery occlusion Central retinal artery occlusion: severe loss of vision Branch retinal artery occlusion: loss of vision and/or visual field defects (depending on which branch of the retinal artery is affected) Retinal vein occlusion Rule of thirds: Visual acuity improves in one-third of cases, remains the same in another third, and worsens in the remaining third. The prognosis is especially poor in the case of ischemic CRVO.

Seizure disorders A seizure is irregular electrical activity in the brain caused by the hyperexcitability of neurons, especially in cortical areas. Hyperexcitability, in turn, is the result of altered cellular electrochemical properties, which may be caused, for example, by electrolyte imbalances. The etiology varies according to age. Seizures may be provoked by acute conditions (e.g., stroke, traumatic brain injury, alcohol withdrawal) or unprovoked, in which case they are indicative of epilepsy. The lifetime risk for experiencing at least one seizure is approx. 3% in the general population. Individuals who experience a single seizuredo not necessarily have epilepsy. Seizures may be classified as generalized or focal. Generalized seizures arise from discharges in both hemispheres, whereas focal seizures begin with discharges in one hemisphere. Depending on the origin of the epileptiform discharge and the type of the seizure, various temporary motor, sensory, autonomic, or psychological symptoms may occur. However, the most frequent clinical presentation involves rhythmic twitching and loss of consciousness (tonic-clonic seizure). After a first seizure occurs, the likely cause must be determined based on medical history (evaluation of provocative factors and seizure type), laboratory tests, and imaging (to detect or rule out structural or metabolic causes). Electroencephalography (EEG) is used to establish the diagnosis. Important antiepileptic drugs are lamotrigine (first-line treatment in focal seizures), valproate (first-line treatment in generalized seizures) and ethosuximide (first-line treatment in typical absence seizures). With appropriate pharmacotherapy, the majority of patients remain seizure‑free in the long term. Epileptic seizures can evolve into ongoing seizure activity (status epilepticus), which is a potentially life‑threatening event and must be addressed as soon as possible (pharmacologic interruption of seizures with a benzodiazepine).

Definition Seizure: abnormal, unregulated electrical activity of cortical neurons that results in transient changes in behavior and/or EEG findings Epilepsy: a chronic neurologic disorder characterized by any of the following: Two or more unprovoked seizures separated by more than 24 hoursOne unprovoked seizure with an underlying predisposition to seizures (recurrence risk over the next 10 years that is similar to the recurrence risk after two unprovoked seizures)Diagnosis of an epilepsy syndrome Symptomatic epilepsy: epilepsy due to an identifiable condition (e.g., brain tumor, structural abnormalities of the brain) that causes an increased predisposition to seizures Cryptogenic epilepsy: epilepsy due to an unknown cause (genetic association suspected) Nonepileptic seizure: seizures that are provoked by acute conditions (e.g., intoxication, metabolic disturbances). See provoked seizure for details. Epilepsy syndromes: epileptic disorders defined by a collection of characteristic clinical manifestations and other features (e.g., age of onset, brain lesions) Epidemiology Prevalence: Infants: ∼ 100/100,000Adults : ∼ 40/100,000The elderly : ∼ 140/100,000 Risk of experiencing at least one seizure up to the age of 75 (in the general population): ∼ 3% Etiology Epilepsy Unprovoked seizure (epileptic seizure): due to a general increase in neuronal hyperexcitabilityGenetic: genetic mutations of ion channels or transmitter receptors, chromosomal abnormalities Cryptogenic (idiopathic) Structural/metabolic: preexisting, chronic cerebral lesion of CNS abnormality (e.g., hypoxic-ischemic injury, PKU, tuberous sclerosis, congenital cerebral malformations) Provocative factors for epilepsy Situational factors that can trigger epileptic seizures in epilepsy patients: Excessive physical exertion Sleep deprivation Strobe light flashing Loud music Provoked seizures Acute symptomatic seizures that are secondary to acute conditions: Metabolic and electrolyte disturbances: hypoglycemia and hyperglycemia, hyponatremia and hypernatremia, hypocalcemia, uremia, thyroid storm, hyperthermia, water intoxication Mass: brain tumors and metastases, hippocampal sclerosis WithdrawalAlcohol withdrawal (most common trigger in adults)Noncompliance with anticonvulsant treatmentMedication withdrawal IntoxicationAcute intoxication: cocaine, ecstasy, carbon monoxide poisoning, metal poisoningPharmacotherapy: amitriptyline, penicillin, maprotiline, lithium, lidocaine, antipsychotics, theophylline Infections: encephalitis, brain abscess, meningitis, septic shock Ischemia: stroke, perinatal injuries Trauma: traumatic brain injury Increased ICP and cerebral edema: eclampsia, hypertensive encephalopathy, cerebrovascular malformation Fever in infants and children (see febrile seizures) NeonatesCongenital (idiopathic; genetic association) Perinatal injury Perinatal or postnatal infections (e.g., CNS infections) Metabolic disorders Infants and childrenFever Idiopathic (genetic association suspected) Infections Traumatic brain injury Brain malformations Metabolic disorders AdolescentsTraumatic brain injury Encephalitis Genetic disorders Illicit substance abuse Younger adultsAlcohol withdrawal Traumatic brain injury Illicit substance abuse Brain tumors Older adults (> 35 years)Alcohol withdrawal Stroke or TIA Traumatic brain injury Brain tumors Metabolic disorders Vascular encephalopathies and vascular dementia (in the elderly) Etiological classification (ILAE 2010) Genetic: without a discernible structural or metabolic cause Structural or metabolic: with a discernible structural or metabolic cause Unknown: no tangible cause (the cause is inferred from the clinical presentation and history) Classification according to anatomical origin and clinical features Focal seizures Focal seizures without dyscognitive featuresFocal seizures with dyscognitive featuresPrimary generalized seizures Classic tonic‑clonic seizures (see grand mal seizure)Further generalized seizuresAbsence (see also generalized epilepsies in childhood)Myoclonic (see juvenile myoclonic epilepsy)Clonic seizuresTonic seizuresAtonic seizures Clinical features Ictal phaseSudden onsetRapid progression of symptomsDuration usually 1-3 minutes Postictal phase Varying degree of confusion, impaired alertnessResidual neurologic symptoms (e.g., Todd's paralysis)Duration usually minutes or hours Symptoms of, e.g., CNS infection, stroke, intoxication, hypoglycemia, electrolyte disturbances → indicative of acute symptomatic seizure Focal seizures Focal seizures are more likely to be caused by focal structural abnormalities. Symptoms depend on the anatomical location of the lesion or disturbance within the brain. Focal seizure with intactconsciousness (simple partial seizures)Focal cerebral regions (confined to one hemisphere)Prodromal symptoms: auras Intact consciousnessMotor symptoms Clonic, involuntary, repetitive movements of the contralateral limbs or facial muscles. Jacksonian march ("march of convulsions"): progressive involvement of muscle groups Sensory and psychiatric symptoms Visual (e.g., hallucinations, micropsia, macropsia)Somatic (e.g., paresthesias)Position (e.g., vertigo)Hearing (e.g., hearing complex sounds)Olfactory (e.g., unusual or intense smells)Autonomic symptoms (e.g. flushing, sweating)Residual neurologic deficits depending on the affected cerebral region Todd's paralysis: Postictal weakness or paralysis of the affected limb or facial muscles (for minutes or up to hours) Focal seizure with impaired consciousness(complex partial seizures)Often the temporal lobe(70-80%)Subsequent bilateral spread Auras: sensory and psychic symptoms (e.g., deja vu, disorientation, fear, vertigo, and visual, acoustic, olfactory, or gustatory hallucinations)Sudden behavioral arrest (e.g., staring without moving)Impaired consciousnessAutomatisms (e.g., fumbling, lip smacking, chewing, swallowing)Confusion Anterograde amnesia AphasiaFatigue, possibly short phase of comaMuscular flaccidity and muscle pain Headache Primarily generalized seizures Symptoms are produced by bilateral cerebral cortex disturbances. Generalized motor seizure Tonic-clonic seizure Prodromal symptoms may occur hours before seizure onset (e.g., sleep disturbances, lightheadedness, mood changes, anxiety/irritability, impaired concentration) Loss of consciousness (sudden, often without any warning) Motor symptoms: Tonic phase:Generalized muscle contractions: rotated eyes, apnea, lateraltongue biting, pooled oral secretions, cyanosis and uttering of an "ictal cry" Increased sympathetic tone: dilated, unresponsive pupils, ↑ HRand ↑ blood pressureClonic phase (rhythmic muscle twitching)Bladder or bowel incontinenceTongue bite lacerationsUnresponsiveness ConfusionAmnesia AphasiaFatigueMuscular flaccidity and muscle pain HeadacheHypersalivation with or without airwayobstruction Clonic seizureLoss of consciousnessRhythmic jerking motor movements (of the entire body or only a part)None Tonic seizureLoss of consciousness (often occur when the patient is drowsy, asleep, or after waking)Muscle contractions (extension or flexion of the head, trunk, and/or extremities)None Myoclonic seizure (associated with epilepsy syndromes)Brief loss of consciousnessMyoclonic: sudden jerky muscle twitching (of the entire body or only a part)None Atonic seizure (also known as drop attacks; associated with epilepsy syndromes)Brief loss of consciousnessSudden loss of muscle tone: sudden head drop or collapse (lasts ∼ 2 seconds)None Non-motor (absence) seizure (common type of generalized epilepsy in childhood.) Brief loss of consciousnessInterrupted motion or activity, blank stare, unresponsiveness Can occur several hundred times a day and usually ceases after 5-20 secondsVery subtle automatisms (often go unnoticed!): lip smacking, eyefluttering, or head nodding are commonNoneConsciousness returns rapidly, without any impairmentPatient often unaware of interruption Diagnostics Confirm a seizure Patient history (from patient or witnesses): e.g., evidence of an aura, observation of typical symptoms (e.g., twitching), identification of provocative factors (e.g., sleep deprivation or unreliable intake of antiseizure medication ) EEG During the seizure (ictal) Epileptiform discharges (e.g., spikes, sharp waves, spike waves, and hypsarrhythmia) are usually detected. If no epileptiform discharges are detected, diagnosis of pseudoseizures should be considered.Between seizures (interictal)Often normal findings (even after provocation via sleep deprivation, hyperventilation, or visual stimuli)Possibly showing epileptiform activity (bursts of abnormal discharges featuring spikes and/or sharp waves) Exclude an underlying condition ECG: In every patient with loss of consciousness during an ictal event, cardiogenic causes (e.g., cardiac arrhythmiasresulting in cerebral hypoxia) should be ruled out. CT/MRI (with and without contrast): structural lesions (e.g., brain tumors) should be ruled out after a first seizure. Laboratory testsBlood GlucoseElectrolytesProlactin Antiepileptic drug levels Toxicology screenCBCESRRapid plasma reagin Creatine kinase Renal and liver function tests Lumbar puncture: cerebrospinal fluid analysis (e.g., if CNS infection is suspected) The first focal seizure or the first focal seizure evolving into a generalized seizure in adults indicates a seizure of structural or metabolic origin and requires further evaluation! Differential diagnoses Psychological disorders: Pseudoseizures: not true seizures; paroxysmal events that may clinically resemble epileptic seizures but have a psychiatric origin Panic attacksPsychogenic hyperventilation Syncope: Vasovagal syncope Stokes-Adams attack Carotid sinus syndrome Cardiac failureOrthostatic hypotension Stroke (including transient ischemic attack ) Migraine Sleep disordersREM sleep behavior disorderNarcolepsy Breath-holding spell (benign condition) Occurs in children (6 months-6 years )Strong association with iron deficiency anemiaClinical features Episodes of prolonged expiratory apneaFollowed by loss of consciousness (syncope)Transient paroxysms of cyanosis or pallorPossibly generalized stiffness and jerky movements of the limbs (anoxic seizure) Triggers: distress, strong emotions (e.g., anger, frustration) due to tantrums or injuryDiagnosis: based on typical presentation of BHS (no confirmatory test exists)Further work-up is generally not necessary. Only if atypical presentation of BHS: EEG to differentiate from epileptic seizuresECG to rule out cardiac causes of syncopeLaboratory analysis: CBC, serum ferritin (rule out iron deficiency anemia)Treatment: reassurance Postictal disorientation is key to differentiating between seizures and syncope. Syncope may be accompanied by twitches; however, patients become completely reoriented after a few seconds! Treatment Acute management Cardiopulmonary resuscitation (ABCs) Avoid hazards Monitor vital signs (especially oxygenation via pulse oximetry) First seizure Long-term medical therapy is usually not required, unless there are abnormalities seen on EEG or MRI (or the patient is in status epilepticus). Remove cause or provoking factors (e.g., stop illicit drug abuse, treat underlying disorders). Recurrent seizures Medical therapy Principles of treatmentIn epilepsy, the seizure threshold is pathologically lowered → Antiepileptic drugs work by raising this lowered threshold and thus protecting against future seizures.Criteria for the choice of antiepileptic drugsType of epilepsy (as per clinical evaluation or instrumental findings)Patient ageComorbidities and contraindications IndicationsRecurrent seizures (2 seizures/6 months) of unknown cause or with a cause that can not be eliminatedAfter the first seizure → only if neuroimaging or EEG show specific findings (e.g., hippocampal sclerosis, characteristic spike‑wave patterns) Focal seizures First‑line treatment: lamotrigine, levetiracetam, phenytoin , carbamazepine, oxcarbazepine, phenobarbital (children)Second‑line treatment: gabapentin, valproate, pregabalin, topiramate Primary generalized seizuresTonic-clonic: First‑line treatment: lamotrigine, valproate , phenobarbital (children)Second-line treatment: carbamazepine, zonisamide Typical absence: First‑line treatment: ethosuximide , valproateSecond‑line treatment: lamotrigine, clonazepamAtypical absence, myoclonic, atonic: First‑line treatment: valproate, lamotrigine, topiramateSecond‑line treatment: clonazepam, felbamate Combination therapy If possible, monotherapy should be maintained → increase dosage before initiating combination therapy If combination therapy is administered, drugs from different classes and/or with different pharmacologic modes of action should be tried. Termination of treatment To be evaluated on a case‑by‑case basisMay be considered if the patient has < 2 seizures/year, an inconspicuous provocation EEG, normal psychological findings, and no hereditary predispositionGenerally possible after 2-5 seizure‑free years with normal EEG results Medications must be tapered cautiously. Nonpharmacological therapy Indications: pharmacoresistance SurgeryPrerequisite: epilepsy that does not respond to medications → often epilepsies with structural origin (most commonly temporal lobe epilepsy)ProceduresResection (surgical removal of pathological lesions)Resection of the anteromedial temporal lobe or of the amygdala and the hippocampus → in patients with temporal lobe epilepsyResection of an entire hemisphere (hemispherectomy) → in patients with severe intractable seizures due to structural cerebral abnormalities confined to one hemisphereDisconnection (surgical breaking of neuronal circuits) Stimulation techniques: vagus nerve stimulation, deep brain stimulation Dietary measures: ketogenic diet Complications Status epilepticus Criteria ≥ 5 min of continuous seizures OR ≥ 2 seizures with consciousness not being fully regained in the interictal period Etiology Common causes are withdrawal from antiepileptic drugs, metabolic disturbances (e.g., hyponatremia), drug toxicity(e.g., tricyclic antidepressants), structural brain lesions/injury (e.g., tumors, trauma, stroke), and CNS infections. Treatment Initial assessment and supportive treatment: Place patient in recovery position to prevent injury.Quick neurological examination (to determine type and cause of status epilepticus) and general medical evaluation (particularly airway, breathing, and circulation)Establish secure IV access (two, if possible), collection of blood for routine blood tests (particularly electrolytes and glucose levels), toxicology screen, antiepileptic drug levels, and arterial blood gas (ABG) analysis Supportive therapy as necessary (e.g., oxygen, glucose, thiamine naloxone )Monitoring of vital signs: especially oxygen saturation (via pulse oximetry), blood pressure, cardiac action, and breathingIf patient does not regain consciousness after seizures stop or nonconvulsive status epilepticus is suspected → continuous EEG monitoringIf acute brain injury (e.g., intracerebral hemorrhage) is suspected → obtain a cranial CTIf CNS infection is suspected → conduct a lumbar puncture Pharmacological interruption of seizures: initial treatment First line: IV lorazepam; second line: IV diazepam or midazolam → if IV access is not possible or drugs are administered by someone who is not a medical professional → select another application form (e.g., rectal diazepam, buccal or intranasal lorazepam/midazolam)If the patient does not respond within 1 minute → administer additional lorazepam (or a second-linebenzodiazepine)If the patient does not respond within another 10-20 minutes → saturation with fosphenytoin via separate access (alternatively: phenobarbital, levetiracetam, or valproate)If seizure activity does not stop despite application of a benzodiazepine and a nonbenzodiazepine antiseizure drug → refractory status epilepticusNo later than 45-60 min after onset: continuous administration of anesthetics with intubation and ICUmonitoring; e.g., thiopental, propofol, or midazolam Nonbenzodiazepine therapy (to prevent recurrence): fosphenytoin or valproatePrognosis Mortality of ∼ 20% (in adults with first occurrence of GCSE) Status epilepticus is a life‑threatening event! If not interrupted, it can lead to cerebral edema, a dangerous rise in body temperature, rhabdomyolysis, and cerebral cardiovascular failure! General complications of seizures and epilepsy Acute Hyperthermia, cardiorespiratory deficits, excitatory toxicity → potentially irreversible tissue damage (particularly to the CNS, for example in the form of cortical laminar necrosis), which in turn may also result in further seizuresPostictal transient anion gap metabolic acidosis with increased lactic acid and reduced serum bicarbonate → usually resolves spontaneously within 60-90 minutes after seizure activity stopsPhysical trauma (e.g., posterior dislocation of the glenohumeral joint) Long‑termAssociated psychiatric disorders (e.g., anxiety, depression and risk of suicide, cognitive impairments) Psychosocial issues (e.g., problems at the workplace) Prognosis Risk of seizure recurrence Overall risk of recurrence After the first unprovoked seizure (within 2 years): ∼ 40%After the second unprovoked seizure (within 1 year): ∼ 60% After a single tonic‑clonic seizure: ∼ 40% In genetic epilepsy: ∼ 25-30% (within 3 months) Patients with normal EEG results: ∼ 15% (within 1 year) Patients with abnormal EEG results: ∼ 40% (within 1 year) Impact of medical therapy Immediate initiation of pharmacotherapy after a first unprovoked seizure lowers risk of recurrence in the short term (within 2 years) but does not significantly improve long‑term risk. Approx. 80% of epilepsy patients who are treated with antiepileptic drugs remain seizure‑free for extended periods (3-5 years).

Overview of stroke A stroke is an acute neurologic condition resulting from a disruption in cerebral perfusion, either due to ischemia (ischemic strokes) or hemorrhage (hemorrhagic strokes). Hemorrhagic strokes are further classified as intracerebral or subarachnoid. Systemic hypertension and other cardiovascular diseases are common risk factors for both ischemic and hemorrhagic strokes. Clinically, strokes are characterized by the acute onset of focal neurologic deficits, including hemiparesis, paresthesias, and hemianopsia. The pattern of clinical features is dictated by the affected vessel. Distinguishing between ischemic and hemorrhagic strokes based on physical examination is difficult and requires initial evaluation with a noncontrast head CT. Further neurovascular imaging may be required before deciding on treatment options. In ischemic strokes, immediate revascularization of the affected vessel is vital to preserve brain tissue and prevent further damage. Hemorrhagic strokes are treated with supportive measures and neurosurgical evacuation of blood. Long-term management of all types of stroke focuses on the management of modifiable risk factors (i.e., hypertension and atherosclerosis).

Definition Stroke: acute neurologic injury caused by ischemia or hemorrhage Ischemic stroke: cerebral infarction due to insufficient cerebral blood flow (hypoperfusion), which results in ischemia and neuronal injury Transient ischemic attack: temporary, focal cerebral ischemia that results in neurologic deficits without acute infarction or permanent loss of function (previously defined as lasting < 24 hours) [1] Hemorrhagic stroke: cerebral infarction due to hemorrhage Intracerebral hemorrhage: bleeding within the brain parenchyma Subarachnoid hemorrhage: bleeding into the subarachnoid space Intraventricular hemorrhage: bleeding within the ventricles Ischemic stroke∼ 85% of all strokesEmbolism Thrombus Small vessel occlusion (lipohyalinosis) Systemic hypoperfusionAge > 65 years Hypertension Diabetes mellitus Atrial fibrillation Carotid artery stenosisSudden onset of focal neurologic deficitsDiagnosisNoncontrast head CT to rule out hemorrhageMRICTA/MRATreatmenttPA (if within < 4.5 hours of onset of symptoms)Intra-arterial thrombolysisThrombectomyAspirin or clopidogrel for secondary preventionPathologyPale infarct → liquefactive necrosis and glial scarring Intracerebral hemorrhage ∼ 10% of all strokes Ruptured cerebral artery or microaneurysm Trauma Reperfusion injury after ischemic stroke Age > 65 years Hypertension Vasculitis Malignancy Ischemic stroke Headache, confusion, nausea Sudden onset of focal neurologic deficits Noncontrast head CT MRI CTA/MRA Reversal of coagulopathy Blood pressure management Surgical intervention if there are signs of herniation or increased ICP Hematoma surrounded by pale infarct and edema → hemosiderin-lined cavity with glial scarring Subarachnoid hemorrhage ∼ 5% of all strokesRuptured berry aneurysm Arteriovenous malformation Trauma Hypertension Tobacco use Family history Rapid onset of severe headache Meningeal signs Sudden onset of focal neurologic deficits Noncontrast head CT CTA Lumbar puncture Reversal of coagulopathy Blood pressure management Prevention of vasospasm Surgical clipping For both ischemic and hemorrhagic strokes, age is the most important nonmodifiable risk factor and arterial hypertension is the most important modifiable risk factor! Epidemiology Stroke is the fifth leading cause of death and the leading cause of disability in the US. Stroke is responsible for ∼ 5% of deaths in the US. [5] See ischemic stroke, intracerebral hemorrhage, and subarachnoid hemorrhage for specific risk factors. Etiology Ischemic stroke (∼ 85%) Hemorrhagic stroke (∼ 15%) Intracerebral hemorrhage (∼ 10%)Subarachnoid hemorrhage (∼ 5%) Stroke symptoms by affected vessel Middle cerebral artery (MCA) (most commonly affected vessel) Contralateral sensory loss Contralateral weakness in the arms, lower half of the face, and lower limbs Gaze deviates toward the side of infarction Contralateral homonymous hemianopia without macular sparing Aphasia if in dominant hemisphere (usually left MCA territory)Broca aphasia (lesion to inferior frontal gyrus, which is supplied by the superior division of MCA)Wernicke aphasia (lesion to superior temporal gyrus, which is supplied by the inferior division of MCA)Conduction aphasia (lesion to supramarginal gyrus, which is supplied by the inferior division of MCA) Hemineglect if in nondominant hemisphere (usually right MCA territory) Anterior cerebral artery (ACA) Contralateral weakness in the lower limbs > upper limbsContralateral sensory loss in the lower limbs > upper limbsAbuliaUrinary incontinenceDysarthriaTranscortical motor aphasiaLimb apraxia Posterior cerebral artery (PCA) General findings Contralateral homonymous hemianopia with macular sparingContralateral sensory loss due to lateral thalamic involvement: light touch, pinprick, and positional sense may be reduced.Memory deficitsVertigo, nauseaLocalized findings Left PCA territory: alexia without agraphia, anomic aphasia, visual agnosiaRight PCA territory: prosopagnosiaMidbrain syndromesMedial midbrain syndrome (Weber syndrome)Lateral midbrain syndrome (Claude syndrome)Paramedian midbrain syndrome (Benedikt syndrome)Dorsal midbrain syndrome (Parinaud syndrome)Thalamic syndromes [11] Decreased arousalVariable sensory lossAphasiaVisual field lossesApathy, agitation, personality changes Posterior inferior cerebellar arteryLateral medullary syndrome (Wallenberg syndrome) [10]Can also be seen with vertebral artery infarctionDysphagia, hoarseness, hiccups, decreased gag reflex: specific to posterior inferior cerebellar artery lesions (vs. vertebral artery)Nystagmus, vertigo Body: contralateral decrease in pain and temperature sensationsFace: ipsilateral decrease in pain and temperature sensationsIpsilateral limb ataxia and dysmetriaAutonomic dysfunction: ipsilateral Horner syndrome Anterior inferior cerebellar arterySee lateral pontine syndrome below.Lenticulostriate arteries (penetrating arteries)See lacunar syndromes below. Basilar arteryConsciousness is usually preserved.Vertebrobasilar insufficiency [12] Vertigo, drop attacks, tinnitus, hiccups, dysarthria, dysphagiaIpsilateral cranial nerve deficitsDiplopiaGait ataxiaParesthesiasPontine syndromes [13]Ventral pontine syndromeLateral pontine syndromeInferior medial pontine syndromeLocked-in syndrome (bilateral basilar artery occlusion)Cerebellar syndromes Extracranial arteriesInternal carotid arteryIpsilateral amaurosis fugaxDysphagia, tongue deviates to ipsilateral side (CN XII)Numerous contralateral symptoms can occur (e.g., hemiparesis, hemisensory loss, homonymous hemianopsia).Common carotid arteryHorner syndromeSigns of middle cerebral artery infarctionVertebral arteryLateral medullary syndrome (see above)Neck painSigns of posterior cerebral artery infarction (see carotid and vertebral artery dissection)Anterior spinal arteryMedial medullary syndrome Lacunar syndromes Pure motor strokePosterior limb of the internal capsule (most common) May also involve the corona radiata, basal pons, medial medullaOften caused by occlusion of the lenticulostriate arteryContralateral hemiparesis of the face, arm, and leg(circumduction gait)In some cases, dysarthriaNo sensory impairmentMost common type of lacunar stroke (> 50%)Pure sensory strokeThalamus (most common)May also involve the posterior limb of the internal capsule, pontinetegmentum, corona radiataContralateral numbness and paresthesia of the face, arm, and legSensorimotor strokePosterior limb of the internal capsule (most common)May also involve the thalamus, lateral medulla, putamenContralateral hemiparesis and sensory impairmentAtaxic hemiparesisPosterior limb of the internal capsule (most common)May also involve the corona radiata, thalamus, cerebral peduncleIpsilateral weakness with impaired coordination (e.g., ataxia, gait instability)Dysarthria-clumsy hand syndromeCaudate, posterior limb of the internal capsule, putamen, base of the ponsContralateral facial and hand weakness with dysarthriaHemiballismusCaudate nucleus, putamen, thalamus, globus pallidus, corona radiata, subthalamic nucleusContralateral, involuntary, large flinging movements of the arm or legInfarction of the posterior limb of the internal capsule is the most common type of lacunar stroke and may manifest clinically with pure motor stroke, pure sensory stroke (rare), sensorimotor stroke, dysarthria-clumsy hand syndrome, and/or ataxic hemiparesis. Brainstem syndromes Pontine syndromes GeneralDecreased level of consciousness or coma (due to disruption of the reticular activating system)QuadriplegiaOcular bobbingFacial palsyDysarthria Ventral pontine syndrome (Millard-Gubler syndrome): due to basilar artery infarctionFacial nerve: ipsilateral facial muscle weaknessAbducens nerve: ipsilateral gaze palsyPyramidal tract: contralateral hemiparesis Lateral pontine syndrome (Marie-Foix syndrome): due to basilar artery and/or anterior inferior cerebellar artery infarctionCorticospinal tract: contralateral weaknessLateral spinothalamic tract: contralateral loss of pain and temperature sensationCerebellar tracts : ipsilateral limb and gait ataxiaCranial nerve nuclei involvement is possible.Facial nerve nuclei: ipsilateral facial muscle weaknessVestibulocochlear nerve nuclei: vertigo, nystagmus, and ipsilateral hearing lossTrigeminal nerve nuclei (motor and sensory): ipsilateral weakness of mastication muscles, ipsilateral loss of facial sensation to pain and temperatureSympathetic tract : ipsilateral Horner syndrome Inferior medial pontine syndrome (Foville syndrome): due to basilar artery infarctionCorticospinal tract: contralateral weaknessFacial nerve nucleus: ipsilateral facial muscle weaknessAbducens nerve nucleus: ipsilateral lateral gaze weakness Locked-in syndrome: occurs with bilateral basilar artery infarctionAnarthria and paralysis of all voluntary musclesBlinking and eye movement remain intact.Consciousness and cognition are not usually affected. Midbrain syndromes Medial midbrain syndrome (Weber syndrome)Ipsilateral lateral gaze weakness (CN III)Contralateral weakness Lateral midbrain syndrome (Claude syndrome) Paramedian midbrain syndrome (Benedikt syndrome) Dorsal midbrain syndrome (Parinaud syndrome): caused by damage to the dorsal midbrainEtiology: stroke, pinealoma, hydrocephalusClinical features: vertical gaze palsy, lid retraction, pupillary light-near dissociation, convergence-retraction nystagmus Medullary syndromes Medial medullary syndrome (Déjerine syndrome): infarct of paramedian branches of the anterior spinal arteryIpsilateral dysfunction of the hypoglossal nerve Contralateral hemiparesisContralateral decrease in proprioceptionCan also occur with vertebral artery infarction Lateral medullary syndrome (Wallenberg syndrome) PutamenContralateral hemiplegia and paresthesiaGaze palsy and ipsilateral deviation of the eyesStupor and comaCerebellumClassic cerebellar signs: ataxia, nystagmus, slurred speechLateral cerebellum: ipsilateral limb ataxiaCerebellar vermis: truncal ataxia, nystagmusFacial weakness, gaze palsyHeadache, vomiting, neck stiffnessNo hemiparesisSee cerebellar syndromes and cerebellum.ThalamusContralateral hemiparesis and paresthesiaMiotic and unreactive pupils, upgaze palsy with gaze deviation away from the side of the lesion (wrong way eyes)CortexFrontal lobeContralateral weakness or paralysis of the leg with relative sparing of the arm Frontal eye fields: gaze deviation toward the affected side and away from the side of hemiplegiaDisinhibition, poor judgmentPoor concentration, orientationPrimitive reflexesParietal lobeContralateral sensory loss DisorientationDominant hemisphereAgraphiaFinger agnosiaAcalculiaNondominant hemisphere: contralateral agnosia (hemispatial neglect)Occipital lobe: contralateral homonymous hemianopsia (with macular sparing)Temporal lobeWernicke aphasia (if dominant hemisphere affected)Contralateral superior quadrant hemianopsiaWatershed border-zoneWatershed areas are most sensitive to profound hypoperfusion [22]Anterior cerebral/middle cerebral cortical border zone: proximal upper and lower extremity weakness (man-in-the-barrel syndrome) Posterior cerebral/middle cerebral cortical border zone: visual dysfunction Initial evaluation Primary survey Clinical assessment and historyIdentify risk factors for ischemic or hemorrhagic stroke, including the presence of carotid bruits. Identify signs (above) that indicate the affected vessel and/or region of the brain.Determine the time of onset of symptoms (e.g., "last known normal"): The time of stroke onset determines whether thrombolytic therapy is an option (see below). Imaging [31][32] Approach: noncontrast head CT to evaluate for acute hemorrhage → diffusion-weighted MRI to detect acute ischemia → consider further neurovascular imaging depending on the type of stroke Noncontrast head CT (first-line imaging) Allows for detection of acute hemorrhage but cannot be used to reliably identify early ischemiaIndicated in all patients suspected of having an acute stroke to rule out intracranial hemorrhage before administering thrombolytic therapy Diffusion-weighted MRI Allows identification of ischemia earlier than a CT (within 3-30 minutes after onset)Allows detection of hyperacute hemorrhageEvaluates reversibility of ischemic injury Perfusion-weighted imaging (PWI): visualizes areas of decreased perfusion and allows quantification of perfusion parameters, e.g., mean transit time (MTT), cerebral blood flow (CBF) and cerebral blood volume (CBV) Perfusion-diffusion mismatch MRI: allows identification of the penumbra (or "tissue-at-risk") See ischemic stroke, subarachnoid hemorrhage, and intracerebral hemorrhage for specific imaging findings and other modalities. Laboratory evaluation Initial: serum glucose Additional evaluation Complete blood count, electrolytesCoagulation parameters (e.g., INR, PTT)Urine drug screen for recreational substances (e.g., cocaine), blood alcohol levelSerum troponin Laboratory studies should not delay imaging for patients with acute stroke. Differential diagnoses NeurologicSeizuresPostictal paralysisBrain tumor Migraine auraCerebral venous sinus thrombosis Toxic/metabolicHyponatremiaHypoglycemiaDKAAlcohol withdrawalDrug intoxication (e.g., heroin, barbiturates)Osmotic demyelination syndrome ENT Vestibular neuritisMeniere diseaseBPPV InfectiousMeningitisEncephalitisMeningoencephalitisCerebral/epidural abscessProgressive multifocal leukoencephalopathy Lyme disease PsychiatricConversion disorderMalingering TraumaTraumatic brain injurySubdural hematomaEpidural hematomaBrown-Sequard syndrome Paraneoplastic syndromes/autoimmune disordersMultiple sclerosisBell palsyGuillain-Barré syndromeAnti-NMDA encephalitisLung cancer If symptoms of a suspected ischemic stroke began less than 4.5 hours prior to presentation and there are no signs of intracranial bleeding, begin reperfusion therapy immediately! Stabilization and monitoring [32] Maintain euvolemia with fluid replacement as needed. Maintain a sufficient oxygen supply and consider intubation if the patient shows signs of increased intracranial pressure (e.g., altered mental state). Maintain euglycemia (e.g., blood glucose levels within 140-180 mg/dL). Maintain normothermia (e.g., antipyretics). Cardiac monitoring (for at least 24 hours) Maintain a normal acid-base status. Electrolyte repletion as needed Analgesia as needed Monitor for signs of elevated intracranial pressure (see elevated intracranial pressure and brain herniation). Seizures should be treated pharmacologically. Evaluate for dysphagia. Blood pressure management [32][38] Always treat hypotension (e.g., with fluid replacement, vasopressors). Ischemic stroke: permissive hypertension See "Treatment" in ischemic stroke.Only treat severe hypertension (> 220 systolic pressure and/or 120 mm Hg diastolic pressure). Hemorrhagic stroke: Reduce systolic blood pressure to approx. 140-160 mm Hg.See "Treatment" in subarachnoid hemorrhage and intracerebral hemorrhage. Nitrates should be avoided because they can increase intracranial pressure. Complications Medical complications [44] Cardiac dysfunction (arrhythmias, myocardial infarction) Aspiration pneumonia Deep vein thrombosis and pulmonary embolism Urinary tract infections Bleeding (e.g., gastrointestinal bleeding) Delirium Depression Neurologic complications [45] All strokesElevated intracranial pressure and brain herniation (Cushing triad)SeizuresSyndrome of inappropriate secretion of antidiuretic hormone (SIADH)Persistent neurologic deficits (hemiparesis, aphasia) and disability [42]Central poststroke pain [46][47]Affects < 10% of all stroke patientsUnilateral facial pain and/or extremity pain associated with previous stroke Initial paresthesia → neuropathic pain (e.g., allodynia, dysesthesia)Can occur with thalamic lesionsNeuropathic pain Ischemic strokeHemorrhagic transformation Vascular dementia Hemorrhagic strokeRecurrent hemorrhageIntraventricular hemorrhageHydrocephalusVasospasm (typically occurs 5-7 days after SAH) → may result in ischemic stroke

Syringomyelia Syringomyelia is a condition in which an abnormal fluid-filled cavity, or syrinx, develops within the central canal of the spinal cord. The syrinx is a result of disrupted CSF drainage from the central canal, commonly caused by a Chiari malformation or previous trauma to the cervical or thoracic spine. In select cases, the syrinx may occur in the brainstem, and is then referred to as syringobulbia. The syrinx initially compresses and permanently damages crossing fibers of the spinothalamic tract. Further expansion may affect other tracts of the spinal cord. Symptoms include dissociated sensory loss, presenting as a cape-like distribution of decreased sensitivity to pain and temperature, and flaccid atrophic paralysis in the upper extremities. MRI is the diagnostic modality of choice. Treatment depends on clinical features and associated findings. Symptomatic treatment commonly suffices in stable courses of disease, while patients with progressive neurological deterioration require surgical decompression.

Epidemiology 3-4% of patients with traumatic spinal cord injury (SCI) develop symptomatic syringomyelia. Sex: ♂ > ♀, especially in SCI-related syringomyelia Age range: 30-40 years; however SCI-related syringomyelia may occur in all age groups Chiari type I is the most common type of malformation and is typically asymptomatic in children. Arnold-Chiari malformation type II is typically associated with myelomeningocele at birthand hydrocephalus later in childhood. Etiology Chiari malformation Posttraumatic SCI (common) Postinflammatory: transverse myelitis; arachnoiditis Postinfectious: meningitis Intramedullary tumors: ependymoma, hemangioblastoma Other congenital malformations: tethered spinal cord Idiopathic Pathophysiology Obstructed central canal of spinal cord (usually cervical spine, may affect the thoracic spine) → impaired CSFdrainage → formation of a dilated fluid-filled cavity in central spinal cord (syrinx) → compression and damage (with reactive gliosis) to crossing neural fibers of the lateral spinothalamic tract first (which affect pain and temperature) → bilateral dissociated sensory loss and dysesthetic pain Expansion of the syrinx may damage: Lower motor neurons in the medial part of the corticospinal tract → initially bilateral weakness → eventualbilateral flaccid paralysis and muscle atrophy Descending hypothalamic fibers in T1 to T4 cord segments → Horner syndromePosterior column (advanced disease) → loss of position sense and vibration sense in the feet Medulla → syringobulbia A hydromyelia is an abnormal widening of the central canal of the spinal cord in which CSF collects, despite there being a connection to the 4th ventricle of the brain Clinical features Often asymptomatic Cape-like distribution (neck, shoulders, arms) of: Dissociated sensory loss Dysthetic pain Muscle atrophy, fasciculations, and areflexia (patients may present with a claw hand deformity) Spastic paraparesis of the lower limbs may occur. Autonomic disturbances: Horner syndrome, anhidrosis, disturbances in bladder and colon function, erectile dysfunction Respiratory insufficiency Other: painless ulcers of the hands, Charcot joints, thoracic scoliosis SyringobulbiaTongue atrophy Loss of pain and temperature sensation in trigeminal nerveNystagmusDysphagiaPalatal and pharyngeal weaknessDiagnostics X-ray or CT: to detect scoliosis and assess the bony spine MRI (confirmatory test): detection of the syrinx (may be septated) and adjacent spinal cord lesions (e.g., tumors, adhesions in arachnoiditis) Differential diagnoses Cervical disk prolapse Amyotrophic lateral sclerosis Multiple sclerosis Other incomplete spinal cord syndromesHemiparaplegic syndrome (Brown-Séquard syndrome)Anterior spinal artery syndromeTreatment Conservative therapy is usually sufficient, but definitive surgical treatment is recommended for patients with progressive neurological symptoms. Surgical treatment Removal of the tumor (if present) Decompression by drainage of CSF fluid from the cavityCerebral shuntLaminectomy and syringotomy Supportive therapy Physiotherapy and psychotherapy Spasticity: baclofen, methocarbamol Analgesia: amitriptyline, NSAIDs, gabapentin (not FDA-approved for use in syringomyelia, but may be considered due to its effectiveness in treating neuropathic pain)

Alzheimer disease Alzheimer disease (AD) is a chronic neurodegenerative disease and the leading cause of dementia. Several causative gene defects (e.g., amyloid precursor protein gene mutations) and risk factors (e.g., old age) have been identified, although the exact mechanism that causes Alzheimer disease is still unknown. The main histopathological features of AD are senile plaques caused by the extracellular deposition of beta-amyloid protein (Aβ protein) in the grey matter of the brain and neurofibrillary tangles due to intracellular accumulation of tau protein. The most common symptom of AD is short-term memory loss. Many cognitive functions, including attention control, reasoning, orientation, and language, are affected during the course of the disease. The diagnosis is primarily based on clinical examination, but neuropsychological tests, cerebrospinal fluid (CSF) analysis, and imaging are sometimes used as well. To date, there is no curative therapy. Symptomatic therapy can be attempted with cholinesterase inhibitors and N-methyl-D-aspartate (NMDA) antagonists (e.g., memantine). AD has a highly variable progression; the meansurvival time following diagnosis is 3-10 years.

Epidemiology AD is the leading cause of dementia and the sixth most common cause of death in the US. Incidence and prevalence increase with age. Incidence∼ 200:100,000 in patients 65-74 years of age ∼ 3700:100,000 in patients ≥ 85 years of age Prevalence1/10 individuals 65 years of age1/3 individuals ≥ 85 years of age Sex: ♀ > ♂ In the US, AD is more common in African Americans and Hispanics than in whites. Genes (chromosome)ProteinsCharacteristicsAmyloid precursor protein (APP) geneAPPLinked to 10-15% of early-onset familial AD casesPatients with trisomy 21 have an increased risk of early-onset AD because of APP overexpression (the APP gene is located on chromosome 21). Presenilin-1PSEN1Linked to ∼ 50% of familial AD cases Earlier onset compared to AD due to mutations of other genes (median is ∼ 43 years)Presenilin-2PSEN2Mutations cause the rarest form of familial AD. Apo εApolipoprotein E(ApoE)Risk of late-onset AD increases with the number of carried Apo ε4 alleles.Apo ε2 alleles may have a protective effect.Apo ε3 alleles neither decrease nor increase risk of developing ADOther risk factors Age Family history of dementia Low socioeconomic and/or educational status Diabetes, obesity, dyslipidemia Hypertension, peripheral atherosclerosis, and cerebrovascular disease Lack of physical activity (independent risk factor) Traumatic brain injuries Environmental factors (e.g., secondhand smoke) Sleep deprivationPathophysiology The following pathophysiological mechanisms contribute to AD: Extracellular senile plaques (neuritic plaques) in the grey matter of the brainAβ protein is the main component of the plaques.Enzymatic cleavage of transmembranous APP by β-secretase and γ-secretase → Aβ peptide aggregation → formation of insoluble plaques together with tau protein and microglia → neurotoxic effect Intracellular neurofibrillary tanglesTangles are composed of hyperphosphorylated tau protein(a microtubule-associated protein). Increased phosphorylation (hyperphosphorylation) of tau → formation of intracellular fibrils → neurotoxic effect Overall reduction of cholinergic functionClinical features Cognitive Common symptoms of cognitive impairment Short-term memory impairment (insidious onset, slow progress with episodic memory affected first)Language impairmentTemporal and spatial disorientation (patients are usually not oriented to person, place, time, or events)Impairment of executive functions and judgment Less common symptoms Primary progressive aphasia ApraxiaAlexiaAgnosiaAcalculia Noncognitive Behavioral changesApathyAggression, irritability, and agitation Mood disorders (e.g., symptoms of depression) Anxiety and mutism Hallucinations and paranoia Hyposmia Insomnia Urinary incontinence Myoclonus Seizures Patients with mild to moderate AD are often able to maintain a social facade and preserve certain skills (e.g., dressing, hygiene routines).Diagnostics Approach To diagnose dementia in patients with memory loss, cognitive and/or functional decline: neuropsychological testing (e.g., Mini-Mental State Examination, Montreal Cognitive Assessment) Rule out reversible causes of dementia. Review medications.Laboratory tests (rule out hypothyroidism and vitamin B12 deficiency)Neuroimaging (rule out vascular dementia, hydrocephalus, tumors)Clinical assessment for depression to rule out pseudodementia: See diagnostic criteria for major depressive disorder. AD can only be definitively diagnosed with neurohistopathological examination, which is only conducted post mortem. Diagnostic findings Synopsis of diagnostic criteriaInsidious onset (symptoms are often first noticed by the patient's relatives)Objectively confirmed progressive loss of function in at least two cognitive domains (usually including memory impairment)Impaired activities of daily living (e.g., difficulties at the workplace)No other plausible explanation (e.g., delirium) Cerebrospinal fluidIncreased phospho-tau proteinDecreased β-amyloid proteins Aβ1-42 CT/MRISigns of generalized or focal cerebral atrophy: enlarged ventricles (ventriculomegaly), narrowing of gyri, and prominent cerebral sulci (hydrocephalus ex vacuo)Disproportionate atrophy of the hippocampus and/or medial temporal lobe EEG: slower basic rhythm Evoked potentials: long latency PETFDG-PET: temporoparietal hypometabolismAmyloid PET: increased amyloid uptake signal Neuropsychological testing (e.g., MMSE and MoCA): Repeated performance measurement is used to track disease progression.Pathology Cerebral atrophyDamage to the hippocampus and parahippocampal cortex (medial temporal lobe structures) is the earliest gross pathological change. Axonal degenerationNeuronal lossDegeneration of cholinergic neurons in the nucleus basalis of MeynertDiffuse cortical atrophy occurs as the disease progresses. Amyloid beta (Aβ): stains with Congo red under polarizationCerebral amyloid angiopathy Extracellular senile plaques Tau proteinIntracellular neurofibrillary tanglesStain with Gallyas silver.reatment There is currently no curative therapy; only symptomatic therapies are available. Pharmacological treatment of dementia Mild-moderate (determined by neuropsychological testing): donepezil, galantamine, rivastigmine (acetylcholinesterase inhibitors) Moderate-severe (may be given in addition to acetylcholinesterase inhibitors): memantine (NMDA-receptor antagonist) Aggression and psychosis: low dose antipsychotics Supportive care (nonpharmacological treatment) Lifestyle modifications: e.g., adhering to a regular sleep schedule, maintaining a familiar environment, removing ambient noise Cognitive rehabilitation: memory training (e.g., puzzles, interactive games) to support memory retention and strategies to compensate for cognitive and functional decline Physical activity: improves physical strength, which slows functional decline Pharmacological treatment of associated symptoms In patients who have not adequately responded to supportive care, the following classes of drugs may be considered: Atypical antipsychotics (e.g., risperidone): in patients with agitation, hallucinations, insomnia SSRIs (e.g., citalopram): in patients with depression Avoid drugs with strong anticholinergic effects (e.g., diphenhydramine).Complications Infections: Aspiration pneumonia is the most common contributing factor to AD-related mortality. Malnourishment/dehydration Cerebral amyloid angiopathy increases the risk of intracerebral hemorrhage.Prognosis The reported survival rate is approximately 3 to 10 years after diagnosis.

Wilson disease Wilson disease (hepatolenticular degeneration) is an autosomal recessive metabolic disorder in which impaired copperexcretion causes copper to accumulate in the body. In its initial stages, Wilson disease leads to copper deposits in the liver. As the disease progresses, copper also accumulates in other organs, most importantly in the brain and cornea. The disease often goes undiagnosed until the typical combination of hepatitis (or even cirrhosis), dementia, and parkinsonismraises clinical suspicion. Kayser-Fleischer rings, brownish copper deposits visible around the iris, are a further indication of Wilson disease. Low serum ceruloplasmin (copper transport protein) concentrations and increased urinary copperexcretion confirm the diagnosis. Genetic testing or liver biopsies with quantitative copper assays can provide further information if the diagnosis is indeterminate. Primary management consists of maintaining a low-copper diet and the administering a chelating agent such as penicillamine. The prognosis is good if the condition is diagnosed and treated early.

Epidemiology Age of onset: 5-35 years (mean age 12-23 years) Prevalence: ∼ 1/30,000 Pathophysiology Autosomal recessive mutations in the ATP7B gene (Wilson gene) on chromosome 13, which encodes for a membrane-bound, copper-transporting ATPase → defective ATP7B proteinInadequate incorporation of copper into apoceruloplasmin → ↓ serum ceruloplasminReduced biliary copper excretion Results in ↑ free serum copper → accumulation in the liver, cornea, CNS (basal ganglia, brain stem, cerebellum), and enterocytes Clinical features Liver: different degrees of liver disease possible, including acute liver failure, acute or chronic hepatitis, and cirrhosisHepatosplenomegalyPortal hypertensionAbdominal painJaundiceAscitesHepatic encephalopathy Kayser-Fleischer rings: Copper accumulation in Descemet membrane of the cornea results in 1-2 mm wide, green-brown rings in the periphery of the iris. While the rings are characteristic for Wilson disease and occur in ∼ 98%of patients who also have neurological symptoms, their absence does not rule out the condition. Neurological symptoms: extrapyramidal motor disturbances, but no sensory changesDysarthriaParkinsonismDroolingTremor (usually asymmetric, affecting the hands), which may be any combination of: Resting tremorIntention tremorWing-beating tremor Behavioral changes (e.g., depression, irritability, psychosis) Cognitive impairmentWilson disease should be suspected in cases of nonspecific, noninfectious liver disease and nonspecific extrapyramidal movement disorders appearing before the age of 35! Diagnostics Slit lamp examination: Kayser-Fleischer rings (best initial test) Blood tests↑ TransaminasesCBC: Coombs-negative hemolytic anemia, thrombocytopenia ↓ Serum ceruloplasmin (normal value > 20 mg/dL)↑ Free serum copper, but ↓ total serum copper ↑ Urine copper excretion (over 24 hours) Liver biopsy: if other tests are inconclusiveHepatic copper concentration (> 250 μg/g dry weight) Histology: copper staining Differential diagnoses Hepatic: autoimmune and viral hepatitis, cirrhosis, hemochromatosis Neuropsychologic: Parkinson disease, Huntington disease, multiple sclerosis, schizophrenia, personality disorders reatment General management Low-copper diet: avoid foods such as organs, shellfish, nuts, and chocolate Regular check-ups: liver biochemical tests every 6 months if disease is stable Liver transplantation in cases of fulminant liver failure Medical therapy Initial therapy: chelating agents Penicillamine: side effects in ∼ 30% of cases (e.g., sensitivity reactions)Alternatives: trientine or zinc salts Maintenance therapy: zinc salts or low dose chelating agentsTreatment with a chelating agent should be administered gradually over the course of 3 to 6 months, as mobilizing the copperstored in tissues too rapidly may exacerbate neurological symptoms!

Fibromuscular dysplasia Fibromuscular dysplasia (FMD), a disease that primarily affects young to middle-aged women, is characterized by the proliferationof connective tissue and muscle fibers within the arterial vessel walls. The resulting stenosis impairs perfusion of the affected organ, causing ischemia. The symptoms of fibromuscular dysplasia vary depending on the site and the degree of stenosis of FMD. The renal, internal carotid, and vertebral arteries are predominantly involved. Carotid and vertebral artery involvement may present with transient ischemic attack (TIA) and/or stroke, while patients with renal FMD usually present with secondary hypertension and chronic renal insufficiency. Bruits at the costovertebral angle and the carotid region are characteristic findings of renal and carotid artery involvement respectively. In rare cases, patients may present with mesenteric ischemia and/or peripheral artery disease as a result of splanchnic or peripheral arterial involvement. The "string of beads" sign, a characteristic finding on angiography, distinguishes FMD from other causes of arterial occlusion. All patients with renal FMD should be treated with ACE inhibitors and/or ARBs, while those with carotid artery involvement should be placed on stroke prophylaxis (low-doseaspirin therapy). Balloon angioplasty without stenting is the definitive treatment.

Epidemiology Age of onset: typically 30-50 years, but can manifest at any age Sex: ♀ > ♂ (8:1)Among children: ♀ ≈ ♂ Ethnicity: increased prevalence among the white population Pathophysiology Fibromuscular dysplasia (FMD) is an idiopathic, non-inflammatory, non-atherosclerotic, developmental condition that primarily affects small and medium-sized muscular arteries. Histopathology The most commonly encountered histology is medial fibroplasia. Pathophysiology FMD results in ischemia by one or more of the following mechanisms: StenosisFormation of saccular aneurysms → aneurysmal ruptureArterial dissection → arterial occlusionFormation of intravascular thrombi → embolization Renal artery stenosis → ↓ renal perfusion → compensatory activation of the renin-angiotensin-aldosterone system → secondary hypertension Disease localization Renal artery (renal FMD; ∼ 75-80% of cases)Usually bilateral renal artery stenosisSecond most common cause of renal artery stenosis after atherosclerosis.Accounts for 30-50% of cases of renal artery stenosis among children and 5-10% of cases among adults. Carotid and vertebral artery involvement (extracranial cerebrovascular FMD; ∼ 65-75% of cases and often bilateral) Clinical features The symptoms of fibromuscular dysplasia are nonspecific and vary depending on the site of FMD, the degree of stenosis, and the underlying pathology (e.g., arterial dissection). Renal FMDClinical features of renal artery stenosisSecondary hypertension Abdominal bruitSymptoms of chronic kidney diseaseFlank or abdominal pain Cerebrovascular FMDHeadache, neck pain, pulsatile tinnitusTIA, amaurosis fugax, stroke, Horner's syndromeCervical bruit Diagnostics ImagingImaging modalities Best initial tests for renal FMD: duplex ultrasonography and/or CT angiography (see "Diagnostics" in renal artery stenosis)Best initial tests for cerebrovascular FMD: CT angiography Gold standard: digital subtraction angiography (DSA) Finding Common finding: "string of beads" sign Less commonly: a single, circumferential/tubular stenotic lesion Laboratory tests: serum creatinine Differential diagnoses AtherosclerosisPatients with atherosclerosis are usually older, male, and have risk factors such as obesity and/or cigarette smoking.On angiography, atherosclerosis affects the proximal segments and ostia of arteries, while FMD affects middle and distalsegments of the artery. Vasculitis (e.g., giant cell/temporal arteritis) Treatment Renal artery FMD: see "Therapy" in renal artery stenosis Cerebrovascular FMDAntiplatelet drugs (e.g., aspirin) for stroke prophylaxis is recommended for all patients.Patients who are symptomatic: percutaneous transluminal angioplasty

Bulbar palsy and pseudobulbar palsy Bulbar palsy is a lower motor neuron palsy that affects the nuclei of the IXth, Xth, XIth, and XIIth cranial nerves. Pseudobulbar palsy is an upper motor neuron palsy that affects the corticobulbar tracts of the Vth, VIIth, IXth, Xth, XIth, and XIIth cranial nerves. Any condition which disrupts or damages the cranial nerve nuclei or corticobulbar tracts can cause bulbar or pseudobulbar palsy (e.g., stroke, multiple sclerosis, infections, brain stem tumors). Both bulbar and pseudobulbar palsy are seen mainly in men over 75 years old and present with dysarthria and dysphagia. In addition, patients with pseudobulbar palsy present with a lack of facial expression, difficulty chewing, and emotional lability. Lower motor neuron signs (atrophy and fasciculations of the tongue, absent gag reflex) differentiate bulbar palsy from pseudobulbar palsy, which presents with upper motor neuron signs (spastic tongue, exaggerated gag, and jaw jerk reflexes). Diagnosis is mainly clinical. CSF analysis and MRI of the brain help identify the etiology. Treatment is mainly supportive.

Epidemiology Age: 75-80 years Sex: ♂ > ♀ Bulbar palsy Brainstem stroke or tumors Neurodegenerative diseases: amyotrophic lateral sclerosis, syringobulbia, multiple sclerosis Autoimmune neuropathies: Guillain-Barré syndrome, myasthenia gravis Infectious neuropathies: poliomyelitis, diphtheria, neurosyphilis Bilateral damage or injury of the nerve nuclei of cranialnerves IX, X, XI, and XII Lower motor neuron palsy of the respective muscles Facial expression: normal Speech: nasal Dysphagia, drooling, nasal regurgitation Tongue WastingFasciculationsInability to protrude the tongue Palatal movement: absent Gag reflex: absent Jaw jerk: normal Emotions not affected Pseudobulbar palsy 5,7 +9,10,11,12Stroke (multiple, recurrent strokes) Neurodegenerative disease: amyotrophic lateral sclerosis, progressive supranuclear palsy, multiple sclerosis Injury or malignancy of the high brainstem Bilateral damage or injury of corticobulbar tracts to nerve nuclei of cranial nerves V, VII, IX, X, XI, and XII Upper motor neuron palsy of the respective muscles Facial expressions: absent (expressionless face) Speech: spastic dysarthria (husky, nasal voice) Difficulty in chewing Dysphagia, drooling, and nasal regurgitation Tongue Spastic, pointedDifficulty in tongue protrusion due to spasticityNo wasting/fasciculations Palatal movement: absent Gag reflex: brisk (exaggerated) Jaw jerk: exaggerated; clonic Emotional incontinence (pseudobulbar affect) Diagnostics Bulbar palsy and pseudobulbar palsy are clinical diagnoses based on clinical features. Tests are performed to diagnose the underlying condition. Investigations to diagnose the etiology Serology for syphilis, poliomyelitisCSF analysis for Guillain-Barré syndrome (albuminocytologic dissociation), multiple sclerosis (oligoclonal bands)MRI brain for stroke, tumors, syringobulbia, multiple sclerosis Treatment No known treatment for irreversible causes of bulbar/pseudobulbar palsy Supportive therapy Anticholinergics to control droolingBaclofen for spasticity of pseudobulbar palsyPercutaneous endoscopic gastrostomy tube (PEG): for patients with severe dysphagia or recurrent aspiration pneumoniaSpeech and language therapyTricyclic antidepressants or SSRIs: for patients with pseudobulbar affect Treat the underlying cause (see "Etiology" in table above)

Intracerebral hemorrhage Intracerebral hemorrhage (ICH) refers to bleeding within the brain parenchyma. The term should not be confused with "intracranial hemorrhage," which encompasses any type of bleeding within the skull, i.e., extradural, subdural, subarachnoid, and intracerebral. The most significant risk factor for spontaneous ICH is arterial hypertension. Symptoms are often nonspecific (e.g., headache), but, depending on the affected vessel and cerebral region, focal neurologic deficits (e.g., hemiparesis) may occur. Compared to ischemic stroke, patients with ICH typically present with more severe headache and symptoms usually progress more rapidly. A noncontrast head CT, the most important diagnostic procedure, shows a hyperdense lesion in acute ICH and a hypodense lesion in hyperacute ICH. Treatment involves management of the underlying and accompanying conditions (e.g., controlling hypertension, reversing coagulopathy) and, in severe cases, neurosurgical intervention. Approximately half of patients with ICH die within 30 days.

Epidemiology ICH is responsible for approx. 10% of all strokes. [1][2] Most commonly affects the deep structures of the brain [3]Putamen/globus pallidus most commonly affectedInfratentorial (e.g., pons, cerebellum) least commonly affected Intraventricular extension occurs in approx. 30% of patients with ICH. [4] Etiology Nontraumatic (spontaneous) Hypertension: most common cause of spontaneous ICH Cerebral amyloid angiopathy: most common cause of spontaneous ICH in individuals > 60 years of ageArteriovenous malformations: most common cause of spontaneous intracerebral hemorrhage in childrenVasculitis (e.g., giant cell arteritis)Neoplasms (e.g., meningioma) Ischemic stroke (due to reperfusion injury)CNS infections (e.g., herpes simplex virus)Septic emboliCoagulopathy (e.g., hemophilia, anticoagulant use)Stimulant use (e.g., cocaine and amphetamines; possibly also caffeine) Traumatic: see traumatic brain injuryPathophysiology Nontraumatic mechanisms of hemorrhageChronic arterial hypertension → lipohyalinosis of lenticulostriate vessels, which supply the basal ganglia → formation and rupture of Charcot-Bouchard microaneurysms → lacunar strokes (ischemia) of the basal gangliaCerebral amyloid angiopathy: deposition of β-amyloid peptides in vessel walls → focal damage with formation of microaneurysms → ruptureStructural abnormalities (e.g., vascular malformations) → exposure of parts of the abnormal vascular segment to excessive strain → ruptureVenous outflow obstruction and stimulant use (e.g., cocaine) → acute arterial hypertensionCoagulopathies: impaired hemostasis → vascular microtraumaInflammatory tissue necrosis → damage to vessels Traumatic: blunt or penetrating injury → damage to vessels Clinical features Headache Absent in small hemorrhagesMost common in cerebellar and lobar hemorrhages [9] Focal neurologic signs and symptoms may occur, depending on the location and size of the hemorrhage (see stroke symptoms by affected vessel and stroke symptoms by affected region in stroke) Course Symptoms typically progress gradually over minutes to a few hoursFocal deficits worsen with expansion of the hematomaLate: symptoms of increased intracranial pressureNausea and vomitingConfusion and loss of consciousnessBradycardiaFixed pupils Diagnostics Initial evaluation Immediate noncontrast head CTBest initial testExpected findings Hyperacute: hypodense lesionAcute: hyperdense lesion with hypodense perifocal edemaChronic: hemorrhage may appear as a hypodense lesionMidline shift and/or mass effect may suggest impending herniation Diffusion-weighted MRIMore sensitive than head CTExpected findings Hyperacute T1: hypointenseT2: hyperintenseAcute: hypointense Subsequent evaluation Laboratory studiesCBC Coagulation parametersBlood glucose levelTroponinToxicology screen Angiography (e.g., CTA and/or MRA): to identify the source of the bleeding if the patient does not have any risk factors Treatment Medical therapy [11] Reverse anticoagulation Blood pressure management [11] Systolic BP > 220 mm Hg → rapidly lower to 140-160 mm HgSystolic BP 150-220 mm Hg → rapidly lower to 140 mm HgRecommended agents: IV labetalol, nicardipine, enalapril, and/or hydralazine Maintain euvolemia Avoid/treat hyponatremia Maintain normoglycemia If there are signs of elevated ICP (e.g., Cushing triad) Consider intubation with hyperventilationHead elevation (30°)IV mannitolRemoval of CSF (e.g., via lumbar puncture)See ICP management Surgical therapy [11] Craniotomy and clot evacuationIndications Signs of brain herniation (e.g., Cushing triad)Brainstem compressionObstructive hydrocephalusCerebellar hemorrhage with progressive neurological deteriorationCerebellar hemorrhage extension > 3 cm [11]Patients with hemorrhage in the basal ganglia or the internal capsule should generally not undergo surgical clot removal. [10] If hydrocephalus is present: ventricular drain, serial LPs, or permanent ventriculoperitoneal shunt may be indicated Patients with signs of brain herniation should be operated on immediately! Complications Elevated intracranial pressure and brain herniation Intraventricular hemorrhage → hydrocephalus Recurrent hemorrhage Vasospasm and cerebral ischemia Dysphagia: can lead to aspiration of food and pneumonia Seizures Hydrocephalus SIADH Deep vein thrombosis See complications of stroke Prognosis Approximately 50% of all patients with ICH die within 30 days

Neuralgic amyotrophy Neuralgic amyotrophy (also referred to as brachial neuritis or Parsonage-Turner syndrome) is a self-limiting inflammatory disorder of the brachial plexus, that mainly affects males between 20-30 years of age. There are two clinically similar, yet etiologically distinct forms of neuralgic amyotrophy (NA). Idiopathic NA is more common, often unilateral, and non-recurrent. It is thought to be an immune-mediated process triggered by preceding viral infection, immunization, or trauma. Hereditary NA is a rare, autosomal dominant condition that often affects both shoulders and is characterized by recurrent symptoms. In both types, patients present with acute onset of excruciating shoulder pain that lasts for weeks followed by patchy lower motor neuron paresis of the proximal muscles in the affected arm. Diagnosis is clinical, with nerve conduction studies and needle electromyography performed to identify which nerves are affected. Treatment is mainly supportive and involves analgesia and physical therapy. Most patients recover complete muscle strength within 2 years.

Epidemiology Incidence: 1-3 cases per 100,000 population per year Peak age: 20-30 years Sex: ♂ > ♀ Etiology Idiopathic NA (more common) Likely immune-mediatedPotential triggers: recent viral infection/immunization; mechanical strain on the arm/shoulder; trauma; surgery; childbirth; vasculitis (temporal arteritis, PAN, SLE) Hereditary NARareAutosomal dominant Pathophysiology The exact pathophysiology is unknown, but it is believed to be multifactorial. Environmental factors (e.g., viral infection, immunization, surgery) → activation of the immune system Mechanical factors (e.g., repetitive strain, recent strenuous exercise) → repeated stretching of the brachial plexusnerves → predisposition of the brachial plexus to immune-mediated injury A combination of the above factors → patchy inflammation of the brachial plexus → axonal injury of the affected nerves → severe burning pain, followed by paresis of the muscles supplied by the affected nerve Clinical features Shoulder painAcute phaseSudden onset of excruciating, burning pain which does not decrease with NSAIDs Mostly unilateral (esp. affects the right shoulder ), radiates to the arm and/or the neckUsually lasts for several weeksChronic phaseContinuous pain lasting ∼ 1 year orIntermittent exacerbations of shooting pain, lasting for a few hours; brought on by certain shoulder positions/actions (arm abduction/elevation) Progressive weakness and atrophy of the shoulder/arm musclesOccurs ∼ 2 weeks after the acute onset of painPatchy involvement of more than one nerve of the brachial plexus Different degrees of lower motor neuron paresis of muscles innervated by the same peripheral nerve Nerves commonly affected: Suprascapular nerve → weak abduction and external rotation of the shoulderLong thoracic nerve → winging of the scapulaAxillary nerve → weak abduction of the armSubscapular nerve → weak internal rotation of the shoulder Sensory loss: hypoesthesia (numbness); paresthesia or dysesthesia (painful sensation to light touch) in the arm, forearm, and/or hand Autonomic dysfunction: edema, excessive sweating, faster growth of hair and nails on the affected limb Diagnostics NA is mainly a clinical diagnosis. Assessment of damage localization and severityNerve conduction studies: show conduction block in the affected nervesNeedle electromyography: show axonal degeneration; help differentiate between muscular and neural causes of weakness Exclusion of differential diagnosesChest x-ray: to rule out Pancoast tumor or thoracic outlet syndromeMRI of the cervical spine: to rule out cervical disc disease/degenerationMRI of the shoulder: to rule out rotator cuff tears/impingement Differential diagnoses Upper limb weakness and/or proximal muscle atrophyPancoast tumorRotator cuff tendinitis/tearCervical radiculopathies, mononeuritis multiplex, amyotrophic lateral sclerosis, thoracic outlet syndrome, acute poliomyelitis Acute severe pain: myocardial infarction, herpes zoster neuritis Treatment There is no specific causative treatment for NA. The condition is self-limiting and is treated symptomatically. AnalgesiaAcute phase: combination of a long-acting NSAID (e.g., diclofenac) and an opiate (e.g., morphine)Chronic phase: gabapentin, carbamazepine, or amitriptyline Physical therapyInitiated after acute pain has subsidedPrevents/minimizes muscular atrophy and preserves normal range of motion of the shoulder joint Surgery: nerve grafts or tendon transfers are possible; only considered in protracted disease courses (> 2 years)Prognosis Prognosis is variableSome patients recover complete muscle strength and are pain-free within 1-2 yearsSome may have pain and paresis for many years, causing significant functional disability RecurrenceIdiopathic NA: often non-recurrentHereditary NA: ∼ 75% of patients will have recurrent NA

Guillain-Barré syndrome Guillain-Barré syndrome (GBS) is an acute postinfectious polyneuropathy characterized by symmetric and ascending flaccid paralysis. In affected patients, cross‑reactive autoantibodies attack the host's own axonal antigens, resulting in inflammatory and demyelinating polyneuropathy. Albuminocytologic dissociation, characterized by elevated protein levels and normal cell counts in cerebrospinal fluid (CSF), is a hallmark finding of GBS. Additionally, muscle and nerve electrophysiology are used to diagnose demyelinating processes. Symptomatic and supportive treatment results in disease remission in about 70% of cases. In severe cases or patients who do not respond to treatment, intravenous immunoglobulin (IVIG) administration and/or plasmapheresis may be used. Potentially acute life-threatening complications such as respiratory insufficiency, pulmonary embolism, and/or cardiac arrest increase mortality. Although GBS is associated with a good prognosis overall, up to 20% of patients remain severely disabled and approximately 5% of cases are fatal, despite immunotherapy.

Epidemiology Incidence: 1-4 cases per 100,000 Sex: ♂ > ♀ (1.5:1) Adults are affected more frequently than children. Etiology About ⅔ of GBS patients experience symptoms of an upper respiratory or gastrointestinal tract infection 1-4 weeks prior to onset of GBS. Pathogens associated with GBS: Campylobacter jejuni, Cytomegalovirus, Epstein-Barr virus, HIV, influenza, and Mycoplasma pneumoniaeCampylobacter enteritis is the most common disease associated with GBS.Cytomegalovirus is the most common virus associated with GBS athophysiology Postinfectious autoimmune reaction that generates cross-reactive antibodies (molecular mimicry) Infection triggers humoral response → autoantibodies against gangliosides or other unknown antigens of peripheral Schwann cells → immune-mediated segmental demyelination → axonal degeneration Clinical features Initial symptoms: back and limb pain, esp. paresthesias affecting distal extremities Advanced symptomsAscending paralysis: Bilateral flaccid paralysis spreads from the lower to the upper limbs in a "stocking‑glove" distribution.Cranial nerve involvement: frequently bilateral facial nerve involvement (facial diplegia)Landry paralysis: involvement of the respiratory musclesReduced or absent muscle reflexesPeripheral, symmetric paresthesias in the hands and feetNeuropathic pain develops in about ⅔ of patientsCardiovascular autonomic dysfunction (arrhythmia), voiding dysfunction, and/or intestinal dysfunction GBS paralysis affects the muscles of respiration, possibly leading to death due to respiratory failure! Acute inflammatory demyelinating polyneuropathyAcute variant of Guillain‑Barré syndrome.Predominant sub-type affecting 60-80% of GBS patients in North America and EuropeAssociated with Campylobacter enteritis and CMVAutoantibodies against various antigensAscending paralysis, autonomic neuropathy, CN defects and pain, clinical nadir ∼4 weeksIntravenous immunoglobulin G (IVIg), plasmapheresis Chronic inflammatory demyelinating polyneuropathy (CIDP)Chronic variant of Guillain‑Barré syndrome. CIDP has not been linked to any infectious agent in particular.Autoantibodies against GM1 gangliosidesSimilar to those of GBS, but lasting > 2 monthsGlucocorticoids, azathioprine, cyclophosphamide, plasmapheresis, or intravenous immunoglobulin therapy (IVIg) Miller-Fisher syndromeA limited variant of GBScharacterized by cranial nerveinvolvementAutoantibodies directed against ganglioside GQ1b, GT1a Ophthalmoplegia, ataxia, and areflexiaIntravenous immunoglobulin G (IVIg) Multifocal motor neuropathy (MMN)A variant of GBS solely affecting the motor neurons.Differential diagnosis for amyotrophic lateral sclerosis (ALS) .Multifocal motor conduction block (detected with electroneurography)Anti‑GM1 ganglioside antibodyElevated protein levels in CSFAsymmetric paralysis and areflexia Initially involves the distal upper limbs Immunosuppression Diagnostics Cerebrospinal fluidAlbuminocytologic dissociation: elevated protein levels and normal cell counts in cerebrospinal fluid (CSF); CSF cell counts higher than 50 cells per μl CSFindicate that GBS is unlikely! Serological screeningTo identify potential pathogens (e.g., Campylobacter jejuni)Detection of antibodies directed against gangliosides (e.g., anti‑GM1 antibodies) Electroneurography: reduced nerve conduction velocity (NCV) due to demyelination : increased F‑wave latency Treatment Supportive managementMonitor cardiac and respiratory function: in some cases, intensive care unit (ICU) treatment and intubation may be indicatedPrevent decubitus and/or thrombosis (esp. pulmonary embolism) High dose of intravenous immunoglobulins PlasmapheresisIn adults: equivalent outcome as IV immunoglobulinsIn children: only recommended in children with rapidly progressing or severe disease Prognosis Up to 70% of patients with GBS have a good prognosis: Disease progression peaks 2-4 weeks after the onset of symptoms. Symptoms then recede in reverse order of their development, i.e., the last symptoms to appear resolve first, as Schwann cells remyelinate peripheral nerve axons. 3-7% of patients with GBS die due to acute complications such as respiratory paralysis (apnea), pulmonary infection, pulmonary embolism, or cardiac dysfunction.

Craniosynostosis Craniosynostosis (CS) is the premature fusion of one or more cranial sutures. It is caused by a mutation in genes that code for fibroblast growth factor. Most affected infants are asymptomatic; CS is usually recognized based on an abnormal head shape in the first year of life. The shape of the skull is determined by which suture is prematurely fused, of which the sagittal suture (scaphocephaly) is the most commonly affected. When multiple sutures are involved, CS may cause hydrocephalus and/or cerebral constriction. Diagnosis is clinical, with skull x-ray and CT scan helping to assess the extent of fusion. Surgery is recommended in all infants for cosmetic reasons and to treat/prevent intracranial complications.

Epidemiology Incidence: 1/2500 births Potential risk factors Hereditary (positive family history)Advanced maternal ageNicotine use during pregnancyUse of clomiphene citrate (used for infertility treatment) Etiology Mutation in genes which encode for the fibroblast growth factor (FGF), FGF receptor, and/or transforming growth factor beta (TGF-β) Altered FGF, FGF receptor, or TGF-β signaling between the dura mater and mesenchyma of the suture → prematurefusion of the skull suture(s) Pathophysiology The skull is composed of 5 separate bones: 2 frontal bones, 2 parietal bones, and the occipital bone In a newborn, these bones are separated by patent sutures and fontanelles. Function of patent sutures and fontanellesAllow compression and/or overlapping of the skull bones during childbirthAllow for growth of the brain Premature closure of one or more sutures → craniosynostosis Skull deformity due to premature fusionSuture/s involvedFeaturesScaphocephaly/dolichocephaly(sagittal synostosis)Sagittal suture Most common type of CS (∼ 45%)Long, narrow skull (boat-shaped) Anterior plagiocephaly(unilateral coronal synostosis)Unilateral coronal suture 2nd most common type of CSLaterally twisted/oblique skull and face Posterior plagiocephaly(unilateral lambdoid synostosis)Unilateral lambdoid suture Rare type of CSTwisted/oblique skull Occipitoparietal flattening on the affected sideLow-set ears on the affected sideTrigonocephalyMetopic suture Common type of CS (∼ 25% of cases)Triangular shaped head Prominent occiput and parietal eminencesClose-set eyes (hypotelorism)BrachycephalyBilateral coronal suturesShort, broad, flattened skullOxycephaly(turricephaly)Bilateral coronal sutures (if left untreated)Long skull (increased craniocaudal dimension) Kleeblattschädel (cloverleaf skull)Multiple cranial sutures (esp. the metopic, coronal, and lambdoid sutures)Rare, but most severe typeTrilobar skull (prominent forehead and temporal bulging)Often associated with hydrocephalus and elevated intracranial pressure Diagnostics Mainly a clinical diagnosis Skull x-ray (AP and lateral views): bony suture bridges or lack of suture clarity Cranial CT (with 3D reconstruction) To assess extent of CSTo identify hydrocephalusHelps plan surgical reconstruction Differential diagnoses The following conditions show patency of sutures similar to craniosynostosis on skull x-ray or ultrasound: Positional plagiocephaly Infant torticollis Treatment Surgery: indicated in all patients either to minimize cerebral constriction or for cosmetic reasons Strip craniectomy or cranial vault remodeling Timing: controversial; mostly recommended at 3-9 months of age

Amyotrophic lateral sclerosis Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig disease, is a neurodegenerative disease with upper and lower motor neuron dysfunction. The disease most commonly manifests between fifty and seventy years of age, often beginning with asymmetric weakness in the hands or feet. However, initial presentation is highly variable and some patients present with atypical/non-specific symptoms such as subtle vocal changes. As the disease progresses, most patients eventually develop one or both of the life-threatening symptoms: respiratory impairment and dysphagia. Riluzoleis the only drug that has proven effective in the treatment of ALS and is indicated for all patients. Multidisciplinary care is extremely important and includes nursing care, physiotherapy, and eventually assisted ventilation and enteral feeding. Most patients will die within 3-5 years, although approx. 30% have a chance of living longer.

Epidemiology Incidence: 2-3 cases/100,000 population per year Sex: ♂ > ♀ Mean age of onset is 65 years Can be sporadic (90%) or familial (10%) Pathophysiology Classically affects the entire motor neuron system at two or more levels (both upper and lower motor neurondegeneration). Can be caused by mutations of superoxide dismutase 1, though the mutation is found only in a minority of patients. Upper motor neurons in the precentral gyrus and, frequently, prefrontal cortex Lower motor neurons in the anterior horn of the spinal cord and brainstem UMNLMNMuscle tone↑ with spasticity↓ flaccidTendon reflexes↑↓FindingsLate atrophyBabinski's signEarly atrophyFasciculations Constant disease progression: it usually starts in one arm and/or leg then progresses to the contralateral side and eventually, after months or years, affects the respiratory system. Early symptoms Symptoms are highly variable and potentially non-specific (e.g., subtle vocal changes or difficulties grasping objects) Asymmetric limb weakness, often beginning with weakness in the hands and feet Bulbar symptoms such as dysarthria and dysphagia (20% of cases at disease onset) Fasciculations, cramps, and muscle stiffness Late symptoms Cognitive impairment (approx. 15% of ALS patients meet the criteria for frontotemporal dementia) Autonomic symptoms (e.g., constipation) and sensory loss are possible but rare Life-threatening symptoms Respiratory failure due to paralysis of respiratory musclesDysphagia due to bulbar weakness Diagnostics Physical examination (including testing reflexes, Babinski's sign, etc.) ElectromyographyDenervation: indicated, e.g., by fibrillations, positive sharp waves, and large amplitudesFasciculations Nerve conduction studies: usually normal MRI and laboratory tests to exclude other potential diagnoses (see "Differential diagnosis" above) Increased creatine kinase Pathology Macroscopic: atrophy of the entire motor system, e.g., narrowing of gray matter due to atrophy of ventral roots Differential diagnoses Multifocal motor neuropathy (MMN) Slowly progressing asymmetrical weakness, esp. in the muscles of the distal extremitiesMuscle atrophy is rareEMG can reveal conduction blocksHighly elevated anti-GM1-ganglioside antibody titers Myasthenia gravisWeakness improves with acetylcholinesterase inhibitorsNo UMN or LMN signs Cervical spondylosisSensory symptomsLMN confined to affected level of spinal compressionMRI shows spinal cord compression Treatment Riluzole (glutamate antagonist): prolongs survival of patients with ALS Edaravone (free radical scavenger): has been shown to slow functional decline in some patients with ALS Multidisciplinary and symptomatic therapy Prognosis Most patients die within 3-5 years 5-year-survival: 30% 10-year-survival: 10-20% Early bulbar and/or respiratory symptoms are associated with a worse prognosis

Spinal muscular atrophy Spinal muscular atrophy (SMA) refers to a group of autosomal recessive motor neuron diseases that are caused by apoptosis of lower motor neurons. Patients typically present during infancy or early childhood with progressive weakness, hypotonia, muscle atrophy, hyporeflexia/areflexia, and varying degrees of bulbar weakness. The severity of disease is related to the age of onset; type 1 SMA (Werdnig-Hoffman disease) is associated with death within the first two years of life as a result of respiratory muscle paralysis or aspiration pneumonia. With other types of SMA, children usually survive to adulthood, but motor milestones may be delayed and joint contractures and/or deformities of the spinecan occur. The diagnosis is confirmed by genetic testing. In 2016, the FDA approved the use of nusinersen, which is highly effective in halting the progression of SMA. Supportive therapy is aimed at preventing respiratory and orthopedic complications.

Epidemiology Incidence: 4-10 per 100,000 live births Sex: ♂ > ♀ Etiology Autosomal recessive inheritance of a defect in the SMN1 gene on chromosome 5q → apoptosis of lower motor neurons (especially the anterior horn cells in the spinal cord) in the later stages of fetal development and postnatal period Pathophysiology Motor neuron disease that only involves the lower motor neurons (spinal ± bulbar motor neurons) → muscle weakness, hypotonia, bulbar symptoms; preserved sensations Motor neurons of cranial nerves III, IV, and VI, and sacral motor neurons not affected → preserved eye movementand continence Type I (Werdnig-Hoffman disease)Relative frequency25%Age of onset0-6 months ypical featuresSevere muscle weakness and hypotoniaSymmetrical involvement of proximal muscles, mostly of the lower extremitiesIntercostal muscle weakness → paradoxical breathing Diminished or absent deep tendon reflexes Severe bulbar palsyRespiratory failureAtrophy and fasciculations in the tongueWeak cry and coughInability to swallow → difficulty feeding, drooling, ↑ risk of aspirationMotor milestonesNever sits or attains head controlPrognosisLife expectancy (< 2 years) Type II 50% Delayed motor milestones Poor weight gain Weak cough Fine hand tremors Joint contractures, kyphosis, and/or scoliosis Able to sit independently, but cannot stand without supportMost children usually survive to adulthood (average life expectancy approx. 30 years). Type III (Kugelberg-Welander disease)Type IV(adult SMA)25% > 18 months10-30 years Variable degree of muscle weakness Cramps, muscle aches Joint pain Able to stand and walk independently Near normal life expectancy The most common causes of death among patients with SMA are respiratory insufficiency (due to respiratory muscle weakness) and aspiration pneumonia (due to bulbar weakness)! The older the age of onset, the better the prognosis! Type I → non-sitters, type II → sitters, type III → walkers Treatment Definitive therapy: intrathecal nusinersen Supportive therapyRespiratory supportNutritional support Physical rehabilitationOrthotics to prevent joint and spine deformitie Diagnostics Genetic testing: best initial and confirmatory test Further tests Laboratory tests: normal or mildly elevated creatine kinaseEMG: spontaneous, large-amplitude, low-frequency electrical activity (rarified interference pattern)Muscle biopsy: atrophy of groups of motor units interspersed with normal or hypertrophied motor units Differential diagnoses Certain viral infections (polio, coxsackievirus, echovirus, West Nile virus) → much more acute onset of flaccid paralysis, ascending paralysis (i.e., starts distally) Hypotonic cerebral palsy → non-progressive weakness Muscular dystrophies → ↑↑ creatine kinase, characteristic findings on muscle biopsy Rare juvenile form of amyotrophic lateral sclerosis → predominantly bulbar weakness with minimal involvement of anterior horn cells Motor neuron degeneration associated with severe arthrogryposis

Hereditary spastic paraplegia Hereditary spastic paraplegias (HSP) are a rare group of inherited neurodegenerative diseases which mainly affect the longest axons of the corticospinal tract and the dorsal column (which supply the lower limbs). HSP is caused by defects in genes which code for proteins essential for fast axonal neurotransmission. HSP can affect any age group. Patients present with upper motor neuron palsy of bilateral lower limbs, gait abnormalities, and urinary urgency/urge incontinence. Dorsal column dysfunction is usually mild. Additional neurological features such as epilepsy, peripheral neuropathy, or cerebellar signs may be present (complicated HSP). Diagnosis is mainly clinical. MRI of the spinal cord may demonstrate spinal cordatrophy. Treatment is mainly supportive, with skeletal muscle relaxants, botulinum toxin, and physiotherapy for muscle spasticity. HSP may be nonprogressive (childhood-onset) or progressive (adult-onset). Patients with progressive HSP are often wheelchair-bound by the age of 70 years. Patients with HSP have a normal life-expectancy.

Epidemiology Incidence: < 10 per 100,000 general population Age of onset: variable (from early childhood till the 8th decade of life) Etiology Genetic defect Autosomal dominant (most common) Autosomal recessiveX-linked inheritance Sporadic mutations Pathophysiology Defect in genes required for normal (fast) neurotransmission in the axons → degeneration mainly of the long axons Primarily affects the longest axons of the corticospinal tract and the dorsal column → progressive upper motor neuronparalysis and dorsal column dysfunction symptoms in the lower limbs Clinical features Pure HSP (Uncomplicated HSP) Pure HSP is characterized by an insidious onset and slow progression of the following symptoms Upper motor neuron paralysis of bilateral lower limbs Spasticity/hypertonicity → contracturesDecreased muscle strength Gait abnormalities: delayed initiation of walking (childhood onset HSP); scissor gait (late onset HSP) Brisk deep tendon reflexes; extensor plantar reflex (Babinski's sign) Dorsal column dysfunction in bilateral lower limbs (usually mild; only detected on examination): decreased/loss of vibration sense, 2-point discrimination sense, and position sense Urinary urgency and urge incontinence Complicated HSP Patients with complicated HSP have all the features of pure HSP as well as additional neurological features, such as: Epilepsy, intellectual disability, dementia Cerebellar or extrapyramidal symptoms Peripheral neuropathy Loss of vision Diagnostics The diagnosis of HSP is based on a positive family history, characteristic clinical features, and the exclusion of other neurological conditions. MRI of the brain and spinal cord: mild atrophy of the cervical and thoracic spinal cord in pure HSP Nerve conduction studies and electromyography: may be normal or show mild motor neuropathy Motor evoked potentials: decreased or absent in bilateral lower limbs (based on severity of paralysis) Molecular genetic testing: to differentiate HSP from other inherited ataxias (spinocerebellar ataxia or Friedreich ataxia) Vitamin B12 levels should be checked; HIV and syphilis testing should also be performed to rule out these conditions. Treatment There is no known cure for HSP. Supportive therapy (for spasticity) Skeletal muscle relaxants or botulinum toxinOrthotic braces, canes, or crutches as requiredPhysiotherapy: passive stretching and exercises to avoid the development of contractures, maintain flexibility Anticholinergics (e.g., oxybutynin, hyoscyamine) for treatment of urinary urgency Prognosis Prognosis depends on the age of onset. Early onset HSP (in childhood): may be nonprogressive; most patients remain ambulantLate onset: progressive; most patients will require wheelchairs by age 70 Life-expectancy: normal

Lyme disease Lyme disease (or borreliosis) is a tick-borne infection caused by certain species of the Borrelia genus (B. burgdorferi in the US), a genus of facultative intracellular bacteria. There are three stages of Lyme disease. Stage I (early localized disease) is characterized by erythema migrans (EM), an expanding circular red rash at the site of the tick bite, and may be associated with flu‑like symptoms. In stage II (early disseminated disease), patients may present with neurological symptoms (e.g., facial palsy), migratory arthralgia, and cardiac manifestations (e.g., myocarditis). Stage III (late disease) is characterized by chronic arthritis and CNS involvement (late neuroborreliosis) with possible progressive encephalomyelitis. Lyme disease is a clinical diagnosis in patients presenting with EM. Serological tests (e.g., Western blot; enzyme-linked immunosorbent assay) can help support the clinical diagnosis, especially if the presence of EM is not known or questionable. Lyme disease is treated with antibiotics; the drugs of choice are doxycycline for localized disease and ceftriaxone for disseminated disease.

Epidemiology Incidence: most commonly reported vector-borne disease in the US Geographical distribution: primarily the Northeast and upper Midwest Etiology PathogenIn the US: Borrelia burgdorferi, an anaerobic, obligate intracellular spirochete bacteria VectorVarious tick species: mainly Ixodes scapularis (deer or black-legged tick) in the northeastern and upper midwestern USIxodes pacificus (western black-legged tick) in the northwestern USIxodes ricinus (castor bean tick) in EuropeTypically found in forests or fields on tall brush or grassThe incidence of Lyme disease is highest between April and October (especially from June to August). Peromyscus leucopus, the white‑footed mouse, is the primary reservoir of B. burgdorferi in the US. Increased risk of disease for: Outdoor workers (landscapers, farmers, etc.)Outdoor enthusiasts (i.e., hikers, hunters, etc.) Clinical features Stage I (early localized Lyme disease) Symptoms develop within 7-14 days after a tick bite. Erythema chronicum migrans (EM) Occurs in 80% of infected individualsUsually a circular, slowly expanding red ring around the bite site with central clearing Typically warm, painlessEM is often the only symptom.Self-limiting (typically subsides within 3-4 weeks) Flu‑like symptoms Stage II (early disseminated Lyme disease) Symptoms develop 3-10 weeks after a tick bite Migratory arthralgia that can progress to Lyme arthritisSpreads from one joint to another Generally in large joints (especially knee or elbow) Early neuroborreliosisCranial nerve disordersMost commonly peripheral facial nerve palsy Nocturnal radicular pain, paresthesia, and paresisMeningitisPolyneuropathy (mononeuritis multiplex, asymmetrical) Lyme carditisRisk of cardiac arrhythmias (e.g., AV Block) and rarely myopericarditisAdams‑Stokes syndrome Cutaneous manifestationsMultiple erythema migrans lesions Ocular manifestations: including conjunctivitis, retinal vasculitis, optic neuropathy, and uveitis Stage III (late Lyme disease) Symptoms develop months to years after the initial infection Chronic Lyme arthritis (10% of cases) Lasts over a year and may be intermittent or persistentTypically in large joints (especially knee or elbow) Late neuroborreliosis manifestations include: Aseptic (lymphocytic) meningitisProgressive encephalomyelitisCognitive impairmentGait abnormalityBladder dysfunctionPsychiatric abnormalities (e.g., depression, anxiety, bipolar disorder etc.)Peripheral polyneuropathy Diagnostics Approach After a tick bite, observe for erythema chronicum migrans. Suspicious rashes may be monitored over several days. If the patient history and clinical presentation indicate Stage I Lyme disease, empiric antibiotics may be started without further testing. If symptoms of Lyme disease arise in a patient with possible exposure (especially if a history of recent travel to an area with high vector density) → conduct two-step serological testing If signs of neuroborreliosis are present and other tests are inconclusive, consider additional procedures, such as a lumbar puncture for cerebrospinal fluid testing. Two‑step serological testing Initial test: enzyme‑linked immunosorbent assay (ELISA) Confirmatory test: Western blot Detect IgG and IgM antibodies against Borrelia Results are only significant with corresponding clinical symptoms because: Positive results only demonstrate exposure to Borrelia (not necessarily current infection).False negative results are possible if seroconversion has not yet occurred (may take up to 8 weeks).Various diseases can lead to a false positive serology as a result of cross-reactions, including: SyphilisRocky Mountain spotted feverSystemic lupus erythematosusRheumatoid arthritis Other tests Cerebrospinal fluid testingSigns of lymphocytic meningitis, including elevated protein (due to a disrupted blood-brain barrier) and pleocytosisMeasure intrathecal IgG or IgM antibodies ArthrocentesisCommonly conducted if signs of arthritis are present, but results do not allow differentiation from septic arthritiswithout PCRSynovial fluid findings Appearance: yellow and cloudyLeukocyte count: 3000-100,000/mm3 with > 50% neutrophilsPCR test: positiveNegative findings: Gram stain, culture, crystals Differential diagnoses For erythema migransCellulitisContact dermatitis (discoid eczema)Erythema marginatum (rheumatic fever)Erythema multiformeGranuloma annulareAnnular erythema For Lyme carditisSee myocarditis.See arrhythmias. For Lyme arthritisSee differential diagnoses of infection-associated arthritis.See differential diagnoses of inflammatory arthritis. For neuroborreliosisSee "Etiology" of major neurocognitive disorder.See "Differential diagnoses" of vitamin B12 deficiency. Lyme diseasePathogen: Borrelia burgdorferiVectorIxodes scapularisIxodes pacificusDistribution: upper midwestern, northeastern US, and West Coast Incubation period: 3-30 daysEarly localized Lyme disease Flu‑like symptomsErythema migrans at the site of tick biteEarly disseminated Lyme disease Migratory arthralgiaFacial nerve palsy, meningitis, polyneuropathyMyocarditis, pericarditis, conduction blocks(e.g., AV block)Multiple erythema migrans lesionsLate Lyme disease Chronic arthritisLate neuroborreliosis (e.g., progressive encephalomyelitis, aseptic meningitis)Confirmatory testTwo-step serological testing ELISA or IFAWestern blot to confirm the diagnosis No neurological manifestations DoxycyclineORAmoxicillinORCefuroximeaxetilNeurological manifestations: intravenous ceftriaxoneTick paralysisTick neurotoxin Incubation period: 2-7 daysWeakness in lower extremities → ascending flaccid paralysis that progresses rapidly over 24-48 hours → can lead to respiratory failure due to respiratory muscle weaknessNo fever or rashNo confirmatory test Locate and remove the tick! Supportive therapy (e.g., ventilatory support in a patient with respiratory failure) Rocky Mountain spotted fever(RMSF)Pathogen: Rickettsia rickettsiiVectorDermacentor variabilisDermacentor andersoniRhipicephalus sanguineusDistribution: northeast and south US Incubation period: 2-14 daysFlu-like symptomsBlanching maculopapular rash (90% of cases): begins on wrists and ankles 2-5 days after onset of fever → spreads to trunk, palms, and soles → becomes petechial and/or hemorrhagic in 50% of casesAnkle and/or wrist swellingGastrointestinal symptoms (e.g., nausea, vomiting, abdominal pain)Meningitis, focal neurological deficitsRapid clinical deterioration with shock and multi-organ dysfunctionConfirmatory testDetection of R. rickettsiiDNA by PCR in a skin biopsy specimen or acute phase whole blood specimenORSerologic test: Four-foldincrease in IgG-specific IFA antibody assayDoxycyclineBabesiosisPathogen: Babesiaspecies (typically Babesia microti)Vector: Ixodes scapularisDistribution: midwest and northeast USIncubation period: 1-6 weeksFlu-like symptomsHemolytic anemia → dark urine and/or icterusMild splenomegaly and/or hepatomegalyGastrointestinal symptoms (e.g., nausea, vomiting, abdominal pain)Typically no rashConfirmatory testPeripheral blood smearshowing intraerythrocyte rings and/or maltese crossORBabesia DNA detection by PCR of bloodMild disease: atovaquone and azithromycinSevere disease : quinine and clindamycin EhrlichiosisPathogen: Ehrlichiachaffeensis, Ehrlichia ewingiiVector: Amblyomma americanumDistribution: southeastern and south-central USIncubation period: 1-2 weeksFlu-like symptomsGastrointestinal symptoms (e.g., nausea, vomiting, abdominal pain)Typically no rash Peripheral blood smear shows morulae within leukocytes. Confirmatory testEhrlichia DNA detection by PCR of bloodORFour-fold increase in IgG-specific IFA antibodyassay between the acute and convalescent serum samplesDoxycyclineAnaplasmosisPathogen: Anaplasma phagocytophilumVectorIxodes scapularisIxodes pacificusDistribution: upper midwest and northeastern USIncubation period: 1-2 weeksFlu-like symptomsGastrointestinal symptoms (e.g., nausea, vomiting, abdominal pain)CoughTypically no rashPeripheral blood smear shows morulae within granulocytes.Confirmatory testDetection of AnaplasmaDNA by PCR of bloodORSerologic test: Four-foldincrease in IgG-specific IFA antibody assay between the acute and convalescent serum samplesDoxycycline Tularemia [9][10]Pathogen:Francisella tularensisVectorDermacentor variabilisDermacentor andersoniAmblyomma americanumDistribution: all states except Hawaii Incubation period: 3-5 daysHigh feverSkin ulcer at the site where F. tularensisenters the bodyTender regional lymphadenopathyConfirmatory testPositive culture from skin lesions and/or lymph nodeaspirate/biopsy ORSerologic test: four-foldincrease in F. tularensis specificantibody titers between the acute and convalescent serum samplesStreptomycinORGentamicinORDoxycycline Tick-borne relapsing fever [11]Pathogen: BorreliahermsiiVector: OrnithodorosspeciesDistribution: western US Incubation period: 4-18 daysRecurring episodes of high fever lasting 3 daysfollowed by an afebrile period of 7 daysArthralgiaGastrointestinal symptoms (e.g., nausea, vomiting, abdominal pain) Less commonly, symptoms of meningitisMacular rash or scattered petechiae in 15-20% of cases Confirmatory testDirect observation of spirochetes in peripheral blood smearsNo CNSinvolvement First-line: tetracyclineSecond-line: erythromycinCNSinvolvement: ceftriaxone StagesPresentationGeneral therapyTherapy in pregnant/nursing patientsLocalized Lyme diseaseErythema migransFlu-like symptomsFirst-line oral antibiotics: Doxycycline AmoxicillinCefuroxime axetilFirst-line oral antibiotics: AmoxicillinCefuroxime axetilDisseminated Lyme diseaseIsolated CN palsyMild carditisBorrelial lymphocytomaInitial arthralgia/arthritisNeurological signs (except isolated CN palsy) MeningitisPolyneuropathyOcular manifestationsChronic neuroborreliosisEncephalopathySevere carditisRecurrent arthritis after oral therapyHospitalize patientIntravenous antibioticsDrug of choice: ceftriaxoneCefotaximePenicillin GDoxycycline is relatively contraindicated in pregnant/nursing women due to its adverse effects on growing bones and teeth! Administer amoxicillin (or cefuroxime axetil) instead! Prevention There is no approved vaccine on the market. Avoid areas known for Lyme disease. Prevent and properly manage tick bites to avoid exposure. Wear protective clothing: e.g., long-sleeved shirts, long pants, and light colors.Use tick repellent and pesticides.Check body for tick bites.Remove ticks immediately! Grasp the tick with tweezers directly above the skin's surface.Carefully pull upward with even pressure. Do not use nail polish remover, adhesives, oils, or similar substances to remove the tick. The tick should be removed quickly rather than waiting for it to detach slowly.Disinfect the site of the bite and dispose of the tickObserve the bite site for early detection of EM.

Progressive muscular dystrophies Muscular dystrophies are a group of progressive diseases that affect the musculoskeletal system. Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) are X-linked recessive diseases, whereas limb-girdle muscular dystrophy (LGMD) may be either autosomal dominant or recessive. Muscular dystrophies are commonly due to mutations involving muscular genes (e.g., dystrophin-protein coding gene). Patients typically present with muscular complaints affecting specific muscle groups, particularly the pelvic girdle musculature. DMD is the most severe form of muscular dystrophy, with disease onset typically occurring at two to three years of age. BMD usually does not become evident before the age of 15. DMD progresses rapidly and typically leads to ambulatory inability by age 12. Diagnosis of DMD and BMD is established based on blood tests that show increased creatinine kinase, whereas diagnosis of LGMD is mainly based on genetic analysis. Treatment of muscular dystrophies is usually supportive and includes physiotherapy, assistive devices (e.g., wheelchair), and psychological support. The life expectancy for patients with DMD is approx. 30 years, whereas patients with BMD and LGMD have a longer life expectancy.

Epidemiology IncidenceDMD: 1/3500BMD: 1/30,000 SexDMD and BMD: only males affected LGMD: affects both genders equally Age of onsetDMD: 2-5 yearsBMD: usually not earlier than 15 years of age Etiology Inheritance pattern DMD and BMD: X-linked recessiveLGMD: either autosomal dominant (LGMD1) or autosomal recessive (LGMD2) Chromosomal defect affects the dystrophin gene (one of the biggest known genes in humans) on the short arm of the X chromosome (Xp21). → Frameshift deletion in DMD→ In-frame deletion in BMD Pathophysiology The dystrophin protein anchors the cytoskeleton of a muscular cell to the extracellular matrix by connecting cytoskeletal actin filaments to membrane-bound dystroglycan that is, in turn, connected to extracellular laminin. Dystrophin geneLargest known protein-coding gene in the human DNA. Therefore, there is an increased risk of spontaneous mutations.Mutations and subsequent alterations of the dystrophin protein → partial (BMD) or almost complete impairment (DMD) of the protein → disturbance of numerous cellular signaling pathways → necrosis of affected muscle cells and subsequent replacement with connective and fat tissue → muscle appears larger ("pseudohypertrophy") Clinical features Duchenne muscular dystrophy (DMD) Onset before age 5 years old Paresis and atrophy starting in the proximal lower limbs (pelvic girdle), later spreading to the upper body and distal areas Weak reflexes Waddling gait (bilateral Trendelenburg's sign) Gower maneuver: To stand up, the patient supports himself on his thighs and uses the hands to essentially "walk" up the body until reaching a standing position. It is a classic sign in DMD but also occurs in e.g., Becker muscular dystrophy, dermatomyositis. Calf pseudohypertrophy (see "Pathophysiology") Inability to walk by approx. 12 years of age Cardiac and respiratory muscle involvementDilated cardiomyopathy: common cause of deathCardiac arrhythmiasRespiratory insufficiency Cognitive impairment Becker muscular dystrophy (BMD) Symptoms identical to those of DMD Slower progression (patients often remain ambulatory into adult life) and milder symptoms Heart involvement is more common compared to DMD. Diagnostics Blood tests: ↑↑ creatine kinase in serum of almost all affected individuals (also, in > 50% of female carriers)↑ serum aldolase Genetic analysis (confirmatory test): detect dystrophin gene mutation Muscle biopsyOnly performed if genetic analysis is inconclusiveAll dystrophies: muscle fibers diameter changes, later in the disease course, necrosis and replacement with adipose tissueDMD: absent dystrophinBMD: reduced dystrophin Differential diagnoses Polymyositis Spinal muscular atrophy Myotonic syndromes Treatment Currently there is no curative treatment for muscular dystrophies! Medical therapyDMD: glucocorticoids (e.g., prednisone) BMD: Glucocorticoids may be used, although their efficacy is low. Supportive therapyPhysiotherapyOrthopedic assistive devices (wheelchair, walkers)Psychological supportVentilation support Prognosis DMD: Life expectancy for patients with DMD is approx. 30 years. BMD: Life expectancy for patients with BMD is 40-50 years.

Ischemic stroke Ischemic stroke is an acute neurologic condition caused by impaired cerebral blood flow (e.g., vascular occlusion or systemic hypoperfusion). Chronic systemic hypertension and cardiovascular disease are the most important risk factors. Clinically, ischemicstroke is characterized by the acute onset of focal neurologic deficits, which are dependent on the cerebral territory covered by the relevant vessel. A noncontrast head CT should immediately be performed to rule out intracranial hemorrhage. Revascularization of the vessels affected in ischemic strokes, for example via tissue plasminogen activator (tPA) or thrombectomy, is vital to preserving brain tissue. Secondary prevention is focused on managing modifiable risk factors (i.e., hypertension, atherosclerosis).

Epidemiology Ischemic strokes account for ∼ 85% of all strokes Nonmodifiable risk factors [5][6][7]Age ≥ 65 yearsSex ♂ > ♀Ethnicity: African Americans, Native Americans, Alaska Natives, and Hispanics are at higher risk.Family history of cardiovascular or cerebrovascular disease Genetic disorders (e.g., sickle cell disease)History of TIAMigraine with aura Modifiable risk factors [5][6]Systemic hypertensionHyperlipidemiaDiabetes mellitusAtherosclerosisCardiovascular diseaseCarotid artery stenosisAtrial fibrillationObesityCoagulopathy , hyperhomocysteinemiaAlcohol abuseTobacco useRecreational drug use (e.g., cocaine can cause cerebral vasospasm)Oral contraceptive useHormone replacement therapy Etiology Embolic strokes (∼ 20%) Most commonly affect the middle cerebral artery (MCA)Cardiac emboliAtrial fibrillationAtrial or ventricular thrombi Rheumatic heart diseaseVentricular aneurysmsAtheroemboliInternal carotid artery Aortic arch (less common)Infectious emboli: bacterial endocarditisParadoxical embolism: in patients with right-to-left cardiac shunt (e.g., persistent foramen ovale or atrial septal defect) Thrombotic strokes (∼ 40%) Large vessel atherosclerosis (∼ 20%) Rupture of an atherosclerotic plaque and exposure of subendothelial collagen → formation of a thrombusThrombus formation most commonly occurs at branch points in arteries (e.g., internal carotid artery bifurcation or where the MCA branches from the circle of Willis).Small vessel occlusion (e.g., lacunar infarct) (∼ 20%): see "Subtypes and variants" below. Global cerebral ischemiaSystemic hypoperfusionShock or bilateral large artery atherosclerosis (e.g., of carotid arteries) → decreased effective oxygen delivery to the whole brainCan result in watershed infarct (see "Subtypes and variants" below)Hypoglycemia: repeated episodes of hypoglycemia (e.g., due to insulinoma) increase the risk of cerebral ischemiaSevere and/or chronic hypoxia: hypoxemia (e.g., due to respiratory arrest) → global tissue hypoxia in the brain Other causesHypercoagulable statesInherited thrombophilia (e.g., factor V Leiden mutation, protein C deficiency)PolycythemiaHormonal contraceptive useHormone replacement therapySickle cell diseaseVasculitis (e.g., giant cell arteritis)Arterial dissection (e.g., due to trauma or fibromuscular dysplasia) Clinical features Sudden onset of focal neurologic deficits (e.g., weakness/paralysis, paresthesias, aphasia, dysarthria) Nonspecific symptoms (e.g., impaired consciousness, nausea, vomiting, headache, seizures) Symptoms depend on the location of the stroke (see stroke symptoms by affected vessels and stroke symptoms by affected region) Subtypes and variants Transient ischemic attack [16] Definition: temporary, focal cerebral ischemia that results in neurologic deficits without acute infarction or permanent loss of function (previously defined as lasting < 24 hours) [1] Etiology: see "Etiology" above Embolic (e.g., due to atrial fibrillation)Large artery thrombus (e.g., due to atherosclerosis of MCA, severe carotid artery stenosis)Small vessel occlusion (e.g., lacunar ischemia due to hypertension) Risk factors: see "Epidemiology" above Clinical featuresAcute transient focal neurologic symptomsTypically, symptoms last < 1 hour.Symptoms depend on the affected territory (see stroke syndromes by affected vessels and stroke syndromes by affected region). Diagnosis: diffusion-weighted MRI to identify areas of ischemia and rule out infarction Treatment: treatment of underlying etiology (e.g., management of hypertension, diabetes mellitus, carotid artery disease, atrial fibrillation) Prognosis: increased risk of future ischemic stroke Lacunar infarct [11][17] Definition: noncortical infarcts characterized by the absence of cortical signs (e.g., no aphasia, hemianopsia, agnosia, apraxia) EtiologyMost common: chronic hypertensive vasculopathy → lipohyalinosis of the small vessels → occlusion of small, penetrating arteries (e.g., lenticulostriate artery) → lacunar stroke resulting in specific lacunar syndromes (see lacunar syndromes)Less common Cardioembolic eventMicroatheroma formationMicrobleed (rare) Risk factorsHypertension Diabetes mellitus Clinical featuresAcute transient focal neurologic symptoms that often have a stuttering courseSymptoms depend on the affected territory. See lacunar syndromesCommonly affected areasInternal capsule, corona radiataPonsBasal ganglia (striatum, putamen, globus pallidus, thalamus, caudate) Diagnosis: diffusion-weighted MRI Pathology: results in a pale infarction at the periphery of the cortex Treatment: same as other ischemic strokes; see "Treatment" below Watershed infarct [6][18] Definition: border-zone infarct in the region between the territory of two major arteries that supply the brain Etiology: sudden decrease in blood pressure or cessation of blood flow through both vessels → ischemia in the susceptible region between two vascular territoriesCortical border zones: territories between the anterior and middle cerebral arteries and between the middle and posterior cerebral arteriesInternal border zones: territories between the superficial and deep branches of the MCA Clinical featuresSigns of systemic hypoperfusion (e.g., tachycardia, low blood pressure, pallor, sweating)Diffuse neurologic deteriorationBilateral visual loss (cortical blindness) Proximal limb weakness with sparing of the face, hands, and feet Initial evaluation Determine the time of onset of symptoms: The time of stroke onset is used to determine treatment options (thrombolytic therapy). Stabilize the patient if needed. Check serum glucose. Emergency imaging Imaging Immediate noncontrast head CT to evaluate for acute hemorrhage prior to administration of thrombolytic therapy Further choice of imaging depends on head CT findings. Diffusion-weighted MRI is a more sensitive test for acute ischemia (e.g., if head CT is negative but clinical suspicion for acute stroke is high).Neurovascular studies (e.g., CTA or MRA) for more specific identification of the occluded vessel Noncontrast CT Ischemic changes can be detected ∼ 6 hours after stroke onset. Findings Acute (within 12 hours of symptom onset)Hyperdense occluded vessels (e.g., hyperdense MCA sign corresponding to acute thromboembolic occlusion of the MCA )Hypodense parenchymaEffacement of the sulci and loss of corticomedullary differentiation12-24 hours after symptom onset: hypodense After 24 hours of symptom onset: hyperdense Diffusion-weighted MRI Ischemic changes can be detected ∼ 3 minutes after stroke onset, but MRI takes longer to perform. Findings T1: hypointense signalT2: hyperintense signal Neurovascular studies CT angiography (CTA) Allows identification of the exact location of the defect (in most cases)Indications When there is a high index of suspicion for stroke but no ischemic changes are found on noncontrast CT or MRI.If the patient cannot receive tPA (e.g., outside of the time window) but may be a candidate for mechanical thrombectomy (see "Treatment" below). MRI angiography (MRA): indications similar to CTA Laboratory evaluation [19] Initial evaluation: serum glucose Subsequent laboratory tests to consider (after emergent imaging is complete) Complete blood count, electrolytes, coagulation parameters (e.g., INR, APTT)Serum troponinUrine drug screen (e.g., cocaine), blood alcohol levelSerum lipids Hypercoagulable workup: consider if patient is < 50 years old and/or has a history of thrombosisProtein C and protein SAntiphospholipid antibodiesVDRL/RPRLyme serologyFactor V Leiden mutationsANAESRRheumatoid factor Immediate imaging or administration of tPA for ischemic stroke should not be delayed to obtain laboratory studies! Additional diagnostic workup ECG to rule out atrial fibrillation and myocardial ischemia Continuous cardiac rhythm monitoring for paroxysmal atrial fibrillation Transthoracic echocardiogram (TTE) and/or transesophageal echocardiogram (TEE) to evaluate for intracardiac thrombus and patent foramen ovale (PFO) Carotid ultrasound to evaluate for carotid artery stenosis For more information on the diagnosis of other stroke types, see diagnosis of stroke. Pathology Patterns of necrosis in ischemic stroke [21] General: infarction → liquefactive necrosis → cystic cavity formation Two main responses to brain tissue ischemiaSelective neuronal necrosis: more likely to occur with transient ischemiaPan-necrosis: more likely to occur with irreversible ischemia (e.g., infarction) Irreversible neuronal injury begins ∼ 5 minutes after tissue hypoxia See cellular changes and adaptive responses. Selective neuronal necrosis Definition: selective destruction of nerve cells with sparing of glial cells MechanismTransient ischemia → subsequent reperfusion (e.g., resuscitation following cardiac arrest) → increased metabolic demand, release of toxic excitatory neurotransmitters → ischemic injuryCertain neurons are more susceptible to ischemic injury Pyramidal cells of the hippocampus: Damage causes anterograde amnesia.Purkinje cells of the cerebellum: Damage causes intention tremor, nystagmus, and ataxia.Pyramidal cells of neocortex: Symptoms depend on the affected brain region. Histology: neuronal necrosis with viable glial cells (which can proliferate and cause a laminar or pseudolaminar tissue architecture) Pan-necrosis Definition: the death of all cell types in a given region of the brain, including neurons, glial cells, and vascular cells Mechanism: permanent ischemia Histology: cystic lesions and loss of tissue architecture 12-24 hoursRed neurons (eosinophilic cytoplasm + pyknotic nucleus)1-3 daysNeutrophilsLiquefactive necrosis3-5 daysMacrophages (microglia; CD40 positive)5-15 daysReactive gliosis (astrocytes)Vascular proliferation> 15 daysGlial scarringCyst formation Treatment Reperfusion therapy Goal is to prevent further tissue ischemia and irreversible infarction Should be administered as soon as possible in eligible candidates (see below for specific indications) Reperfusion therapy should not be delayed - "time is brain"! However, intracranial hemorrhage is a contraindication for reperfusion therapy and must be ruled out first. IV thrombolytic therapy [19] Definition: administration of intravenous recombinant tPA (e.g., alteplase, tenecteplase) to break down blood clots IndicationsAcute ischemic stroke after ruling out intracranial hemorrhage Initial onset of symptoms ≤ 4.5 hours [19]Age ≥ 18 years ComplicationsBleedingIntracranial and extracranial hemorrhageAngioedema Exclusion criteriaCurrent conditions Intracranial bleedingActive internal bleeding or bleeding diathesisHypertension > 185/110 mm HgAnticoagulation (prolonged PTT or INR > 1.7)Low platelet countHypoglycemia < 50 mg/dL or hyperglycemia > 400 mg/dLMinor stroke or TIAPreexisting conditions Previous intracranial hemorrhageHead trauma or ischemic stroke (within the past 3 months)Recent intracranial or intraspinal surgeryArterial puncture at a noncompressible site (within the past 7 days)Intracranial neoplasm, arteriovenous malformation, or aneurysm Intra-arterial thrombolysis [19] Definition: intra-arterial (not intravenous) administration of a thrombolytic agent (e.g., prourokinase) Indication: MCA stroke patients with onset of symptoms < 6 hours who are not eligible for IV thrombolytic therapy Mechanical thrombectomy [19] Definition: physical retrieval of the occluding thrombus via a catheter (usually through the femoral artery) Indications: proximal large artery occlusion in anterior cerebral circulation (usually in addition to intravenous thrombolytic therapy) Blood pressure management [19] Elevated blood pressure is generally tolerated in acute ischemic stroke (permissive hypertension). For patients with severe hypertension (> 220 mm Hg / > 120 mm Hg) Patients who do not undergo thrombolytic therapy: Reduce blood pressure by ∼ 15% within the first 24 hours of strokeonset.Patients who undergo thrombolytic therapy: Reduce blood pressure to ≤ 185 mm Hg / ≤ 100 mm Hg prior to administering tPA. Supportive care See "Treatment" in overview of stroke. Other Prevent post-stroke complications (see "Complications" in overview of stroke) Secondary prevention (see below) Early rehabilitation (physiotherapy, occupational and speech therapy) and mobilization Prevention Primary prevention: management of modifiable risk factors to decrease the likelihood of having a first stroke [28]Healthy diet Physical activity Weight lossSmoking cessationMedical management of risk factors (e.g., hypertension, diabetes, atrial fibrillation, dyslipidemia) Secondary prevention [12][19]Antiplatelet therapy (e.g., aspirin or clopidogrel)Start 24-48 hours after symptom onset of ischemic stroke Contraindicated for 24 hours after thrombolytic therapyMedical management of risk factorsHypertension: lifestyle modifications, antihypertensive medicationsAtrial fibrillation: anticoagulation (e.g., warfarin)Diabetes mellitus: lifestyle modifications, glycemic controlHyperlipidemia: lifestyle modifications, statin therapyThrombophilia: anticoagulationMedical management and/or carotid endarterectomy for carotid artery stenosisThe single most important treatable risk factor for secondary stroke prevention is hypertension! [12]

Dissection of the carotid and the vertebral artery Carotid or vertebral artery dissection describes the separation of the tunica media and tunica intima of a vessel. This can lead to thrombosis of the false lumen, which can, in turn, lead to stenoses or embolisms with the risk of stroke. Dissections of the carotid and vertebral artery primarily affect young adults and may occur spontaneously or as a result of a major trauma (e.g., car accidents). The initial symptoms are usually headaches (temporal and occipital for carotid and vertebral artery dissectionrespectively), which may be followed by features of ischemia (e.g., stroke) a few hours or days later. Duplex ultrasonography may provide a rapid diagnosis, but definitive diagnosis requires CT angiography or MR angiography. Treatment is primarily conservative and involves blood thinners, anticoagulants, and antiplatelet therapy. Severe cases may require surgery.

Epidemiology Mean ageCarotid artery: ∼ 45 yearsVertebral artery: 40 yearsImportant causes of stroke in young patients Sex: ♀:♂ (3:1) for vertebral artery dissection Dissection of the carotid artery occurs more frequently than dissection of the vertebral artery (∼ 4:1) Etiology Frequently caused by penetrating or blunt trauma (e.g., high impact car accidents) but up to 40% of cases result from mild trauma (e.g., minor sports injuries) or other mechanical triggering events (e.g., coughing, sneezing, chiropractic maneuvers) Spontaneous dissection Ehlers-Danlos syndrome and Marfan syndromeFibromuscular dysplasiaHypertensionCystic medial necrosisRespiratory tract infectionOral contraceptive use Clinical features Dissection of the carotid artery Non-ischemic features Ipsilateral headache and facial/neck pain (constant, severe, throbbing or sharp) Partial horner syndrome: ptosis and miosis Pulse-synchronous tinnitusNeck swelling with ecchymosisReduced taste sensationCranial nerve lesions, usually caudal nerves (VI-XII) Ischemic features Symptomatic middle cerebral artery infarction (see stroke) Amaurosis fugax (ischemic retina) Dissection of the vertebral artery Non-ischemic featuresOccipital headachePosterior nuchal pain Ischemic features: Vertebrobasilar insufficiency (leads to stroke resembling lateral medullary dysfunction, e.g., Wallenberg syndrome) Ipsilateral loss of taste and facial pain and numbness (most common symptom)Contralateral pain relief and reduced temperature sensationVertigoAtaxiaCentral Horner syndromeDysphagia and dysarthria or hoarseness Nausea, vomiting Carotid or vertebral artery dissection is the separation of the tunica media and tunica intima of a vessel. This can lead to thrombosis of the false lumen, which can, in turn, lead to stenoses or embolisms with the risk of stroke! Diagnostics Duplex ultrasonography: high resistance flow or complete absence of flow in affected artery Helical CT angiography (replacing MRI as diagnostic modality of choice ) Changed caliber of vesselOval or slit-like crosssection of vessel MR angiographyIntramural bloodMural expansionIrregular vessel marginsFilling defectsExtravasation of contrast Caliber changes of vessel Conventional angiography Intimal flapDouble lumenLong tapered segment of contrast in distal portion of internal carotid artery Baseline monitoring parameters (e.g., INR, PT, aPPT) should be performed before administering anticoagulant therapy! Treatment Treatment should be initiated after an intracerebral hemorrhage has been ruled outHeparin therapy followed by oral anticoagulation for 3-6 months and/orAntiplatelet agents for 1 year Possibly angioplasty/stenting or surgical intervention may be warranted in severe cases Asymptomatic pseudoaneurysms do not usually require treatment and most dissections heal spontaneously!

Carpal tunnel syndrome Carpal tunnel syndrome (CTS) is a peripheral neuropathy caused by chronic or acute compression of the median nerve by the transverse carpal ligament. It is characterized by both sensory disturbances (pain, tingling, and numbness) and motor symptoms (weakness and clumsiness of the thumb) in the area innervated by the median nerve distal to the carpal tunnel. Several occupational and non-occupational risk factors (e.g., manual labor, age, sex, diabetes) have been associated with the syndrome. The presence of clinical symptoms and signs of CTS (e.g., the hand elevation test, carpal compression test, and Phalen's test) should raise suspicion, but diagnosis must be confirmed with specific neurological tests (e.g., EMG, ENG). Conservative management (i.e., immobilization with a splint, local steroid injections, and ultrasound therapy) may be effective in patients who only experience mild to moderate symptoms. Surgical release of the transverse carpal ligament with decompression of the median nerve is indicated in acute cases or patients with moderate to severe symptoms (atrophy of the thenar eminence).

Epidemiology Most common entrapment neuropathy in the upper extremity (90% of all cases) Etiology The following risk factors are associated with CTS: Previous fracture of the distal radius (most important risk factor) Traumatic dislocation of the lunate Manual work: increased risk in workers using vibrating tools or prolonged, forceful, and repetitive flexion/extension of the wrist Rheumatoid arthritis and other types of chronic inflammation of the tendon sheaths Pregnancy and puerperium: Recent studies show that CTS may affect up to 62% of pregnant women. Obesity Osteoarthritis Diabetes with peripheral polyneuropathy Hypothyroidism Pathophysiology The carpal tunnel is a narrow fibro-osseous structure at the level of the palmar aspect of the wrist, delimited by carpal bones on the bottom and on the sides, and by the transverse carpal ligament on the top. It contains flexor tendons and the median nerve. Any event or condition that increases the pressure within the carpal tunnel causes a compression of the structures within it: Compression → impaired blood flow and altered microvascular structure of the median nerve → inflammatory reaction → edema and hypoxia → axonal degeneration Clinical features Mild to moderate Sensory symptoms on the palmar surface of the thumb, index, and middle finger; and radial half of the ring finger Burning sensation/paresthesiaLoss of sensation/numbness Symptoms worsen at night The palmar surface of the thenar eminence is spared! The sensory innervation of this area is supplied by the superficial branch of the median nerve, which arises 5-7 cm proximal to the carpal tunnel and is therefore not compressed. Moderate to severe Motor symptoms Weakened pinch and grip: Patients often complain of dropping objects.Rare: thenar atrophy with muscle flattening and impaired thumb opposition. The "pope's blessing" (inability to flex the first three digits when making a fist) is not a symptom of CTS! It is only seen in proximal lesions of the median nerve! Diagnostics Provocative tests: There is no agreement as to which provocative test should be used to support the diagnosis of CTS. Several authors suggest combining two or more provocative tests to improve the specificity of the diagnosis. Hand elevation test: The hand is held above the head of the patient for approx. two minutes. The test is considered positive if the symptoms of CTS (paresthesia and numbness) are reproduced. This test is easy to perform in a clinical setting and has higher sensitivity and specificity than all other tests. Carpal compression test or Durkan's test: By applying moderate compression with the finger directly over the proximal edge of the carpal tunnel, the examiner may elicit paresthesia in the median nerve distribution. Phalen's test: The wrist is actively or passively held in full flexion. If occurrence or aggravation of paresthesia in the fingers innervated by the median nerve is perceived within one minute, the test is positive. This finding is considered highly specific (approx. 85%) for the diagnosis of CTS. Tinel's sign: Percussion or tapping with the fingertips over the carpal tunnel leads to shooting pain and/or paresthesias in the fingers that are innervated by the median nerve. Electrophysiological testsNerve conduction studies (NCS; confirmatory test): prolongation of the distal motor and sensory latencyElectromyogramPattern of neurogenic disorder: abnormal spontaneous activityDecreased activity, potentials with large amplitude Treatment Mild to moderate symptoms Conservative treatmentImmobilization of the wrist with a padded, volar splint worn during the nightSteroid injection (e.g., triamcinolone)Short-term treatment with NSAIDs Moderate to severe symptoms (or no response to conservative treatment) Open or endoscopic release of the transverse carpal ligamen

Cerebral palsy Cerebral palsy (CP) is a heterogenous group of disorders affecting the muscle tone and the development of movement and posture. CP results from a non-progressive damage to the brain in utero or during infantile development up to the age of 3 years. Depending on the affected brain area, spastic, ataxic, or dyskinetic cerebral palsy develops. While, in many cases, there is no identifiable cause, risk factors for cerebral palsy are prematurity, perinatal complications such as chorioamnionitis, birth trauma with intracerebral hemorrhage, or postnatal infections such as meningitis. The diagnosis of CP is usually not made before later in infancy when children fail to meet certain milestones (e.g., inability to roll over or sit independently). Physical indicators of spastic cerebral palsy include spastic paresis of multiple limbs and jointcontractures, scissors gait, and persistence of primitive reflexes. Patients with non-spastic cerebral palsy present with dysarthria and abnormal involuntary movements (choreoathetoid, dystonic, or ataxic) that worsen with stress. Seizure disorders and intellectual disability are associated with all types. Diagnosis is mainly based on the clinical picture but cranial ultrasound or MRI can help identify the causative lesion (e.g., hemorrhage, brain malformation). Since there is no cure, management follows a multidisciplinary approach with a focus on treating contractures (e.g., bracing, antispasmodics, physical therapy, surgery) and ensuring social participation (e.g., speech therapy, social support). Depending on the severity and type of cerebral palsy, patients may be slightly restricted or severely disabled and unable to walk.

Epidemiology Most common motor disability in children Approx. 2/1000 live births in developed countries Etiology Idiopathic (most cases) Risk factors: Preterm birth and low birth weight (most important risk factors) TORCH infectionPerinatal asphyxiaIntracranial hemorrhage Structural abnormality of the brainNeonatal seizuresKernicterusPostnatal infection (e.g., meningitis, encephalitis) Classification Spastic cerebral palsy: spastic paresis of one or more limbs (75% of cases) Non-spastic cerebral palsy : Dyskinetic: abnormal involuntary movements (choreoathetoid, dystonic)Ataxic: intention tremor, lack of balance and coordination Clinical features Patients may present with mixed types of cerebral palsy (e.g., combination of spastic and athetoid CP). All types Patients do not reach certain milestones Intellectual disability (50%) Seizure disorder (35%-50%)Joint contracturesAttention deficit hyperactivity disorder Spastic type: ↑ Muscle tone in one or more limbs ↑ DTRsPersistence of primitive reflexes (e.g., positive Babinski sign) Toe walking or equinus deformityMuscle weakness and/or atrophyScissor gait (as a result of spastic paraplegia of the hip adductors) Hip dislocationScoliosisHearing or vision impairment Non-spastic type: Abnormal involuntary movements that worsen with stress and disappear with sleep ChoreaAthetosis Dystonia AtaxiaDysarthria and dysphagiaDefinite hand preference before 1 year of age, suggests a one-sided muscle weakness and is a red flag for hemiplegia! Diagnostics Diagnosis is mainly based on the clinical picture. Cranial ultrasonography (early neonatal period): e.g., intracerebral hemorrhage and/or hypoxic-ischemic injury, structural abnormalities MRI (in older infants): to detect causative lesion (e.g., periventricular leukomalacia, congenital malformation, intracranial hemorrhage) Treatment There is no curative therapy for cerebral palsy. A multidisciplinary approach is employed in management to improve function and quality of life. Antispasmodics (e.g., botulinum toxin, baclofen, dantrolene, benzodiazepines) Physical therapy Surgery (e.g., to treat scoliosis or relieve joint contractures) Bracing to prevent contractures Speech therapy for dysarthria Nutritional support for dysphagia Special tuition for intellectual disability Social and psychological support

Meningioma Meningiomas are almost always benign, slow-growing brain tumors that arise from arachnoid cap cells of the arachnoid villi. As meningiomas may remain asymptomatic for long periods of time, they are often an incidental finding. Tumorcompression can lead to a wide variety of neurological symptoms (i.e., headaches, seizures, parasthesias) that are generally specific to the structure(s) being compromised. Contrast imaging typically shows an enhanced round tumor with well-defined margins that often resembles a snowball. Management depends on the location and grade of the tumor, as well as patient-specific factors such as age, comorbidities, and accompanying symptoms. Treatment generally consists of surgical intervention, radiotherapy, or a combination of both. In some cases (e.g., asymptomatic elderly patients, or those with slow-growing meningiomas), a "watch and wait" approach with regular tumor monitoring may be safer than invasive therapy.

Epidemiology Most common primary brain tumor in adults Sex: ♀ > ♂ (3:2) Peak incidence: patients in their 60's Etiology Mostly idiopathic Exposure to ionizing radiation: Radiotherapy for head and neck tumors, dental x-rays Multiple meningiomas may develop in patients with type II neurofibromatosis. Clinical features General clinical featuresMostly asymptomatic General symptoms of CNS tumors (e.g., seizures) Features related to tumor locationFalx cerebri (25% of cases): paraparesis (initially presents with foot drop) and uncontrolled micturitionSupratentorial convex surface (20% of cases): headache, seizures, neurological deficits Sphenoidal wings (20% of cases): visual defects, hypesthesia of the face (see superior orbital fissure syndrome, orbital apex syndrome, and cavernous sinus syndrome) Olfactory groove (10% of cases): anosmia, visual defects (see olfactory groove syndrome, Foster-Kennedysyndrome) Posterior crania fossa (10% of cases): sensorineural hearing loss, facial nerve palsy (see cerebellopontine angle syndrome) Intraventricular (2% of cases): headache, papilledema (see obstructive hydrocephalus) Spinal meningioma (2% of cases): back pain, paraplegia (see cord transection syndromes)Foramen magnum (2% of cases)Early: specific pattern of sensory and motor deficits (unilateral upper extremity → ipsilateral lower extremity → contralateral lower extremity → contralateral upper extremity)Late: spastic quadriparesis and lower cranial nerve palsies leading to atrophy and fasciculations (e.g., of the sternocleidomastoid muscle, the trapezius muscle, and the tongue) Diagnostics MRI: Imaging modality of choicePlain MRI findings Round, sharply demarcated space-occupying lesion (resembling a snowball) with radiological features of an extra-axial tumorT1 → isointense ; T2 → isointense or hyperintenseDural tail sign Contrast MRI findings Significant enhancement of the meningioma Sunburst appearance Spinal meningioma: ginkgo-leaf sign . CT: hyperdense lesion, sometimes calcified Brain tumor biopsy: may be indicated if the tumor is inoperable or imaging is inconclusive. Pathology Gross findingsEncapsulated, round, grayish-white tumorFirm to hard consistencyCross-sectional surface: gray, granular Microscopic findingsMesenchymal origin (arachnoid cap cells)Onion peel arrangement of tumor cellsPsammoma bodiesIncreased vascularity Most meningiomas are benign (WHO grade I) tumors Treatment Surgical resection: first line treatment Radiotherapy In the case of inoperable tumors Postoperatively, if the tumor was incompletely resectedAs an adjuvant therapy in the case of all grade II and III meningiomas Active surveillance: consider in a slow-growing asymptomatic tumor in an elderly patient Prognosis WHO Grade I: good prognosis (recurrence rate ∼20%)

Benign paroxysmal positional vertigo Benign paroxysmal positional vertigo (BPPV) is a disease of the inner ear caused by small particles (otoliths) dislodging and migrating within the endolymph fluid into one of the semicircular canals. When provoked by certain head movements, these particles change position and stimulate the vestibular system, which leads to episodes of vertigogenerally lasting less than a minute. Patients are typically aware of what movements trigger symptoms (e.g., quickly lying down or reclining the head). Diagnostic maneuvers that provoke vertigo attacks are used to identify BPPV. Treatment involves carrying out repositioning maneuvers to remove the particles from the semicircular canals.

Epidemiology Most common type of peripheral vestibular vertigo Sex: ♀ > ♂ Peak incidence: > 60 years of age Etiology Often idiopathic In rare cases, traumatic Pathophysiology BPPV is caused by semicircular canal dysfunction. Dislodged particles (otoliths) disrupt the endolymph → stimulation of the hair cells on cupulas → signal sent to the brain through the vestibulocochlear nerve that is disproportional to current positioning and movement → severe vertigo attacks lasting several seconds Clinical features Vertigo attacksSudden ("paroxysmal") and recurrentTriggered by certain head movements ("positional")Lasts several seconds (generally ≤ 1 minute)A propensity to fall towards the healthy sideTypically associated with nystagmus (towards the affected side)Sometimes nausea or even vomiting Not associated with hearing or neurological symptoms Common triggersRolling over in bed, lying down quicklyQuick rotation of the head, reclining, etc.Vertigo occurs with a latency of a few seconds BPPV does not cause any neurological (i.e., gait disturbances) or cochlear (i.e., hearing loss or tinnitus) symptoms! Diagnostics Suspected cases are confirmed with provocative diagnostic testing. Positive Dix-Hallpike test The patient sits with their legs extended.The head is rotated by about 45° (affected side facing downwards).The head is then quickly reclined.If right-sided BPPV: rotational nystagmus with a counterclockwise rapid phase occurs after a few seconds. In contrast, left-sided BPPV presents with a clockwise rapid phase.Rotational nystagmus to the opposite side is common when returning to a sitting position. Differential diagnoses Consider other diagnoses if attacks last longer than one minute, or if hearing or neurological symptoms (e.g., gait disturbances) are present (see differential diagnoses for vertigo) reatment First-lineEpley repositioning maneuver: removes otoliths from the semicircular canals via the effects of gravity following a targeted movement (80-100% success rate; recurrences are frequentIn resistant cases: surgical obliteration of the affected canal Chronic use of antivertigo drugs (e.g., dimenhydrinate) are contraindicated in BPPV because they may exacerbate unsteadiness by inhibiting central compensation!

Spinal stenosis Spinal stenosis is characterized by the narrowing of the central spinal canal, intervertebral foramen, and/or lateral recess causing progressive nerve root compression in the cervical, thoracic, or lumbar spine. It is commonly caused by degenerative joint disease in middle-aged or elderly individuals. The main symptoms are neck pain or load-dependentlower back pain with radiation to the buttocks and legs. Spinal extension (standing or walking downhill) exacerbates pseudo- or neurogenic claudication, while back flexion (sitting or walking uphill) improves symptoms. An MRI provides the diagnosis. Treatment involves conservative therapy (analgesia, physiotherapy), while refractory cases require surgical decompression of the spinal cord (laminectomy).

Epidemiology Prevalence: 5:1000 in persons > 50 years of age Age range: middle-aged and elderly population Sex: ♀ > ♂ when associated with degenerative disease Etiology Progressive narrowing of the central spinal canal, intervertebral neural foramen and/or lateral recess (cervical C2 or lumbar spine L1) caused by: Degenerative joint disease (most common)Spondylolisthesis (antero- or posterior)Disc space narrowingFacet joint hypertrophy Iatrogenic: following spinal surgery such as laminectomy Systemic disease: Paget's disease, ankylosing spondylitis, tumors Trauma Congenital malformations: spinal dysraphism (uncommon) Clinical features Lumbar stenosis Load-dependent lower back painUnsteady wide-based gait, reduced lower extremity reflexesNeuropathic claudication: a group of typical symptoms (see table below) of spinal stenosis affected by postural changes Diagnostics X-ray: degenerative joint changes MRI (confirmatory test): evidence of spinal stenosis (compression of spinal nerves, nerve roots or spinal cord)Possible alternative: CT Neuropathic claudication Bilateral radiation of pain to buttocks and/or legs Associated cramping, numbness, weakness, or tingling in the legs Exacerbating factorsSpinal extension : standing, walking downhill, or even at rest Relieving factorsSpinal flexion : sitting, cycling, walking uphill, bending forward Vascular claudication Completely resolved with rest/standing (unless advanced, then pain at rest may occur) ABI abnormal Treatment Symptomatic treatmentNSAIDSPhysiotherapy, which focuses on exercises that promote stability and abdominal muscle strengtheningEpidural steroid injections if symptoms persist despite above treatment (may improve ∼ 50% of cases) Surgery: if conservative therapy failsRemoval of any bony attachmentsLaminectomy (decompression surgery): removal of the dorsal part of the vertebra (lamina) which covers the spinal cordRecurrence is common

Persistent postural-perceptual dizziness Persistent postural-perceptual dizziness (PPPD), originally known as phobic postural vertigo (PPV), is an idiopathicdisorder that presents with a persistent sensation of non-rotational dizziness or unsteadiness and hypersensitivity to motion, lasting at least 3 months. It is the most common cause of chronic dizziness and it often follows an event that caused acute vertigo or dizziness, such as vestibular neuritis or panic attacks. Typically, patients recover from the initial acute disease, but the feeling of dizziness persists. Treatment consists of vestibular rehabilitation, psychotherapy and, if necessary, SSRIs.

Epidemiology Most common vestibular disorder in people 30-50 years of age Etiology Idiopathic, but it often follows an event that caused acute vertigo or dizziness (e.g., vestibular neuritis, Ménière's disease, brain injury, panic attack) Clinical features Persistent sensation of non-rotational dizziness or unsteadiness for at least 3 monthsSymptoms are present ≥ 15 of every 30 days, although most patients experience daily symptomsDizziness typically worsens with motion of both the patient and his or her surroundings PPPD patients often suffer from anxiety and/or depressive disordersDiagnostics There are no tests for PPPD and physical examination is usually unremarkable.Treatment The following measures are indicated for all patients: Lifestyle changes: good dietary habits Vestibular rehabilitation Cognitive-behavioral therapy Drug of choice: serotonin reuptake inhibitors (SSRIs)Prognosis The majority of patients recover completely or improve considerably.

Myotonic syndromes Myotonic syndromes are a heterogenous group of inherited disorders with similar pathological mechanisms. Myotonic dystrophies, the most prevalent myotonic syndromes, are one of the most common forms of adult-onset muscular dystrophy. Both types, myotonic dystrophy type I (Curschmann-Steinert disease) and myotonic dystrophy type II (proximal myotonic myopathy), are autosomal dominant conditions with CTG trinucleotide repeat and CCTG tetranucleotide repeat expansions respectively. Type I is a severe (often life-threatening) form of disease, while type II is usually mild. Both present with skeletal muscle weakness and myotonia, muscle pain, heart conduction defects, cataracts, testicular atrophy, and frontal balding. Electromyography may confirm myotonia that is not identified during clinical examination; however, genetic tests usually confirm the diagnosis. As no curative therapy exists, treatment is symptomatic. Except for DM1, patients with myotonic syndromes have a normal lifespan.

Epidemiology Myotonic dystrophiesOne of the most common forms of adult-onset muscular dystrophyMyotonic dystrophy type I: congenital, juvenile, or adult onsetMyotonic dystrophy type II: usually adult onset Etiology Myotonic dystrophiesAutosomal dominant conditionType 1: CTG trinucleotide repeat expansion of the DMPK geneType 2: CCTG tetranucleotide repeat expansion of the ZNF9 gene (CNBP gene) Clinical featuresSkeletal muscle weakness and myotonia (delayed muscle relaxation following normal muscle contraction) Muscle pain Arrhythmias Cataracts Testicular atrophy or features of ovarian insufficiency (i.e., infertility) Hypogammaglobulinemia Features of insulin resistance Frontal balding Cognitive impairment Myotonic dystrophy type I (DM1, Curschmann-Steinert disease) Most common in the distal sections of extremities: face, neck, forearm, foot dorsiflexor, intrinsic muscles of the hand. Myopathic facies Long, narrow faceHollowed cheeks, and high arched palatePtosisSternocleidomastoid muscle wasting Clinical myotonia: Classically manifests as difficulty releasing a handshake. Respiratory involvement, dysphagia, dysarthria, irritable bowel-like symptoms (e.g., abdominal pain, bloating), impaired sleep, daytime somnolence are common Myotonic dystrophy type II (DM2, proximal myotonic myopathy) Most common in the proximal muscles: neck flexors, hip flexors, elbow flexors, finger flexors Mild clinical myotonia Uncommon symptoms: respiratory muscle involvement, dysphagia, dysarthria, irritable bowel-like symptoms (e.g., abdominal pain, bloating), impaired sleep, daytime somnolence are uncommon Diagnostics Electromyography (EMG): identifies myotonia Genetic diagnostics (confirmatory test): detection of trinucleotide repeat expansion mutation in leukocytes Biopsy: to distinguish between an inflammatory and a metabolic cause of the myopathy Other supportive tests ↑ CK, IgG and IgM hypogammaglobulinemia, ↑ FSH and ↓/↔︎ testosteroneECG: to exclude cardiac arrhythmias and other abnormalitiesMRI: signs of global atrophy Myotonic dystrophies Type 1 (DM1; Curschmann-Steinert disease)Congenital, juvenile, or adult-onset Severe disease Skeletal muscle weaknessand myotonia is more common in the distalmuscles of all extremities: face, neck, forearm, foot dorsiflexor, intrinsic muscles of the handMyopathic faciesMild disease Type 2 (DM2; ProximalMyotonic Myopathy, PROMM)AdulthoodAutosomal dominant Type 1: CTG trinucleotide repeat in the region of the DMPK gene (a gene that encodes dystrophiamyotonica protein kinase) Autosomal dominant Expanded CCTG tetranucleotide repeat expansion on the ZNF9 gene (CNBP gene)Myotonin-protein kinase in skeletal and heart muscle, gonads, and brain Skeletal muscleweakness and myotonia is more common in the proximal muscles: neck flexors, hip flexors, elbow flexors, finger flexors Myalgia Arrhythmias Cataracts Testicular atrophy or features of ovarian insufficiency (i.e., infertility) Frontal balding Skeletal muscleweakness and myotonia is more common in the proximal muscles: neck flexors, hip flexors, elbow flexors, finger flexors Duchenne muscular dystrophy 2-3 years of ageX-linked recessive Chromosomal defect affects the dystrophin gene on the short arm of the X chromosome(Xp21)→ Frameshift mutation in DMD Complete impairment (DMD) of the dystrophin protein Paresis and atrophystarting in the proximallower limbs, later spreading to the upper body and distal areas Weak reflexes Bilateral Trendelenburg's sign Gower maneuver Calf pseudohypertrophy Becker muscular dystrophy Usually > 15 years of age X-linked recessive Chromosomal defect affects the dystrophin gene on the short arm of the X chromosome(Xp21) → point mutation in BMD Partial impairment (DMD) of the dystrophin protein Symptoms identical to those of Duchenne muscular dystrophy Slower progression and milder symptoms Heart involvement is more common compared to DMD. Non-dystrophic myotonic syndromes Myotonia congenita Thomsen (Thomsen's disease) From childhood Autosomal dominantChloridechannel No atrophy, but hypertrophy Initial difficulties in muscle relaxation Primarily affected muscles: legs, eyes, tongue, jaw Myotonia congenita Becker (Becker's disease) Autosomal recessive 5-35 years Chloridechannel No atrophy, but hypertrophy Initial difficulties in muscle relaxation Primarily affected muscles: legs, eyes, tongue, jaw Possibly upper extremities affected Paramyotonia congenita Eulenburg (Eulenburg's disease) From infancy Aut Dom Sodium channel Muscle weakness in the cold Treatment Incurable Symptomatic treatment (e.g., analgesia, physiotherapy, walking aids, pacemaker, medical therapy for myotonia ) Regular monitoring (i.e., of respiratory compromise, dysphagia) Genetic counseling and testing ognosis The course of DM1 is chronic progressive. Cardiac complications reduce life expectancy. DM2 has a milder disease course.

Neural tube defects Neural tube defects (NTDs) are one of the most common congenital central nervous system (CNS) malformations. They develop between the 3rd and 4th week of pregnancy and are often caused by folic acid deficiency. The deficiency results in improper closure of the neural plate in the embryo, mainly at the caudal or cranial ends. The formation of defects at the caudal end is more common and is known as spina bifida. Spina bifida may occur without any apparent clinical features (spina bifida occulta), or manifest with protrusion of the meninges, and potentially also the spinal cord(myelomeningocele), through a gap in the vertebrae. Myelomeningoceles predominantly cause symptoms of sensory and motor function loss, such as bladder dysfunction and paraplegia. NTDs at the cranial end can cause cranial fissuremalformations; the most severe manifestation of this, anencephaly, is incompatible with life. The diagnosis of NTDs is often established during pregnancy via ultrasound and detection of elevated alpha-fetoprotein levels in the amniotic fluid. Treatment involves prophylactic administration of antibiotics and swift surgical closure of the defect to avoid CNSinfections. Supplementation with folic acid is an important preventative measure and should ideally be initiated 4 weeksprior to conception.

Epidemiology NTDs occur between the 22nd and 28th day post-conception ; the neural tube in the embryo closes during this time. Incidence: 1-2 cases per 1000 births Etiology Maternal folic acid deficiency during pregnancy; disorders or drug intake affecting folate metabolism Concomitant chromosomal aberrations (e.g., trisomy 13 and 18); genetic mutations in the folate and homocysteinemetabolism pathways Associated maternal conditions: diabetes mellitus, obesity, fever/hyperthermia during first trimester Spina bifida DefinitionSpina bifida occulta: failure of one or more vertebrae to close completely; the spinal cord, spinal meninges, and overlying skin remain intactSpina bifida cystica: failure of one or more vertebrae to close completely; the meninges (meningocele) and potentially the spinal cord (myelomeningocele) may protrude through the gap Location: primarily in the lower lumbar to sacral region SymptomsSpina bifida occulta: usually asymptomatic; possibly visible dimple, collection of fat, or patch of hair on the skin above the defectSpina bifida cysticaSymptoms of spinal cord dysfunction Varying degrees of motor loss, possible flaccid paralysisSensory deficitsBladder and bowel dysfunctionFurther symptoms Developmental delays, cognitive impairment, progressive neurological symptomsSkeletal malformations (esp. of the spine and lower extremities), joint contractures, back painHydrocephalus Cranial defects Definition: cranial cleft formation with involvement of the skull and brain Acrania: absent skull bonesAnencephaly: variable presentations of diminished cranium and forebrain, as well as cerebellumEncephalocele: protrusion of the brain via an opening in the skullCranial meningocele: protrusion of meninges through parietal foramina or abnormal bony openings of the skull Location: variable Symptoms: malformations and neurological deficits that vary in severity; in severe cases always lethal The most common NTDs are myelomeningocele, anencephaly, and encephalocele. Congenital dermal sinus Definition: mainly lumbar or lumbosacral fistulae; extend from the surface of the skin to the spinal canal and frequently end in a dermoid or epidermoid cyst Diagnostics Prenatal screeningElevated levels of alpha-fetoprotein (AFP) in amniotic fluid at 13-15 weeks' gestation Fetal ultrasonography at 20 weeks' gestation CT scans and cranial ultrasonography (in infants) to monitor possible hydrocephalus MRI for assessment of spinal cord malformations Differential diagnoses Tethered cord syndrome Definition: abnormal stretching of the spinal cord caused by adhesions or obstructions that tether the cord to the base of the spinal canal EtiologyMeningeal adhesions Terminal filament adhesions or thickeningLipoma, dermoid cystsTumors Symptoms(Motion-dependent) back painSensory and motor deficits, skeletal malformations (e.g., foot deformities, scoliosis)Bladder/bowel dysfunctionChildren may begin to stumble after learning to walk.Skin lesion on lower back (e.g., discoloration, nevi, hemangioma) Diagnosis: MRI shows abnormally low position of the conus medullaris. Treatment: removal of structure tethering the spinal cord (e.g., adhesiolysis, resection of lipomas) → prevents progressive deterioration, corrects existing conditions (e.g., urinary retention) Treatment The baby is usually delivered by cesarean section. Prophylactic administration of broad-spectrum antibiotics Surgical closure within 72 hours after birth ; close monitoring and possibly elective surgery for closed defects Placement of a ventriculoperitoneal shunt in cases of hydrocephalus Prevention Folic acid supplementation400-800 μg/day at least 4 weeks prior to a planned pregnancyIntake should continue through the first trimester. Women who have had a child with an NTD or have one themselves should take 4 mg/day starting 4 weeks prior to trying to conceive.

Transient global amnesia Transient global amnesia (TGA) is a neurological disorder resulting in acute, transient memory loss. The etiology of this form of amnesia remains unclear, but certain triggers have been identified (e.g., strenuous physical exercise, psychological stress). Affected patients experience sudden memory loss and an impaired ability to retain any new information. Additionally, they may be disoriented to time and place, but retain full knowledge of self-identity. Transient global amnesia resolves after a maximum of 24 hours, after which time the patient spontaneously returns to their normal state of consciousness. The diagnosis is established based on the history of the episode (onset, duration, nature of amnesia). However, an EEG or contrast CT may be performed to rule out transient amnesia caused by other conditions. Transient global amnesia is predominantly associated with a good prognosis and does not indicate an underlying or impending cerebroischemic condition.

Epidemiology Peak incidence: 50-70 years (patients are rarely < 40 years)Etiology Idiopathic Precipitating factors Vigorous physical exercise or exhaustion due to overworkWorking bent over (e.g., gardening)Psychological stressSudden immersion in cold or hot waterClinical features Abrupt onset Episodes last between 1-24 h, but never > 24 h (mean duration 6-8 h) Nature of amnesia: anterograde or partial retrograde The patient may appear anxious and distraught, with desperate attempts to orientate themselves. The attack resolves over hours, with older memories returning first, followed by a gradually increasing capacity to retain new information.iagnostics If the diagnosis is clear, further diagnostic procedures are not necessary. If the diagnosis is uncertain: MRI: evidence of typical focal, hyperintense lesions in the hippocampus EEG: exclude differential diagnoses (e.g., epileptic amnesic attacks)Treatment Outpatient management is possible under the supervision of a caregiver. Monitoring for at least 24 h is advisable if an alternative diagnosis is suspected. No medical therapyPrognosis Resolves spontaneously within 24 h Approximately 3-20% of patients may experience a further episode.

Idiopathic intracranial hypertension Idiopathic intracranial hypertension (IIH), often referred to as pseudotumor cerebri or benign intracranial hypertension, is a condition of unknown etiology that manifests with chronically elevated intracranial pressure (ICP). It predominantly affects obese women, especially such who have gained significant weight over a short period of time weight, but certain drugs (growth hormones, tetracyclines, excessive vitamin A) are also associated with the condition. The most common symptoms are diffuse headaches, although various visual symptoms and pulsatile tinnitus are also common. Ophthalmologic examination is crucial for confirming the diagnosis and usually reveals bilateral papilledema and possibly loss of vision. MRI is often done to rule out other causes of increased ICP. Lumbar puncture typically shows an elevated opening pressure. Acetazolamide is the first-line therapy, whereas surgery is only used as a last resort. Even with treatment, the condition often worsens over the course of months to years, and permanent symptoms are common.

Epidemiology Predominantly affects obese women aged 15-45 years Etiology Idiopathic Risk factors ObesityCertain medications, including: Growth hormoneTetracyclinesExcessive vitamin A or derivatives Pathophysiology A mismatch between production and resorption of CSF (cause unknown) → ↑ ICP → damage to structures of the CNSand especially to the optical nerve fibers Clinical features Diffuse headaches Visual symptomsTransient vision loss Photopsia (seeing flashes of light)DiplopiaRetrobulbar pain Pulsatile tinnitus Cranial nerve disorders (especially CN VI) Back pain Diagnostics The following tests should always be performed Ophthalmologic examinationOpthalmoscopy: bilateral papilledema Visual field test may show peripheral loss of vision MRITo rule out other causes of increased ICPUnremarkable brain parenchymaPossible abnormalities of the sclera and/or optic nerve (e.g., scleral flattening)Empty sella Lumbar punctureElevated opening pressure >20-25 cm H2O (with patient lying on the side, legs extended)Normal CSF analysis with no signs of inflammation or bleeding Treatment Discontinue any offending agents Weight loss Medical therapy (first line)AcetazolamideAdd furosemide if acetazolamide alone is not sufficient Surgery: if conservative measures failOptic nerve sheath fenestration: small patches of dura surrounding the optic nerve are removed, allowing CSF to drain into the periorbital fatCSF shunt Prognosis Typically worsens over months to years, until the condition stabilizes Even with treatment, many patients will have persistent symptoms (up to 60%) Severe loss of vision (or even blindness) occurs in up to 14% of patients

Narcolepsy Narcolepsy is a neurological disorder of the sleep-wake cycle characterized by excessive daytime sleepiness, cataplexy, sleep paralysis, and hallucinations upon waking or falling asleep. It most commonly manifests in teens and young adults with excessive daytime sleepiness. Primary narcolepsy is either caused by orexin deficiency (type 1) or is idiopathic(type 2). Secondary narcolepsy can occur as a result of brain damage or other genetic syndromes. Diagnosis requires an established history based on questionnaires or a sleep diary as well as a polysomnogram and multiple sleep latency test or an abnormal orexin A (hypocretin-1) level in the cerebrospinal fluid (CSF). No cure has yet been found, but daytime sleepiness can be managed with CNS stimulants (e.g., modafinil) and a regimen of scheduled naps. Cataplexy, hallucinations, and sleep paralysis are treated with antidepressants or sodium oxybate.

Epidemiology Prevalence: 25-50:100,000 [1] Incidence: ∼ 0.8:100,000 individuals per year Sex: ♂ = ♀ Bimodal distribution: first peak at 15 years; another smaller peak around age 35 Etiology Primary narcolepsy Narcolepsy type 1 Loss of hypothalamic neurons, which produce orexin A and orexin B (i.e., hypocretin-1 and hypocretin-2) → severe orexin deficiency The exact etiology is unknown, but both genetic and environmental factors seem to be implicated. Genetic predisposition [4]Narcolepsy type 1 is strongly associated with a variation of the HLA-DQB1 gene called HLA-DQB1*06:02Positive family history increases the riskEnvironmental factors: e.g., streptococcal pharyngitis, exposure to H1N1 influenza antigens during vaccination(autoimmune cross-reactivity) [2] Narcolepsy type 2 IdiopathicNo changes in orexin levels Secondary narcolepsy Cerebral damage (e.g., tumor, stroke, inflammation, vascular malformation) Genetic syndromes (e.g., Niemann-Pick disease type C and Prader-Willi syndrome) Clinical features Excessive daytime sleepiness (EDS): Affected individuals experience an irresistible urge to sleep and sudden, short sleep attacks (< 30 minutes), which may occur in inappropriate situations (e.g., while driving a car). One of the earliest manifestations of narcolepsyEpisodes of excessive sleepiness can occur even if affected individuals have had adequate sleep. Abnormal REM sleepCataplexy (60-70% of cases): sudden muscle weakness in a fully conscious person, triggered by strong emotions(affected individuals may experience buckling of the knees upon laughing.) Typically manifests months or even years after EDSThe loss of muscle tone is similar to that observed during REM sleep. Typically manifests as partial cataplexy: isolated weakness of distinct muscle groups (e.g., neck muscles weaken and head tilts forward)Usually resolves within a few seconds, at most two minutes Sleep paralysis (∼ 50% of cases): Complete paralysis occurs for 1-2 minutes after waking or before falling asleep; external stimuli (e.g., stirring or addressing the affected individual) can relieve paralysis. Hypnagogic hallucinations (∼ 50% of cases): vivid, often frightening visual or auditory hallucinations that occur as the patient falls asleep Hypnopompic hallucinations: experienced while waking up (less common than hypnagogic hallucinations) Automatic behavior: During narcoleptic episodes, patients often perform routine repetitive tasks automatically without conscious awareness of their environment. Other: depression, obesity, impotence or low sex drive, headaches, decreased functional performance Hypnagogic hallucinations occur while going to sleep. Diagnostics Diagnostic criteria [8]Irresistible urge to sleep or daytime sleep lapses ≥ 3 times/week for at least 3 monthsAt least one of the following: Cataplexy plus specific findings on a multiple sleep latency test and polysomnographyAbnormal CSF orexin A levels HistorySleep diaryNarcolepsy questionnaires Sleep studiesPolysomnography (PSG) Conducted in a sleep laboratory during sleep, typically over the course of two daysPSG measures brain waves via electroencephalography (EEG), eye movements via electrooculography (EOG), and muscle activity via electromyography (EMG). PSG findings are characterized by EEG beta waves that appear abnormally early after falling asleep (shortened REM sleep latency).Multiple sleep latency test (MSLT) Measures time needed to fall asleep during daytime naps to assess excessive daytime sleepinessPolysomnography is made during the day; five opportunities to nap are provided For a conclusive MSLT, patients must have at least six hours of normal sleep as assessed by PSG prior to the test. Supports diagnosis if patient both: Falls asleep with a mean latency of ≤ 8 minutesShows sleep-onset REM periods (SOREMPs) within 15 minutes after sleep onset in at least 2 out of the 5 opportunities provided Decreased CSF orexin A levels: supports diagnosis if ≤ 110 pg/mL or < ⅓ of mean values in healthy persons Additional testsHuman leukocyte antigen (HLA) haplotype testing: helpful in cases where additional objective evidence of narcolepsy is wantedDiagnostics to rule out secondary narcolepsy (e.g., brain imaging) Treatment General approach Sleep hygiene recommendations Take scheduled naps throughout the day to reduce the urge to sleep.Ensure regular sleep periods during the night. Avoid substances that disturb the sleep-wake cycle (e.g., alcohol, antipsychotics, opiates). Consultations with family and employer (e.g., people with narcolepsy require a place to sleep at their workplace) Automobile accidents are a concern! Patients should take treatment and be symptom-free to be allowed to drive. Medical therapy Choice of medication depends on the occurrence and relative extent of excessive daytime sleepiness, cataplexy, and/or nocturnal sleep disturbances. More than one medication may be required. Excessive daytime sleepinessCNS stimulants Drug of choice: modafinil (nonamphetamine CNS stimulant)Alternatives Methylphenidate and amphetamines (preferred in children) Solriamfetol: selective dopamine and norepinephrine reuptake inhibitor that promotes wakefulness [11]Pitolisant: highly selective H3 receptor antagonist/inverse agonist for the treatment of EDS and cataplexy [12] Cataplexy, sleep paralysis, and sleep hallucinations SSRIs (e.g, citalopram) or SNRIs (e.g., venlafaxine) Nighttime sodium oxybate (highly effective for severe cataplexy) Sodium oxybate (i.e., GHB) is used recreationally for its ability to induce sedation and euphoria, and it has a high potential for misuse.The drug is tightly regulated and only distributed through a restricted program to minimize the risk of misuse, especially among young patients. Sodium oxybate should never be taken with alcohol or other CNS depressants because doing so may cause life-threateningrespiratory depression!

Cirrhosis Cirrhosis is a condition caused by chronic damage to the liver, most commonly due to excessive alcohol consumption or hepatitis C infection. Other causes may include inflammatory or metabolic diseases, such as primary biliary cirrhosis or hemochromatosis. Cirrhosis is characterized by hepatic parenchymal necrosis and an inflammatory response to the underlying cause. Subsequent hepatic repair mechanisms lead to fibrosis and abnormal tissue architecture, which impair liver function. Patients may present with a range of symptoms, including jaundice, ascites, hepatosplenomegaly, and typical skin manifestations such as spider angioma or palmar erythema. Men may further display signs of feminization (e.g., gynecomastia, hypogonadism). In severe cases, accumulation of toxic metabolites or involvement of further organs can lead to complications such as hepatic encephalopathy or hepatorenal syndrome. Laboratory tests show signs of hepatocyte destruction (e.g., elevated liver enzymes, hyperbilirubinemia) or impaired hepatic synthetic function (e.g., prolonged prothrombin time, low albumin). Abdominal ultrasonography typically shows a shrunken, heterogeneous liverparenchyma with a nodular surface. Biopsy is the method of choice for confirming the diagnosis. However, it is usually only performed if previous testing was inconclusive. Management consists of treatment of the underlying disease (e.g., avoiding toxic substances, antiviral drugs), adequate calorie intake, and medication for treating complications (e.g., spironolactone for ascites). In cases of decompensated cirrhosis, interventional procedures (e.g., paracentesis to drain ascites) may be used to alleviate symptoms or bridge the time until liver transplantation is possible.

Epidemiology Prevalence: approx. 0.27% in U.S. adults Sex: ♂ > ♀ (2:1) Responsible for approx. 1-2% of all deaths in the United States; most deaths occurring in the fifth to sixth decade of life Etiology HepatotoxicityLong-standing alcohol abuse (one of the two most common causes of chronic liver disease in the USA)Medications (e.g., acetaminophen, amiodarone or chemotherapy drugs such as methotrexate)Ingesting aflatoxin created by Aspergillus Inflammation(Chronic) viral hepatitis B, C, and D (see, e.g., "Hepatitis C") → Chronic hepatitis C is now the most common cause of cirrhosis in the USPrimary biliary cirrhosis Primary sclerosing cholangitisAutoimmune hepatitisParasitic infections (e.g., schistosomiasis, leishmaniasis, malaria) Metabolic disordersNon-alcoholic steatohepatitis (NASH) HemochromatosisWilson's diseaseAlpha‑1 antitrypsin deficiencyHepatic vein congestion or vascular anomaliesBudd-Chiari syndrome Cardiac cirrhosis (congestive hepatopathy)Osler‑Weber‑Rendu syndrome Cryptogenic cirrhosisCirrhosis of uncertain etiology despite adequate diagnostical efforts Child-Pugh score Points123Serum albumin g/dL> 3.52.8-3.5< 2.8Serum bilirubin mg/dL< 2.02.0-3.0> 3.0INR< 1.71.7-2.3> 2.3 AscitesNoneMildModerateHepatic encephalopathyNoneMinimalAdvanced Pathophysiology Although many factors contribute to the development of cirrhosis, cytokine‑mediated activation of stellate cells has been identified as a central element, as these cells promote fibrosis, which ultimately leads to cirrhosis. Hepatic inflammation → hepatocyte destruction which triggers repair mechanisms → excess formation of connective tissue (fibrosis) → loss of normal liver function (exocrine and metabolic) Inflammatory cytokines → hepatocyte destruction and stellate cell activation → excess collagen production → loss of normal liver function (exocrine and metabolic) Further pathophysiological mechanisms: Intrahepatic shunting between the portal vein and tributaries of the vena cava Portal hypertension (→ esophageal varices)Impaired liver functionDecreased synthesis ofCoagulation factors → bleeding diathesisUrea → ↑ ammonia → hepatic encephalopathy Albumin → ascites Bile acids → ↓ intestinal absorption of fat‑soluble vitaminsTransport proteins for hormones Further possible consequences Poor metabolism of medications → accumulation with increased risk of toxicityIncreased insulin resistance (diabetes mellitus secondary to liver disease)Impaired hepatic metabolism of estrogen and androstenedione (which is then converted to estrogen by aromatase in adipose cells) → hyperestrogenismLimited enzymatic activation of vitamin D → secondary hyperparathyroidism Clinical features Nonspecific symptoms (patients are often initially asymptomatic) Fatigue, malaise, weight lossJaundice PruritusAsterixis Fetor hepaticus Dupuytren's contracture Abdominal symptomsHepatomegaly (possibly causing RUQ pain) Splenomegaly Ascites Skin changesGenerally dry and atrophicTelangiectasia: most commonly spider angiomata Caput medusae: periumbilical dilation of subcutaneous veins Palmar erythema (plantar erythema also possible)White nails with ground glass opacity Clubbed nails Hormone disordersHyperestrogenismChanges in the hepatic metabolization of sex hormones causes an imbalance in the estrogen‑androgen ratio, resulting in a marked increase of systemic estrogen levels. In men, increased estrogen causes feminization. As liver insufficiency worsens, plasma testosterone concentrations decrease. GynecomastiaHypogonadism (testicular atrophy)Decreased body hair (e.g., loss of chest hair, female pattern of pubic hair distribution)Reduced libido; erectile dysfunction; infertilityPalmar erythema; spider angiomataAmenorrhea Gynecomastia can also be caused by treatment with spironolactone! Diagnostics Laboratory tests Signs of hepatocyte destruction↑ Liver enzymes (AST, ALT) ↑ Bilirubin ↑ Gamma‑glutamyl transpeptidase (GGT) ↑ Alkaline phosphatase ↑ GLDH ↑ Ammonia Signs of impaired hepatic synthesis↑ Prothrombin time (↑ INR) ↓ Total protein (↓ albumin)↓ Cholinesterase See liver function tests Macrocytic anemia due to vitamin deficiency (B12, folic acid) Microcytic anemia due to chronic blood loss Thrombocytopenia in hypersplenism Serum protein electrophoresis↓ Albumin band↑ Gamma band Alpha‑1, alpha‑2, and beta globulin fractions are unchanged Imaging studies Abdominal ultrasound should be performed first. Possible findings include: Liver form and structureNodular liver surfaceAtrophy of the right lobeLoss of structural homogeneity (hyperechoic or variable increase in echogenicity) with fibrous septa. Liver size: initially enlarged, atrophies and shrinks with disease progressionHypertrophy of the caudate lobe Other possible findings Loss of intrahepatic portal and liver veins Complications of cirrhosis such as portal hypertension. CT scan Typical findings Relative hypertrophy of the left and caudate lobeRegenerative nodulesIrregular liver surfaceIndirect findings: ascites, splenomegaly, portocaval collaterals Biopsy Indication: Although biopsy is the gold standard for diagnosis, it is unnecessary in the light of clinical, laboratory, and ultrasound evidence. However, it can aid in identifying the etiology of the cirrhosis if prior testing was inconclusive. Screening procedures and monitoring the disease course HCC screening: abdominal ultrasound for patients with cirrhosis every 6 months and periodic monitoring of alpha-fetoprotein (AFP) Early diagnosis of hepatocellular carcinoma is possible. Before taking a biopsy, check the patient's coagulation status as the risk of bleeding may be increased! Pathology FindingsFibrosisReplacement of normal liver tissue with collagenous regenerative nodules (histological staging is based on the size of the regenerative nodules) Size of the regenerative nodules OccurrenceMicronodular1-3 mmFollowing a chronic active process such as diseases with slow progression; e.g.: Chronic hepatitis B or CAlcoholic hepatitisMacronodular> 3 mmFollowing diffuse parenchymal necrosis with relapses or acute course; e.g.: Relapse or fulminant viral hepatitisIntoxications (e.g., death cap poisoning)Both1-3 mm and > 3 mmPossible in every type of liver‑damaging disease Treatment General approachTreatment of the primary condition Avoidance of hepatotoxic substances (e.g., alcohol, medication) Routine vaccinations (influenza, pneumococcal disease, hepatitis A/B, tetanus ) Balanced diet with adequate calorie intake, no protein restriction Supplemental B vitamins Vitamin B complex with thiamine (B1) and pyridoxine (B6)Vitamin B12 substitution Medication (for treatment of complications see respective section) Non‑selective beta blockers (e.g., propranolol) to lower portal pressure and prevent variceal bleeding (see treatment of portal hypertension). Spironolactone and furosemide to manage ascites and edema in patients with hypoalbuminemiaIn cases of coagulation factor deficiency (possibly combined with thrombocytopenia): leads to coagulation disturbances and bleeding diathesis Treatment with vitamin K substitution Cryoprecipitate transfusion Interventional proceduresIndicationsRefractory ascitesRecurring esophageal varicesBridging time until possible liver transplantMethodsParacentesis of ascites to decompress abdomen TIPS (transjugular intrahepatic portosystemic shunt) to lower portal pressure Surgery: A liver transplant is the only curative option in advanced liver disease. Complications The following complications are covered in separate sections below or in other separate cards: Portal hypertension Hepatic encephalopathy Hepatorenal syndrome Portal vein thrombosis Pulmonary complications of portal hypertensionHepatopulmonary syndromePortopulmonary hypertension Tumors (late complication) Hepatocellular carcinoma (HCC) Decompensated cirrhosis Definition: worsening of liver function in cirrhosis characterized by the presence of jaundice, ascites, variceal hemorrhage, or hepatic encephalopathy Clinical manifestationsHematologic manifestations Coagulopathy : Prolonged prothrombin time (PT)Prolonged international normalized ratio (INR)Prolonged activated partial thromboplastin time (aPTT)This condition does not respond to Vitamin K because the liver cannot utilize it for the synthesis of coagulation factorsComplications caused by portal hypertensionEsophageal variceal hemorrhageAscites and subsequent spontaneous bacterial peritonitisMetabolic complications or associated organ impairmentJaundiceHepatic encephalopathyHepatorenal syndromeHepatopulmonary syndrome The associated ascites and edema as well as the high risk of bleeding considerably increase the risk for hypovolemic shock! Hepatic encephalopathy Definition: Hepatic encephalopathy (HE) is defined as fluctuations in mental status and cognitive function in the presence of severe liver disease. Hepatic dysfunction results in inadequate elimination of metabolic products with subsequent accumulation of neurotoxic metabolites (like ammonia). TriggersDeterioration of liver functionInfections (e.g., spontaneous bacterial peritonitis)Gastrointestinal bleeding ConstipationPortal vein thrombosisHypovolemia/exsiccosis and electrolyte disturbances (hypokalemia, hyponatremia)Renal failureExcessive protein consumption Clinical manifestations Disturbances of consciousness, ranging from mild confusion to comaMultiple neurological and psychiatric disturbances like:Asterixis Fatigue, lethargy, apathyMemory lossImpaired sleeping patternsIrritabilityDisoriented, socially aberrant behavior (for e.g., defecating/urinating in public, shouting at strangers, etc.)Slurred speechMuscle rigidity DiagnosticsElevated blood ammonia levels Assessment of mental status Number connection test: completed slower than the age-normalized standard or cannot completePsychometry‑based diagnostic method (e.g., Mini‑Mental State Examination, MMSE) TreatmentGeneral measures Avoidance of trigger substances (e.g., hepatotoxic medication, alcohol)Treatment of further complications which might aggravate HE (see "Triggers" above)Lactulose: synthetic disaccharide laxativeFirst-line treatment for HE Improves HE by decreasing absorption of ammonia in the bowel: lactulose is converted to lactic acid by intestinal flora → acidification in the gut leads to conversion of ammonia (NH3) to ammonium (NH4+) → ammonium is excreted in the feces → decreased blood ammonia concentrationRifaximin [21]Non‑absorbable antibioticMay be added to lactulose to prevent recurrent episodes of HE after the second episode Hepatorenal syndrome (HRS) Definition: deterioration of kidney function in patients with advanced liver disease. The condition is caused by renal vasoconstriction resulting in hypoperfusion of the kidneys. Triggers: loss of volumeDrainage of ascitesGastrointestinal bleedingForced diuresisExcess use of laxatives (lactulose) SymptomsOliguria up to anuria with progressive kidney failureClinically associated with decompensated cirrhosisRenal water retention leads to edema and hydrops (ascites, pleural, or pericardial effusion) Diagnosis Serum creatinine > 1.5 mg/dLElevated BUN:creatinine ratio (> 20:1)Protein excretion < 500 mg/dHyponatremia with relative sodium deficiency Low sodium excretion in urine (< 10 mmol/L) See also fractional excretion of sodium TherapyGeneral measures: improvement of liver function if possible (e.g., cessation of alcohol use) Pharmacotherapy: combination of midodrine, octreotide, and albumin Surgical/interventionalPlacement of a transjugular intrahepatic portosystemic shunt (TIPS) A liver transplant is the only curative option in advanced liver disease Portal vein thrombosis Definition: complete or partial closure of the portal vein EtiologyComplication of cirrhosis or chronic liver disease Myeloproliferative syndromeThrombophilia (e.g., antiphospholipid syndrome) or general risk factors of phlebothrombosis.Chronic mesenteric venous thrombosisLocal complications of intra-abdominal malignancy (e.g., pancreatic carcinoma) or inflammation (e.g., liver abscess) Symptoms: The condition can take many different courses, depending on the extent of thrombosis and the speed of manifestation. Long standing cases of portal vein thrombosis are often asymptomatic (incidental finding) Esophageal variceal hemorrhageAbdominal pain (right upper quadrant, or generalized )Hepatic encephalopathy Jaundice and pruritus due to portal cholangiopathy Hypersplenism DiagnosticsColor duplex sonographyEchogenic or isoechoic thrombus in the portal veinWidening of the portal veinDecreased flow velocity or complete halt of flow Dilated, coiled periportal veinsVariable portion of mostly echogenic thrombus material in the portal veinCT or MRI of the abdomen with contrast agent TherapyTreatment with anticoagulants for 3-6 months results in fibrinolysis and recanalization (complete recanalization occurs in about 50% of cases). Treatment of complications (such as stopping acute bleeding from esophageal varices)Transhepatic thrombolysis with tissue plasminogen activator. Recommended in acute portal vein thrombosis TIPS Pulmonary complications of portal hypertension Hepatopulmonary syndromeDefinition: A condition characterized by hypoxemia, intrapulmonary vasodilatation, and portal hypertension in the presence of cirrhosis. Clinical findingsDyspneaPatients may also manifest with platypnea or orthodeoxia TherapyThe only definitive treatment is a liver transplant. Long‑term treatment with oxygen (as in patients with COPD) is recommended. Prognosis is very poor. Portopulmonary hypertensionDefinition: portopulmonary hypertension is a form of pulmonary arterial hypertension (PAH), which is associated with portal hypertension. It is a well recognized complication of chronic liver disease.Clinical findings: same symptoms as pulmonary hypertension Diagnostic: echocardiography; right heart catheter for specific diagnosticsTherapy: supportive measures, no causal therapy Further pulmonary complications in cirrhosisPneumonia: especially due to immunosuppression, possibly increased risk of aspiration in hepatic encephalopathy.Interstitial lung edema with decreased oxygenation Atelectasis: Diaphragm is elevated because of massive ascites (also promotes pneumonia). Prognosis Survival is poor in patients with decompensated cirrhosis unless they receive liver transplantation. One‑year survival rate based on Child‑Pugh score: Child‑Pugh class A: almost normalChild‑Pugh class B: 80%Child‑Pugh class C: 45%

Spinocerebellar ataxia Spinocerebellar ataxia (SCA) refers to a group of progressive neurodegenerative diseases of genetic origin. Currently, more than 30 types have been identified, most of which are autosomal dominant, such as SCA3. Trinucleotide repeat expansions in a disease-associated protein (e.g., CAG repeats in ataxin-1) are commonly the underlying genetic anomaly. Patients usually present between the ages of 30-50 with slowly progressive symptoms of cerebellar ataxia, including incoordination of gait, hand, speech, and eye movements. The diagnosis is reached on the basis of family history and neurological examination, but neuroimaging and molecular genetic testing help identify the specific cause and type of SCA. To date, there is no effective treatment. Therapy is directed towards alleviating symptoms. The prognosis depends on individual genetic properties, but most patients progressively develop severe, irreversible disability, while retaining full mental capacity, within 15 years of symptom onset.

Epidemiology Prevalence: ∼ 1-4/100,000 Age of onset: 30-55 years Most common type (worldwide): SCA3 Etiology Primarily autosomal dominant inheritance Currently, more than 30 different mutations have been identified, including: SCA1: mutation on chromosome 6; corresponding protein is Ataxin-1SCA2: mutation on chromosome 12; corresponding protein is Ataxin-2SCA3: mutation on chromosome 14; corresponding protein is Ataxin-3CAG trinucleotide repeat expansion is a common feature Clinical features Features common to all types of SCA: Cerebellar ataxiaProgressive gait ataxia (usually broad-based)Progressive limb ataxia including tremorNystagmusDyssynergia , dysmetria, dysdiadochokinesia, and/or dysarthria may be present. Further clinical features : Type of ADCAImportant SCA typesClinical featuresType ISCA1-SCA4, SCA8, SCA10, SCA12-SCA23, SCA25, SCA27, SCA28AtaxiaOptic atrophyParalysis of extraocular musclesDementiaExtrapyramidal symptoms Type IISCA7AtaxiaPigmentary maculopathy and subsequent blindnessType IIISCA5, SCA6, SCA11, SCA26, SCA29, SCA30, and SCA31Only ataxia; usually late onset Diagnostics The diagnosis is based on family history and neurological examination. Further tests help identify the specific cause and type of SCA. Neuroimaging (CT/MRI): cerebellar atrophy is a finding common to all SCAs Molecular genetic testing: precise identification of SCA typeTreatment There is currently no effective causative therapy available and therefore treatment focuses on symptom management. Canes, braces, and wheelchairs for gait ataxia Use of special devices to assist with fine movements (e.g., handwriting, buttoning clothes, use of eating utensils) Speech therapy for dysarthria and severe speech deficits Most patients progress to severe, irreversible disability within 15 years of onset of symptoms.

Migraine Migraine is characterized by recurrent episodes of typically unilateral, localized headaches that are frequently accompanied by nausea, vomiting, and sensitivity to light and sound. In approximately 25% of cases, patients experience an aura preceding the headache, which involves reversible focal neurologic abnormalities, for example, visual field defects (scotomas) or paresis lasting less than an hour. Migraine is a clinical diagnosis. Treatment of attacks consists of general measures (e.g., bedrest and protection from outer stimuli) together with administration of nonsteroidal anti-inflammatorydrugs (e.g., aspirin) and antiemetics (e.g., prochlorperazine) if nausea is present. In severe cases, triptans may be added. Prophylactic treatment (e.g., beta blockers) may be indicated if migraines are especially frequent or long lasting, or if abortive therapy fails or is contraindicated.

Epidemiology Prevalence: ∼18% of females and ∼6% of males Peak incidence: 30-40 years Migraine is the second most common type of headache. Etiology The exact pathophysiology is unclear. Genetic predisposition Potential triggers Emotional stressWeather changesCertain food and beverages: alcohol, nicotine, citrus fruits, dairy products, food containing tyramine (e.g., chocolate, red wine)Poor sleeping habitsHormonal changes in women: menstruation, hormone intake (oral contraceptive pills) Pathophysiology The pathophysiology of migraine is not fully understood. Different aspects contribute to the development and severity of migraine, such as Vascular dysregulation: vasodilation appears to play a role and there is an association between migraine and disorders with generalized vasospasms Dysregulation of pain sensitization in the trigeminal system Cortical spreading depression: continuously spreading depolarization of neuronal cells in the cortex Clinical features Migraine is characterized by recurrent attacks and may occur with aura (∼ 25% of cases) or without aura (∼ 75% of cases). A typical migraine attack passes through four stages, with aura (if present) appearing before the headache. However, migraine patterns may differ and not follow the characteristic stages. Prodrome (facultative, ∼ 60% of patients): 24-48 hours before the headache startsExcessive yawningDifficulties writing or readingSudden hunger or lack of appetiteMood changes Aura (only present in ∼25% of patients): paroxysmal reversible focal neurologic symptoms Visual disturbances Scintillating scotomaArch-shaped scotomaAppear over ∼ 15-30 minStarts centrally and shifts peripherallyDifferential diagnosis: photopsia in posterior vitreous detachmentCentral scotomaFlashing lightsDistorted color perceptionFortification spectra ParesisImpaired sensibility, paresthesiaDizzinessAphasia HeadacheLocalization: typically unilateral, but bilateral is possible , especially frontal, frontotemporal, retro-orbitalDuration: usually 4-24 hours, rarely over 72 hoursCourse: progression of pulsating, throbbing, or pounding painExacerbated by physical activityAccompanying symptoms: photophobia, phonophobia, and nausea/vomiting Postdrome (facultative) Feeling of exhaustion or euphoriaMuscle weaknessAnorexia or food cravings The typical migraine headache is "POUND": pulsatile, one-day duration, unilateral, nausea, disabling intensity Diagnostics Diagnosis can be made if there is a history of characteristic migraine attacks With aura: ≥ 2 attacksWithout aura: ≥ 5 attacks Physical exam to exclude red flag symptoms, such as : ↑ blood pressure Tenderness of the superficial temporal artery Neck stiffness; fever Severe headache with sudden onset and stiff neck Painful ocular movements Cranial nerve dysfunction Neuroimaging should be used in headaches with an unusual clinical presentation or persistent neurologic or psychopathologic abnormalities. Patients diagnosed with migraines should be screened for cardiovascular disease (especially in smokers and/or if taking oral contraceptives) Differential diagnoses See differential diagnoses of headache Paroxysmal hemicrania Medication overuse headacheTreatmentStop causative medication. Abrupt withdrawal is preferred.Consider tapered withdrawal in the inpatient setting. Treatment Management consists of abortive and/or preventative therapy and varies according to each individual. Abortive therapy General measures: limit stimuli (i.e., light, loud noises) and activity (bed rest) Mild to moderate attacks: NSAIDs (e.g., aspirin or ibuprofen) Severe attacks: triptans (e.g., sumatriptan) or ergotamine (do not combine these agents!)Take early (at the onset of headache) for the best effectFor greater efficacy: combine with NSAIDs Initial therapy if nausea/vomiting is present: intravenous or intramuscular antiemetics (e.g., prochlorperazine, chlorpromazine) Children: ibuprofen and family counseling AgentsSumatriptan, almotriptan Mechanism of action5-HT1 receptor agonist → vasoconstriction of (dilated) cranial and basilar arteriesMost effective if taken at the onset of headacheIndicationsMigraine headachesCluster headachesSide effects Temporary blood pressure increase (very common)Paresthesia and sensation of cold in the extremitiesDizziness, malaise, flashesFrequent intake (≥ 10x/month) can lead to headaches Coronary ischemia (rare)ContraindicationsCoronary artery diseasePeripheral artery diseaseHypertensionPregnancy and breastfeeding Prophylactic therapy Non-pharmacologicalLifestyle changes: exercise in moderation ), avoid potential triggersProgressive muscle relaxationBiofeedback trainingAcupuncture PharmacologicalIndications Frequent attacks (e.g., ≥ 3 attacks/month)Long-lasting attacks (e.g., > 12-24 hours) or auraAbortive therapy fails or is contraindicatedAgents Beta blocker (e.g., metoprolol, propranolol, bisoprolol)Tricyclic antidepressant (e.g., amitriptyline)Anticonvulsants (e.g., topiramate or valproate)Calcium channel blockers (e.g., flunarizine)

Restless legs syndrome Restless legs syndrome (RLS), also referred to as Willis-Ekbom disease (WED), is a relatively common, neurological sleep disorder characterized by unpleasant sensations in the legs and a strong urge to move them. The urge increases during periods of rest, especially in the evenings, and may diminish with movement. Primary RLS is idiopathic and is often associated with a positive family history. Secondary RLS is less common and can result from a variety of underlying conditions, including iron deficiency, attention deficit hyperactivity disorder (ADHD), uremia, and Parkinson's disease. Diagnostic tests are used to exclude secondary causes of RLS (these tests include ferritin levels, vitamin levels, autoantibody assays, thyroid profile, etc.) Treatment for primary RLS includes levodopa and dopamine agonists, while secondary RLS is managed by treating the underlying causes. If left untreated, RLS can cause significant social and functional impairment.

Epidemiology RLS affects approx. 5-15% of the general US population Sex: ♀ > ♂ Peak incidencePrimary: < 45 years of age (often misdiagnosed as growing pains in childhood)Secondary: Although onset of symptoms occurs at < 20 years of age, most cases are diagnosed after 45 years Etiology Primary (common): idiopathic, but is familial in 25-75% of cases SecondaryChronic conditions Iron deficiency with or without anemia, vitamin deficiencyPeripheral neuropathy (i.e., in diabetes mellitus)End-stage renal disease (uremia)Inflammatory conditions: celiac disease, rheumatoid arthritis, inflammatory bowel diseasesPsychiatric: depression, anxiety disordersNeurological: Parkinson's disease, polyneuropathies, spinal cord diseases, multiple sclerosisDrugs: antidepressants (e.g., TCAs, SSRIs, SNRIs), dopamine antagonists (neuroleptics, metoclopramide, MDMA), lithium, beta blockersPregnancy Pathophysiology The pathophysiology of RLS remains unclear Studies suggest that abnormal dopamine pathways in the brain and impaired iron homeostasis (leading to iron deficiency in the substantia nigra) are the most prominent pathophysiological mechanisms involved. Clinical features A recurrent urge to move the legs that is typically relieved by movement and worsened by rest. Often worse in the evening and at night. May occur exclusively at night. Often accompanied by dysesthesias (e.g., pain, pins and needles, itching, tickling, or crawling sensations). ∼ 85% of patients exhibit associated periodic leg movements of sleep (PLMS): This is characterized by involuntary and forceful dorsiflexions of the foot during sleep. Can often lead to social, mental, and/or functional distress and impairment Occurs in the absence of any other explicable cause of symptoms Clinical features of underlying disease in secondary RLS are seen Diagnostics Additional testing may be indicated to rule out an underlying disease, including conducting laboratory tests, nerve conduction studies, polysomnogram, and needle electromyogram. Laboratory testsIron studies (best initial) Other: kidney function, TSH, vitamin B12, folic acid, Mg2+, CBC Polysomnogram: quantification of periodic limb movements of sleep (PLMS) Needle electromyogram and nerve conduction studies: if a polyneuropathy or radiculopathy is suspected reatment Treatment for primary RLS is largely symptomatic. Depending on the underlying cause, secondary RLS can be completely cured. Intermittent treatment may be necessary for recurrent cases with spontaneous remission. GeneralLifestyle changes: abstinence from coffee, nicotine, and alcoholDiscontinue offending agent (e.g., dopamine antagonists)Supplemental iron if serum ferritin < 50 ng/mLTreatment of other underlying conditions Medical therapy: indicated in patients with significant functional and sleep impairmentDopamine agonists (first-line drugs): pramipexole, ropinirole, rotigotine, cabergoline, levodopa with carbidopa Anticonvulsants: gabapentin or pregabalin If not responsive to any other therapy, benzodiazepines (e.g., clonazepam) or opioids (e.g., codeine) may be used.

Vascular dementiaVascular dementia (VD) describes gradual cognitive decline caused by small or large vessel disease. Important risk factors include hypertension, diabetes mellitus, hyperlipidemia, and advanced age. Large vessel changes primarily lead to thrombotic and/or embolic vascular occlusion, resulting in localized infarctions. In contrast, small vessel changes generally lead to more diffuse lesions. Common symptoms are cognitive impairment, motor disorders and changes in behavior. The severity of symptoms and the mode of onset (insidious or sudden) depend on the number of vascular events and the extent of cerebral damage. Vascular dementia is primarily a clinical diagnosis that is supported by evidence of cerebrovascular lesions on imaging. Management consists of treating underlying conditions (e.g., hypertension) and, in some cases, antiplatelet drugs.

Epidemiology Second most common type of dementia (10-20% of cases). Prevalence increases with age (∼ 1-4% in patients ≥ 65 years)Etiology VD may occur as a result of a prolonged and severe cerebral ischemia of any etiology; primarily Large artery occlusion (usually cortical ischemia)Lacunar stroke (small vessel occlusion resulting in subcortical ischemia)Chronic subcortical ischemia Risk factors Advanced ageHistory of strokeUnderlying conditions associated with cardiovascular disease: chronic hypertension, hyperglycemia, hypercholesterolemiaand hypertriglyceridemia, obesityTraumatic brain injury with intracranial or intracerebral hemorrhagePathophysiology Lesions of the smaller (microangiopathy) and larger (macroangiopathy) cerebral arteries share common risk factors and pathological features but produce distinct clinical entities. Small vessel disease Predominantly caused by lipohyalinosis, microatheroma, and/or amyloid beta deposition ) of cerebral vessels → thickening of the intima and/or the vessel wall, inflammation, thromboembolisms → vessel stenosis, occlusion or rupture → cerebral ischemia → VD Mainly causes infarcts or chronic ischemia in subcortical white matter (e.g., internal capsule) and/or in small penetrating arteries (lacunes) → diffuse white matter disease (infarctions or chronic ischemia), subcortical lacunar infarct, or the combination of both (known as Binswanger's disease, which has multiple synonyms) Large vessel disease Primarily caused by atherosclerosis (risk factors include hypertension, diabetes, and hyperlipidemia) Usually in the form of repeated cortical ischemic events → progressive damage to neural networks (multi-infarct dementia). If the affected area is large and/or significant enough (strategic infarctions ), a single ischemic event may suffice to bring on VD (single-infarct dementia) Clinical features Symptoms depend on the location of ischemic events and therefore vary widely between individuals, but a progressive impairment of daily life is common. Because of the diverse clinical picture, the term "vascular cognitive impairment" is gaining popularity over VD . Dementia due to small vessel disease Symptoms tend to progress gradually or stepwise and comparatively slower than in multi-infarct dementia Generally associated with signs of subcortical pathologyEarly symptomsImpaired memoryReduced executive functioningLoss of visuospatial abilitiesConfusion ApathyMotor disorders (e.g., gait disturbance, urinary incontinence) Later symptoms: Further cognitive decline: loss of judgement, disorientationMood disorders (e.g., euphoria, depression) Behavioral changes (e.g., aggressiveness)Advanced stages: Further motor deterioration: dysphagia, dysarthria Dementia due to large vessel disease Usually sudden onset Multi-infarct dementia: typically, stepwise deterioration Generally associated with signs of cortical pathologyCognitive impairment in combination with asymmetric or focal deficits (e.g., unilateral visual field defects, hemiparesis, Babinski reflex present)Symptoms depend on the affected cerebral region(s): see "Clinical features" of stroke Diagnostics VD is a clinical diagnosis (as with all dementias; see the Mini-mental state examination) based on medical history and clinical features, which is supported by imaging findings. UltrasoundDoppler examination of critical vessels (particularly the carotid arteries) for signs of cerebrovascular risk (e.g., atherosclerosis)Echocardiography to evaluate the risk of cardioembolic events Cranial CT: microangiopathic lesions located in white matter, multiple lacunar lesions Functional imaging (PET-CT): may be helpful in distinguishing between VD and Alzheimer's disease (AD). VD: hypoperfusion and hypometabolism more pronounced in the frontal lobeAD: hypoperfusion and hypometabolism more pronounced in the parietal and temporal lobes Cranial MRI : multiple lacunar and white matter lesions (periventricular and in the semioval center) Conduct laboratory tests to rule out other potential causes or comorbidities (e.g., glucose levels, TSH) Differential diagnoses The clinical findings of vascular dementia are often similar to other types of dementia, e.g. Alzheimer's disease. However, there are some distinguishing features (see differential diagnosis of dementia subtypes) Metabolic and endocrine disorders (e.g., vitamin B12 deficiency, hypothyroidism) Infections (e.g., neurosyphilis) Multiple sclerosis Space-occupying lesions (e.g., brain tumors or chronic subdural hematoma) Depression Treatment VD results in an irreversible loss of cognitive skills; management is therefore aimed at symptomatic treatment of dementia (e.g., memory therapy) and prevention of additional ischemic events. For symptomatic treatment of dementia, see major neurocognitive disorder. Eliminate individual risk factors: e.g., antihypertensive therapy, treatment of diabetes, weight reduction Consider antiplatelet drugs (assess risk of bleeding prior to administration!)

Ménière disease Ménière disease is an idiopathic condition affecting the inner ear, in which impaired resorption of endolymphatic fluid causes it to accumulate in the membranous labyrinth (endolymphatic hydrops). The disease usually manifests episodically with a triad of symptoms: vertigo, hearing loss, and tinnitus. Episodes may last from minutes to hours and decrease in frequency as patients age. Hearing loss tends to worsen with every episode. Diagnostic tests show low-frequencyhearing loss, typically with horizontal nystagmus. Acute episodes are treated with bed rest and vestibular suppressants, while long-term prevention therapy focuses on lifestyle changes such as adopting a low-sodium diet and reducing both alcohol consumption and stress. For patients who do not respond to these measures, interventional and/or surgical treatment may be necessary to shut down the vestibular organ.

Epidemiology Sex: ♀ > ♂ Onset: 20-60 years of age Peak incidence: 40-60 years Prevalence: 70-90 in 100,000 individuals in the US Pathophysiology All patients with Ménière disease have impaired endolymph resorption that results in endolymph hydrops; however, not all patients with endolymphatic hydrops have symptoms of Ménière disease. The cause of impaired resorption is unknown. There are currently two main theories about why some patients develop symptoms: Endolymph hydrops: accumulation of fluid in the endolymphatic sac. Rupture theory: fluid accumulation in the endolymphatic sac → tear in the Reissner membrane → increased perilymphatic potassium → depolarization of the afferent acoustic nerve fibers → symptom onset Compression theory: impaired endolymph resorption → compression of the semicircular canals → symptom onset The endolymph is rich in potassium and perilymph is rich in sodium. In Ménière disease, the concentration of potassium in the perilymph increases! Clinical features GeneralRecurrent episodes of acute, unilateral symptoms that last from minutes to hours.Frequency of these episodes decreases as patients age.In 30% of patients, the disease eventually affects both sides. Ménière triadPeripheral vertigoTinnitusSensorineural hearing loss: Low-frequency loss increases with each episode that may lead to deafness after several years. Additional symptomsNausea and vomitingEar fullnessHorizontal nystagmus Diagnostics Diagnostic criteria (American Academy of Otolaryngology) [8]Two or more episodes of vertigo that last 20 minutes to 12 hoursLow-frequency to mid-frequency sensorineural hearing loss on audiometryFluctuating tinnitus or ear fullnessNo other diagnosis is suspected Evaluation of hearing lossTuning fork testsWeber test: lateralization to the healthy ear Rinne test: bilaterally positive Pure tone audiometry: low-frequency hearing lossSuprathreshold audiometry: displays positive recruitment Electroencephalography : normal auditory evoked potentials (AEPs) Vestibular evaluation: declining peripheral vestibular function in the affected ear Imaging: MRI or CT can rule out CNS lesions (e.g., tumors, aneurysms or stenosis of the posterior circulation, Arnold-Chiari malformations, multiple sclerosis). Consider serological screening for neurosyphilis. Differential diagnoses Syphilis Traumatic endolymphatic hydrops (due to e.g., head trauma, barotrauma) See differential diagnoses of vertigo. Treatment ConservativeLifestyle adjustments Avoid dietary and environmental triggers (caffeine, alcohol, and stress).Low-sodium dietVestibular rehabilitation therapy in patients with persistent disequilibrium symptoms between attacksBed restMedical therapy Acute: vestibular suppressants (e.g., dimenhydrinate, benzodiazepines, meclizine); antiemetics (e.g., promethazine, ondansetron)Prophylaxis: histamine analog (betahistine); diuretics (hydrochlorothiazide or triamterene) InterventionalIntratympanic gentamicin injection: repeated application of gentamicin to the middle ear cavity through a small incision in the eardrum (paracentesis); reduces vertigo attacks Sacculotomy: The endolymphatic sac and duct (part of the vestibular organ) are surgically exposed in order to promote drainage of endolymph. Vestibular neurectomy: Surgical lysis of the vestibular bundle entering the internal auditory canal. In some cases, the procedure is associated with hearing loss.

Complex regional pain syndrome Complex regional pain syndrome (CRPS) is characterized by pain, typically in a limb, that is more prolonged and/or severe than would be expected given the initial injury. The pain may be accompanied by sensory abnormalities (e.g., hyperesthesia, allodynia), signs of vegetative dysfunction (e.g., changes in the temperature and color of the skin), and/or loss of motor function. The pathogenesis of CRPS is unclear. On physical examination, patients present with pain and multiple accompanying signs of vegetative and motor dysfunction on the affected side. Although osseous changes may occur in CRPS, diagnosis is based on clinical findings rather than imaging. Multimodal treatment initiated in the early stages of the condition can result in remission and consists of physical and medical therapy (e.g., NSAIDs, anticonvulsants, low-dose tricyclic antidepressants).

Epidemiology Sex: ♀ > ♂ Peak incidence: 40-50 years The upper limbs are affected more often than the lower limbs. Etiology The pathogenesis of CRPS is unknown. However, it can often be linked to an inciting event: Trauma (> 60% of cases)Iatrogenic (e.g., amputation or carpal tunnel surgery) Medical conditionsCarpal tunnel syndromeAcute MI Malignancy: e.g., lung cancer, breast cancer, ovarian cancer, brain tumorsCNS disorders: e.g., traumatic brain injury, stroke, tumor Idiopathic (∼ 10% of cases) Clinical features Symptoms usually develop within 4-6 weeks following a trauma Pain excessive in duration or severity given the inciting event Sensory: hyperesthesia and/or allodyniaVasomotor: hypo-/hyperthermia and/or hypo-/hyperpigmentation of the skinSudomotor/edema: hypo-/hyperhidrosis and/or edemaMotor/trophic: ↓ range of motion and/or strength, tremors, and/or changes in nail and hair growth Diagnostics CRPS is a clinical diagnosisAll four of the following criteria must be met: Persistent pain disproportionate to the original injuryAt least one symptom in three of the following four categories, as reported by the patient: sensory, vasomotor, sudomotor/edema, motor/trophicAt least one sign in two of the following four categories, as assessed by the physician during examination: sensory, vasomotor, sudomotor/edema, motor/trophicExclusion of other possible etiologies (e.g., infection, radiculopathy, neuropathy, vascular disorder) Additional diagnosticsIndication: confirmation of the diagnosis in unclear cases X-ray (low sensitivity) Generalized, patchy demineralization in the periarticular region, which increases over time Subperiosteal bone resorption with preservation of joint spaceTriple-phase bone scintigraphy (high sensitivity and specificity only during first year of the condition): evaluation of increased radiotracer uptake during the mineralization (i.e., third) phase on the affected side compared with the contralateral sideDifferential diagnoses Infection (e.g., tenosynovitis, osteomyelitis) Compartment syndrome Peripheral vascular disease Deep vein thrombosis Peripheral neuropathy Thoracic outlet syndrome Rheumatoid arthritis Raynaud phenomenon Conversion disorder Factitious disorder Treatment Patient education: Explain that the condition, although painful, is not a result of ongoing tissue damage in the region. Psychological interventions: identification and treatment of psychological factors that contribute to pain; treatment of comorbid anxiety or depression; relaxation techniques Physical and occupational therapy: first-line therapyEnsuring daily function and motion of the affected limbDesensitization techniquesLymph drainage for the treatment of edemaHot/cold contrast therapy Medical therapyIndicated for pain management, which facilitates movement of the affected limbNSAIDs and glucocorticoidsAnticonvulsants or low-dose tricyclic antidepressants: may help if the pain is neuropathic in natureTopical lidocaine or capsaicin creamMedications that retard bone resorption CalcitoninBisphosphonates Interventional proceduresIndicated in patients who do not improve with noninvasive therapyTrigger point injections, regional sympathetic nerve block, spinal cord stimulation Prevention Vitamin C supplementation following fractures Early mobilization after injury

Hyperprolactinemia Hyperprolactinemia, which refers to the increased production of prolactin by the anterior pituitary, occurs physiologically during pregnancy, lactation, and periods of stress. Pathological hyperprolactinemia is most often the result of pituitary adenomas and less commonly due to primary hypothyroidism and/or dopamine antagonists (e.g., metoclopramide, haloperidol). Women with pathological hyperprolactinemia present with galactorrhea, loss of libido, infertility, menstrual dysfunction, and/or osteoporosis. Men generally present with loss of libido, erectile dysfunction, and/or gynecomastia. The diagnosis is confirmed by repeated measurement of early morning prolactin levels. After ruling out hypothyroidism, a cranial MRI should be performed to detect pituitary adenomas. Management consists of dopamine agonists (e.g., bromocriptine, cabergoline) and treating the underlying cause.

Epidemiology Sex: ♀ > ♂ Prevalence: ∼ 0.4% of the general population Hyperprolactinemia is the most common form of hyperpituitarism. Etiology Prolactin-secreting pituitary adenomas (prolactinomas) Damage to the hypothalamus and/or infundibular stalk Severe primary hypothyroidism: ↓ T3/T4 → ↑ TRH → ↑ prolactin DrugsDopamine antagonists: Antiemetics: metoclopramideAntipsychotics (e.g., haloperidol, risperidone)Certain tricyclic antidepressants: e.g., clomipramine Catecholamine depletors: e.g., reserpineDopamine synthesis inhibitors: α-methyldopa Oral contraceptive pills Verapamil Opiate analgesics Histamine H2-receptor antagonists (cimetidine, ranitidine) Certain types of focal epilepsy: directly after temporal lobe seizures, due to close proximity to the hypothalamus. Chronic renal failure Stimulation of the reflex suckling arc in the chest wall (e.g., following chest wall surgery, post-herpes zoster) Physiological causes: stress, pregnancy, lactation, nipple stimulation, crying baby, sexual orgasm, sleep, exercise Pituitary adenomas are the most common cause (∼ 50%) of pathological hyperprolactinemia! Pathophysiology ↑ Prolactin → galactorrhea ↑ Prolactin → ↑ central dopamine (prolactin-inhibiting hormone) → suppression of GnRH → ↓ LH, ↓ FSH → ↓ estrogen, ↓ testosterone → hypogonadotropic hypogonadism ↑ ProlactinGalactorrhea (especially premenopausal women) Galactorrhea is rare. ↓ LH + ↓ FSHPrimary and/or secondary amenorrhea, or irregular mensesInfertility Clinical features of ↓ testosterone (see below)↓ TestosteroneLoss of libidoLoss of libido, erectile dysfunction, infertilityGynecomastia Reduced facial and body hairOsteoporosis↓ EstrogenAtrophic endometrium and vaginal atrophy (menopausal symptoms)Osteoporosis (after several years)Little to no noticeable effects Patients with hyperprolactinemia due to a pituitary adenoma may also present with bitemporal hemianopsia and headache Diagnostics Laboratory testsBasal prolactin level Prolactinoma is the most likely cause if the prolactin blood level is permanently > 200 ng/mL. Hypothyroidism and drug-induced hyperprolactinemia (with the exception of risperidone) usually result in mild elevations of prolactin (< 100 ng/mL).Prolactin stimulation test : a prolactinoma is the most likely diagnosis if the prolactin blood level does not increase TSH, T4 levels: to exclude primary hypothyroidismIn premenopausal women: pregnancy test Cranial contrast MRI: to rule out pituitary adenomas Treatment Dopamine agonists (treatment of choice): bromocriptine, cabergoline, quinagolide Treat the underlying causeTranssphenoidal resection of the pituitary adenoma (see "Therapy" in pituitary adenomas)Discontinue or lower the dose of the offending drugTreatment of primary hypothyroidismRenal transplant for patients with CRF

Multiple sclerosisMultiple sclerosis (MS) is a chronic, degenerative disease of the CNS that is caused by an immune-mediated inflammatory process. This process results in the demyelination of white matter in the brain and spinal cord. MS has a higher prevalence among women and people in temperate regions such as Europe and North America. Impaired vision (due to retrobulbar neuritis) is usually the first manifestation of the disease. Other neurological deficits also appear as the disease progresses. The most common clinical course is characterized by exacerbations (relapses) followed by periods of complete/incomplete remission. MRI, which is the investigation of choice, reveals demyelinated sclerotic plaques in white matter. Differential diagnosis of MS includes other chronic demyelinating diseases and neurological infections (e.g., borreliosis, neurosyphilis). Acute exacerbations of MS are treated with high-dose glucocorticoids. Between relapses, patients may be treated with disease-modifying drugs (e.g., β-interferon, glatiramer acetate). No definitive therapy is available for MS.

Epidemiology Sex: ♀ > ♂ (2:1) Age of onset: 20-40 years of age Ethnicity: ↑ prevalence among the white population Prevalence is greater among people in temperate zones. Etiology Unclear Genetic predisposition Environmental triggers UV radiation, insufficient vitamin D consumption, cigarette smokingPathogens: EBV, HHV 6 Pathophysiology Immune-mediated damageExact cause remains unknownCharacterized by inflammation, demyelination, and axonal degenerationMost commonly accepted theory: Activation of autoreactive T-lymphocytes → inflammatory processes → focal demyelination with partial preservation of axons (acute plaques) → loss of axons and atrophy of oligodendrocytes(chronic plaques) → gliosis → inadequate remyelinationThere is evidence for Th1 immune response involving myelin basic proteins Most common sites of demyelination in MSPeriventricular areasBrainstemCerebellumSpinal cord Clinical features Optic neuritis (most often the earliest manifestation): impaired vision and color blindness Internuclear ophthalmoplegia (INO) as a result of a lesion in the medial longitudinal fasciculus (MLF) Ipsilateral medial rectus weakness but an intact convergence reflexDisconjugate, lateral gaze nystagmus in the contralateral eye Demyelination of spinal cord tractsLhermitte's sign: a shooting electric sensation that travels down the spine when the patient flexes his/her neck Absent abdominal reflex Pyramidal tract lesion: upper motor neuron weakness characterized by spasticity, hyperreflexia, and a positive Babinski's sign (see upper vs lower motor neuron lesions)Involvement of the dorsal spinal column : loss of vibration and fine touch sensations, numbness, paresthesias, sensory ataxia Cerebellar involvement → Charcot's neurological triad Scanning speechNystagmusIntention tremors Cranial nerve palsies Autonomic dysfunction: bowel and bladder disorders, impaired sexual activity Change in mental state: memory deficits, impaired concentration, and/or depression Uhthoff's phenomenon: a reversible exacerbation of neurological symptoms following physical exertion, a warm bath, or fever In 60% of cases of optic neuritis, fundoscopy is normal. Neither the patient nor doctor are able to see anything! Uhthoff's phenomenon triggered by a viral infection can be confused with an exacerbation of MS! Relapsing-remitting MS (RR-MS)Exacerbations occurSymptoms remit almost completely between exacerbations90% Secondary progressive MS (SP-MS)Exacerbations occurContinuous worsening of symptoms in between exacerbationsArises from RR-MS (as per definition)Primary progressive MS (PP-MS)No exacerbationsContinuous worsening of symptoms from the very onset of the disease10% Diagnostics Instrument-based diagnostics Plain MRI (brain and spine): investigation of choiceMultiple sclerotic plaques (most commonly seen in periventricular white matter) with finger-like radial extensions (Dawson's fingers) Contrast MRI (with gadolinium): enhancement of active lesion during and up to 6 weeks after the exacerbation Electrophysiological studies: slowed nerve conduction → increased latency of visually evoked potentials (VEP) For more detailed information, see McDonald's criteria.Lumbar puncture for CSF examination Only indicated if MRI is inconclusive Findings Lymphocytic pleocytosisOligoclonal bands (↑ production of IgG subfractions)Differential diagnoses Autoimmune diseases Other causes of inflammatory demyelinationNeuromyelitis optica (Devic's disease) Acute disseminated encephalomyelitis (ADEM, acute demyelinating encephalomyelitis) Vasculitis resulting from connective tissue disorders (e.g., SLE, polyarteritis nodosa, granulomatosis with polyangiitis, Behcet's disease) Infections Neuroborreliosis: diagnosed by CSF examination (intrathecal Borrelia-specific antibodies, lymphocytosis) Neurosyphilis: diagnosed by a TPHA screening test Progressive multifocal leukoencephalopathy (PML): perform an HIV test HIV-encephalopathy: perform an HIV testTreatment Summary of step-wise therapy for multiple sclerosis The goal is to begin treatment as early as possible to treat the primary exacerbation, prevent further exacerbations, and slow down the disease process. Therapeutic strategies include Escalation therapy: Patients who do not respond to first-line therapy with disease-modifying drugs (DMDs), are switched to second-line DMDs.Induction therapy: Patients with severe disease activity at onset, first receive strong immunosuppressant drugs , followed by long-term maintenance therapy with DMDs.IndicationRelapsing remitting MS(RR-MS)Secondary progressive MS (SP-MS)Primary progressive MS (PP-MS)Treatment of acute exacerbationFirst line: high-dose glucocorticoids (methylprednisolone)Second line: plasmapheresisNo exacerbations presentPrevention of exacerbationsFirst line Glatiramer acetateInterferon therapy (IFN-β)Second line: natalizumabInterferon therapy (IFN-β)IV glucocorticoid and/or cyclophosphamide pulses IV methotrexateThere is no established therapy for PP-MS Supportive therapy is essential. Treatment of acute exacerbations First line: high-dose glucocorticoid therapy for 3-5 days (methylprednisolone 500-1000 mg/d IV or PO) If symptoms decrease: End glucocorticoid therapy by slowly tapering the dose.Prophylaxis against side effects of corticosteroids: proton pump inhibitors to prevent gastritis and LMW heparinfor thromboprophylaxis (see → side effects of glucocorticoids) Second line: plasmapheresis Disease-modifying MS therapy (prevention of exacerbations) Interferon beta Suppresses T cell activity → ↓ proinflammatory cytokines and ↓ lymphocyte invasion of the CNS First-line drug in all forms of MS Injection site necrosis Flu-like symptoms Liver dysfunction Thrombotic microangiopathy Depression Glatiramer acetate(copolymer-1) Acts as a decoy for T cells instead of neuronal myelin Chest painHypersensitivity reactionsLipoatrophy MitoxantroneA strong, non-selective immunosuppressant Third-line drug in RR-MS Bone marrow suppression Myocardial toxicity Secondary acute myeloid leukemia (AML) FingolimodA sphingosine-1-phosphate analog which decreases lymphocyteinvasion of the CNSFirst-line drug in RR-MSHemophagocytic lymphohistiocytosis (HLH) AlemtuzumabA monoclonal antibody against the superficial antigen CD52, which is found on the surface of immune cells.(T-cells, B-cells, NKT cells, and monocytes)As a consequence, both B- and T-lymphocytes numbers decrease drastically. SC/IVThird-line drug in RR-MSSecondary, B-cell mediated autoimmune phenomena (e.g., formation of autoantibodies, ITP, glomerulonephritis)NatalizumabAn an antibody against α4-integrin, natalizumab decreases lymphocyte invasion of the CNS. Second-line drug in RR-MSRisk of progressive multifocal leukoencephalopathy in patients with (latent) JC virus infection Supportive therapy Spasticity: dantrolene, baclofen ,physiotherapy Painful paresthesias: carbamazepine, amitriptyline Urinary retention: intermittent catheterization and parasympathomimetic drugs Urinary incontinence: parasympatholytic agents (e.g., oxybutynin) Erectile dysfunction: sildenafil Depression: antidepressants Special patient groups Multiple sclerosis in pregnancy Effect of pregnancy on MS: Decreased relapse rate of MS during pregnancy Increased relapse rate in the postpartum period The long-term clinical course of MS remains unchanged. Effect of MS on pregnancy: ↑ rate of caesarean sections and ↓ birth weights when compared to mothers without MS

Trigeminal neuralgia Trigeminal neuralgia (formerly tic douloureux) is a condition affecting the trigeminal nerve that is characterized by excruciating shooting or stabbing facial pain followed by a burning ache. It is caused by either neurovascular compression from a neighboring vessel (the classical form) or nerve damage resulting from an underlying condition (the painful form), such as multiple sclerosis. Women and older patients are primarily affected, with the peak incidence between 60-70 years of age. Affected individuals experience episodes of facial pain lasting several seconds and occurring up to one hundred times per day. Attacks may happen at rest, but are often triggered by light touch or movements like chewing. Episodes can last from days to years before remitting, but typically reoccur. The excruciating, persistent painoften leads to psychological distress, ranging from dysphoria to severe depression with suicidal tendencies. Diagnosis is based on the patient's medical history and clinical manifestations. Trigeminal neuralgia is managed conservatively with carbamazepine as the drug of choice. Surgery is indicated if medical treatment is not sufficiently effective.

Epidemiology Sex: ♀ > ♂ (2:1) Peak incidence: 60-70 years Etiology Classical trigeminal neuralgia: caused by neurovascular compression, generally by an aberrant loop of a neighboring artery or vein (usually the superior cerebellar artery) Painful trigeminal neuropathy: Multiple etiologies are possible. The condition may be caused by underlying disease (e.g., multiple sclerosis), structural lesions (e.g., tumor, cyst, aneurysms), or ischemia in the trigeminal nerve. Clinical features Unilateral facial pain: paroxysmal, severe shooting or stabbing (like an electric shock), followed by a burning acheLasts several seconds (in rare cases, several minutes) and may appear up to 100 times per dayTypically shoots from mouth to the angle of the jaw on the affected side in most cases Occurs either at rest or triggered by movements such as chewing, talking or touch (e.g., brushing teeth, washing face); becomes worse with stimulation Facial spasms may occur Psychological distress: ranging from dysphoria to severe depression with suicidal tendencies Usually progressive courseDiagnostics Clinical diagnosis If symptomatic trigeminal neuralgia is suspected, possible underlying conditions should be investigated (esp. via head MRI). Consider multiple sclerosis in a young female patient with bilateral trigeminal neuralgia!Treatment Trigeminal neuralgia is usually managed conservatively. Surgery is indicated if conservative treatment is not sufficiently effective. In cases of symptomatic trigeminal neuralgia, treatment of the underlying condition should be considered. Subsequent coexisting conditions (e.g., depression) should be managed as appropriate. Conservative therapy Drug of choice: carbamazepine Surgical treatment Microvascular decompression (Jannetta procedure) Ablative therapy Gamma knife radiosurgery

Myasthenia gravis Myasthenia gravis (MG) is an autoimmune neuromuscular disease characterized by generalized muscle weakness. The pathophysiology of MG involves autoantibodies directed against postsynaptic acetylcholine receptors (AchR), thereby impairing neuromuscular transmission. Women are more frequently affected and about 10-15% of cases are associated with thymoma. The most common initial symptoms are ptosis and/or diplopia due to ocular muscle weakness, with the disease usually progressing to generalized weakness within two years. At that point, patients have difficulties standing up, climbing stairs, and possibly even swallowing and/or chewing. Muscle weakness worsens throughout the day with increased activity and improves after rest. MG is diagnosed according to patient history, physical examination, antibody testing, and electromyographic evaluation. All patients should be screened for thymomas via CT as they can be surgically removed, allowing for possible curative treatment. The treatment of choice consists of acetylcholinesterase inhibitors, possibly in combination with immunosuppressive drugs if symptoms persist. Acute exacerbations, as seen in myasthenic crisis, should be treated with either IV immunoglobulins or plasma exchange.

Epidemiology Sex: ♀ > ♂ (3:2) Age of onsetPossible at any ageOccurs more often in: ♀ : 20-40 years♂ : 60-80 years Etiology Autoimmune: autoreactive antibodies directed against postsynaptic acetylcholine receptors or receptor-associated proteinsAssociation with other autoimmune diseases: especially Hashimoto thyroiditis, rheumatoid arthritis, sarcoidosis, systemic lupus erythematosus Associated withThymoma (the most common primary tumor in the anterior mediastinum) in 10-15% of patientsThymic hyperplasia in 65% of patients In rare cases, can also be caused by graft-versus-host reaction after allogeneic stem cell transplantation (especially in children) Main clinical formsOcular myasthenia: only the extraocular and/or eyelid musclesGeneralized myasthenia: all skeletal muscles may be involved; especially the ocular, bulbar, limb, and respiratory muscles Pathophysiology Thymus involvement: It is hypothesized that the thymus is involved in the pathogenesis of MG.Muscle-like (myoid) cells in the thymus express AChR → thymic T cells target myoid cells → AChR antibody production → antibodies target postsynaptic AChRs of normal muscle cells, competing with acetylcholine (ACh) → impaired signal transduction in the NMJ resulting in: Skeletal muscle weakness and fatigueAChR decay and reduced receptor density on the postsynaptic membrane AChR antibodiesSeropositive MG (85% of cases): positive for antibodies against the acetylcholine receptor (AChR), or against muscle specific tyrosine kinase (MuSK) Seronegative MG (15% of cases): negative assays for both AChR antibodies and MuSK antibodies Clinical features Clinical course Symptoms worsen with increased muscle use throughout the day and improve with rest. Sometimes associated with exacerbating factors, including: Medications: muscle relaxants, beta blockers, benzodiazepines, aminoglycosides, low-potency antipsychotics, tricyclic antidepressants, d-penicillamineStressInfectionPregnancy Clinical manifestations Smaller muscles responsible for fine movements (i.e., the eye muscles) tend to be affected first, while larger muscles become affected later on. Eye muscle weakness: most common initial symptomPtosis DiplopiaBlurred vision Bulbar muscle weaknessSlurred speech, difficulty chewing and/or swallowing Proximal limb weaknessRising from a chairClimbing stairsBrushing hair Weakness of respiratory muscles Diagnostics Suspected cases of MG are generally confirmed via EMG and AChR antibodies and should receive a chest CT to rule out thymoma. AChR antibody test (most specific test)85% of patients with generalized MG have antibodies100% of patients with thymoma have antibodies Other associated antibodies: anti-MuSK Electromyography (EMG): a decremental response following repetitive nerve stimulation Chest CT: always indicated in newly diagnosed MG patients to rule out thymoma Edrophonium test (Tensilon test)Symptoms improve rapidly after administration of a short-acting acetylcholinesterase inhibitor High false positive rate Differential diagnoses Lambert-Eaton myasthenic syndrome (LEMS)Description: LEMS is a rare autoimmune disease that reduces neuromuscular transmission and leads to muscle weakness.Pathophysiology: Autoantibodies are directed against presynaptic voltage-gated calcium channels → impaired acetylcholine release in the NMJ.Association: small-cell lung carcinoma (in ⅔ of LEMS cases)Clinical featuresProximal muscle weaknessReduced or absent reflexesAutonomic symptomsDry mouth ConstipationOrthostatic dysregulationDiagnosticsPhysical examination Active muscle contraction or repeated muscle tapping increases reflex activity.Lambert's sign: Muscle strength improves after muscle use. EMG: Repetitive nerve stimulation results in incremental responses.Confirmatory test: serologic detection of antibodies directed against voltage-gated calcium channels Congenital myasthenic syndrome Genetic defects in proteins of the neuromuscular junction (NMJ) lead to neuromuscular diseasePresents with similar symptoms as MG (depends on the type of defect), but typically start during infancy or childhood Amyotrophic lateral sclerosis Chronic progressive external ophthalmoplegia (for ocular symptoms) Treatment First line: cholinesterase inhibitors Drug of choice: pyridostigmineProvides symptomatic reliefSide effects: see symptoms of cholinergic crisis Supplemental immunosuppressants: if symptoms persist despite anticholinesterase treatment GlucocorticoidsAlternatives: azathioprine, cyclosporine, mycophenolate mofetil Rapid immunomodulating therapies: in cases of myasthenic crisisPlasmapheresisIV immune globulin Thymectomy: can be beneficial even if a thymoma is not presentNot for patients with MuSK antibody-associated MG without a thymoma Complications Myasthenic crisisAffects 15-20% of patients with MG Generally occurs during the active phase within 5-7 years after onsetAcute, life-threatening exacerbation of myasthenic symptoms that leads to respiratory failure → early endotracheal intubationPotential triggers InfectionSurgery, anesthesiaPregnancyMedicationsNot to be confused with cholinergic crisis Cholinergic crisisShared symptomsMuscle weakness, dyspnea, sweating, agitation, disorientation, drowsiness, urinary and fecal urgency Myasthenic crisis Tachycardia Cold and faint Cholinergic crisis Miosis Bradycardia Fasciculations Bronchial secretion Prognosis The prognosis of ocular MG is good. Mortality Without treatment: up to 30%With treatment: less than 5%

Huntington disease Huntington disease (HD) is a neurodegenerative movement disorder characterized by involuntary and irregular movements of the limbs, neck, head, and/or face (chorea). This autosomal-dominant inherited disease is caused by mutations (increased number of CAG trinucleotide repeats) in the huntingtin gene which eventually leads to dysfunction of subcortical motor circuits. Symptom onset depends on the individual extent of the genetic abnormalities but usually occurs around 40 years of age. In later stages, psychiatric symptoms like dementia and depression are common. To date, no disease-modifying treatment is available. Management involves symptomatic treatment and supportive care. On average, HD leads to death within 19 years.

Epidemiology Sex: ♂ = ♀ Peak incidence: ∼ 40 years of age One of the most common hereditary diseases of the brain. Etiology Increased number of CAG repeats in the huntingtin gene on chromosome 4 (most likely due to DNA polymerasemalfunction) → expression of an altered huntingtin protein 40 or more repeats → development of HD is almost certain Huntingtin is physiologically expressed throughout the CNS, but its exact function is not known. InheritanceAutosomal dominantAnticipation: increase in the number of CAG repeats in subsequent generations Pathophysiology Summary: Molecular and cellular changes lead to neuronal loss and gliosis in the striatum (particularly in the caudate nucleus) and, subsequently, the thalamus and the cortex PathomechanismOverall levels of abnormal huntingtin protein correlate with the severity of symptoms.The striatum normally controls movement via inhibitory outputs to the globus pallidus internus (direct pathway) and globus pallidus externus (indirect pathway).Direct pathway: striatal projections inhibit the internal globus pallidus, which normally inhibits the thalamusand its excitatory projections to the cortex (→ activation of the direct pathway generally results in increased transmission to the cortex)Indirect pathway: striatal projections inhibit the external globus pallidus, which normally inhibits the subthalamic nucleus. The subthalamic nucleus possesses excitatory projections to the internal globus palliduswhich in turn projects to the thalamus and ultimately to the cortex (→ activation of the indirect pathway generally results in decreased transmission to the cortex)In HD, the indirect pathway is commonly affected earlier than the direct pathway. Early stages: only the indirect pathway is affected → increased dopaminergic transmission → excess cortical activity → hyperkinetic/choreatic movementsLater stages: both pathways are affected, which, together with additional factors, causes an overall decrease of excitatory thalamic transmission to the cortex → hypokinetic/akinetic symptoms Clinical features Initial stagesMovement dysfunctionChorea (involuntary, irregular, nonrepetitive, arrhythmic movements of the limbs, neck, head, and/or face)Oculomotor disorders (e.g., reduced velocity in optokinetic nystagmus, hypometric saccades)HyperreflexiaSensory deficitsAutonomic symptoms (hyperhidrosis, urinary incontinence) Advanced stagesMovement dysfunctionHypokinetic motor symptoms (dystonia, rigidity, bradykinesia) Akinetic mutism (inability to move or speak)Motor impersistence (inability to sustain simple voluntary acts, e.g., tongue protrusion)Dysarthria and dysphagiaCognitive decline and behavioral changesDementia (particularly executive dysfunction)Depression (possibly including suicidal tendencies)ApathyAnxietyAggression and psychosis Cachexia (due to dysphagia and high energy consumption) Atypical symptomsGait ataxiaMyoclonus or seizures Chorea characterizes the early stages of the disease while hypokinetic/akinetic symptoms may dominate later on! Dementia, depression, and behavioral disorders are common in advanced stages! Diagnostics Patient history Genetic testing, e.g. polymerase chain reaction Imaging is rarely used CT/MRI: Atrophy of the striatum, most pronounced in the caudate nucleusFDG-PET: disorder of glucose metabolism in the striatum (apparent early) Differential diagnosis of choreoathetoid movement disorders Epidemiology & etiologySigns & symptomsDiagnosticsHuntington diseaseAlmost always younger or middle-aged men or womenGenetic (CAG trinucleotide repeats)Motor symptoms Motor impersistenceDystoniaDysphagiaNeuropsychiatric symptoms (e.g., inappropriate laughing/crying, psychosis, akinetic mutism)Genetic testing (→ CAG repeats)CT/MRI (→ brain atrophy)Sydenham choreaUsually children, especially girlsCNS manifestation of rheumatic feverMotor symptoms Muscle weaknessMotor impersistenceNeuropsychiatric symptoms (e.g., inappropriate laughing/crying, obsessive-compulsive behavior)Atypical symptoms: fever, fatigue, malaiseDiagnosis of rheumatic fever (e.g., ↑ CRP)Wilson diseaseUsually younger or middle-aged men or womenGenetic (mutations in hepatic coppertransport protein ATP7B)Motor symptoms Asymmetrical tremorParkinsonismDystoniaAtaxiaGeneral signs of liver disease (e.g., jaundice, hepatomegaly)Signs of copper deposition (e.g., Kayser-Fleischer rings)Neuropsychiatric symptoms (e.g., psychosis, anxiety, mood disorders)Laboratory (e.g., ↓ ceruloplasmin, ↑ liver enzymes)Abdominal imaging (→ hepatomegaly and/or splenomegaly)Liver biopsy (if other diagnostics are inconclusive) Creutzfeldt-Jakobdisease Very rare Infectious (prionparticles) Rapid progression Motor symptoms MyoclonusHypokinesiaAtaxia, nystagmus Neuropsychiatric symptoms (e.g., sensory disturbances, mutism, sleep disorders) EEG (e.g., periodic sharp wave complexes during illness) Laboratory (e.g., 14-3-3 protein in CSF) MRI (→ abnormalities in caudate nucleus and/or putamen) Systemic lupus erythematosus(SLE) Most commonly affects women of childbearing age Chronic inflammatory, possibly autoimmune (exact cause unknown) Motor symptoms SeizuresAphasia Hemiparesis Neuropsychiatric symptoms (e.g., confusion, coma) Fatigue, fever, myalgia, weight change Arthritis, arthralgia Cardiovascular, pulmonary and/or renal disorders (e.g., vasculitis, pleural effusion) Hair loss, photosensitive skin lesions, rash, oral/nasopharyngeal ulcers Laboratory (e.g., antinuclear antibodies, antiphospholipid antibodies, complement levels, ↑ ESR, ↑ CRP, altered urine, ↑ protein-to-creatinine ratio) Ballismus Rare disorder typically affecting elderly diabetic patients Hemorrhagic or ischemic stroke Nonketotic hyperglycemia Brain metastases Infectious (e.g., HIV) Motor symptoms Involuntary, proximal, violent, and large-amplitude movements of one or both extremities (e.g., kicking, flinging) Typically unilateral (e.g., hemiballism)Can be associated with chorea and athetosisMay be present as a transient symptom during the acute phase of stroke CT/MRI (→ changes in the basal ganglia) Contralateral subthalamic nucleus Other regions of the basal ganglia can cause a similar manifestation Treatment General approachOngoing physiotherapeutic, ergotherapeutic, and logotherapeutic carePsychotherapy (if needed)Consultation of specially trained counselors (if genetic diagnostics are employed) Medical therapyHyperkinetic/choreatic movements Monoamine‑depleting drugs (e.g., tetrabenazine)Atypical neuroleptics (e.g., clozapine)NMDA-receptor antagonists (e.g., amantadine)Psychosis: atypical neuroleptics (e.g., clozapine)Depression: SSRIs (e.g., citalopram) Prognosis Progressive Mean duration of illness: approximately 19 years Cause of death: often respiratory insufficiency or aspiration pneumonia

Tourette syndrome Tourette syndrome is a severe neurological movement disorder characterized by tics, which are involuntary, repeated, intermittent movements or vocalizations. It is a genetic disorder that commonly presents in boys and is often associated with attention deficit hyperactivity disorder (ADHD) or obsessive-compulsive disorder (OCD). Diagnosis is based upon multiple motor tics and at least one vocal tic, lasting for longer than a year, and the exclusion of other suspected medical conditions. Treatment is symptomatic and includes behavioral therapy and dopamine antagonists. Approximately 50% of cases resolve by adulthood.

Epidemiology Sex: ♂ > ♀ Age of onset: usually 2-15 years of age Etiology Hypothesized to be a combination of environmental, social, psychological, and genetic factors Autosomal dominant inheritance is possible (rare) AssociationsADHD and/or OCD (most common)Learning disabilitiesSleep disordersConduct disorder and oppositional defiant disorderMood and anxiety disorders Clinical features TicsSudden and rapid involuntary, intermittent, nonrhythmic movements or vocalizations without any recognizable purposeTemporarily suppressibleAn urge or sensation preceding the tic is relieved by its onset. SimpleComplexVocal ticsThroat clearingGruntingLip smackingBarkingSniffingCoprolalia: uttering obscene or socially inappropriate words or phrases Echolalia: repeating vocalizations of othersMotor ticsFacial grimacingBlinkingShoulder shruggingHead jerkingJumpingTwisting the bodyEchopraxia: repeating movements of others Diagnostics Clinical diagnosis based on all of the following: Multiple motor tics and at least 1 vocal tic with a variable anatomical location, frequency, number, frequency, complexity, type, or severity over time Onset before 18 years of age Lasting > 1 year Not explained by other medical conditions or substance use (e.g., cocaine) Differential diagnoses Other tic disordersSporadic transient tic disorder (occurs in up to 25% of normal children) Motor and/or vocal ticsOnset before 18 years of ageSymptoms occur for less than 1 year (resolve spontaneously) Not explained by any other medical conditions or substance abuseDo not meet the criteria for Tourette's syndrome Persistent motor tic disorder or persistent vocal tic disorderMotor or vocal tics (not both)Onset before 18 years of agePersist > 1 yearNot explained by any other medical conditions or substance abuseDo not meet the criteria for Tourette's syndrome Stereotypic movement disorderStereotypic, uncontrolled, repetitive movements lasting ≥ 4 weeksMore common in children, especially boys, with neurological disorders and developmental retardationIncludes rocking movements, hair pulling, hair twisting, and self-destructive behavior (e.g., head banging, picking at skin, hitting oneself) Seizures (see seizure disorders) Tardive dyskinesia Symptoms worsen in severity, frequency, and during voluntary movement unlike in Tourette's syndrome Huntington's disease Treatment Support: Counseling and education (caregivers and patients) Behavioral therapyIndicated for mild, nondisabling symptomsInvolves habit reversal training or Comprehensive Behavioral Intervention for Tics (CBIT) Medical therapyIndicated for severe or refractive cases despite behavioral therapy Alpha-adrenergic agonists: guanfacine (often first-line therapy), clonidine (very sedating) Typical neuroleptic drugs: pimozide or haloperidol (FDA-approved but may cause tardive dyskinesia) Atypical neuroleptic drugs: risperidone (increasingly preferred because of fewer side effects)Dopamine depleting drugs: tetrabenazine (may be used as first-line therapy to avoid side effects of neurolepticdrugs i.e., dopamine blockade) Prognosis Symptoms peak during adolescence and improve during adulthood. May resolve spontaneously by 18 years of age (50% of cases)

Subdural hematoma Subdural hematoma (SDH) refers to bleeding between the dura mater and arachnoid membrane. It is caused by head trauma that results in a tear in the bridging vein, which connects the superficial cerebral veins to the dural venous sinuses. The onset of symptoms may be acute, subacute, or chronic. Symptoms of SDH include headaches, changes in mental status, and focal neurologic deficits. CT and MRI scans are used to diagnose SDH, which presents as a crescent-shaped collection of blood that crosses the suture lines but not the falx or tentorium. Treatment may be surgical (e.g., trephination) or supportive, depending on the size of the subdural hematoma. Supportive therapy involves close clinical monitoring, normalizing coagulation parameters of patients on anticoagulant therapy, and preventing intracranial hypertension The prognosis of patients with chronic SDH is significantly better than those with acute SDH.

Epidemiology Sex: ♂ > ♀ (3:1) Etiology Rupture of the bridging veins caused by: Blunt head trauma (most common) Shaken baby syndrome Frequent falls (e.g., due to old age, alcohol abuse, epilepsy, hyponatremia) Nontraumatic intracranial hemorrhage Anticoagulation therapy or coagulopathyRuptured intracranial aneurysmArteriovenous malformationIntracranial tumors Idiopathic, or iatrogenic (i.e., surgical) causes SDH may occur after trivial trauma in patients with multiple risk factors! Classification Classification is based on the onset of symptoms after the inciting event. Acute SDH: immediately after trauma or rapidly within 72 hours Subacute SDH: 4-21 days after trauma Chronic SDH: > 21 days after traumaPathophysiology SDH is a form of intracranial hemorrhage in which blood accumulates between the dura mater and arachnoid membrane. Tearing in bridging veins → low-pressure venous bleeding. Clinical features Symptoms and their onset depend on the size, location, and rate of growth of the SDH. Headache Impaired consciousness and confusion Focal neurologic signs (i.e., hemiparesis , gait, speech, or visual impairment, personality changes, or a dilated or nonreactive pupil ) Memory impairment Both SDH and epidural hematoma can occur after head trauma and cannot be differentiated based on symptoms alone! Diagnostics SDH is diagnosed on brain imaging. Non-contrast head CT scan is the modality of choice. MRI is indicated when CT scan is inconclusive but suspicion for subdural hematoma is high. Appearance on brain imaging Crescent-shaped, concave hemorrhage that crosses suture lines but not the midline Varies depending on clot age and organization: CTMRI Acute SDHHyperdense with respect to the cortex Hypointense to isointense with respect to grey matterSubacute SDHIsodense with respect to the cortex after 10-14 days Mostly hyperintense Chronic SDHHypodense with respect to the cortex and may appear isodense with respect to cerebrospinal fluid Mostly isointense with respect to cerebrospinal fluid In contrast to SDH, epidural hematoma is lentiform on imaging and does not cross suture lines but can cross the falx or tentorium! Treatment Treatment depends on size and onset of SDH, as well as the patient's condition. General measuresClose clinical monitoring (especially neurological status)Measuring and optimizing intracranial pressure; see ICP managementNormalizing of clotting parameters Conservative treatmentIndicated if no clinical signs of herniation are present and the neurological status is stable, midline shift < 5 mm, and the hematoma is < 10 mmMonitoring with serial CT scans Surgical decompressionIndications (Only one of the following criteria must be met.) Clinical signs of herniationUnstable neurologic statusMidline shift > 5 mmHematoma > 10 mmProcedures Trephination and drainage of hematoma: A burr hole is drilled in the skull and the hematoma is drained.Craniotomy and evacuation of hematoma: A bone flap is removed from the skull and the hematoma is evacuated. Prognosis The prognosis of chronic SDH is better than that of acute SDH.

Vestibular neuritis Vestibular neuritis is idiopathic inflammation of the vestibular nerve that most frequently occurs following viral infections of the upper airways. The disorder manifests with acute-onset vertigo, nausea, vomiting, and gait instability in otherwise healthy patients. Management involves bed rest, corticosteroids, and antivertigo agents (e.g., dimenhydrinate); vestibular rehabilitation therapy may accelerate recovery. Symptoms typically resolve in 2-3 weeks with treatment.

Etiology Vestibular neuritis is an idiopathic disease. It tends to occur more often after upper airway infections Clinical features Acute onset of symptoms in otherwise healthy patients. Severe symptoms last for 1-2 days, mild symptoms may persist for weeks or even months: Severe vertigoNausea and vomitingGait instabilityNystagmus Increased risk of falling towards the affected side Patient history may include recent infection of the upper airways. No cochlear symptoms (e.g., hearing loss, tinnitus)! Diagnostics Vestibular neuritis is a clinical diagnosis. Positive head thrust test: The examiner turns the patient's head rapidly towards the affected side; the test is considered positive if the patient is unable to maintain visual fixation. Imaging studies (to rule out stroke or brain tumors, but not for routine diagnostics) MRIMRACT Audiogram: unremarkable Imaging studies are indicated in patients older than 60 years, as well as those with persistent vestibular symptoms, headache, vascular risk factors, or focal neurologic symptoms to rule out a lateral medullary/cerebellar stroke! Ménière disease Vertigo lasts for minutes to hours Cochlear symptoms: hearing loss, tinnitus Benign paroxysmal positional vertigo Vertigo for only a few seconds Vertigo is always triggered by movement (e.g., lying down, reclining) Persistent postural-perceptual dizziness Not actually vertigo, but a sensation of dizziness that lasts for at least 3 months Vestibular neuritis Severe vertigo for 1-2 days Mild symptoms (e.g., nausea) may persist for weeks or monthsPatient history may include recent infection of the upper airways Central vertigo Site of underlying disorderCNS (cerebellum, brainstem) Associated cerebellar symptoms (e.g., ataxia, dysmetria)Marked Sense of motionMild Associated skew deviationPresentAssociated nystagmusCan be torsional, horizontal, or vertical Direction of nystagmus changes with gaze change.Gaze fixation worsens nystagmus.Associated hearing loss and/or tinnitusRareAssociated focal neurological findings (e.g., diplopia)CommonCausesDemyelination (e.g., multiple sclerosis)Brainstem ischemia (e.g., vestibular nucleistroke)Cerebellar infarction and hemorrhagePosterior fossa tumorsVestibular migraineTransient ischemic attack Peripheral vertigo Inner ear (e.g., vestibulocochlear nerve, semicircular canals) Torsional and horizontal (never vertical) Direction of nystagmus does not change with gaze change. Gaze fixation improves nystagmus. Ménière disease (endolymphatic hydrops) Benign paroxysmal positional vertigo (semicircular canaldebris) Otitis media Acoustic neuroma Vestibular neuritis Treatment Bed rest Corticosteroids (e.g., prednisolone) Symptomatic treatment Antivertigo agents (e.g., dimenhydrinate, meclizine)Antiemetics (e.g., droperidol)Sedatives (e.g., diazepam) Vestibular rehabilitation therapyVestibular rehabilitation is generally used to treat patients with permanent vestibular injury, but it may also speed up recovery in patients suffering from vestibular neuritis.

Cluster headache Cluster headache (CH) is a type of primary headache that mostly affects adult men. Patients present with recurrent, fifteen minute up to three hour attacks of agonizing, strictly unilateral headaches in the periorbital and forehead region (areas innervated by the trigeminal nerve). These attacks are associated with ipsilateral symptoms of increased cranialautonomic activity, e.g., lacrimation, conjunctival injection, rhinorrhea, or partial Horner syndrome. Cluster headaches tend to occur in episodic patterns ("cluster bouts") followed by months of remission, but are considered chronic if remission between bouts lasts less than one month. Diagnosis is based on the patient's history, in particular on the exact description and timing of the headaches. Acute episodes are treated with 100% oxygen or triptans, while verapamil is used for preventative treatment.

Epidemiology Sex: ♂ > ♀ (3:1) Peak incidence: 20-40 years Etiology Not entirely understood Risk factor: tobacco use Possible triggers: alcohol, histamine, seasonal fluctuations Clinical features Headache characteristicsAgonizing painStrictly unilateral, periorbital, and/or temporalShort, recurring attacks that usually occur in a cyclical pattern ("clusters") May become chronic (less common), with interruptions of less than one month between cluster bouts Attacks often wake patients up during sleep. Ipsilateral autonomic symptomsConjunctival injections and/or lacrimationRhinorrhea and nasal congestionPartial Horner syndrome: ptosis and miosis, but no anhidrosis Restlessness and agitation iagnostics Based on patient history and physical examination Rule out any suspected underlying disease Neuroimaging Doppler ultrasound carotid artery dissection Differential diagnoses See learning card on "Headache" for more information regarding differential diagnoses. Paroxysmal hemicraniaEpidemiologyRare; the exact prevalence is unknown Equal gender distribution: ♀ = ♂Clinical featuresSevere unilateral attacks of periorbital pain that recur several times per dayCranial autonomic dysfunction (e.g., lacrimation, conjunctival injection) Attacks are generally more frequent (usually ≥ 5 per day) and shorter (2-45 min) than cluster headaches and may occur at any time of the day. Treatment: no established treatment for acute attacks Prevention: indomethacin Treatment Medical therapy AcuteOxygen therapy with FiO2 100%First-line: triptans (e.g., sumatriptan) or zolmitriptan Pain relievers (i.e. NSAIDs) are generally not recommended because their onset of action is too slow. Prevention First-line treatment: verapamil Steroids (e.g., prednisone) are very effective at ending a cluster cycle and may be used to bridge the time until verapamil becomes effective.Second-line treatment: lithium, topiramate, ergot derivatives Interventional therapy Interventional procedures (e.g., ablative injections, deep brain stimulation) may be considered in patients with cluster headache who do not respond to medical therapy.

Epidural hematoma Epidural hematoma occurs as a result of head trauma and subsequent acute hemorrhage, primarily from the middle meningeal artery between the skull and the dura mater. Typical symptoms are due to compression of the brain and appear after a lucid interval that follows an initial loss of consciousness. Increased intracranial pressure leads to a decline in mental status and anisocoria, in which the ipsilateral pupil is dilated. Diagnosis is confirmed by CT (biconvex, hyperdense, sharply demarcated mass). Emergency treatment is necessary and involves neurosurgical opening of the skull and hematoma evacuation. For epidural hematoma limited to the spine, see spinal epidural hematoma.

Epidemiology Sex: ♂ > ♀ (4:1) Peak incidence: 20-30 years Pathophysiology The epidural space is a potential space between the dura mater and the calvarium. Head trauma (usually severe) → skull fracture (often temporal bone) → rupture of a middle meningeal artery → ↑ intracranialpressure → CN III palsy , herniation Nontraumatic causes of epidural hematoma are very rare. Clinical features Typical clinical course Initial loss of consciousness following head traumaTemporary recovery of consciousness (lucid interval) Renewed decline in mental status Elevated intracranial pressureHeadacheNausea and vomitingIpsilateral anisocoriaHypertension, bradycardia, and respiratory irregularity (Cushing's reflex) Contralateral focal symptoms/hemiplegia Impaired mental status, seizures, coma Clinical signs of skull fracture (e.g., local hematoma, swelling, laceration) Diagnostics Imaging of choice: noncontrast head CT scan Biconvex , hyperdense lesionMost epidural hematomas are located in the temporoparietal junction and are sharply demarcated. Hematomas are limited by suture lines. In some cases, an accompanying cranium fracture may be seen. Noncontrast head CT scan is key for the diagnosis of epidural hematoma! Epidural hematoma EtiologyTraumatic rupture of middle meningeal artery Clinical featuresLucid interval, then loss of consciousnessHeadacheHemiplegiaCT findingsBiconvex, hyperdense lesion located between the brain and the calvarium, limited by suture lines ManagementSurgical drainage Subdural hematoma Traumatic rupture of a bridging vein Increasing headacheover days or weeks Changes in mental status Less frequently: lucid interval Crescent-shaped, homogenous lesion between the brain and the calvarium, not limited by suture lines Surgical drainage Subarachnoid hemorrhageMost cases secondary to rupture of a saccular aneurysm or arteriovenous malformation (AVM) Trauma Sudden, severe headache Loss of consciousness Extensive area of hyperdense signals around the circle of Willis (most common location) Medical therapy to reduce vasospasm Surgical intervention: clipping or endovascular repair Intracerebral hemorrhage Most cases secondary to hypertension Rupture of AVM Trauma Headache Focal neurologic deficits Loss of consciousness Solitary hyperdense lesion, surrounded by hypodense edema (most commonly within the basal ganglia or internal capsule) Supportive care Surgical clot removal (depends on the location and extent of the hemorrhage) Ischemic strokeCommonly due to embolisms, thrombi, or microangiopathicchanges Arterial hypertension and increasing ageare the most important risk factors Headache Focal neurologic deficits Loss of consciousnessHyperdense MCA sign Effacement of sulci Loss of cortico-medullarydifferentiation Edema Supportive care Thrombolytic therapy Anticoagulation Mechanical thrombectomy Treatment Initial resuscitationIV fluids (if hypotension is present)Intubation Management of elevated intracranial pressureHead elevationIf patient is intubated, hyperventilationOsmotic diuresis with mannitol or hyperosmotic saline solution Surgical managementFirst-line: urgent craniotomy and hematoma evacuationSecond-line: emergency burr hole Prognosis Mortality rate: depends on preoperative condition of patient Almost zero in patients without severe neurological impairment (GCS > 8) Patients in deep coma: ∼ 20% Factors associated with a worse prognosis Low Glasgow Coma Scale scores before surgical interventionDelay in treatmentAge > 75 years

Friedreich ataxia Friedreich ataxia (FDRA) is an autosomal recessive disorder involving trinucleotide repeat expansion that leads to progressive neurodegeneration. It affects multiple spinal cord tracts, causing muscle weakness and impaired coordination of all limbs. A staggering gait in childhood is the resulting main symptom. Other features include skeletal abnormalities, cardiomyopathy, and diabetes. The clinical course is mainly determined by the extent of the loss of mobility and cardiac involvement. Diagnosis requires confirmation with genetic tests. Because there is no curative therapy available, the prognosis is poor.

Epidemiology The most common autosomal recessive ataxia Peak incidence: 8-15 years (most cases < 25 years) Most common in white populations Etiology Trinucleotide repeat expansion (of the nucleotide triplet GAA) in the FXN gene on chromosome 9 → intramitochondrial accumulation of iron and dysregulation of cellular antioxidant defense → oxidative damage and degeneration of both CNS and PNS Clinical features NeurologicalProgressive ataxia (muscle weakness and impaired coordination) of all limbs Bilateral lower limbs equally affected Wide-based steppage gait with dysmetria and frequent fallingTitubation while standing or sitting Torso and arms Action and intention tremorsChoreiform movementsAssociated impaired proprioception, vibration sense (pallhypesthesia), and loss of deep tendon reflexesDysarthria and dysphagia (may be accompanied by uncoordinated breathing) Skeletal deformitiesSecondary scoliosis Foot deformity: foot inversion (pes cavus) with hammertoes Concentric hypertrophic cardiomyopathy: palpitations, arrhythmias, dyspnea, exercise intolerance Diabetes mellitus Personality changes (e.g., emotional lability) Diagnostics A specific trinucleotide repeat expansion assay should be performed in all suspected cases. ECG: T-wave inversion and ventricular hypertrophy Echocardiography: symmetric, concentric ventricular hypertrophy Nerve conduction studiesSensory: absent or reduced sensory nerve action potentials (SNAP)Motor: normal until advanced stages MRI brain and spinal cord: cervical spine atrophy (minimal cerebellar atrophy) reatment No curative treatment available Multidisciplinary supportive care: genetic counseling, physiotherapy, and speech and language therapy Treatment of cardiologic, orthopedic, and metabolic (i.e., diabetes) features of the disease Prognosis Nonambulation is common by age 20-30. Average age at death: 37 years Cause of deathMost common: heart failure due to hypertrophic cardiomyopathyRespiratory complications

Subarachnoid hemorrhage Subarachnoid hemorrhage (SAH) refers to traumatic as well as nontraumatic bleeding into the subarachnoid space. SAH most often results from head trauma. Nontraumatic SAH is responsible for 5-10% of all strokes and is most commonly caused by the rupture of an aneurysm involving the circle of Willis. SAH typically presents with severe headache, nausea, vomiting, and/or acute loss of consciousness. Acute bleeding in the subarachnoid space appears hyperdense on noncontrast CT scan, which is the initial recommended test in diagnosis. CT angiography and lumbar puncture may be necessary for further evaluation if the initial noncontrast head CT is unremarkable. Treatment consists of carefully lowering blood pressure and preventing cerebral vasospasm. Definitive management typically consists of clipping or coiling the bleeding aneurysm to prevent potentially fatal rebleeding. SAH has a high mortality rate as a result of complications such as rebleeding and secondary ischemic strokes due to vasospasm.

Epidemiology TraumaticHead trauma is the most common cause of SAH.40-60% of patients with traumatic brain injury have subarachnoid bleeding. [1] NontraumaticRuptured cerebral aneurysm is the most common cause of nontraumatic SAH.Peak incidence: approx. 50 years of age♀ > ♂ (3:2)Nontraumatic SAH is responsible for 5-10% of all strokes. [2] Etiology Traumatic: traumatic brain injury Nontraumatic (spontaneous) Causes Ruptured aneurysms, most commonly in the circle of Willis Berry aneurysms (approx. 80% of cases of nontraumatic SAH):Round, saccular aneurysms located at major branches of large arteriesMultifactorial etiology High risk of ruptureRuptured arteriovenous malformation (AVM) (approx. 10% of cases of nontraumatic SAH) Others: cortical thrombosis, angioma, neoplasm, infectionTriggers: most cases unknown, may be triggered by an acute rise in blood pressure (e.g., caffeine consumption, fits of anger, physical exertion) Risk factors [5]SmokingHypertensionHigh alcohol consumptionPositive family history Methamphetamine and cocaine use Clinical features Thunderclap headacheSudden, severely painful headache HolocephalicRadiates to the neck and backMay present with opisthotonus Meningeal signs : Neck stiffnessPhotophobiaNausea and vomitingKernig signBrudzinski sign Nonspecific signsImpaired consciousness (somnolent to comatose) Fever Sweating, hemodynamic instability Signs due to mass effectCranial nerve disorders Altered mental status (e.g., delirium)Focal neurologic deficits: see stroke symptoms by affected vessel and stroke symptoms by affected region.Seizures Prodromal symptoms due to sentinel leak (a "warning leak")30-50% of patients with SAH report prodromal symptoms days-to-weeks prior to SAH. [8]Sudden, severe headacheTransient diplopiaLikely due to low-grade leak of blood into the subarachnoid space → thrombus formation → fibrinolysis → hemorrhage Diagnostics Initial evaluation Immediate noncontrast head CTBest initial testSensitivity is almost 100% within the first 6 hours of hemorrhage [8]Findings: shows blood in subarachnoid space (hyperdense) Lumbar puncture (LP) Best test if head CT is negative but suspicion for SAH remains high Findings↑↑ RBC count: red discoloration ↑ Protein (gamma globulin) ↑ Or normal opening pressureXanthochromia: the yellowish discoloration of CSF is due to the presence of xanthematin, a yellow pigment derived from hematin that is released when RBCs break down ↑ WBCs Normal glucose Subsequent evaluation Angiography: if CT and lumbar puncture are negative but clinical suspicion for SAH is still high and/or to identify the source of ongoing bleeding (prior to intervention).Digital subtraction angiography (DSA) CT angiography (CTA) Additional testing to consider Chest x-ray: to exclude pulmonary complications (e.g., pulmonary edema)Serum troponin in all patients: predicts neurological complications and outcomeCoagulation parameters: to evaluate for coagulopathyECG: to exclude myocardial ischemia (e.g., ↓ left ventricular function) Treatment Medical therapy [9] Reverse anticoagulation Blood pressure managementTarget SBP < 160 mm Hg is reasonable to prevent rebleeding [9] Recommended agents: beta blockers, calcium channel blockers Prevent vasospasm in all patients: administer calcium channel blocker (drug of choice: oral nimodipine) Maintain euvolemia Avoid/treat hyponatremia Maintain normoglycemia If patient has elevated ICP:Consider intubation with hyperventilationHead elevation (30°)IV mannitolSee ICP management Seizure prophylaxis [9]Consider seizure prophylaxis in the immediate posthemorrhagic period Consider long-term anticonvulsants in patients with a high risk for seizures (e.g., with a history of prior seizures). Surgical therapy [9] Should be performed as early as possible to prevent rebleeding Definitive treatment options for aneurysmal SAHSurgical clippingFollowing a craniotomy, the neck of an aneurysm is surgically occluded with the help of metal clips.Treatment of choice but more invasive than coilingEndovascular coilingPlatinum coils are placed into the aneurysm to induce thrombotic occlusion of the aneurysm.Less invasive than clipping but higher risk of recurrent bleeding Consider for poor surgical candidatesThe decision on which procedure to perform should be made on an individualized basis. If the patient has hydrocephalus: ventricular drain, serial LPs, or permanent ventriculoperitoneal shunt may become necessary. Use of nitrates should be avoided, since they may raise ICP! Complications VasospasmOccurs in approx. 30% of patients with SAH [9]Transcranial doppler ultrasound study can help identify vasospasm. Pathophysiology Impaired CSF reabsorption from the arachnoid villi → nonobstructive (communicating) hydrocephalus → ↑ intracranialpressure → ↓ cerebral perfusion pressure → ischemiaRelease of clotting factors and vasoactive substances → diffuse vasospasm of cerebral vessels → ischemiaCan lead to ischemic strokeMost common in patients with nontraumatic SAH due to a ruptured aneurysmUsually occurs between 3-10 days after SAH Recurrent bleedingOccurs in 4-14% of patients with SAH in the first 24 hours [9]Risk of rebleeding is highest in the first 2-12 hours after SAHThe cumulative risk of recurrent bleeding within the first six months is about 50%. HydrocephalusOccurs in 20-30% of patients with SAH [7]Acute obstructive hydrocephalus Usually occurs within minutes to hours after SAHCan lead to coma and death Chronic communicating hydrocephalusUsually occurs weeks or months after SAHSAH impairs CSF resorption from the arachnoid villi. Other complications [9]Elevated ICP: hypertension, bradycardia, and irregular breathing (see Cushing triad) Seizures SIADHHyponatremia due to volume depletion and/or cerebral salt wasting (rare)Cardiac dysfunction (e.g., arrhythmias, acute MI)Terson syndrome (20% of cases): preretinal hemorrhage due to SAH Prognosis Approx. 30% mortality rate in the U.S. within the first 30 days [9] Survivors: increased rates of neurologic impairment (e.g., cognitive, mood changes, functional, epilepsy) and increased risk of recurrent SAH

Leprosy Leprosy (Hansen disease) is a chronic infectious disease caused by prolonged exposure to Mycobacterium leprae, an acid-fast, slow-growing, fastidious bacillus. Leprosy primarily occurs in tropical and/or developing countries and is rarely observed in the US. There are various forms whose descriptions differ among two different classification systems, but the three cardinal clinical manifestations of leprosy are hypopigmented skin lesions, nerve thickening, and peripheral nerve palsies. Long-standing cases of leprosy classically develop deformities as a result of contractures following motor nerve palsies and/or repeated injury due to sensory loss. Other chronic complications include uveitis, orchitis, and nasal septal perforation. Patients with leprosy may also present with acute lepra reactions that are characterized by painful skin lesions and neuritis. The diagnosis is usually confirmed with the help of a biopsy. Lepromin tests aid in the classification of various forms of leprosy. Treatment consists of prolonged MDT (multi-drug therapy) with dapsone and rifampin. Clofazimine is added to the therapeutic regimen in patients with multibacillary leprosy.

Epidemiology US statisticsIncidence: 100-200 new cases annually Prevalence: ∼ 4,000 cases in total Sex: ♂ > ♀ Peak incidence: 10-20 years Endemic to tropical regions: India, Brazil, Indonesia, Nepal, Myanmar, Nigeria Etiology Pathogen: Mycobacterium leprae is an obligate, intracellular, acid-fast bacilli that cannot be cultured. Route of transmission Respiratory droplet transmissionClose contact with fomites, infected soil, and/or infected individuals Transmission usually requires prolonged exposure, and some individuals seem more predisposed than others Infectious type: multibacillary leprosy (see "Pathophysiology" below) Reservoirs: infected humans, nine-banded armadillos Lepromatous leprosy (LL) ↑ Th2 response →Reciprocal inhibition of Th1 response →inadequate cell-mediated immune response → many lepra bacilli↑ Antibody production (hypergammaglobulinemia); Nerve lesions are the result of M. leprae invasion. M. leprae grows best at cool sites in the body (skin, mucous membranes, peripheral nerves, anterior chamber of the eye, upper respiratory tract, testes). Tuberculoid leprosy (TT) ↑ Th1 response →Strong cell-mediated immune response → granuloma with epitheloid cells and lymphocytesbut few or no lepra bacilli Nerve demyelination is the result of a T-cell mediated response. Clinical features Incubation period: 3-5 years The clinical manifestations vary depending on the type of leprosy (LL, TT, or intermediate forms collectively known as Borderline leprosy, which is explained in further detail in extra information) Lepromatous leprosy (LL) Cutaneous manifestationsMultiple symmetrical macules, plaques, and/or nodulesNodules in the face may coalesce → leonine facies Nodules may ulcerateHypesthesia of the skin lesion is less common and occurs only in late stages of the diseaseSupraciliary and ciliary madarosis Nerve involvement*Occurs late but is more extensiveAcral, distal, symmetrical anesthesiaUsually begins as a "glove and stocking" neuropathy that spreads proximally Systemic manifestationsEarly prodromal symptoms: nasal stuffiness, epistaxisHepatomegaly Non-tender lymphadenopathy Tuberculoid leprosy (TT) Th1 Few (usually 1-3 lesions), localized, hypopigmented macules, plaques, and/or papules with well-defined, erythematous, and/or raised margins Lesions are dry, scaly, anhidrotic Hair loss Hypesthesia of the skin lesion is common and occurs early.Occurs early but is localized Asymmetric enlargement of one or many peripheral nerves Acute neuritis does not occur. Systemic Not involved. *Nerve involvement leads to nerve enlargement and peripheral nerve palsies which present with sensory, motor, and/or autonomic deficits. Ulnar nerve palsy : clawing of the fourth and fifth fingers, wasting of dorsal interosseous nerves, loss of sensation Peroneal nerve palsy: foot dropPosterior auricular nervePosterior tibial nerve The three cardinal clinical manifestations of leprosy are hypopigmented skin lesions, nerve thickening, and peripheral nerve palsies! Lepromatous leprosy (LL) AFB smear microscopy is positive for AFB at any one location Foamy histiocytes full of bacilli Few lymphocytes Numerous lepra bacilli Tuberculoid leprosy (TT) Smears are negative for AFB at all locations Granulomas formed by epithelioid cells and Langhans giant cells Many lymphocytes with a a CD4::CD8 ratio of 1.2:1 No lepra bacilli Lepromin test*** *Modified Ziehl-Neelsen staining of scrapings from skin lesions, nasal swabs, and/or slit skin smears from ear lobes are used to screen for leprosy.BI is primarily used to classify leprosy **Punch biopsy followed by histopathological examination with modified Ziehl-Neelsen staining is used to confirm the diagnosis. ***Lepromin test: Antigen is injected intradermally on the ventral forearmThe test is positive if induration is > 5 mm Measures the ability of a patient to mount a T cell response. Does not diagnose leprosy. Can be positive in patients with no exposure or infection to leprosyCan distinguish between lepromatous leprosy (negative result due to inadequate cell-mediated response) and tuberculoid leprosy (positive result due to strong cell-mediated immune response). Diffuse hypergammaglobulinemia associated with lepromatous leprosy can cause false positive VDRL, RF, and/or ANA tests and thus result in diagnostic confusion! Lepromatous leprosy (LL) 12M Dapsone Rifampin Clofazimine Tuberculoid leprosy (TT) 6 months Dapsone Rifampin upportive therapy Treatment of lepra reactions (see "Complications" below) Rehabilitation Physiotherapy to prevent contracturesSurgery to correct deformities (e.g., tendon transfer surgery for ulnar nerve palsy) Complications Secondary deformities Bone destruction → shortened digits, autoamputationNeuropathic ulcers on the dorsum of the footCharcot joints Nose: saddle nose deformity, anosmia, septal perforation EyeLagophthalmos and corneal insensitivity → corneal ulcersInvasion of the anterior chamber → chronic uveitis → blindness Orchitis → testicular atrophy → hypergonadotropic hypogonadism Reactive amyloidosis Lepra reactions (see extra information for more details)Patients may attribute lepra reactions to side effects of medications and stop them. Therefore, they should be warned about possible lepra reactions and told to seek treatment as soon as they occur. Treatment of leprosy should not be stopped when lepra reactions occur.The presence of tender nerves in a patient with leprosy indicates a lepra reaction!

Spasticity Spasticity is defined as a velocity-dependent increase in muscle tone that manifests with resistance to movement and involuntary muscle spasms and contractions. It is caused by a lesion in the descending motor pathways. Common etiologies of spasticity include multiple sclerosis, stroke, tumor, cerebral palsy, and spinal or peripheral nerve injury. Nerve conduction studies and imaging of the brain and/or spinal cord may be requested to determine the underlying etiology. The management of spasticity is broad and may include physical and occupational therapy, pharmacotherapy (i.e., muscle relaxants such as diazepam, tizanidine, baclofen, or dantrolene; paralytics such as botulinum toxin), or surgery.

Etiology An upper motor neuron lesion, commonly caused by: Stroke Subdural or epidural hemorrhage Cerebral palsy Brain tumor Multiple sclerosis Hydrocephalus Amyotrophic lateral sclerosis Hereditary spastic paraplegia Spinal cord injury (e.g., trauma, tumor) Pathophysiology The mechanism of spasticity is not completely understood. It is thought that upper motor neuron damage leads to loss of descending inhibitory inputs → increased muscle stretch reflex → increased muscle toneClinical features Increased muscle tone and velocity-dependent resistance to movement Elicited by flexion and extension of various muscles with alternating speedClasp knife phenomenon: initial resistance ("catch") when a limb is moved rapidly, followed by a sudden decrease in resistance; observed in patients with upper motor neuron lesions Upper extremity flexors and lower extremity extensors are usually more affected. Must be distinguished from rigidity Involuntary muscle spasms or contractions Diagnostics Clinical diagnosis Further tests (e.g., nerve conduction studies or brain imaging) depend on the suspected underlying etiology Treatment Physiotherapy: including splinting of the affected extremity Medical therapy: The most commonly used medication is baclofen; however, a variety of treatments (single and/or in combination) may be used and depend on patient-specific factors and patient response. Oral muscle relaxantsBaclofenDantroleneOral benzodiazepinesDiazepamClonazepamOral alpha-2 adrenergic agonists TizanidineClonidineIntramuscular injections: botulinum toxin A, lidocaine, or phenolIntrathecal infusion Baclofen: central acting muscle relaxantContraindications: renal failure Therapeutic guidelines: should always be started at a slow dose and gradually increased to minimize potential side effects (particularly hypotension, sedation, nausea, depression).Plasma half-life: 3-4 hoursEffectAgonist of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA)Stimulated presynaptic and postsynaptic GABA receptors in the spinal cord → direct inhibition of impulse transmissionAnalgesic in addition to muscle relaxant Surgical therapy: for severe spasticity refractory to medical treatment Selective dorsal rhizotomy: surgical destruction of nerves in the lower spinal cord in order to reduce muscle tone to the lower extremities Orthopedic surgery Lengthening of muscles and tendonsTransfer of tendons to attachment points where they cannot contract the joint into a deformed positionOsteotomy if muscle contracture has led to joint deformity Complications Musculoskeletal deformity Impaired mobility Reduced functional independence Pain Prognosis The prognosis of spasticity depends on the underlying condition.

Subclavian steal syndrome Subclavian steal syndrome (SSS) is a condition in which the subclavian artery proximal to the origin of the vertebral arterynarrows or becomes occluded, usually due to atherosclerosis. This blockage results in a lack of blood reaching the ipsilateral arm through the subclavian artery, which can lead to a reversal of blood flow in the affected vertebral artery so that blood from the contralateral side can flow through the circle of Willis to supply the affected arm. The condition is mostly asymptomatic. If symptoms occur, they are mainly caused by ischemia of the affected arm and include limb pain, fatigue, paresthesia, and cold skin. Neurological symptoms such as dizziness or even syncope are rare and usually only occur in the presence of cerebrovascular lesions. A characteristic diagnostic sign is a discrepancy in blood pressure between the arms of > 15 mm Hg. Imaging (e.g., ultrasonography) can identify a reversal of blood flow and/or atherosclerosis that confirms the diagnosis. Endovascular intervention or surgery are used to treat symptomatic SSS.

Etiology Atherosclerosis Takayasu's arteritis Pathophysiology Stenosis of the subclavian artery proximal to the origin of the vertebral artery → hypoperfusion distal to the stenosis → reversal of blood flow in ipsilateral vertebral artery → compensation through collateral arteries → reduced blood flow in the basilar artery → reduced cerebral perfusion upon exertion involving the affected arm Clinical features Most patients are asymptomatic Limb ischemia (on exertion)Pain, paresthesiaPale, cool skinWeak, delayed radial pulseDisparity in BP > 15 mm Hg Neurologic symptoms (rare) Dizziness, vertigoOcular findings (e.g., diplopia)Syncope Subtypes and variants Coronary-subclavian steal syndromeIn patients with an internal thoracic artery (internal mammary artery) bypass Stenosis of the subclavian artery proximal to origin of the internal mammary artery (IMA) → exertion of the ipsilateral arm → flow reversal in the IMA graft → symptoms of angina pectoris Diagnostics Imaging of the cerebral and upper extremity arteries, e.g., via Doppler ultrasound, duplex ultrasound, or magnetic resonance angiography, shows reversal of blood flow and/or atherosclerosis. Treatment Asymptomatic patients usually do not require treatment apart from lifestyle changes to prevent progression of atherosclerosis. Symptomatic patients: angioplasty and stenting or surgical revascularization

Stiff person syndrome Stiff person syndrome (SPS) is a rare disorder that manifests with progressive muscle stiffness and rigidity. It is caused by an autoimmune process in which antibodies are formed against glutamic acid decarboxylase (GAD) or another protein in the gamma-aminobutyric acid (GABA) synthesis pathway. This leads to reduced levels of GABA, which then causes loss of CNS inhibition and increasing muscle stiffness. SPS is associated with autoimmune disorders (particularly type 1 diabetes mellitus). Less commonly, it occurs as a paraneoplastic process. Treatment of SPS consists of symptomatic treatment with benzodiazepines and muscle relaxants as well as immune modulation therapy with IVIG and immunosuppressants. Prognosis is poor, with most patients experiencing progressive gait disorders and disability.

Etiology Autoimmune disease: Anti-GAD or anti-amphiphysin antibodies (proteins involved in the GABA synthesis pathway) are present in approx. 70% of cases. Antibody production may be: IdiopathicParaneoplastic (rare; secondary to breast cancer, lung cancer, and lymphoma) Associated with autoimmune diseases (type 1 diabetes mellitus, thyroiditis, vitiligo, pernicious anemia) Pathophysiology Anti-GAD antibodies → decreased GAD → decreased GABA → loss of CNS inhibition → increased muscle tone and rigidity Clinical features Generalized increase in skeletal muscle rigidity (hands, feet, and face remain unaffected); particularly in the muscles of the proximal extremities, neck and back. Progressive rigidity may lead to lumbar or cervical hyperlordosis as well as gait abnormalities that may, in turn, cause falls and fractures. Episodic painful muscle spasms triggered by external (e.g., noise) and internal (e.g., emotional upset) stimuli Partial SPS: disease variant in which symptoms are limited to one extremity Diagnostics Laboratory findingsDetection of anti-GAD antibodies (in 60-90% of cases)Paraneoplastic SPS is usually anti-GAD antibody-negative; anti-amphiphysin antibodies may be detected in some cases Electromyography: continuous motor unit activity that can be reduced by administering intravenous diazepam CSF: possible pathological findings: oligoclonal bands Treatment Curative For suspected paraneoplastic etiology: identification of the tumor and treatment! Symptomatic Enhancement of GABA signaling High-dose oral diazepam or clonazepam (first-line treatment)Oral baclofen (muscle relaxant) (second-line treatment in combination with benzodiazepines or as an alternative to benzodiazepines) Immunosuppressive therapy: immunoglobulins, plasmapheresis, rituximab

Cervical myelopathy Myelopathies are neurological disorders due to compression of the spinal cord. Myelopathies can be cervical, thoracic, or lumbar. Cervical myelopathy is the most common type of myelopathy in adults above 55 years of age. Etiologies include degenerative changes of the spine, spinal trauma, infection, tumors, and autoimmune disorders. Onset can be acute, step-wise, or insidious. Clinical features vary depending on the level of the lesion and include local pain, stiffness, and impaired sensation, hypotonia, and hyporeflexia at the level of the lesion, and spasticity and hyperreflexia below the level of the injury level. Diagnosis is confirmed by MRI or myelography. Treatment includes conservative management for degenerative disease or immediate surgical decompression in acute compression.

Etiology Causes for compression of the spinal cord include: Blunt or penetrating trauma (e.g., fracture, epidural hematoma)Infection (e.g., abscess)Radiation therapyAutoimmune disorders (e.g., rheumatoid arthritis, neuromyelitis optica)Neoplasms (e.g., meningiomas, nerve sheath tumors, metastases) or cysts (e.g., epidermoid cysts)Ossification of the posterior longitudinal ligament (OPLL)Congenital narrowing of the cervical spinal canalDegenerative diseases Spinal stenosisAnkylosing spondylitis Discogenic myelopathy (central disc herniation)Multiple sclerosis Pathophysiology Intramedullary or extramedullary (i.e., originating from within or outside the spinal cord) mass lesions compress the spinal cord and impair its perfusion → mechanic and ischemic axonal injury → intramedullary edema → further narrowing of the medulla Clinical features Features depend on the level of compression and the onset may be sudden (e.g., with trauma), step-wise, or slowly progressive (e.g., degenerative diseases) Neck, shoulder, upper limb, or lower limb pain (neck stiffness may be present) Signs and symptoms of lower motor neuron lesions at the level of the lesion (e.g., weakness and atrophy in the arms and/or hands in lesions of the thoracic spine) Signs and symptoms of an upper motor neuron lesion below the level of the lesion (e.g., abnormal spastic gait is often an early sign; hyperreflexia or a positive Babinski's sign may be present) Impaired sensation (e.g., numbness, impaired proprioception, ataxia) Impaired bladder and bowel control Damage to the spinal cord and the nerve roots (radiculopathy) often occur simultaneously! Pain is not commonly an early symptom. Therefore patients may not be diagnosed until myelopathy becomes severe! Diagnostics MRI of the spine : determines the site of narrowing of the medulla and the underlying pathology Myelography (possibly with CT): when MRI is contraindicated (e.g., in patients with metal implants) Differential diagnoses Subacute combined degeneration of the spinal cord Amyotrophic lateral sclerosis (Lou Gehrig's disease)(no sensory loss) Syringomyelia Treatment Conservative treatment (i.e., analgesia, corticosteroid therapy , bracing, physiotherapy): indicated perioperatively, for severe cases (e.g., degenerative cervical myelopathy ), and mild cases Decompression surgery: typically indicated in acute or advanced cases

Polyneuropathy Polyneuropathy is a disorder that involves damage to multiple peripheral nerve fibers. The condition can be caused by diabetes mellitus, alcoholism, hereditary diseases, toxins, infection, or other inflammatory conditions. The classic presentation is a symmetric distal burning or loss of sensation. Further clinical features depend on whether an axonal or demyelinating nerve injury has occurred. Diagnostic tests such as electrodiagnostic studies are indicated in the case of atypical clinical features, unknown etiology, and/or severe or rapidly progressive symptoms. Management involves treatment of the underlying disorder and symptomatic therapy (e.g., control of neuropathic pain).

Etiology Diabetes mellitus and alcohol use disorder account for most cases in developed countries. Idiopathic HereditaryCharcot-Marie-Tooth diseaseKrabbe diseaseAdrenoleukodystrophyMetachromatic leukodystrophy ToxinsEndogenousMetabolic/endocrine causes: diabetes mellitus, acromegaly, pregnancyHereditary causes: hereditary motor and sensory neuropathy (HMSN), hereditary sensory neuropathy (HSN), amyloidosis, porphyriaExogenousAlcoholHeavy metals (lead poisoning, arsenic, thallium)Solvents (e.g., trichloroethylene) Medication (e.g., chemotherapeutic agents)Malnutrition/intestinal malabsorption InflammatoryVasculitisConnective tissue disordersGranulomatous diseases Radiation exposure Guillain-Barré syndromeCritical illness polyneuropathy InfectiousBacterial: borreliosis, diphtheria, leprosyViral: AIDS, CMV, VZV, herpes zoster, measles, mumps, rubella, influenza EnvironmentalProlonged exposure to coldHypoxemiaVibration-induced damage Clinical features General Symmetric distal sensory loss (glove and stocking pattern) May be accompanied by neuropathic pain, paresthesias, and motor weakness Burning-foot syndrome: burning pain, tingling, pins-and-needles sensation, or formication . hyperhidrosis Atrophy and paresis of muscles: e.g., "stork legs" in the case of HMSN type I Sensory ataxia: e.g., sensory ataxia due to vitamin B12 deficiency ↓ Deep tendon reflexes Axonal Slow decline over years Affects longer axons first (begins in lower extremities → sternum (intercostal nerves) → head) Early disease: sensory symptoms > motor symptoms Distal muscle wasting: feet, lower legs, hands (severe cases) Distal sensory loss (pain, temperature, proprioception, vibration) Reduced or absent distal reflexes (usually begins in the ankles) Chronic idiopathic axonal polyneuropathy (CIAP) Diabetes Alcohol use disorder Charcot-Marie-Tooth disease Leprosy HIV Borreliosis Hypothyroidism Toxic polyneuropathy (e.g. due to cisplatin, doxorubicin) Acute Axonal Guillain-Barré syndrome DemyelinatingGeneralized muscle weakness: distal > proximalDistal sensory loss (abnormal vibration and proprioception > pain or temperature) Diffusely reduced or absent reflexesChronic inflammatory demyelinating neuropathy(CIDP) Hereditary motor sensory neuropathies Uremic polyneuropathy Toxic polyneuropathy (e.g. due to diphtheria toxin, suramin, amiodarone) Guillain-Barré syndrome Diabetic polyneuropathy Definition: progressive peripheral nerve injury due to chronic hyperglycemia Clinical featuresSensory deficits Distal symmetric sensory loss and/or motor weakness (common); less commonly, random involvement of multiple peripheral nerves (mononeuritis multiplex) Burning feet syndrome with worsening of symptoms at nightCranial nerve involvement is very common (especially of the oculomotor and abducens nerve). Trophic skin changes (due to autonomic neuropathy): anhidrosis, edema, ulcers Autonomic features: erectile dysfunction, gastric atony, postprandial diarrhea, tachycardia at rest, impaired pupillary toneDiabetic amyotrophy: initially painful proximal muscle weakness; distal sensory loss may occur TreatmentControl of blood glucoseFoot careNeuropathic pain management (e.g. with tricyclic antidepressants or gabapentin)Alpha-lipoic acid (antioxidant) Alcoholic polyneuropathy Definition: progressive peripheral nerve injury as a result of thiamine deficiency due to a chronic alcohol use disorder Clinical featuresSensory deficits Symmetrically decreased distal perception (especially joint position sense)Burning feet syndromeAtrophy and paresis of distal muscles; a hypoactive ankle jerk reflexHyperpigmented, anhidrotic, and atrophic skinCalf cramps Treatment: thiamine and cessation of alcohol use (see alcohol use disorder) Hereditary motor sensory neuropathies Definition: progressive hereditary peripheral nerve disorders due to impaired Schwann cell growth and function EtiologyUsually autosomal dominantAssociated with scoliosis and foot deformities (flat feet, high arches, hammer toes) Characteristic feature: ascending flaccid paralysis and atrophy, which begins distally; sensory deficits may occur later (type I, III, and IV cause hypertrophic neuropathy) Important typesHMSN type I (Charcot-Marie-Tooth disease)Distal symmetric sensorimotor polyneuropathy with atrophy of the calf muscles ("stork legs") and pes cavusdeformity (sensory loss occurs late)Intrinsic hand musculature may become involved after several years.May be associated with sleep apneaNerve biopsy: repeated demyelination and remyelination evident in large nerve fibers (onion peel appearance)Nerve conduction studies: ↓ impulse conduction velocity HMSN type IV (Refsum disease)Etiology: autosomal recessive defect affecting alpha-oxidation in peroxisomes → phytanic acid is not metabolized to pristanic acid → accumulation of phytanic acidClinical features Symmetrical, ascending polyneuropathyAtaxiaSensorineural hearing lossAnosmiaIchthyosisCataracts and nyctalopia caused by retinitis pigmentosaShortened fourth toeTreatment: diet to reduce plasma phytanic acid levels ; plasmapheresis in severe casesHMSN type VAssociated with hereditary spastic paraplegiaCombination of spastic spinal paralysis, type VI and VII HSMN, and ocular symptomsNerve conduction studies: normal or mildly ↓ nerve conduction Treatment: See "Treatment" below. Diagnostics Further tests are usually indicated in patients with atypical clinical features, an unknown etiology, and/or severe or rapidly progressive symptoms. Electrodiagnostic studiesNerve conduction studies on the sural nerve: to determine the type of neuropathy and with it the possible cause Primary demyelination: ↓ impulse conduction velocity, normal amplitudeAxonal degeneration: normal impulse conduction velocity, ↓ amplitudeElectromyography (EMG): e.g., spontaneous electrical activity at rest (denervation potentials) in the case of axonal degeneration Laboratory tests (selection depends on the suspected underlying disorder) Abnormal CBC, ESR, and other markers of inflammation↑ Fasting and postprandial serum glucoseAbnormal thyroid function testsPositive rapid plasma reaginSerum electrophoresis and urine electrophoresisHepatitis screenLumbar puncture to exclude infectionsVitamin B12 and folic acid levelsSerum levels of toxins (such as lead, thallium, and arsenic)Delta aminolevulinic acid levels (porphyria, lead intoxication)Borrelia antibodies (Lyme disease) If necessary: nerve-muscle biopsies (useful to identify a small fiber sensory neuropathy or infiltrative disorders), skin biopsy (useful to identify small fiber sensory neuropathies), molecular genetic tests for suspected hereditary disorders Differential diagnoses Mononeuritis multiplex (multiple mononeuropathy) Definition: a group of disorders characterized by ≥ 2 isolated mononeuropathies; e.g., concurrent sciatic neuropathy and radial neuropathy Etiology: axonal damage caused by systemic conditions; e.g., diabetes mellitus, rheumatoid arthritis, vasculitides, SLE, Lyme disease, amyloidosis, HIVClinical features: painful, asymmetrical sensory and motor symptomsDiagnostics: confirm with electrodiagnostic testing and test for possible etiology.Treatment: analgesia and treatment of underlying condition Radicular neuropathy: associated with acute onset of severe back pain that radiates to the legs and arms Amyotrophic lateral sclerosis: asymmetric limb weakness with fasciculations and muscle stiffness Peripheral vascular disease: trophic skin changes and pain exacerbated by walking Differential diagnosis of impaired sensation and sensory ataxia Polyneuropathy Acute or chronic demyelinationand/or axonal degeneration due to: Toxins: e.g., in diabetes mellitus oralcohol useTraumaInflammationor infection Symmetrical distal loss of all the types of sensation (stocking-and-glove distribution) Lower motor neuron signs: distal flaccid paresis Burning-footsyndrome and neuropathic painare common. Multiple sclerosis Immune-mediatedchronic demyelination of white matter in the brain and spinal cord Loss of all the types of sensation is possible (distribution depends on the lesion). Upper motor neuron signs Internuclear ophthalmoplegia(INO) Lhermitte sign Charcot neurologic triad-scanning speech, nystagmus, and intention tremors Exacerbations followed by periods of remission Subacute combined degeneration Chronic demyelination of dorsal columns, lateral corticospinal tracts, and spinocerebellar tracts due to vitamin B12 deficiency Loss of position and vibration sense below the level of the lesion Upper motor neuron signs: spastic paresis LCST Megaloblastic anemia Neuropsychiatric symptoms Tabes dorsalis Demyelination of the dorsal columns and the dorsal root ganglia due to Treponema palliduminfection(tertiary syphilis) Loss of position and vibration sense below the level of the lesion NO MOTOR Symptoms Argyll Robertson pupils Sharp, shooting pain in the legs and the abdomen Gumma, aortitis Compressive myelopathy Spinal corddemyelination and ischemia that is caused by compression due to: Disc herniationOsteophytesTumors and metastasesLoss of pain and temperature sensation below the level of compression is most common SCT Lower motor neuron signs at the level of the lesion Upper motor neuron signsbelow the level of cord compression Back pain Treatment Definitive therapy: Treat the underlying disease. Symptomatic therapyPain managementAntidepressants (amitriptyline, duloxetine), anticonvulsants (gabapentin, carbamazepine, pregabalin) Analgesics: opioids Topical therapy (lidocaine patches, capsaicin patches/ointment) Physical therapy and foot care Treatment efficacy can only be assessed after 2-4 weeks of therapy! Since complete pain relief is often not possible, a tolerable level of pain can be an acceptable treatment goal!

Generalized epilepsy in childhood Pediatric generalized epilepsy syndromes are a diverse group of conditions with onset in infancy or childhood. The International League Against Epilepsy (ILAE) classifies generalized epilepsy syndromes according to the etiology as either idiopathic, symptomatic, or cryptogenic. In idiopathic generalized epilepsy syndromes, the most common form of childhood epilepsy, genetic causes are suspected. The symptomatic forms are associated with metabolic or structural abnormalities, while the etiology of cryptogenic epilepsies is unknown. The syndromes are further classified according to the patient's age at onset, as well as clinical and EEG characteristics. A detailed patient history, including a description of seizures, offers vital diagnostic clues. The diagnosis may be confirmed with an EEG. With adequate treatment, idiopathicepilepsy syndromes have a good prognosis. In comparison, symptomatic epilepsy syndromes do not respond well to treatment and have a relatively poor prognosis, often resulting in developmental delays and cognitive impairments.

Etiology Etiology of seizures according to age InfantsCongenital (idiopathic; genetic association)Secondary to Perinatal or postnatal infectionsHead traumaMetabolic disorders ChildrenIdiopathic (genetic association suspected)Secondary to Metabolic disordersStructural abnormalities of the cerebrumInfectionsHead traumaFebrile seizures Childhood absence epilepsy (pyknolepsy) 6-7 years Sex: ♂ < ♀ Absence seizures lasting 5-10 seconds up to 100x/dayBrief unresponsivenesswithout convulsionsAmnestic during seizures; children appear to be staringor daydreamingLip smacking, eye flutteringor head nodding are commonNo postictal phase Atypical absence seizure: more gradual onset and ending, duration of > 30 seconds. Triggers: hyperventilation, lights 3 Hz spikes and waves in all regions of the brain 1st line: ethosuximide 2nd line: sodium valproate 3rd line: lamotrigine 80% of children are seizure-free with treatment Usually subsides before adulthood Juvenile absence epilepsy 9-13 years Sex: ♂ = ♀ Absence seizures Tonic-clonic seizures (on awakening) are common Photosensitivity less common Regular 3-4 Hzspikes and waves in all regions of the brain 1st-line: valproic acid Avoid triggers: sleep deprivation, alcohol, drugs, flickering lights 60% are seizure-free under treatment Transition to juvenile myoclonic epilepsypossible Juvenile myoclonic epilepsy (Janz syndrome) 12-20 years Triad of seizures : Bilateral symmetrical myoclonic jerks, primarily after awakening, without impaired consciousnessGeneralized tonic-clonicseizuresAbsence seizures with impaired consciousness Triggers: sleep deprivation, alcohol consumption, flickering lights Irregular 3-5 Hzpolyspikes and waves with frontocentral predominance Responds well to antiseizure drug therapy; seizures become less frequent in adulthood Life-long treatment usually required (high risk of recurrence) Increased risk of psychiatric comorbidities Infantile spasms (West syndrome) 3-7 months Sex: ♂ > ♀ Perinatal infections Hypoxic-ischemicinjury PKU Tuberous sclerosis complex Idiopathic Sudden symmetric, synchronous spasms, usually in clusters of 5-10 Jerking flexion(jackknife movement) or extension of the neck, torso, and extremities Followed by a tonic phase Hypsarrhythmia: characteristic finding in interictal EEG; high-voltage delta waves with irregular multifocal spikes and slow waves Ictal EEG: very heterogeneous First-linetreatment: ACTH, prednisone, or vigabatrin Poor; increased mortality Neurodevelopmental delay, regression of psychomotor abilities in > 85% of cases In ∼ 50% of casesspasms cease before age 5 years Most cases develop other forms of epilepsy ) Lennox-Gastaut syndrome3-5 yearsSex: ♂ > ♀Majority of cases due to structural brain abnormalities 40% of cases are cryptogenic Multiple types of seizures: myoclonic, tonic, atonic, absencesDevelopmental delaysFrequently periods of status epilepticusMultifocal sharp and slow wavesAbnormal interictal EEG: slow spike-wavepatternAttempt anticonvulsive treatment, e.g., valproic acid, clobazam, lamotrigine, felbamate [13] Ketogenic diet, vagus nervestimulation, surgery (see therapy of epilepsy)Poor; only 10% are seizure-free under treatmentDevelopmental delay, cognitive impairment, and psychotic symptomsMortality rate of 3-7% Diagnostics Seizure history (see diagnosis of epilepsy) EEG: abnormal electrical discharges Laboratory analysisRule out metabolic abnormalities (e.g., hypoglycemia, electrolyte abnormalities)Toxicology screening; determine anticonvulsant plasma levels in previously diagnosed patients receiving medical treatmentBlood cultures and lumbar puncture in febrile patients Cranial MRI and CT scan: rule out structural brain abnormalities (e.g., tumors)

Facial nerve palsy Facial (nerve) palsy is a neurological condition in which function of the facial nerve (cranial nerve VII) is partially or completely lost. It is often idiopathic but in some cases, specific causes such as trauma, infections, or metabolic disorders can be identified. Two major types are distinguished: central facial palsy (lesion occurs between cortex and nuclei in the brainstem) and peripheral facial palsy (lesion occurs between nuclei in the brainstem and peripheral organs). Central facial palsy manifests with impairment of the lower contralateral mimic musculature. In contrast, peripheral facial palsy leads to impairment of the ipsilateral mimic muscles and also affects the eyelids and forehead. Additionally, peripheral facial palsycan cause various sensory and autonomic disorders (depending on the exact location of the lesion). Diagnosis can usually be made clinically while patient history often helps in evaluating the underlying etiology. Idiopathic facial nerve palsy is treated with oral glucocorticoids and, in severe cases, antivirals. Treatment of the other types depends on the underlying cause. Most cases of idiopathic facial palsy heal completely within 3 weeks.

Etiology Idiopathic (50% of cases): acute idiopathic peripheral facial palsy is also known as Bell palsy Secondary Trauma (e.g., temporal bone fracture) Infection (e.g., herpes zoster, borreliosis, HSV infection, HIV infection)TumorsPregnancy Diabetes mellitusGuillain-Barré syndromeSarcoidosisAmyloidosisStroke Pathophysiology The muscles responsible for eyelid and forehead movements are innervated by fibers from both sidesCentral facial palsy: unilateral lesion between cortex and brainstem nuclei → muscles of the eyelids and foreheadare still supplied by input from the other side → function is preservedPeripheral facial palsy: unilateral lesion between nuclei and muscles → no input to the ipsilateral eyelid and forehead muscles → paralysis The lower facial muscles are only innervated by fibers from the contralateral hemisphere (via ipsilateral nuclei and the ipsilateral peripheral nerve) → paralyzed in both central and peripheral facial palsy Central (signs are contralateral to the lesion) Mouth drooping Yes Peripheral (signs are ipsilateral to the lesion) Inability to frown Inability to close the eyelids completely Additional signs of peripheral facial palsy Sensory disturbances (painful sensation around or behind the ear or numbness of one side of the face, taste disorders, hyperacusis ) Dry mouth (as a result of decreased saliva production) Ocular features (lagophthalmos , decreased lacrimation , ectropion ) Synkinetic involuntary movements of the facial muscles (e.g., facial spasms while closing the eyes) In central facial palsy, paralysis is contralateral to the lesion and eyelid and forehead muscles are not affected!Ask about symptom onset and duration, recent infections, and outdoor trips Ask patient to perform facial movements (e.g., frown, whistle, inflate cheeks, smile, show teeth/grimace, close eyes tightly , blink) → observe inabilities and asymmetriesBell's phenomenonTreatment Prednisone In severe cases Valacyclovir for 1 week Eye care with, e.g., artificial tears Traumatic facial nerve palsy: surgical decompression or nerve repair Prognosis Idiopathic facial palsy: complete recovery in ∼ 85% of cases (within 3 weeks) Misdirected regrowth of nerve fibers can lead to persistent disorders (e.g., synkinesias)

Dystonia Dystonia is a movement disorder characterized by sustained or intermittent muscle contractions causing involuntary movements, fixed postures, or both. The disorder may be idiopathic, hereditary, or acquired. Acquired dystonia is most commonly due to drugs (antipsychotics), metabolic disorders, cerebrovascular disease, or traumatic brain injury. Dystonia is classified according to the anatomic distribution of the symptoms into focal, multifocal, segmental, and generalized dystonia. Treatment involves pharmacologic management with levodopa or anticholinergic agents, as well as treatment of the underlying cause if possible. Focal dystonias respond well to periodic botulinum toxin injections in the affected muscle.

Etiology Idiopathic (familial or sporadic) Hereditary (evidence of inherited genetic mutation) AcquiredDrugs: dopamine antagonistsHigh-potency typical antipsychotics (e.g., haloperidol) are more likely than atypical antipsychotics to induce acute dystonia. MetoclopramideNeurologic disorders: Huntington diseaseMetabolic: Wilson diseaseHypoxic or structural cerebral injury Infections: encephalitis , HIVPsychogenic: conversion disorder Most cases of acute dystonia are caused by antipsychotic drugs! Focal dystonia OverviewAffects a single region of the body The majority of cases are idiopathic.Onset typically in adulthood (usually > 30 years)Patients may have sensory tricks (gestes antagonistes) with which they are able to suppress spasms (e.g., touching the affected region). ConditionsSpasmodic torticollis: cervical dystonia Abnormal head movements or fixed head posture Geste antagoniste: a voluntary maneuver that temporarily reduces the severity of dystonic postures or movements Blepharospasm: eye dystoniaIncreased blinking or involuntary eye closure (bilateral, symmetrical)Spasmodic dysphonia: laryngeal dystonia or voice dystoniaVoice breaks or strained voice (most common) Weak, breathy voice Oromandibular dystonia: involuntary movements of the tongue, jaw, and/or face (e.g., jaw clenching, jaw opening) Writer's dystonia (writer's cramp): non-painful contractions of hand muscles that are provoked by specific tasks (e.g., writing) Segmental dystonia Affects ≥ 2 adjacent regions of the body Meige syndrome: blepharospasm with oromandibular dystonia Generalized dystonia OverviewAffects the trunk and at least two additional regions of the body Typically early onset (< 21 years of age) Conditions Dopa-responsive dystonia (Segawa syndrome): rare, genetic disorder with onset in childhood (< 10 years; ♀ > ♂) Dystonia that responds well to treatment with levodopaParkinsonism Neuroleptic-induced acute dystoniaTorsion dystonia (dystonia musculorum deformans): rare, idiopathic disorder with onset in childhood Initial focal dystonia: involuntary movements of the limbs, torso, and neckProgression to generalized dystonia Treatment All treatments can be used for generalized dystonia, but botulinum toxin injections are typically reserved for focal dystonia. First-line: levodopa/carbidopa Second-lineAnticholinergics (benztropine, trihexyphenidyl) or antihistamines (diphenhydramine) Periodic botulinum toxin injections for focal dystonia Deep brain stimulation Treat underlying disorder of acquired dystonia Cessation of causative drug Supportive measures: physiotherapy, ergotherapy

Elevated intracranial pressure and brain herniatio Intracranial pressure (ICP) is the pressure that exists within the skull and all of its compartments (e.g., the subarachnoid space and the ventricles). ICP varies with the relative position of the head towards the rest of the body and is periodically influenced by normal physiological factors (e.g., cardiac contractions). Adults in supine position have a physiological ICP of 15 mm Hg or less while a pressure of 20 mm Hg or more indicates pathological intracranial hypertension. Elevation of ICP may occur in a variety of conditions (e.g., intracranial tumors) and can result in a decrease in cerebral perfusion pressure (CPP) and/or herniation of cerebral structures. Symptoms of raised ICP are generally nonspecific (e.g., impaired consciousness, headache, vomiting). However, more specific symptoms may be present depending on the affected structures (e.g., Cushing triad if the brainstem is compressed). Brain imaging (e.g., showing a midline shift) and physical examination (e.g., papilledema) can detect ICP elevation, but not necessarily rule it out. Therefore, ICP monitoring and quantification is vital in at-risk patients. Management usually involves osmotic diuretics such as mannitol or hypertonic saline. Further therapeutic options include controlled hyperventilation, removal of CSF, and decompressive craniectomy

Etiology Idiopathic intracranial hypertension CNS inflammation, infection, and/or abscess Space-occupying lesionsIntracranial hemorrhage or hematomaAneurysm Intracranial tumors Elevated venous pressure (e.g., as a result of heart failure) Increased CSF (hydrocephalus) Metabolic disturbances (e.g., hyponatremia, hepatic encephalopathy) Epilepsy and seizures Pathophysiology Physiology Physiological ICP is ≤ 15 mm Hg in adults (in supine position), children generally have a lower ICP ICP varies with the relative position of the head towards the rest of the body and is influenced by certain physiological processes (e.g., cardiac contractions, sneezing, coughing, Valsalva maneuver). Expansion of either blood, CSF, or tissue within the skull → limited capacity for the intracranial volume to increase within the rigid skull → increase in intracranial pressure Consequences of elevated ICP Decreased cerebral perfusion pressure (CPP)CPP is the effective pressure that delivers blood to the cerebral tissue.CPP = mean arterial pressure - ICPTherefore, if the ICP rises, the CPP diminishes (as long as the arterial pressure remains constant). Brain tissue herniationAs a bony structure, the skull is rigid and can not expand to compensate elevated internal pressure.Increased pressure gradient within the skull in the presence of inflexible brain structures (e.g., tentorium cerebelli) → flexible brain tissue shifts → possible brain tissue herniationThis may result in direct physical damage or in blocking of cerebral vessels and subsequent ischemia. Cushing triad ↑ Intracranial pressure → ↓ perfusion pressure within the brain → compensatory activation of the sympathetic nervous system to maintain cerebral perfusion → ↑ systolic blood pressure → stimulation of aortic arch baroreceptors → activation of the parasympathetic nervous system (vagus) → bradycardia↑ Pressure on brainstem → dysfunction of respiratory center → irregular breathing Clinical features GlobalCushing's triad: irregular breathing, widening pulse pressure and bradycardiaReduced levels of consciousnessHeadache Vomiting Papilledema Psychiatric changes In infants: macrocephaly, bulging fontanel, sunset sign FocalDiplopia Cerebral herniation syndrome → see "Subtypes and variants" below Subtypes and variants Cerebral herniation syndromes Subfalcine herniation: cingulate gyrus of one hemisphere is compressed and herniates under the falx cerebri → compression of: Contralateral hemisphere → obstruction of the foramen of Monro → hydrocephalusPericallosal arteries → hemiparesis (predominantly lower limbs) Uncal herniation: medial temporal lobe (the uncus) herniates at the tentorial incisure → Compression of: Ipsilateral oculomotor nerve palsy → fixed and dilated pupilIpsilateral posterior cerebral artery → cortical blindness with contralateral homonymous hemianopiaContralateral cerebral peduncle → ipsilateral paralysis + Kernohan's phenomenon (a syndrome of uncal herniationcharacterized by pupillary dilation ipsilateral to the herniation, due to CN III compression) and, paradoxically, ipsilateralweakness (due to contralateral cerebral peduncle compression). This is unusual because commonly, an ipsilateral brain lesion results in contralateral motor symptoms. It occurs in patients with increased ICP caused by intracranial hemorrhage or cerebral edema.) → Downward shift of the brainstem → brainstem hemorrhages → focal deficits, impaired consciousness, death Foramen magnum herniation: structures of the posterior fossa (e.g., cerebellar tonsils, medulla) herniate at the foramen magnum → impaired consciousness, decerebrate posturing, apnea, impaired circulation, death iagnostics Imaging CT/MRI: may indicate mass lesions, midline shift, or effacement of the basilar cisterns Ultrasound (e.g., ocular sonography): measures the optic nerve sheath diameter Clinical examination and imaging may indicate elevated ICP, but cannot rule it out! Additionally, these tests do not allow quantification of intracranial pressure, which is necessary to determine CPP! Invasive ICP monitoring IndicationsPatients at risk of elevated ICP Closed head trauma Patients that have a non-surgical intracranial hemorrhage and undergo or have undergone major nonneurological surgery and can not be properly evaluated. Patients suffering from moderate head injury. Placement of monitorsIntraventricular (gold standard)Technique: implantation of monitoring device directly into the ventriclesAdvantages: highest accuracy, allows for treatment of elevated ICP and/or diagnostic collection of CSF samples via drainage system Analysis: > 20 mmHg indicates elevated intracranial pressure that requires treatmentICP is not static but influenced by cardiac action and other factors. → ICP changes in a complex cyclic manner. → represented as distinct waveforms (normal, A wave, B wave, C wave) Treatment Acute stabilization and treatment Resuscitation and emergency measures (head elevation, controlled hyperventilation and IV mannitol) Cardiopulmonary support Sedation, analgesia, antipyretic therapy, antiseizure medication ICP management General approach Goal of ICP management is generally to keep ICP < 20 mm Hg.Positioning : e.g., head elevation (about 30 degrees), avoiding neck flexion/rotation or circumstances that may provoke Valsalva responses Fluid management: patients should be euvolemic, blood hypoosmolarity should be avoidedHyperventilation: up to a pCO2 of 26-30 mm Hg Hypothermia Causal treatment (e.g., removal of brain tumor) if possible Medical therapy Osmotic diuretics IV mannitol: can generally be administered every 6-8 hours, effects last for up to 24 hoursIV hypertonic saline: particularly for short-term treatment Removal of CSF via an intraventricular monitor with drainage system (e.g., external ventricular drain or lumbar drain) or a cerebral shunt (e.g., in hydrocephalus patients) Decompressive craniectomy: removal of part of the skull, allowing the brain to expand and reduces ICP.Complications Irreversible loss of brain function (brain death) Definition: irreversible, complete loss of function of the entire brain (including the brainstem), even if cardiopulmonary functions can be upheld by artificial life support. Requirements for the diagnosis of brain deathClinical settingLoss of brain function must be attributable to a specific cause (e.g., clinical or radiologic evidence of acute, severe damage to the CNS that is consistent with brain death).Irreversible loss of brain function Factors that may impede proper clinical judgment must be absent. Complicating or mimicking conditions (e.g., electrolyte imbalances, locked-in syndrome)Abnormal core temperature Abnormal systolic blood pressureIntoxication or effects of CNS-depressing drugs/neuromuscular blockadeNeurological examinationComa (with a known cause)Absence of brainstem reflexesPupillary light reflex (shining of light into the eye normally causes pupils to constrict in adaptation to bright light)Vestibuloocular reflex: stimulation of the vestibular system via e.g., rapid head movement or caloric stimulation in the ear, normally elicits eye movement in the opposite direction i.e., away from the stimulation Oculocephalic reflex: rapid rotation of the head to one side normally elicits eye movement in the opposite direction; this allows the image on the eye's fovea to remain central and stabilized despite movement of the head Corneal reflex (touching of the cornea, e.g., with a sterile cotton swab, normally triggers blinking)Gag reflex (touching of either side of the pharynx, e.g., with a sterile tongue depressor, normally triggers gagging)Cough reflex (stimulation of the larynx or the respiratory epithelium normally provokes coughing)No reaction to irritation of trigeminal nerve branches (normally painful)Deep tendon reflexes are occasionally seen in brain-dead patients who have intact spinal cords Apnea (absence of breathing drive) Ancillary brain death tests: only to be performed if clinical examination and/or apnea testing are inconclusive, or if patient is < 1 yearElectroencephalography (EEG) Practical steps for determination of brain death: The American Academy of Neurology has published a practical guide that consists of four steps. It cites specific measures and interpretations (e.g., limits of body temperature) that can be used to determine brain death, although not all of them are evidence-based (see "Tips & Links") ManagementIf brain death is proven, no consent is required to remove life support or other forms of treatment (e.g., antibiotic therapy).If the surrogate decision-maker disagrees with the physician's decision, it is judicious to consult a hospital's ethical committee If spontaneous breathing is present, the medulla is intact! If the corneal reflex is present, the pons is intact! If the pupillary light reflex is present, the midbrain is intact! Cerebral edema Definition: excess accumulation of fluid within the brain parenchyma as a result of damage to the blood-brain barrier and/or the blood-CSF barrier [19]Vasogenic: extracellular accumulation of fluids as a result of impaired capillary permeability secondary to breakdown of endothelial tight junctions Cytotoxic: intracellular accumulation of fluids as a result of impaired Na+/K+-ATPase function EtiologyCerebral infarction (stroke)Iatrogenic (Rapid lowering of glucose or rapid correction of hypernatremia)Trauma (particularly in closed head injury)Toxic (e.g., lead intoxication)Inflammatory (e.g., meningitis)Space-occupying lesions (e.g., brain tumors, intracranial hemorrhage) Management: treatment of raised ICP

Major neurocognitive disorder Major neurocognitive disorder (previously called dementia) is an acquired disorder of cognitive function that is commonly characterized by impairments in memory, speech, reasoning, intellectual function, and/or spatial-temporal awareness. The potential causes of dementia are diverse, but the disorder is mainly due to neurodegenerative and/or vascular disease and as such, most forms are associated with increased age. Initial diagnosis should focus on the patient history, followed by cognitive assessments (e.g., the mini‑mental state exam) and physical examination. To confirm or rule out specific etiologies, additional laboratory tests or imaging studies are often necessary. Pharmacotherapy is available, but is often met with little success because of the chronic and progressive nature of dementia. An important differential diagnosis is pseudodementia, which is primarily associated with cognitive deficits in older patients with depression. In contrast to dementia patients, individuals suffering from pseudodementia can often recall the onset of their cognitive impairments, exaggerate their symptoms, and are remarkably responsive to treatment with antidepressants.

Etiology Neurodegenerative brain diseases Alzheimer disease (> 50% of dementia cases) Parkinson disease Frontotemporal dementia Dementia with Lewy bodies Progressive supranuclear palsy Huntington disease Additional causes Cerebrovascular disease (20% of dementia cases)Multi-infarct dementiaDiffuse white matter disease (subcortical arteriosclerotic encephalopathy) Hypoxic brain damage Normal pressure hydrocephalus After head trauma, intracranial bleeding or brain tumors Drug/alcohol‑related (e.g., Wernicke‑Korsakoff syndrome) Wilson disease Vitamin deficiencies (thiamine, B6, B12, folate) Metabolic: exsiccosis, uremia, electrolyte imbalances, hypothyroidism and hyperthyroidism, hypoparathyroidism, and hyperparathyroidism Environmental toxins Inflammatory/infectious SyphilisProgressive multifocal leukoencephalopathyHIVCreutzfeldt-Jakob disease Clinical features Memory impairment Additional cognitive impairmentSpeech: aphasia, word-finding difficulties, semantic paraphasiaIntellectual capacities, reasoning, planning capabilities, and self-controlSpatial-temporal awareness (however, the awareness of oneself remains stable for a long time)Apathy Changes in personality, mood, and behaviorEarly stages: depressionLater stages: seemingly unconcerned mood and cognitive impairment is downplayed Diagnostics General Personal and collateral history of cognitive and behavioral changes Drug history Screening for depression Physical and neurological examination Diagnostic criteria for major neurocognitive disorder (previously dementia) in accordance with DSM-5 Significant cognitive decline in at least one of the following domains Learning and memoryLanguageExecutive functionComplex attentionPerceptual-motorSocial cognition Cognitive deficits interfere with everyday life, patient becomes dependent on help with complex activities (e.g., paying bills) Cognitive deficits do not occur exclusively in the context of a delirium Cognitive deficits are not better explained by another mental disorder (e.g., major depression) Cognitive assessment Mini-Mental State Examination (MMSE) Definition: a screening tool that assesses the degree of cognitive impairment in individuals with suspected dementia Diagnostic criteriaA maximum of 30 points is possibleA patient who scores 24 points or less is generally considered to have dementia. 20-24 points: mild dementia13-20 points: moderate dementia< 13 points: advanced dementia Montreal Cognitive Assessment (MoCA) Definition: a screening tool that assesses cognitive impairment Includes testing of memory, visuospatial ability (e.g., by drawing a clock and copying a drawing of a cube), executive function, attention, language, abstraction (e.g., identifying similarity between a train and a bicycle), recall, and orientationto time and place. Diagnostic criteriaA maximum of 30 points is possible 18-25 points: mild cognitive impairment10-17 points: moderate cognitive impairment< 10 points: severe cognitive impairment Saint Louis University Mental Status Examination (SLUMS) Definition: a screening tool to assess the degree of cognitive impairment in individuals with suspected dementia Diagnostic criteriaA maximum of 30 points is possibleA patient who scores 19 points or less suffers from neurocognitive impairment Clock-drawing test Procedure: The patient is given a sheet of paper with an empty circle on which they are asked to draw a clock indicating the current time (including numbers and hands). Purpose: If an individual is unable to correctly draw the numbers and hands on the clock, a deficit in spatial or abstract thinking may be present. These deficits are commonly already present during the early stages of dementia. Neuropsychologic testing Lab tests In all patients: screening for vitamin B12 deficiency (cobalamin) and hypothyroidism More specialized tests should be ordered in patients with a rapid progressive course of dementia, young patients (< 60 years), or patients with symptoms giving reason to suspect the presence of a certain diseaseSerum electrolytes, renal and liver function tests, folate, homocysteineCeruloplasmin: decreased in Wilson disease (may be associated with symptoms of dementia)ApoE genotyping Lumbar puncture and CSF analysis (only in selected patients with suggestive clinical features or other abnormal tests)To reveal CNS infection/inflammation (e.g., in meningitis or encephalitis) Imaging In all patients: noncontrast head CT or MRI To detect reversible causes of dementia (e.g., brain tumor, subdural hematoma, NPH, past cerebral ischemia)Multiple lacunar infarcts in vascular dementiaReduced hippocampal volume in Alzheimer disease PET, SPECT: in selected patients with suggestive clinical features/abnormal other tests to distinguish between different neurodegenerative disorders (e.g., Alzheimer disease, atypical parkinsonian disorders, and frontotemporal dementia) EEG: when structural abnormality is suspectedCourse of disease Distinctive clinical featuresStudies & imagingPathologyAlzheimer disease(AD)Slowly progressive, over ∼ 8-10 yearsEpisodic impairment of memoryCharacteristic order of language impairment: naming → comprehension → fluencyAD is a clinical diagnosisDiffuse cortical atrophyHippocampal atrophyCSF↓ Beta amyloid↑ Phosphorylated tauNeuritic plaques (amyloid betapeptides, mainly accumulating extracellularly)Neurofibrillary tangles (abnormally phosphorylated tau protein, which accumulates intracellularly)Vascular dementia(VD)May present with abrupt cognitive decline and stepwise deterioration Asymmetric or focal deficits (e.g., hemiparesis)CT/MRI usually shows lacunar infarctsDementia with Lewy bodies (DLB)Steady decline; typically over ∼ 8-10 years but more rapid progression is possibleVisual hallucinationsand parkinsonian motor disordersAttention impairmentSPECT: may reveal decreased occipital perfusion/metabolismLewy bodies (intracellular aggregations of mainly α-Synuclein)Frontotemporal dementia (FTD)Usually manifests between ages 40-69Behavioral variant FTD(most common) → early changes in personality, apathyCSF: ↑ Aβ 1-42PET or SPECT to reveal metabolic disorders in the frontal and temporal lobesFocal cortical atrophyNormal pressure hydrocephalus(NPH)Potentially reversibleClassic clinical triadGait disorderDementiaUrinary incontinence CT/MRI: relative dilatation of ventricleswith periventricular hyperintensities Lumbar puncture alleviates symptoms Unspecific cerebral atrophy Wernicke encephalopathy(WE) & Wernicke-Korsakoffsyndrome (WKS) Potentially reversible WE (classic clinical triad)ConfusionAtaxiaOphthalmoplegia WKS Severe anterograde and retrograde amnesia, apathy, confusion, anosognosiaOther cognitive capacities remain comparatively intact. No specific laboratory test or imaging study is available to definitively rule out Wernicke encephalopathy or Wernicke-Korsakoff syndrome Acute WE: gliosis, inflammation, and/or necrosis, particularly in periventricular structures (e.g., the medial thalamus) Chronic WE/WKS: atrophy of the mamillary bodies Late neurosyphilisProgresses many years after primary infection (∼ 20 years)Signs of late neurosyphilis include: Frontotemporal dementia, psychosis, cognitive dysfunction, personality changesParesisArgyll Robertson pupilTabes dorsalisPossibly other signs of tertiary syphilis, including: GummaCardiovascular syphilisMay have history of primary or secondary syphilisPositive (screening) nontreponemal tests(e.g., RPR, VDRL)Positive (confirmatory) treponemal tests (e.g., TPPA, FTA-ABS)Direct detection possible via darkfield microscopyPseudodementiaAssociated with major depression, especially in elderly patientsCognitive deficits typically manifest after mood symptomsTypically sudden onsetMimics dementiaComplaints of memory lossMostly depressed moodPatients are able to recall onset of symptoms.Patient gives short answers, e.g., "I don't know"Cognition usually improves after effective antidepressant therapy.No specific tests availableStructural or metabolic abnormalities that are associated with depression (e.g., lesions of the limbic system)Normal agingInsidious onset, typically starting in the sixth/seventh decadeMild decline in some cognitive areas → episodic and working memory affected firstProcedural and semantic memory typically preservedIndependence in daily activities is preservedNo specific tests availableGeneral loss of brain volume(white matter more affected than grey matter) Treatment Memory training Cognitive capabilities can be improved through targeted stimulation (e.g., practicing image recognition, completing arithmetic or combinatorial problems). Recalling past memories Pharmacotherapy Cholinesterase inhibitors Recommendation: Particularly mild to moderate cases of Alzheimer dementia or vascular dementiaMay be beneficial in cases of dementia with Lewy bodies, frontotemporal dementia, and Parkinson disease Drugs: donepezil, rivastigmine, galantamine Effect: Reversible cholinesterase inhibition leads to increased acetylcholine (ACh) concentration and can thus improve symptoms of some types of dementia. Adverse side effects: (see symptoms of cholinergic crisis) Memantine Recommendation: Particularly moderate to advanced cases of Alzheimer disease or vascular dementiaMemantine may be used in combination with cholinesterase inhibitors. Effect: NMDA-receptor antagonism Adverse side effects: mostly affect the central nervous systemHeadaches and dizzinessConfusion and hallucinationsEpilepsy In general, anticholinergic substances (e.g., tricyclic antidepressants) should be avoided, as they may lead to further deterioration in cognitive functioning!

Tetanus Tetanus (lockjaw) is an acute disease caused by neurotoxins from the bacterium Clostridium tetani. C. tetani is ubiquitous in spore form and enters the body through broken skin (e.g., deep puncture wounds). Its toxins then cause uncontrolled activation of alpha motoneurons, leading to muscular rigidity and spasms. Patients classically present with a triad of trismus, risus sardonicus, and opisthotonus. Despite treatment with anti-tetanus toxoid immunoglobulin and antibiotics(e.g., metronidazole), the overall prognosis is poor once symptoms begin. Therefore, vaccination as primary prevention is crucial.

Etiology PathogenClostridium tetani: a gram-positive, obligate anaerobic, spore-forming rodProduces neurotoxins tetanospasmin and tetanolysinUbiquitous (especially animal feces and soil) Route of infectionClostridial spores contaminate a wound (e.g., through dirt, saliva, feces)Localized ischemia, necrosis, foreign bodies and/or coinfection with other bacteria predispose to infectionWounds with compromised blood supply create anaerobic conditions that are required for the germination and multiplication of C. tetani. Deep, penetrating wounds (e.g., knife, gunshot, animal bites)Open fracturesSurgical procedures (e.g., bowel, biliary tract, or dental surgery)Septic abortionBurnsUmbilical stump infections Groups with a higher risk: non-immunized individuals, those with diabetes, neonates, IV drug abusers, certain patient groups (i.e., postsurgical, obstetric, dental) [1] Pathophysiology Ubiquitous C. tetani spores contaminate a wound → bacteria reproduce under anaerobic conditions → production of neurotoxins tetanospasmin and tetanolysin Tetanospasmin: reaches the CNS through retrograde axonal transportToxin binds to receptors of peripheral nerves and is then transported to interneurons (Renshaw cells) in the CNSvia vesicles [2][3]Acts as protease that cleaves synaptobrevin, a SNARE protein → prevents the release of inhibitory neurotransmitters (i.e., GABA and glycine) from Renshaw cells → uninhibited activation of alpha motor neurons →muscle spasms, rigidity, and autonomic instability Tetanolysin: causes hemolysis and has cardiotoxic effects Clinical features Incubation period: 3-21 days (average: ∼ 10 days) Generalized tetanus: painful muscle spasms and rigidity Trismus: lockjaw due to spasms of the jaw musculatureCommonly the first tetanus-specific signRisus sardonicus: grinning caused by cramps of the facial musclesNeck stiffnessOpisthotonus: backward arching of spine, neck, and head caused by spasms of the back muscles Abdominal rigidity Life-threatening complicationsLaryngospasm and/or respiratory muscles spasms → respiratory failure [4]Autonomic dysfunction → circulatory arrest and shock [4] Neonatal tetanus Occurs in infants of inadequately immunized mothers after unsterile management of the umbilical stump Typically occurs 5-8 days after birth, but incubation period can be up to a several weeks Typically a rapid onset of symptoms as axonal length in infants is shorter than in adults [5] Symptoms include: Difficulty opening the mouth and feeding due to trismus and risus sardonicusMuscle stiffness and opisthotonusClenched hands Other types Localized tetanus: Patients present with painful muscle contractions in areas surrounding injury site only. Cephalic tetanusIn patients with open head or neck injuries.Initially, only affects cranial nerves (especially flaccid paralysis of CN VII), which can be mistaken for stroke. Diagnostics Tetanus is a clinical diagnosis based upon muscle spasms and rigidity associated with an entry point for bacteria and inadequate immunization.[6] Wound culture and serology may confirm the diagnosis but have low sensitivity and specificity Treatment In addition to initial supportive care, management should focus on controlling the infection, eliminating toxin production, and neutralizing circulating toxins. Wound cleaning and debridement Antibiotic treatment Drug of choice: metronidazoleAlternative: penicillin G Active and passive immunizationSingle IM dose of human tetanus immunoglobulin (HTIG) Tetanus toxoid-containing vaccine: for example, TdaP, Td, DTaP, DT, depending on age, previous immunization, or allergies (see tetanus prophylaxis after injury in "Prevention" section below for details) Inject in a separate site from HTIGIf patient has not received initial immunization before infection: second and third dose 1-2 months and 6-12 months later, respectivelyThe still intact receptor binding site of the tetanus toxoid induces antibody production and memory cell formation (active immunity). Supportive care: transfer to ICU, ventilation, benzodiazepines and/or paralytics for control of muscle spasms Prevention Tetanus vaccination [7] Tetanus toxoid-containing vaccines according to age groupsFor children < 7 years of age: DTaP (diphtheria, tetanus, and acellular pertussis)DT (diphtheria, tetanus): for children who cannot tolerate the pertussis vaccineFor adolescents and adults: Tdap (tetanus, diphtheria, pertussis): recommended for patients 11-64 years of age, but may be considered for children > 7 years oldTd (tetanus, diphtheria): for patients > 11 years old Initial immunization recommendations: children < 7 years of age → 5 doses of DTaP (see "Immunization schedule"): Booster recommendationsChildren 11-12 years of age: single dose of Tdap [8]Adults 19-64 years of age: single dose of Tdap [8] Adults ≥ 19 years of age: Td (tetanus, diphtheria) every 10 years Women should get one shot of Tdap during every pregnancy to protect the baby. Vaccination historyClean, minor woundsAll other wounds Unknown or < 3 tetanus toxoid dosesActive immunization with tetanus toxoid (Td or Tdap)Active immunization with Td or Tdap AND passive immunizationwith HTIG ≥ 3 tetanus toxoid dosesActive immunization with Td or Tdap if last vaccination≥ 10 years agoActive immunization if last vaccination ≥ 5 years ago

Radial neuropathies Radial neuropathies are conditions caused by acute or chronic injury to the radial nerve. Clinical presentations vary with the mechanism, site, and extent of nerve injury. The radial nerve arises from the posterior cord of the brachial plexus, which comprises cervical roots C5-T1. Within the upper extremity, the radial nerve has lateral cutaneous sensory branches and innervates extensors. When injured, radial neuropathies are therefore characterized by sensory symptoms of pain, paresthesia, and numbness, as well as motor symptoms of weakness of extension at the elbow, wrist ("wrist drop"), and/or fingers. Several risk factors are associated with subtypes of radial neuropathies, including crutch use, intoxication, fracture of the humerus or radius, use of tight watch bands or handcuffs, and repetitive pronation and supination. The patient history and examination, including Tinel's sign, may be sufficient for diagnosis in some cases, but x-ray is necessary in the presence of trauma, and electrodiagnostics, though less useful than in carpal tunnel syndrome, may be considered if symptoms persist. Conservative management, consisting of local corticosteroid injections and counseling to reduce risk factors, is typically the treatment of choice in nontraumatic cases. Surgical decompression, with approach varying by location, may be considered in refractory cases.

Etiology Risk factors vary according to the location of the injury: Axilla: improper crutch useMid-arm: Fracture of humerus (radial nerve runs in spiral groove)Compression of the radial nerve due to draping of arm over furniture (saturday night palsy) or pressure on mid-arm; more likely in the setting of intoxication, anesthesia, or sleep (honeymoon palsy)Elbow: radial tunnel syndrome (controversial diagnosis ) due to chronic compression within the radial tunnelDeep forearm: posterior interosseous nerve syndrome (a syndrome characterized by weakness of muscles in the extensor compartment of the forearm) due to fracture of the radial head or chronic soft tissue compressionSuperficial forearm or wrist: superficial radial nerve compression, called "cheiralgia paresthetica," often due to tight wristwatches or handcuffs or repetitive pronation and supination Site of lesionSensory symptomsMotor symptomsAxillaAll belowAll belowParalysis of the triceps muscle may occur if the radial nerve is injured in the axilla.Mid-armAll belowNumbness, paresthesia, pain along lateral posterior armAll belowWrist dropParalysis or weakness of the hand and finger extensors (decreased grip strength)The patient cannot extend their hand at the wrist joint.Elbow (radial tunnel)Pain and tenderness following extension or repetitive pronation/supinationSometimes weakness of extension and supination, secondary to pain (not to missing innervation!)Deep forearm (proximalposterior interosseous nerve)None Paralysis of the finger extensors (no true wrist drop!)Superficial forearm and wrist (superficial radial nerve)Deficits on the radial side of the dorsum of the hand (thumb, index finger, and the radial half of the middle finger) None The higher (more proximal) the lesion, the greater the number of extensor muscles involved! Diagnostics History: Inquire about risk factors, including substance use, trauma, and causes of compression.Ask the patient to describe the timeline of symptoms, history of similar symptoms, and associated symptoms such as joint pain. Physical examination: Focus the exam on the most proximal location of injury, if known reatment The treatment of choice depends on the severity and persistence of symptoms. Conservative therapyRestNSAIDsLocal glucocorticoid injections (if needed) Physical therapy Surgical therapy in severe and treatment-resistant cases: nerve decompression, neurorrhaphy, nerve transplantation, tendon transfer Orthopedic repair of fractures, dislocations, or other traumatic injury

Syncope Syncope is a sudden, completely reversible loss of consciousness secondary to an acute reduction of cerebral perfusion, which may last from several seconds up to minutes. The most frequent form is vasovagal syncope, which is triggered by emotional stress or prolonged standing, and may be diagnosed with the tilt table test. Orthostatic syncope may occur upon suddenly standing up after prolonged sitting or lying down. It is caused by a drop in blood pressure. This relatively benign cause may, however, lead to life-threatening injuries as a result of falls. A thorough medical investigation is necessary as syncopes may also be the result of a serious cardiovascular disorder (e.g., cardiac arrhythmia or valvular stenosis). The treatment strategy is dependent on the cause of the syncopes.

Etiology TLOC (transient loss of consciousness): temporary syncope of unknown origin Cardiac syncope Heart's inability to meet an increased oxygen demand (e.g., during exertion)→ reduced cerebral perfusionArrhythmogenic syncopeBradycardia/tachycardia → ↓ ejection fractionSick sinus syndromeVentricular tachycardiaAtrioventricular blockSupraventricular arrhythmiasAdams-Stokes syndromeTorsades de pointes Cardiovascular syncopeStructural outflow obstructionMassive MIAortic stenosisMitral valve prolapseAtherosclerosisPulmonary embolism Pulmonary hypertensionHypertrophic cardiomyopathySevere asymmetric septal hypertrophyCardiac tamponade Reflex syncope(Most common cause) Neurally mediated syncope that can be due to parasympathetic hyperactivity(cardioinhibitory response), sympathetichypoactivity (vasodepressor response), or a combination of both → vasodilatation (vasodepressor response) and/or bradycardia (cardioinhibitory response) → reduced BP → reduced cerebral perfusion Neurocardiogenic syncope (subtype of vasovagal syncope)Prolonged standing (and no compensatory heart rate acceleration)Common in younger patients(unusual to have first episode after age 40)Can be recurrentEmotional syncope (subtype of vasovagal syncope)Pain or emotional stressPainFearSight of bloodInjuryCarotid sinus syndromeIncreased carotid sinus sensitivity(frequently associated with arteriosclerotic changes in the carotid sinus) → ↓ systolicblood pressure when pressure is applied to the carotid sinusPressure on the carotid sinuses (e.g., during a massage, when shaving, tightening a necktie)Other situational syncopesVagotonic, peripheral vascular dilationCoughSwallowMicturition syncopes(commonly seen in males with prostatichyperplasia) Orthostatic syncope(postural hypotension)Standing up/postural change→ insufficient counterregulation due to autonomic dysfunction (e.g. decreased baroreceptor sensitivity in the elderly)→ reduced cerebral perfusionSympathotonic orthostatic hypotensionWhen standing up: ↓ systolic blood pressure despite excessive sympathotonic counter regulation (significant heart rate increase) → reduced cerebral perfusionHypovolemia(dehydration, hemorrhage, use of diuretics such as thiazides),Medications(vasodilators such as alpha-blockers, and ganglionic blocking agents)Prolonged bed restAsympathotonic orthostatic hypotensionWhen standing up: ↓ systolic blood pressure without sympathotonic counterregulation (steady or even reduced heart rate) → reduced cerebral perfusionDiabetic autonomic neuropathiesParkinson's autonomic dysfunctionPostural tachycardia syndrome (PoTS, orthostatic intolerance)When standing up: no significant drop in blood pressure, but massive heart rateincrease within 10 minutes of standing up Clinical features Prodrome: presyncopeVasovagal: impairment of senses, nausea, pallor, warmth, diaphoresis, lightheadedness, and hyperventilationOrthostatic: lightheadedness, nausea, and dizzinessCardiac: no prodrome; often sudden fall Rapid onset loss of consciousnessAccompanied by complete loss of muscle toneLast seconds to minutes followed by spontaneous recoveryConvulsive syncope: common form in which loss of consciousness is accompanied by myoclonic movements Diagnostics Patient history: Determine triggers, ask witnesses how patient behaved during event, and medication/medical/family history. Routine investigationsECG (for all patients!) CBC (↓ serum Hb) Additional tests Cardiac origin suspected (see also cardiac arrhythmia) Cardiac monitoring (If ECG is not diagnostic and a cardiac cause is strongly suspected): sinus bradycardia< 40/min, sinus pauses > 3 seconds, atrioventricular (AV) or bundle branch blocks Stress ECG (ischemia)Echocardiography: if structural heart disease is suspected or ECG is abnormalCardiac enzymesCarotid ultrasound with dopplerPulmonary origin suspected : chest x-ray (suspected pneumonia, lung mass) and ventilation/perfusion scanning (suspected pulmonary embolus)Neurological origin suspected : head imaging (CT, MRI, or MRA showing ischemia or hemorrhage) and EEG(seizure)Other laboratory tests : abnormal electrolytes, abnormal urinalysis ↑ BUN/creatinine ratio (assess for signs of hypovolemia in orthostatic hypotension), stool occult blood testManeuvers Testing for orthostatic hypotension or vasodepressor syncopePatient is asked to stand after being in supine position for at least 5 minutes → Blood pressure is measured each minute for at least 3 minutes.If systolic BP decreases by ≥ 20 mm Hg and the diastolic BP decreases by ≥ 10 mm Hg, or BP < 90 mm Hg→ orthostatic hypotensionCoinciding bradycardia → vasodepressor syncopeTilt table testDetermines if vasovagal or orthostatic syncope is presentProcedure The patient is strapped onto a tilt table in a supine position for 15 minutes, and then is raised passively to an angle of around 70°.Positive: reflex hypotension (systolic blood pressure < 90 mm Hg) and bradycardia (vasovagal) or slow progressive hypotension (orthostatic) with presyncope or syncopeNegative (normal): increased heart rate along with barely changed blood pressure and no clinical signs of syncope or presyncope Differential diagnoses Non-syncopal eventsMedical history and clinical featuresDiagnosisSeizureEpileptic symptoms (e.g., aura, postictal state, lateral tongue biting, bladder/bowel incontinence)Abnormal EEGBrain lesions visible in imaging (CT, MRI)Subclavian steal syndromeOccurs when straining the ipsilateral armRare: complete loss of consciousnessFocal-neurological signs during an attack (e.g., double images, dysarthria)Duplex ultrasound of the carotid and subclavian arteries showing stenosisVertebrobasilar insufficiency"Drop attacks" can be seen with a TIA in the vertebrobasilar circulation.Other neurologic deficits will be seen as well.CT/MRIHypoglycemiaDiabetesClinical symptoms: symptoms of autonomic counterregulation (e.g., restlessness, sweating, pale skin)↓ Blood glucoseCraniocerebral injuryConsiderable head trauma (e.g., from falling) leading to traumatic brain injuryIsolated eventPathology on imaging (CT, MRI)HeatstrokeThe body is unable to regulate the core body after it becomes elevated.Syncope can precede exertional heatstroke.Elevation in: Creatinine kinaseCBCAST/ALTNormal ECGHyperventilationCan occur when stressedOften occurs in patients with panic disordersArterial blood gas: respiratory alkalosisCryptogenic drop attacksThe cause of many falls, especially in older patients, remains elusive despite extensive diagnostic testing. These falls/attacks are called cryptogenic drop attacks. Treatment Treat underlying conditionArrhythmogenic syncopes may require a pacemaker or treatment with antiarrhythmic drugs.Patients with carotid sinus syndrome should be advised to avoid tight collars and remain hydrated. Vasovagal syncopesPhysiological counterstrategies: Crossing the legs, tensing muscles, lying down, and elevating the legs can reverse the syncope.Avoid triggers Orthostatic syncopesSufficient intake of sodium and fluidsCompression stockingsAdjust medications (e.g., diuretics)Fludrocortisone if unable to manage episodes with nonpharmacological interventions omplications Depends on the underlying condition Cardiac syncope is associated with one-year mortality rates of up to 33%. Fall injuries

DeliriumDelirium is a neurocognitive disorder characterized by impaired attention, awareness (reduced orientation to the environment), and other disturbed cognitive functions (e.g., memory, language, or perception). Symptoms develop acutely and tend to fluctuate throughout the day. Delirium occurs as a direct physiological consequence of another medical condition. It is most often a complication of polypharmacy, especially in elderly patients, and is also commonly seen in patients admitted to the ICU. Although delirium is a reversible confusional state, it warrants urgent medical attention because it may be the first sign of serious underlying disease. Treatment of delirium focuses on treating the underlying illness and reducing exposure to exacerbating factors. Antipsychotic medications are used for the treatment of agitation in delirious patients.

Etiology The exact mechanism responsible for delirium is unknown. Pediatric, elderly (> 65 years), and hospitalized patients are particularly susceptible. Can be secondary to: Metabolic diseases (most common cause; also referred to as metabolic encephalopathy)Liver or kidney failureDiabetes mellitusHyperthyroidism or hypothyroidismVitamin deficiencies (e.g., vitamin B12, folic acid, or thiamine deficiency)Electrolyte abnormalitiesInfection (e.g., UTIs are a common cause in elderly patients; pneumonia, meningitis)Trauma (e.g., hip fracture, head injury)CNS pathology (e.g., stroke, brain tumor)Hypoxia (e.g., anemia, cardiac failure, COPD, pulmonary embolism)Acute cardiovascular disease (MI, shock, vasculitis)Drugs and toxins (also referred to as toxic encephalopathy) AnticholinergicsBenzodiazepines and barbituratesAntidepressants and antipsychotics (especially those with anticholinergic activity, e.g., quetiapine)OpioidsDiuretics (may cause electrolyte abnormalities)Recreational drugs (intoxication/withdrawal)Alcohol useHeavy metals (e.g., arsenic, lead, mercury)Sleep deprivationMajor surgeryHearing or vision lossOngoing symptoms, including: ConstipationUrinary retentionPainDehydration Clinical features The main symptom is an acute (hours to days) alteration in the level of awareness and attention. Other features may include: IllusionsHallucinationsDeficits in memoryReversal of the sleep-wake cycleEmotional labilityAgitation, combativeness The severity of symptoms fluctuates throughout the day and worsens in the evening (termed sundowning). The duration of symptoms depends on the underlying illness. Diagnostics If the cause of delirium is not obvious based on the patient history and physical findings: Start with complete blood count, serum glucose, electrolytes, and urinalysis.If medication or substance use is suspected: urine toxicology or serum drug levelsIf a metabolic etiology is suspected: serum creatinine, BUN, liver function tests, arterial blood gasIf pneumonia is suspected: chest x-rayIf a cardiac etiology (e.g., myocardial infarction, arrhythmia) is suspected: ECG If the patient has focal neurological deficits or the initial workup is negative, further tests may include: Neuroimaging (CT, MRI) Lumbar puncture: to rule out meningitis/encephalitis EEG: usually shows diffuse slowing of background activity in patients with delirium; also useful in patients with a history of head trauma, stroke, or brain lesions Further diagnostics that may be considered: Blood cultureHIV; syphilis serologyThyroid function testsVitamin B12, folate, and thiamine levelsDepression screen Delirium vs. dementiaDeliriumDementiaOnsetSuddenProdromal phase might precedeInsidiousCourseRapid and fluctuatingHours to daysSlowly progressive deteriorationMonths to yearsLevel of consciousnessDecreasedIntactAttentionImpaired (fluctuating)Usually alertImpaired in the advanced phaseMemoryRecent memory lossRecent, then remote memory lossThought processDisorganizedImpoverishedHallucinationsPresent (often visual or tactile)Present in 30% of patients in the advanced phasePsychomotor activityIncreased or decreasedUsually normalEEGUsually abnormalUsually normalReversibilityReversibleUsually irreversible Treatment Identify and treat the underlying cause. Discontinue the causative medications (e.g., benzodiazepines and anticholinergics). Supportive medical care Manage agitation initially with nonpharmacologic strategies (see "Prevention" below).Administer antipsychotics if the patient is agitated and/or poses harm to themselves or others.Haloperidol is used most commonly; however, it should not be used in patients with delirium that is due to alcohol or benzodiazepine withdrawal because it lowers the seizure threshold.Alternative: atypical antipsychotics (e.g., olanzapine)Maintain adequate hydration and nutrition.Reduce pain, preferably with nonopioid medications.Prevent aspiration, incontinence, and skin breakdown. Benzodiazepines are deliriogenic. Do not treat delirious patients with benzodiazepines unless the delirium is due to alcohol or benzodiazepine withdrawal, in which case haloperidol is contraindicated because it lowers the seizure threshold! revention Nonpharmacologic approachReduce exposure to modifiable risk factors.Reorient the patient regularly. Arrange for regular visits from family and friends.Arrange for constant observation, preferably by a family member or friend.Reduce the amount of noise, procedures, and medication administration occurring at night. Provide physical and occupational therapy to mobilize the patient as soon as possible.Minimize the use of restraints as much as possible.Provide visual and hearing aids for patients with impairments. Pharmacologic DexmedetomidineCholinesterase inhibitors (e.g., rivastigmine, donepezil)Second-generation antipsychoticsMelatonin

Persistent vegetative state Persistent vegetative state (PVS) is a clinical condition in which function of the cortex is impaired while function of the brainstemis preserved for a period of more than one month. Traumatic brain injury and diffuse cerebral hypoxia are the most common etiologies. Patients in PVS may appear awake but are not aware or conscious, and they are unable to communicate with others or purposefully interact with their environment. However, they are still able to breathe on their own, sleep-wake cycles are preserved, and autonomic function is at least partially retained. PVS is a clinical diagnosis, and it is important to differentiate it from coma (no sleep-wake cycles) and brain death (no sleep-wake cycles or brainstem function). No definitive treatment exists. Although most patients remain in a vegetative state for years, a few may recover spontaneously. A vegetative state is declared permanent when recovery is very unlikely (i.e., PVS due to trauma lasting more than 1 year or PVS due to a nontraumatic cause lasting more than 3 months).

Etiology Traumatic brain injury Diffuse cerebral hypoxia Other causes of severe damage to the cerebral hemispheres and/or thalamus (e.g., neurodegenerative diseases, CNSinfections, metabolic disturbances, toxins, developmental malformations of the CNS) Pathophysiology Widespread damage to the white matter of both cerebral hemispheres and/or the thalamus bilaterally, without damage to the brainstem. This results in reduction of cortical function with preserved brainstem control of respiration, cardiac function, sleep-wake cycles, and reflexes.Clinical features Usually preceded by comatose state requiring intensive care and gradual recovery of autonomic function But lack of recovery of higher mental function after 1 month and the following features: Intact sleep-wake cycles with periods of wakefulnessLoss of perceptual and self-awarenessLack of purposeful response to external stimuli (e.g., tactile, auditory, visual, etc.)Inability to communicate and lack of apparent language comprehensionDisconjugate eye movements with loss of fixationOccasional nonpurposeful limb movements and spontaneous smiling, crying, grunting, or screamingAutonomic function and reflexes retained to variable degreesSufficient cardiovascular, respiratory, and thermoregulatory functionSufficient gastrointestinal and renal function but bowel and bladder incontinenceVariable preservation of reflexes (e.g., pupillary, corneal, vestibulo-ocular, gag, cough)Diagnostics Clinical diagnosis based on ≥ 1 month of intact sleep-wake cycles, loss of perception and self-awareness, and autonomic functions retained to variable degrees NeuroimagingCT/MRI: nonspecific diffuse or multifocal abnormalities involving the gray and white matter; decrease in cerebral blood flowPET: diffuse reduction of the glucose metabolic rate of the brain EEG: diffuse generalized polymorphic delta and/or theta activity Persistent vegetative state Sleep-wake cyclesPresent Coma Respiratory function Depressed, variable Locked-in syndrome Perceptual and self-awareness Sleep-wake cycles Quadriplegia and pseudobulbar palsy; eye movement preserved Brain death Prognosis The vegetative state is defined as permanent if recovery is very unlikely. Likelihood of recovery depends on etiologyPVS due to trauma → recovery unlikely after ≥ 12 monthsPVS due to nontraumatic etiology → recovery unlikely after ≥ 3 months Low life expectancy Withdrawal of life support may be considered if the chances of recovery are very low (e.g., ≥ 12 months in traumatic PVS). However, in patients without advanced directives, it is a complicated legal and ethical question that requires discussion with family members and experts. Treatment Treatment is supportive; no definitive treatment exists.

Median nerve neuropathy The median nerve is a peripheral nerve originating in the cervical roots C5-T1 of the brachial plexus. It supplies motor innervation to the anterior forearm flexors, the thenar muscles, and the two lateral lumbricals as well as sensory innervation to the lateral palm and anterior, lateral three and a half fingers. Motor and sensory deficits depend on whether the lesion is proximal (above the elbow) or distal (below the elbow). While proximal lesions present with the "hand of benediction," distal lesions present with either the "pinch sign" (anterior interosseous nerve syndrome) or, in the case of carpal tunnel syndrome, with mildly impaired thumb and index finger motion. Both proximal lesions and carpal tunnel syndrome result in reduced sensation in the area of the thumb, index and middle finger. Anterior interosseus nerve syndrome does not cause any sensory deficits. Chronic injuries to the nerve result in atrophy of median nerve innervated muscles while acute injuries do not have this feature. Treatment is mostly conservative and focuses on rest and immobilization.

Etiology Traumatic: e.g., fractures (humerus fracture causing proximal lesion), carpal bone dislocations, or penetrating injuries(gunshots, lacerations, etc) Chronic compression: e.g., in the carpal tunnel (see carpal tunnel syndrome) or between the forearm muscles (anterior interosseous nerve syndrome) or by a nerve sheath tumor (schwannoma of the median nerve) Anatomical principles The median nerve runs from the axilla to the elbow, in the medial side of the arm in the medial bicipital groove. It enters the forearm through the two heads of the pronator teres muscle. After branching off into a motor nerve (anterior interosseous nerve), it courses distally between the superficial and deep layers of the forearm's flexor compartment to reach the wrist, where it branches off into a sensory nerve (the palmar cutaneous branch of the median nerve) before entering the hand through the carpal tunnel. LocationMotor deficitSensory deficitProximal (above elbow)Hand of benedictionThumb opposition and abductionWrist pronation and flexionFlexion of index and middle fingerThenar muscle atrophy (chronic injury)ThumbIndex and middle fingerRadial side of ring fingerDistal (below elbow)Anterior interosseous nerve syndrome: flexion of distal joints of thumb and index finger ("Pinch sign")noneDistal (within wrist)Carpal tunnel syndrome: Mild impairment of flexion of index finger, long finger, and thumb (less severe than in other median nervelesions!)Thenar muscle atrophy (chronic injury)Recurrent branch of median nerve: Innervates muscles of the thenar eminenceDamaged with lacerations of the radial-sided wrist and proximal palmResults in loss of thumb flexion, opposition, and abduction without sensory or other motor deficitsInjury produces median claw appearence of the hand (or ape hand deformity if both proximal and distalinjuries are present)Palmar cutaneous nerve:Purely sensory nerve arising from median nerve proximal to the carpal tunnelProvides sensation to the palmThumbIndex and middle fingerRadial side of ring fingerA high/proximal lesion of the median nerve manifests in the hand of benediction, while a low/distal lesion does not! Diagnostics Physical examinationBottle sign In the case of carpal tunnel syndrome, the following signs are also present:Tinel's signPhalen's sign Diagnostic proceduresNerve conduction study Electromyography (EMG) Treatment Avoid repetitive wrist activities See treatment for carpal tunnel syndrome

Brain abscess A brain abscess is a focal, suppurative lesion that may occur in one or more regions of the brain. It may be caused by the direct spread of sinus, ear, and/or dental infections, inoculation of pathogens following open skull fractures, and/or hematogenous spread from infective foci. During the course of the disease, the infected brain tissue softens and is subsequently encapsulated by granulation tissue. Clinical manifestations include headache, fever, neurological deficits, seizures, nausea, vomiting, and other features of raised intracranial pressure. Given these clinical findings, the main differential diagnosis is primary or metastatic brain tumor. Contrast CT reveals an intraparenchymal lesion with a hypodense center and peripheral ring enhancement. Treatment of brain abscesses involves surgical drainage of the abscess followed by systemic antibiotic therapy. nfectious diseases Tetanus Lyme disease Human immunodeficiency virus Toxoplasmosis Tuberculosis Rabies Meningitis Herpes simplex encephalitis Creutzfeldt-Jakob disease Brain abscess Shingles Measles Syphilis Leprosy

Etiology Usually an otogenic, sinus, oral, or meningeal (e.g., meningitis) source of infection Other sources: septic foci , open skull fractures, and/or neurosurgical procedures Pathogens Viridans streptococci (∼50% of cases), often secondary to sinusitisStaphylococcus aureus (10-15% of cases)Coagulase-negative staphylococci (∼10% of cases)Obligate anaerobes (e.g., Bacteroides species; 15-40% of cases) Gram-negative aerobic bacteria (e.g., Enterobacteria, Pseudomonas species; 15-30% of cases) Parasites (e.g., neurocysticercosis in patients from Latin America, Sub-Saharan Africa, and Asia)In immunocompromised states: Toxoplasma, Aspergillus, Candida, Mucormycosis (also known as Zygomycosis), Cryptococcus Pathophysiology Entry of pathogens via contiguous spread, direct inoculation, or hematogenous spread→ Early cerebritis: infiltration of neutrophils (occurs during the first 3-5 days) and cerebral edema→ Late cerebritis (after 2-3 weeks): necrosis, liquefaction, and infiltration of macrophages→ Eventually forms a fibrotic capsule around the lesion Clinical features Clinical features depend on the size and location of the lesion. Dull persistent headache A ruptured abscess is associated with a sudden worsening of headache and meningism. Symptoms of raised intracranial pressure (e.g., vomiting, papilledema, altered mental status) Focal neurological deficits Fever Generalized or focal seizures (∼ 30% of cases) Diagnostics Laboratory tests ↑ CRP, ↑ ESR LeukocytosisBlood cultures CT/MRI : intraparenchymal lesions with a central hypodense (necrotic) area and peripheral ring enhancement Biopsy (and drainage): microscopic examination and culture Best confirmatory test; entails either craniotomy for complete excision, or image-guided aspiration; distinguishes an abscess from a tumorCultures also determine the infective organism and its antibiotic sensitivities. Infections are often multibacterial; tailoring of antibiotic therapy to specific bacterial sensitivities is especially important given the length of treatment. Differential diagnoses Other intracranial lesions with ring enhancement: Brain metastases Tuberculomas Neurocysticercosis Subacute hemorrhage and/or infarction Treatment Early surgical drainage and biopsy of the abscess Antibiotic therapy for 6-8 weeks (usually IV ) Indications If brain abscess < 2.5 cm, history of symptoms < 1 week, and no signs of ICP → antibiotic therapy without surgical drainage may be attempted In all other cases → begin immediately after abscess biopsy/drainageInitial empirical therapy (e.g., third-generation cephalosporin + metronidazole ± vancomycin) Specific antibiotics may be used once the causative organisms and their antibiotic sensitivities are known. Intracranial pressure management Seizure prophylaxis (e.g., anticonvulsants) Prognosis If treated early: high survival rates and low rates of residual neurological sequelae Multiple, deep, ruptured, or inadequately treated abscesses have a poor prognosis

Locked-in syndrome Locked-in syndrome (LIS) is a rare condition caused by bilateral damage to the ventral pons, most often due to a stroke. LIS is characterized by quadriplegia and bulbar palsy, caused by the interruption of the corticospinal and corticobulbar tracts in the pons. The only remaining voluntary muscle movements include vertical eye movement and blinking. Consciousness, awareness, cognition, and sensation are preserved. Diagnosis of pontine damage is made on a CT or MRIof the brain. Preserved cognition is diagnosed via EEG and neuropsychological testing. Management in most patients includes tracheostomy, mechanical ventilation, placement of a feeding tube, and physiotherapy. Patients learn to communicate through blinking and/or eye movements and the help of computer programs/speech synthesizers. Some patients may recover a certain degree of motor control, speech, and swallowing ability.

Etiology Ventral pontine damage/injuryBilateral ventral pontine stroke (most common)Ischemic stroke Hemorrhagic stroke Direct trauma to the ventral ponsPontine demyelination (e.g., multiple sclerosis affecting the ventral pons, central pontine myelinolysis)Brain tumor or brain abscess affecting the ventral ponsAcute disseminated encephalomyelitis (postinfectious or postimmunization) Severe peripheral nervous system diseases (rare) Amyotrophic lateral sclerosisGuillain-Barré syndromeMyasthenia gravis Clinical features Locked-in syndrome is typically preceded by a loss of consciousness and subsequent coma lasting for days or weeks. The following symptoms are detected on regaining consciousness: Paralysis of voluntary musclesParalysis of all 4 limbs and torso (quadriplegia) → spasticity, ↑ deep tendon reflexes, positive bilateral Babinski's signBulbar palsy: inability to speak (anarthria) or swallow (dysphagia) Respiratory abnormalitiesCheyne-Stokes breathing, apnea, loss of voluntary control of breathingOften requires tracheostomy and mechanical ventilation Preservation of the following functionsNormal consciousness, language comprehension, cognition, and ability to make decisions Vertical eye movements and voluntary blinking Cutaneous sensation Diagnostics CT/MRI of the brain: indicated in all patients to identify the underlying cause EEGIndicated in all patients to rule out brain deathUsed to measure visual/auditory evoked potentials → nearly normal EEG in LIS Lumbar puncture: indicated if an infectious etiology or Guillain-Barré syndrome is suspected Neuropsychological testingPerformed once the patient is stable to assess cognitionPatients communicate with eye movements or blinking in response to the test questions → normal or near-normalcognition Demonstration of preserved cognition, vertical eye movements, and blinking in a quadriplegic, anarthric patient is diagnostic of LIS! Differential diagnoses Persistent vegetative state (PVS) Akinetic mutism Treatment In acute phase Supportive therapy (airway, breathing, circulation)Treat the underlying, often life-threatening, disorder (see "Etiology" for causes) In the rehabilitative phase Respiration: most patients require tracheostomy and mechanical ventilationFeeding: initially feeding tube; possibly gastrostomy Physiotherapy: passive stretching exercises; skeletal muscle relaxants and/or botulinum toxin for spasticity; frequent position change to avoid pressure soresSpeech: eye-gaze sensor-controlled computer communication programs, computer/internet use; use of speech synthesizers; eyelid blinking to communicate yes/no Prognosis Patients with LIS may show Complete recovery (transient LIS): e.g., in patients with Guillain-Barré syndromeModerate recovery: recovery of some motor function, ability to breathe and/or swallow, independence in some activities of daily living Minimal to no recovery

Wernicke encephalopathy and Korsakoff syndrome Wernicke encephalopathy is an acute, reversible condition caused by severe thiamine (vitamin B1) deficiency, often due to chronic heavy alcohol use. Inadequate intake, impaired absorption, or increased excretion of thiamine can also cause Wernicke encephalopathy. The classical triad of confusion, oculomotor dysfunction, and gait ataxia is seen in about a third of patients. Chronic thiamine deficiency, especially in patients with alcohol use disorder, frequently progresses to Korsakoff syndrome, which is characterized by irreversible personality changes, anterograde and retrograde amnesia, and confabulation. The diagnosis of both Wernicke encephalopathy and Korsakoff syndrome is clinical, but laboratory tests confirming thiamine deficiency and brain imaging may be considered in ambiguous cases. Wernicke encephalopathy is an emergency and requires immediate high-dose IV thiamine therapy followed by long-term thiamine supplementation. Abstaining from alcohol is vital in both conditions. While the prognosis in Wernicke encephalopathy is good if treated accordingly, that in Korsakoff syndrome is generally poor.

Etiology Wernicke encephalopathy and Korsakoff syndrome are caused by a severe deficiency of thiamine (vitamin B1). Thiamine deficiency can be due to:Chronic heavy alcohol use (most common) → inadequate intake, absorption, and hepatic storage of thiamineInadequate intakeThiamine-deficient diets Anorexia nervosa, starvationMalabsorptionIncreased demand (hypermetabolic states)Pregnancy and lactationHyperthyroidismSystemic diseasesMalignancyIncreased loss DiarrheaHyperemesisDialysis Pathophysiology Thiamine pyrophosphate (TPP) is the active form of thiamine. TPP is a cofactor for important enzymes involved in cerebral glucose and energy metabolism (see glycolysis and gluconeogenesis). The brain requires a constant source of thiamine to function properly. Thiamine deficiency → decreased cerebral glucose metabolism and mitochondrial dysfunction → depleted ATP and increased free radicals → injury of neuronal elements (e.g., myelin sheaths, blood-brain-barrier, decreased neurotransmitters, etc.) → impaired axonal conduction → symptoms of Wernicke encephalopathy and Korsakoff syndrome Clinical features Wernicke encephalopathy (acute, reversible) Should be suspected in any patient with a history of chronic heavy alcohol use who presents with one/more symptoms of the classic triad of Wernicke encephalopathy Confusion (most common) Oculomotor dysfunction Gaze-induced horizontal/vertical nystagmus (most common)Diplopia Conjugate gaze palsyGait ataxia: wide-based, small steps Other manifestations Autonomic dysfunction: hypotension, syncope, hypothermiaPeripheral neuropathy: paresthesia, foot drop, decreased deep tendon reflexesCardiovascular dysfunction: tachycardia, exertional dyspneaDiencephalic involvement: vegetative disorders (coma and stupor) Korsakoff syndrome (chronic, irreversible) Korsakoff syndrome is a late development in patients with persistent vitamin B1 deficiency. It is most often seen in thiamine deficiency due to chronic heavy alcohol use. Confabulation: Patients produce fabricated memories to fill in lapses of memory. Anterograde and retrograde amnesia (anterograde > retrograde) Personality changes (in frontal lobe lesions): apathy, indifference, decrease in executive function Disorientation to time, place, and person Hallucinations Diagnostics Usually a clinical diagnosis In ambiguous cases Laboratory tests↓ Serum thiamine levels↓ Erythrocyte transketolase activity (thiamine dependent) ↑ Serum lactate and pyruvateEvidence of alcohol-related liver dysfunction in patients with chronic heavy alcohol use Brain MRI: T2-weighted hyperintense lesions in the mammillary bodies, midbrain tectal plate, dorsomedial nucleiof the thalamus, cerebellum, and around the aqueduct and the third ventricle MRI signs of periventricular hemorrhage and/or atrophy of mammillary bodies is a frequent finding in both Wernicke encephalopathy and Korsakoff syndrome! Laboratory tests or imaging should not delay treatment! Pathology Petechial lesions and small vessel hemorrhage in the mesencephalon, mammillary bodies, ventricle walls, and dorsomedial nucleus of thalamus Atrophy of the mammillary bodies Microscopic spongiosis, capillary proliferation, and hemosiderin deposits (due to recurrent bleeding) Differential diagnoses Wernicke encephalopathy (conditions that manifest with an acute onset of delirium/ataxia) Cerebellar strokeHypoxia/hypercarbia (post cardiac arrest)Postictal stateCNS infections (e.g., meningitis)Tabes dorsalis Korsakoff syndrome (conditions that present with amnesia, disorientation) Alzheimer diseaseLewy body dementiaParkinson disease Treatment Wernicke encephalopathy Immediate IV administration of high-dose vitamin B1/thiamine upon suspicion of Wernicke encephalopathy until symptoms recede, followed by a lower dose Long-term oral replacement of vitamins B1, B6, B12, and folic acid (vitamin B complex) Abstinence from alcohol Korsakoff syndromeOral thiamine supplementation to prevent further progression to irreversible complicationsAbstinence from alcoholPsychiatric and psychological therapyMemory strengthening exercises and aidsThe use of signs and arrows at home can help with orientation. Because glucose increases thiamine demand and will worsen encephalopathy, IV glucose infusions must be administered AFTER thiamine! Prognosis Wernicke encephalopathy: Oculomotor dysfunction resolves, in general, within hours, ataxia within days, and confusion within weeks. Korsakoff syndrome: Symptoms are often irreversible.

Cushing syndrome Cushing's syndrome, or hypercortisolism, is an endocrine disorder that is most often caused iatrogenically by the exogenous administration of glucocorticoids. Less commonly, Cushing's syndrome can result from endogenousoverproduction of cortisol. Primary hypercortisolism is the result of autonomous overproduction of cortisol by the adrenal gland (e.g., adrenal adenoma, adrenal carcinoma). Secondary hypercortisolism, on the other hand, is the result of increased production of adrenocorticotropic hormone (ACTH), either by pituitary microadenomas (Cushing's disease) or by ectopic, paraneoplastic foci (e.g., small cell lung cancer). Typical clinical features include central obesity, thin, easily bruisable skin, abdominal striae, secondary hypertension, hyperglycemia, and proximal muscle weakness. Since serum cortisol levels vary diurnally, 24-hour urine cortisol measurement, midnight saliva cortisol levels, and/or dexamethasone suppression test are used to diagnose hypercortisolism. Serum ACTH levels and CRH stimulation test are used to identify the cause of hypercortisolism, imaging is then employed to localize the tumor. Treatment of endogenous hypercortisolismprimarily involves surgical removal of the source of excessive cortisol (e.g., adrenalectomy) or ACTH (e.g., transsphenoidal hypophysectomy). If surgery is contraindicated, drugs that suppress cortisol synthesis (e.g., metyrapone) may be used instead.

Exogenous (iatrogenic) Cushing's syndrome Hypercortisolism as a result of prolonged glucocorticoid therapy Most common cause of hypercortisolism Primary hypercortisolism (ACTH-independent Cushing's syndrome) 5-10% ♂ < ♀ (1:4) Autonomous overproduction of cortisol by the adrenal gland → ACTH suppressionAdrenal adenomas Adrenal carcinoma Macronodular adrenal hyperplasia Secondary hypercortisolismPituitary ACTH production (Cushing disease) ∼ 75% ♂ < ♀ (1:4) Pituitary adenomas → ACTHsecretion Ectopic ACTH production ∼ 15% ♂ = ♀ Paraneoplastic syndrome → ACTH secretionSmall cell lung cancerRenal cell carcinoma While the term "Cushing's syndrome" can be applied to any cause of hypercortisolism, "Cushing's disease" refers specifically to secondary hypercortisolism that results from excessive production of ACTH by pituitary adenomas! Secondary hypercortisolism is also called ACTH-dependent Cushing's syndrome because hypercortisolism is the result of increased ACTH levels. Clinical features SkinThin, easily bruisable skin with stretch marks (classically purple abdominal striae) and/or ecchymosesDelayed wound healingFlushing of the faceHirsutismAcneIf secondary hypercortisolism: often hyperpigmentation (darkening of the skin due to an overproduction of melanin), especially in areas that are not normally exposed to the sun (e.g., palm creases, oral cavity)Caused by excessive ACTH production because melanocyte stimulating hormone is cleaved from the same precursor as ACTH.Hyperpigmentation is not a feature of primary hypercortisolism. Neuropsychological: lethargy, depression, sleep disturbance, psychosis MusculoskeletalOsteopenia, osteoporosis, pathological fractures, avascular necrosis of the femoral head Muscle atrophy/weakness Endocrine and metabolicInsulin resistance → hyperglycemia (see diabetes mellitus) → mild polyuria in the case of severe hyperglycemia Dyslipidemia Weight gain characterized by central obesity, moon facies, and a buffalo hump ♂: decreased libido♀: decreased libido, virilization, and/or irregular menstrual cycles Secondary hypertension (∼ 90% of cases) Increased susceptibility to infections Peptic ulcer disease Cataracts Consider a diagnosis of hypercortisolism in patients who present with proximal muscle weakness, central obesity, thinning skin, weight gain, sleep disturbance, and/or depression. Patients with secondary hypercortisolism due to ectopic ACTH production may present with rapid onset of hypertension and hypokalemia without other typical features of Cushing's syndrome. Diagnostics General laboratory findings Hypernatremia, hypokalemia, metabolic alkalosis Hyperglycemia: due to stimulation of gluconeogenesis enzymes (e.g., glucose-6-phosphatase) and inhibition of glucose uptake in peripheral tissue Hyperlipidemia (hypercholesterolemia and hypertriglyceridemia) Leukocytosis (predominantly neutrophilic), eosinopenia, thrombocytosis Screening for hypercortisolism Any one of the following can be used as an initial screening test ↑ 24-hour urine cortisol ↑ early morning serum cortisol levels following a low-dose dexamethasone suppression test ↑ midnight salivary cortisol↑ midnight serum cortisol Identifying the cause of hypercortisolism Hormone analysis Once glucocorticoid therapy has been ruled out, the following tests are used to identify the cause of hypercortisolism: Serum ACTH levelsLow (< 5 pg/mL): suspect primary hypercortisolism (adrenal adenoma, carcinoma)Normal or elevated(> 20 pg/mL): suspect secondary hypercortisolism If secondary hypercortisolism is suspected: one of the following tests may be used to differentiate between Cushing's disease and ectopic ACTH productionHigh-dose dexamethasone suppression test Adequate suppression of cortisol levels to less than 50% of baseline: Cushing's diseaseNo suppression: ectopic ACTH productionCRH stimulation testACTH and cortisol levels increase further: Cushing's diseaseNo increase in ACTH or cortisol levels: ectopic ACTH productionOnly Cushing's disease remains (partially) susceptible to suppression (high-dose dexamethasone suppression test) or stimulation (CRH test) of cortisol secretion! Primary hypercortisolism↓ ACTH Cushing's disease High-dose dexamethasone suppression test ↓ Cortisol CRH Test ↑ ACTH,↑ Cortisol Ectopic ACTH secretion High-dose dexamethasone suppression test ↔︎ Cortisol Imaging to localize the tumor If primary hypercortisolism is suspected: CT and/or MRI of the abdomen for adrenal tumorsThe adrenal cortex contralateral to the tumor shows atrophy due to reduced ACTH stimulation If Cushing's disease is suspected: CT and/or MRI of the skull (see "Diagnostics" in pituitary adenoma)In Cushing's disease, CT and/or MRI of the abdomen shows bilateral hyperplasia of both the zona fasciculata and zona reticularisIf no findings are present on neuroimaging, perform bilateral sampling of the inferior petrosal sinus in order to measure ACTH levels If ectopic ACTH production is suspected: chest x-ray and/or CT, abdominal CT, pelvis CT In the diagnosis of hypercortisolism, hormone analysis always precedes imaging because microadenomas of the pituitary do not always appear upon imaging. Furthermore, imaging can reveal inactive adrenal tumors (incidentalomas) and pituitary tumors in many healthy individuals! Treatment Exogenous Cushing's syndrome Consider lowering the dose of glucocorticoids Consider the use of alternatives to glucocorticoids (e.g., azathioprine) Endogenous Cushing's syndrome Inoperable disease Drugs to suppress cortisol synthesis: metyrapone, mitotane, ketoconazole Operable disease: surgical therapy is the treatment of choice Pituitary adenoma: transsphenoidal resection of the pituitary adenoma (see "Therapy" in pituitary adenoma)ACTH-secreting ectopic tumor: resection of the ectopic foci (e.g., bronchial carcinoid)Adrenocortical tumor: laparoscopic or open adrenalectomy (surgical procedure to remove one or both adrenal glands)Nelson syndrome (or post adrenalectomy syndrome): can occur after bilateral adrenalectomy in patients with a previously undiscovered pituitary adenoma Pathophysiology: bilateral adrenalectomy → no endogenous cortisol production → no negative feedback from cortisol on hypothalamus → increased CRH production → uncontrolled enlargement of preexisting ACTH-secreting pituitary adenoma → increased secretion of ACTH and melanocyte-stimulating hormone → symptoms of pituitary adenoma and ↑ MSHClinical features: headaches, bitemporal hemianopia, cutaneous hyperpigmentationDiagnostics: high levels of beta-MSH and ACTH; pituitary adenoma on MRI confirms diagnosisTreatment: pituitary radiation therapy or surgery ollowing surgical therapy, patients who develop adrenal insufficiency require lifelong glucocorticoid replacement therapy! Patients who develop severe hypokalemia due to mineralocorticoid effect of cortisol may be treated with spirolonolactone (aldosterone antagonist)!

Astrocytoma Astrocytomas are neuroepithelial tumors (gliomas) that arise from the supportive tissue of the brain. These tumors are classified by the WHO into four separate grades depending on the extent of abnormality. Astrocytomas initially present with general symptoms including headaches and/or epileptic seizures, which are rapidly replaced by focal symptoms such as progressive paralysis or aphasia. Low-grade astrocytomas are usually localized, slow-growing, and occur predominantly in younger populations (children and adults aged 20-40). Grade IV astrocytomas, on the other hand, are rapidly growing glioblastomas, which are the most common malignant primary brain tumors in adults aged 50-60. Diagnosis is established based on the patient's clinical history and MRI findings. The treatment for astrocytomas is surgical resection, which may need to be combined with radiotherapy and/or chemotherapy in higher grade tumors. The prognosis is usually poor for higher grade tumors regardless of whether they receive treatment, with a life expectancy of several months (maximum of 2 years). However, low-grade astrocytomas can often be completely cured with effective surgical resection.

IPilocytic astrocytomaChildren and young adults (< 20 years)Most common: posteriorcranial fossa(infratentorial) CerebellumLess common: optic pathway (optic glioma), hypothalamus, cerebral hemispheres (supratentorial)Vomiting, ataxiaFailure to thrive(impaired growth)Often associated with neurofibromatosis type IWell-demarcatedcystic lesion often with a bright contrast-enhancingsolid nodule in the wall of the cystMRI: T1 hypointenseT2 hyperintenseSurgical resectionGood Optic gliomaMost frequently children (< 10 years)Optic nerve or chiasmSporadic episodes of vision impairmentBulging of eyeball or impaired eyemovementsOften associated with neurofibromatosis type IMRI: T1 hypointenseT2 hyperintenseNo treatment in asymptomatic patients with no signs of growth of tumorSurgical resectionRadiotherapy of unresectable tumors , or after surgery IIDiffuse astrocytoma20-40 yearsof age Cerebral hemisphereGeneral clinical features of brain tumors (e.g., epileptic seizures)MRI: T1 hypointenseor isointenseT2 hyperintenseCT: hypodense, no contrast enhancementComplete surgical resection often not possible ; resection until definable margins can be attempted Percutaneous radiotherapyfor very diffuse, unresectable tumorsIIIAnaplastic astrocytoma30-50 yearsof age Cerebral hemisphereGeneral clinical features of brain tumors (e.g., epileptic seizures)MRI: T1 hypointenseT2 hyperintenseInhomogenous, perifocal edemaIn contrast to glioblastoma, no necrosis CT: positive mass effect, hypodense, variable contrast enhancementTumor debulking through surgery Percutaneous radiotherapy/chemotherapy IVGlioblastoma65-75 yearsof ageMost common malignant primary nervous system cancerWhite matterof the cerebral hemisphere (possibly bilateral = butterflyglioma)General clinical features of brain tumors (e.g., epileptic seizure) Apoplectic glioma: mimics an intracranial hemorrhage; symptoms of raised ICP MRI: T1 mixedT2 hyperintenseIrregular, enhancing margins with a necrotic corePerifocal edemaMay also have multifocal enhancementsMidline shiftCT: Garland-likecontrast enhancement, significant mass effect Surgical resectionPalliative percutaneous radiotherapy/chemotherapy(temozolomide)GlucocorticoidsVariableBrainstem glioma 3-10 yearsof ageComprise 15% of all childhood brain tumorsBrainstemVomitingAtaxiaCranial nervedeficitsHydrocephalusMRI: T2 hyperintense, no contrast enhancementSurgical resection is often difficultAstrocytomas nearly always stain positive for glial fibrillary acidic protein (GFAP).

Neurocutaneous syndromes Neurocutaneous syndromes (phakomatoses) are a group of inherited diseases that affect various organs, most notably the central nervous system and skin. The most common neurocutaneous disorders are neurofibromatosis type I and II, tuberous sclerosis, Sturge-Weber syndrome, ataxia telangiectasia, and von Hippel-Lindau disease. These disorders usually follow an autosomal dominant pattern of inheritance and display characteristic skin findings. Neurofibromatosis type I, for example, typically presents with café au lait spots, Lisch nodules, and axillary freckling, in addition to multiple neurofibromas. The diagnosis is based on clinical findings and is confirmed by genetic testing. Treatment of these congenital disorders is symptom-oriented since there is no curative therapy available.

IncidenceNeurofibromatosis type I: 1/3000Tuberous sclerosis: 1/6000Neurofibromatosis type II and von Hippel-Lindau disease: ∼ 1/36,000Sturge-Weber syndrome: 1/50,000Ataxia telangiectasia: 1/100,000 Neurofibromatosis type I and type II, tuberous sclerosis, and von Hippel-Lindau disease: autosomal dominantinheritance or spontaneous mutation Ataxia telangiectasia: autosomal recessive inheritance Sturge-Weber syndrome: noninherited developmental anomaly Mutation of tumor suppressor gene → loss of function → ↑ risk of cancer developmentNeurofibromatosis I: neurofibromin 1 gene (NF1) affected; encodes neurofibromin protein on chromosome 17Neurofibromatosis II: neurofibromin 2 gene (NF2) affected; encodes Merlin protein (tumor suppressor protein) on chromosome 22Tuberous sclerosis: TSC1 gene or TSC2 gene affected; encodes Hamartin or Tuberin protein, respectively von Hippel-Lindau disease: deletion of VHL gene, a tumor suppressor gene on chromosome 3 Ataxia telangiectasia: repair of double-strand DNA breaks affected; responsible for ATM gene → ↑ cancerdevelopment Sturge-Weber syndrome: somatic mutation of GNAQ gene → malformation of capillaries Neurofibromatosis type 1 (von Recklinghausen disease) Dysfunction of melanocytesCafé au lait spots Lisch nodules Axillary and inguinal freckling (hyperpigmentation) Multiple neurofibromas Soft, painless nodules; typically manifest under or on the skin Malignant transformation possibleSeizures when the CNS is involved Scoliosis present in about ⅓ of patients. Bone involvement (e.g., cortical thinning, fractures, pseudarthrosis) Optic gliomas (i.e., tumor of optic nerve), possibly causing vision abnormalities Associated with pheochromocytoma and Wilms' tumor Additional findings: short stature [7] , macrocephaly, hypertension Neurofibromatosis type 2Bilateral vestibular schwannomas (also known as acoustic neuromas) → ipsilateral tinnitus, hearing loss, vertigoMultiple cerebral and spinal tumorsMeningiomas Ataxia telangiectasia (Louis-Bar syndrome) Classic triad of 3 As Progressive cerebellar ataxia Spider angiomas: telangiectasias on face and conjunctivaeIgA deficiency Susceptibility to infections (e.g., otitis media, sinusitis, pneumonia) Increased sensitivity to radiation Increased risk of malignancy (lymphoma, leukemia, gastric carcinoma) Other neurological symptoms: athetosis, chorea, myoclonus, neuropathy, slurred speech, oculomotor apraxia Sturge-Weber syndrome (encephalotrigeminal angiomatosis)Port-wine stain (nevus flammeus/"birthmark" in the dermatome regions V1 and V2 of the face)Vascular malformations of the choroid and the CNS (e.g. leptomeningeal angioma, often on the same side as the port-wine stain)Early-onset glaucoma Epilepsy or epileptic spasms in infancyIntellectual disability Tuberous sclerosis Intellectual disability (caused by brain lesions) Infantile spasms or seizures Skin manifestationsAdenoma sebaceum: reddish nodules in a butterfly appearance around the nose and cheeks (facial angiofibroma); acne-like appearance≥ 3 ash-leaf spots Shagreen patch Small benign tumorsBrain tumors HamartomasGiant cell astrocytomaCardiac rhabdomyoma (> 50% of patients→ symptoms of congestive heart failureRenal cysts or renal angiomyolipoma : can present with a feeling of abdominal fullness and/or macrohematuria.Ungual fibromas von Hippel-Lindau diseaseCharacterized by development of numerous benign and malignant tumorsHemangioblastomas in the retina, cerebellum, brainstem, and spineBilateral renal cell carcinomaPheochromocytomaRenal and pancreatic cysts Diagnostics General Take family history Genetic testing detects defective gene Dermatological exam Specific NeurofibromatosisMRI of the brain and spine with gadolinium enhancement (detection of neurofibromas, meningiomas)Ophthalmological exam (optical glioma in NF-1) Auditory testing (acoustic neuromas in NF-2) Tuberous sclerosisECG: cardiac rhabdomyoma (ventricular hypertrophy, arrhythmias)EEG: seizure activityAbdominal MRI: renal angiomyolipomacCT/MRI: brain tumorsTSC1 mutation on chromosome 9 or TSC2 mutation on chromosome 16 (tumor suppressor genes) Sturge-Weber syndromeOphthalmological exam to rule out glaucomaAngiography: abnormal vesselsMRI of the brain with gadolinium: enhancement of leptomeningeal angiomasEEG: seizure activity von Hippel-Lindau diseaseRenal function (elevated BUN and creatine in blood)Search for pheochromocytoma (elevated levels of plasma catecholamines and urinary catecholamine metabolites)UltrasoundOphthalmic to look for hemangioblastomas of the retinaAbdominal to look for renal/pancreatic cysts and renal cell carcinomaCT/MRI of the brain and abdomen (hemangioblastomas, renal cell carcinoma, cysts) Ataxia-telangiectasiaLaboratory studies: ↑ alpha-fetoprotein (AFP), IgA deficiency (IgG and IgE may also be low), lymphocytopeniacCT/MRI: cerebellum atrophy Treatment Since there are no curative treatment options available, treatment of neurocutaneous syndromes focuses on multidisciplinary symptom control. NeurofibromatosisExcision or resection of neurofibromas, meningiomas, acoustic neuromas, and optic gliomasSurgery for kyphoscoliosis in neurofibromatosis type 1 Tuberous sclerosisAnticonvulsants and adrenocorticotropic agents (e.g., prednisone) for seizure control and infantile spasms Removal of angiofibromas (laser treatment/electrosurgery)Immunosuppressants (e.g., mTor inhibitors like sirolimus, everolimus) to treat renal angiomyolipoma and inoperablegiant cell astrocytoma von Hippel-Lindau diseaseOphthalmic surgery: to prevent visual loss due to retinal hemangioblastomasNeurologic surgery: excision of cerebral hemangioblastomasRenal surgery: nephrectomy or radiofrequency ablation in the case of renal cell carcinoma Sturge-Weber syndromeAnticonvulsants (or surgery) for seizure controlGlaucoma treatment (medical and/or surgical)Laser therapy for removal of port-wine stain Ataxia telangiectasia: antibiotics and regular injections of immunoglobulins

Lumbar punctureA lumbar puncture is a diagnostic and therapeutic procedure in which a spinal needle is passed into the subarachnoid space. It enables drainage or collection of cerebrospinal fluid (CSF) as well as administration of intrathecal medications. CSF analysis may aid in the diagnosis of meningitis, multiple sclerosis, intracranial hemorrhage, or meningeal carcinomatosis. In addition, drainage of CSF can lead to symptomatic improvement in patients with idiopathic intracranial hypertension and normal pressure hydrocephalus. There are no absolute contraindications to a lumbar puncture, although increased intracranial pressure, bleeding disorders, and spinal abscesses all increase the risk of complications. A common and unpleasant, albeit harmless, complication of lumbar puncture is a post-lumbar puncture headache.

Indications Diagnosis of diseases with altered CSF compositionCentral nervous system infections (bacterial, viral, mycobacterial)Central nervous system malignancies and paraneoplastic syndromesGuillain-Barré syndromeMultiple sclerosisNeuroborreliosisSubarachnoid hemorrhage (SAH) Intrathecal administration of pharmaceuticalsAntibioticsChemotherapyAnesthesiaContrast CSF pressure measurementIdiopathic intracranial hypertension (pseudotumor cerebri)Normal pressure hydrocephalusSuspected meningitis or SAH in a patient with a negative CT scan is an urgent indication for a lumbar puncture! Contraindications There are no absolute contraindications to performing a lumbar puncture. However, there are several relative contraindications: Increased intracranial pressureDue to the risk of cerebral herniation CT should be performed prior to lumbar puncture if increased intracranial pressure is suspected Thrombocytopenia, bleeding disorder, or ongoing anticoagulation Epidural abscess Initial resistance followed by a noticeable loss of resistance indicates piercing of the ligamenta flava/dura and entry into the dural sac.Needle passes through the following structures: skin, fascia, fat, supraspinous ligament, interspinous ligament, ligamentum flavum, epidural space (in case lumbar puncture is performed for epidural anesthesia, needle should be stopped here), dura mater, arachnoid mater, and subarachnoid space.To keep the spinal cord alive, insert the needle between L3(-three) or L5(-five). Cerebrospinal fluid analysisOpening pressures (see also elevated intracranial pressure and brain herniation)AppearanceCell type (number/μL)LactateProteinGlucoseNormal≤15 mm Hg Colorless and transparentAcellular (< 5 WBCs and < 5 RBCs)1.2-2.1 mmol/L15-45 mg/100 mL40-75 mg/100 mL(60% of serum levels)Multiple sclerosisNormalColorless and transparent↑ WBCs (< 50)NormalNormal to ↑NormalGuillain-Barré syndromeNormalColorless and transparent↑ WBCS (< 10)Normal↑↑NormalSubarachnoid hemorrhage, strokeNormal or ↑ Bloody or xanthochromic (i.e., pink or yellow if hemorrhage > 6 hprior to sampling)↑ RBCs, ↑ WBCs Normal↑ (gamma globulin)NormalBrain tumorsNormal or ↑Colorless and transparentDrop metastases Normal↑↓Pseudotumor cerebri(idiopathic intracranial hypertension)↑↑Colorless and transparentAcellularNormalNormalNormalMeningitis↑-↑↑Colorless and transparent or cloudyPleocytosis, lymphocytosis, or granulocytosisSee cerebrospinal fluid analysis in meningitisVariableNormal or ↑Normal or ↓ Gram stain and culture to differentiate pathogens (see diagnosis of meningitis) Detection of special markers, e.g., tumor markers, tau protein, PCR, or serology Disruption of the blood-brain barrier (i.e., infections, autoimmune diseases, CNS malignancies) or intrathecal production of IgG(i.e, multiple sclerosis, CNS infections such as Lyme disease) → increased immunoglobulins (oligoclonal bands) → increased CSFprotein! Complications Post-lumbar puncture headacheEtiology: CSF leakage after lumbar puncture Risk factorsFemaleYoung (20-40 years old)Low BMIClinical featuresFrontal or occipital headache that presents up to 48 hours after the procedure (worsens when patient is upright, improves when patient is supine)Pain can last up to 15 daysNausea, vomiting, dizziness, tinnitus, and visual disturbancesTreatmentOral analgesicsSufficient fluid intakeBed restEpidural blood patchIndicated in severe refractory post-lumbar puncture headacheInvolves epidural injection of autologous blood at the site of lumbar puncturePrevention: use of thin, atraumatic cannulas → CSF leak syndrome is rarer Infection: spinal epidural abscess, meningitis HemorrhageCSF may appear bloody if there is cutaneous vessel injury during lumbar puncture.Rarely, lesion of the venous plexus in the central subarachnoid space NeuropathyShooting pain radiating to a leg (due to contact with a nerve root)Resolves when needle is withdrawn and redirected medially Transient abducens nerve palsy Brain herniation (see elevated intracranial pressure and brain herniation)

TremorTremors are the most common movement disorder and are defined as rhythmic, involuntary movements of one or more parts of the body. Tremors are classified as resting or action tremor (i.e., postural and intention tremors). Resting tremorstypically occur in patients with Parkinson's disease (PD) and usually present as asymmetrical tremors that occur during rest. Postural tremors are usually essential or physiologic. Essential tremors are the most common type of tremor and usually involve the hands and head. They characteristically improve with alcohol consumption. Physiologic tremors occur when holding a position against gravity and are enhanced by increased sympathetic stimulation (e.g., caffeine, anxiety). Intention tremors suggest cerebellar lesions, which typically occur with strokes, trauma, or tumors. Patients present with a coarse hand tremor that is aggravated by goal-directed movements. A combination of tremor types is also possible. The diagnosis of tremors is typically clinical. Further laboratory tests and imaging may be required to determine the underlying condition. Treatment depends on the type of tremor.

Resting tremor Pill-rollingIdiopathic Parkinson disease or side effect of neuroleptic medication (caused by a dysfunction of the basal ganglia ) Rigidity, bradykinesia, postural instability Improved byAction Action tremor Postural tremor Essential With certain postures; worse with voluntary movement Physiologic With certain postures; enhanced with sympatheticstimulation (e.g., stress) Intention tremorCoarse Cerebellar lesion (e.g., stroke, trauma, multiple sclerosis, chronic alcoholism) Slow zigzag movement towards a target ("Intention tremor") Ataxia, hypotonia, gait instability, difficulties with rapid movements, dysarthria, nystagmus Resting tremor Age of onset: ∼ 60 years EtiologyParkinson's diseaseDrug induced parkinsonism (neuroleptics, metoclopramide)Progressive supranuclear palsy Clinical featuresTypically, asymmetric resting tremor of the extremities at a low frequency (4-6 Hz, rarely up to 9 Hz) "Pill-rolling" of hands that subsides with voluntary movementsIn early Parkinson's disease, unilateral tremors are common. Worsens with emotional stressReduced with target-directed movementOften associated with rigidity, bradykinesia, and postural instability (also see "Parkinson's disease") DiagnosisTypically a clinical diagnosisMRI for atypical presentations Treatment: dopaminergic agents (see medication for Parkinson's disease) Postural tremor Essential tremor Most common form of tremor Bimodal distribution: teens and 6th decade of life (common in elderly patients) Etiology: Positive family history (50-70%; autosomal dominant inheritance) or sporadic; benign form Clinical featuresLocalization: hands (about 90%), head (about 30%; "yes-yes" or "no-no" motion), voice (about 15%)Mostly bilateral postural tremor with a frequency of 5-10 HzSlowly progressive Worse with voluntary movement , stress, fatigue, and caffeineResolves at restImproves with alcohol consumption Diagnosis: Usually a clinical diagnosis of exclusion TreatmentDrugs of choice: propranolol or primidone Alternatives (if propanolol and primidone are unresponsive or contraindicated) Other beta blockers (e.g., atenolol, sotalol)Other anticonvulsants (e.g., gabapentin, topiramate) including certain benzodiazepines (e.g., alprazolam, clonazepam)In drug-resistant cases Deep brain stimulation (DBS) Thalamotomy Physiologic tremor A physiologic tremor does not suggest a disorder , while an enhanced physiologic tremor oscillations, more visible), may be more significant and debilitating Age of onset: may occur at any age Etiology: enhanced by sympathetic stimulation Stress, exercise, or fatigueIntoxication: mercury poisoning, caffeine, alcoholDrug-induced: valproate, lithium, SSRIs, tricyclics, beta-2 agonists, levothyroxine, immunosuppressants (e.g., daclizumab, basiliximab)Withdrawal: alcohol, benzodiazepines, barbiturates, marijuanaMedical conditions: hyperthyroidism or pheochromocytoma, Lewy body dementiaOther: magnesium deficiency, hypoglycemia , Wilson's disease Clinical featuresUsually a fine bilateral postural tremor in the hands and fingers (∼ 10 Hz)Occurs while holding a position against gravity (e.g., extending arms in front of body) Diagnosis: depends on suspected underlying cause (thyroid function tests, blood glucose level, review of medications, history of substance use) Treatment: usually reversible once the underlying cause is treated; propranolol may be considered under certain conditions Orthostatic tremor EpidemiologyRareSex: ♀ > ♂Age of onset: 60 years (usually) Etiology: unknown Clinical features: long periods of standing may lead to: Trembling feeling in the legsSubjective feeling of unstable balance, and falling over DiagnosisClinical diagnosis: (Synchronized) shaking of the legs may be seen or felt by the examiner.Electromyography of the legs while patient is standing; detection of 13-18 Hz tremor Treatment Symptom-basedMedicinal: clonazepam, gabapentin Intention tremor EtiologyCerebellar stroke, tumor, or traumaMultiple sclerosisDrug-induced: alcohol, lithiumWilson's disease Clinical featuresCoarse hand tremor with a frequency of < 5 Hz Worse with goal-directed movements Other cerebellar signsDysmetria (abnormal heel-to-shin and finger-to-nose testing)Dysdiadochokinesia(inability to perform rapid alternating hand movements)Dysarthria, nystagmus and abnormal gait DiagnosisCT/MRI: cerebellar lesionsIgG in CSF if multiple sclerosis is suspectedScreen for alcohol abuse or toxic lithium blood levels TreatmentPhysical therapyThalamotomy Additional types of tremors Flapping tremor (Asterixis) EtiologyMetabolic encephalopathy (especially alcohol-induced hepatic encephalopathy) Wilson's diseaseClinical featuresIrregular, high oscillations when arms and hands are extended In Wilson's disease: ascites, jaundice, Kayser-Fleischer rings, muscle spasms, and mental symptomsDiagnosisDetermine cause of encephalopathy (e.g., blood tests, CSF analysis, cCT/MRI, EEG)See also Wilson's diseaseTreatment: see "treatment" sections of hepatic encephalopathy and Wilson's disease Psychogenic tremorEtiologyConversion disorderOther psychiatric disordersClinical featuresMostly postural tremor with a sudden onset Worsens under direct observation and diminishes with distractionDiagnosisAsk about somatization in past historyDiagnosis of exclusionTreatment: cognitive-behavioral therapy

Disorders of the visual pathway The visual pathways transmit signals from the retina to the visual cortex (striate cortex, brodmann area 17)The visual pathway consists of rods/cones (first neuron), bipolar cells (second neuron), and ganglioncells (third neuron, the axons of which form the optic nerve). The first and second neurons are located entirely within the retina, the third neurononly partially. An area within an otherwise normal visual field where vision is temporarily or permanently reduced or absent is referred to as scotoma (blind spot). Larger visual field defects that affect a quarter, half or the entire vision of an eyeare called anopia (blindness).

RetinaCones and rods transform light into visual signals, which are projected to the brain via the optic nerve.Central scotoma occurs in case of macula involvement Paracentral scotomaOccurs in case of macula involvement with foveal sparing (e.g., hydroxychloroquine/chloroquine maculopathy)Seen as concentric rings of hypopigmentation and hyperpigmentation on the macula ("bull's eye maculopathy")Diseases of the retinaRetinal detachmentRetinal vessel occlusion Optic nerveTransmits visual information from the ipsilateralretina to the brainAfferent limb of pupillary reflex and accomodation reflexIpsilateral blindness (anopia),scotomaCentrocecal scotoma: loss of vision in the fovea centralis region and a blind spotPupillary light reflex: loss of afferent limb → absent direct pupillary light reflex Optic neuritis (MS)Optic atrophyRetinal vessel occlusionAnterior ischemic optic neuropathyPapilledema Optic chiasmFibers from nasal part of the retina cross to contralateral sideFibers from the temporal part of the retina do not cross to the contralateral sideMiddle lesions (crossing fibers) → bitemporal heteronymous hemianopsia Bilateral lesions (non-crossing fibers) → binasal hemianopsiaPituitary adenomaCraniopharyngiomaParasellar aneurysm of the internal carotid arteryMeningioma Optic tractTransmits information of the ipsilateral, nasal visual fieldcontralateral, temporal visual fieldProjects to lateral geniculate nucleus, pretectal area, superior colliculi, suprachiasmatic nucleiContralateral homonymous hemianopsia Middle cerebral artery(MCA) infarction Lateral geniculate nucleus (LGN) Transmits information of the ipsilateral, nasal visual fieldcontralateral, temporal visual field Projects to primary visual cortex via optic radiations Contralateral homonymous hemianopsia MCA infarction Optic radiationsAnterior/lateral bundle in Meyer loopPasses through the temporal lobe in close proximity to the inferior horn of the lateral ventricleTransmits information of the superior visual field from the lower retinaProjects to the lingual gyrus Posterior/medial bundle Located in the parietal lobe, passes through the internal capsuleTransmits information of the inferior visual field infromation from the upper retinaProjects to the cuneus gyrus More common than optic tract or LGN lesionsAnterior/lateral bundle (Meyer loop)Contralateral upper homonymous quadrantanopsia (pie in the sky)Posterior/medial bundle Contralateral lower homonymous quadrantanopsiaMCA infarctionUpper quadrantanopsiaindicates temporal lobelesionLower quadrantanopsiaindicates parietal lobelesion Visual cortexLocated in the calcarine sulcus of the occipital lobeContralateral homonymous hemianopsia with macular sparingPosterior cerebral artery (PCA) infarction Unilateral visual field loss → pathology mainly in front of the optic chiasm. Bilateral visual field loss → pathology mainly in or behind the optic chiasm Remember that the Meyer Loop transmits the signal from the Lower retina, Looping around the inferior horn of the Lateral ventricle. Prechiasmal visual pathway damage Prechiasmal damage to the visual pathway mainly involves the optic nerve.For retinal diseases see table above. Optic nerve Optic neuritis Definition: inflammation of the optic nerveRetrobulbar neuritis: inflammation of the retrobulbar part of the optic nervePapillitis: inflammation of the intrabulbar part of the optic nerve EtiologyMost common cause: multiple sclerosisInfections Toxic Clinical featuresVision impairment: blurry vision, sudden vision loss, color blindness, visual field defects (e.g., central scotoma)Retrobulbar pain (increased pain caused by eye movements) DiagnosticsOphthalmoscopyRetrobulbar neuritis: normal ophthalmoscopic findingPapillitis: poorly defined papilla, hyperemia, hemorrhage at the border of the papilla Visual evoked potential (VEP)Neurological examination TreatmentHigh-dose treatment with glucocorticoidsCorresponding treatment in the case of multiple sclerosis Optic atrophy Definition: irreversible loss of axons in the optic nerve EtiologyMost common causes: optic neuritis, glaucomaVascular Hydrocephalus, orbital/intracranial lesionHereditary: Leber optic atrophy, Krabbe disease, autosomal-dominant optic atrophy Clinical features:Vision impairment: blurry vision, color blindness, visual field defects (e.g., central scotoma) DiagnosticsFundoscopy Perimetry Anterior ischemic optic neuropathy (AION) Definition: segmental or generalized infarction of the anterior part of the optic nerve EtiologyNonarteritic form due to atherosclerosis (NAION)Arteritic form due to giant cell arteritis (AAION) Clinical featuresSudden unilateral loss of visionWedge-shaped and altitudinal visual field defects AAION: other symptoms of giant cell arteritis DiagnosticsFundoscopy Laboratory findings AAION: ↑ ESR and CRPNAION: normal ESR and CRPAAION: temporal artery biopsy TreatmentAAION: immediate high-dose systemic glucocorticoidsNAION: trial of hemodilution and systemic glucocorticoid therapy PrognosisTypically poor: permanent loss of visionInvolvement of the other eye is common during the course of the disease. Papilledema Definition: swelling of optic disc due to elevated intracranial pressure Etiology:Hypertensive emergencyIdiopathic intracranial hypertension (pseduotumor cerebri)Intracranial tumors (e.g., medulloblastoma)HydrocephalusCerebral abscessHypervitaminosis A Clinical featuresAcute: usually asymptomatic, can present with loss of visual acuity due to enlargement of blind spotChronic (rare): impaired vision, can cause visual field defects and blindness DiagnosticsFundoscopy Acute: Edematous, poorly defined, prominent optic disc with blurry marginsWidened blind spotRadial hemorrhage around the disc marginLater stages of disease: optic atrophy possibleCranial CT or MRI to detect cause of increased intracranial pressure Neovascularization of retina and uvea Damage in the region of the optic chiasm EtiologyMost commonly: compression by pituitary adenoma (prolactinoma), craniopharyngioma, meningioma, aneurysmsof the internal carotid arteryDemyelination, multiple sclerosisTrauma PathophysiologyMedial lesion (e.g., pituitary adenoma) → temporal visual field defects Lateral lesion (e.g., aneurysm of the internal carotid artery) → nasal visual field defects Clinical featuresVisual field defects/impaired vision: most commonly bitemporal heteronymous hemianopsia TreatmentDepending on the cause Neurosurgical Pharmacological Retrochiasmal visual pathway damage Definition: damage in the region of the optic tract, lateral geniculate nucleus, optic radiation, or visual cortex EtiologyCerebral ischemia/hemorrhage TumorsTraumaOther causes Clinical featuresVisual field defects/impaired vision: most commonly homonymous hemianopsia and homonymous quadrantanopsia DiagnosticsPerimetry Imaging: CT, MRI

Complete spinal cord injury Complete spinal cord injury is the complete sensory and motor loss below the site of spinal cord injury following acute or chronic destruction, compression, or ischemia of the spinal cord. Initially, this may present as spinal shock, which is an acute physiological loss or depression of spinal cord function. It presents as a flaccid areflexic paralysis below the level of the injury with autonomic features (e.g., hypotension and bradycardia). After some days to weeks the spinal shock wears off and a complete spinal cord injury may remain. It presents with spastic paresis, hyperreflexia, and continued sensory loss. Acute stabilization, a thorough neurological examination, and imaging is required for adequate diagnosis. Treatment involves acute care (e.g., analgesia, urinary catheterization) and definitive treatment (bracing or surgery). Symptomatic treatment, assistant devices, and physical therapy can improve mobility and quality of daily life. Less than five percent of cases fully recover after complete spinal cord injury.

Spinal shock Definition: acute physiological loss or depression of spinal cord function (loss of all sensorimotor functions below the level of injury) that lasts several hours to weeks following a spinal cord injury Etiology: Traumatic spinal cord injury PathophysiologyDamaged neurons→ loss of intracellular potassium into the extracellular space→ hyperpolarized neurons→ poor axonal transmission and transient physiologic reflex depression Clinical featuresFlaccid areflexic paralysisParaplegia or tetraplegia, if cervical cord is involvedSensory disturbances: analgesia and anesthesiaAreflexia: absence of the proprioceptive and polysynaptic reflexes (e.g., abdominal reflex)Loss of bladder control: urine retention, bladder distention, and dribbling incontinenceLoss of bowel control: paralytic ileusImpaired breathing Hypotension and bradycardia Absent bulbocavernosus reflex → incontinence Male patients might develop priapismAfter 48-72 hours: spasticity, hyperreflexia, and clonus Diagnostics and treatment: see evaluation and diagnosis of spinal cord injury PrognosisUsually reversible, it is difficult to predict the outcome and remaining disabilities in this acute phase.Poor, if transition to complete spinal cord injury occursBetter, if transition to incomplete spinal cord syndrome occurs Complete spinal cord injury Definition Complete bilateral loss of sensation and motor function below a spinal cord injury lesion. Epidemiology ∼ 25% of annual spinal cord injuries in the US Etiology Incomplete spinal cord syndromes may develop into complete spinal cord lesions Trauma (complete transection) Spinal tumors, multiple sclerosis, or myelitis Extradural pathologies (e.g., spinal epidural hematoma, spinal epidural abscess), infarction, or acute disc herniation Pathophysiology Acute or chronic spinal cord injury (e.g., fracture, dislocation, or penetrating injury) → destruction (e.g., trauma), compression (e.g., hematoma), or ischemia (e.g., injured spinal arteries) of spinal cord → incomplete or complete spinal cord injury Clinical features Symptoms of complete spinal cord injury occur 6-8 weeks after spinal shock has worn off. Spared sensory levels above lesion Reduced sensation next to caudal level Bilaterally absent sensory and motor function below the lesion (including lowest sacral segments S4-S5)Acutely, spinal shockImpaired sensation (i.e., to pain, position, etc.)Muscle hypertonia with spastic paresis Increased proprioceptive reflex: hyperreflexiaInexhaustible clonus: e.g., ankle clonusAnal reflex remains absentPathological reflexes: e.g., upgoing plantar reflex (also known as the Babinski reflex)Spastic bladder: involuntary urination caused by contractions Possibly erectile dysfunction in men Evaluation and diagnosis of spinal cord injuries Stabilize patientABCDE approach (airway, breathing, circulation, disability, and exposure) in the fieldStabilize spine Log-rolling of patientBackboard for transferRigid cervical collar Neurological exam: Exclude spinal shock (i.e., determine bulbocavernosus reflex) or neurogenic shockDetermine level of injuryDetermine extent of injury (complete or incomplete)Exclude associated injuries ImagingComplete spinal imaging (cervical, thoracic, lumbar): plain x-rays or CT, if available CT is superior to MRI for imaging fractures of the vertebraeMRI: can provide further information on extent of ligamentous/disc injuries, spinal cord pathology, or epidural hematoma Management of spinal cord injuries AcuteIntensive medical care and analgesia Insert urinary catheter VTE prophylaxis (e.g., heparin)IV corticosteroids to reduce swelling and inflammation in the spinal cord DefinitiveBracing (e.g., with gunshot wounds) or surgical repair (e.g., decompression and stabilization of spine fracture)C1-C4 tetraplegia: phrenic nerve pacemakers may be indicated; a tracheostomy and/or ventilator may be needed Rehabilitation (multidisciplinary care) Walking aidsPhysical, occupational, and psychotherapyPressure ulcer prophylaxis, osteoporosis prophylaxis, treatment of pneumonia and urinary tract infections Prognosis Early mortality: 4-20% < 5% chance of recovery In complete thoracic and lumbar injury, up to ∼ 8% of patients can still walk with the assistance of special devices. Leading causes of death are pneumonia, pulmonary embolism, and suicide. Prevention: Avoid risk-taking behavior (e.g., diving head first into shallow water or drunk diving) and implement safety precautions in high-risk occupations In acute spinal cord injury (spinal shock), flaccid paralysis and a complete absence of reflexes occur below the injury. A change in symptoms occurs after a period of 6-8 weeks and includes spastic paralysis, recurrence of proprioceptive reflexes as hyperreflexia, and the presence of pathological reflexes (e.g., plantar reflex)!

Skull base syndromes Skull base syndromes are caused by malignancies or inflammatory conditions that affect the base of the skull and the cranial nerves exiting the skull. The location of the pathology can often be determined by characteristic features produced by nerve damage and other localizing space-occupying effects (e.g., pain, proptosis). Syndromes primarily involving the cranial nerves are discussed in a separate learning card (see cranial nerve palsies).

Superior orbital fissure syndrome 3,4,V1,6 Etiology: sphenoid wing meningioma and rarely, trauma Clinical featuresUpper eyelid ptosisProptosis of the eyeOphthalmoplegiaDilated and fixed pupilLoss of sensation of the upper eyelid and forehead due to damage to the trigeminal nerve Foster-Kennedy syndrome I,II EtiologyFrontal lobe tumors, typically parasellar or subfrontal meningiomasEspecially olfactory groove meningioma: meningiomas arising from the cribriform plate and frontosphenoidal suture (see meningiomas) Clinical featuresIpsilateral atrophy of the optic nerve Contralateral papilledema Anosmia Orbital apex syndrome 3,4,6 Etiology: damage to the orbital fissure or the optic canal resulting from an inflammatory condition or space-occupyinglesion Clinical featuresOphthalmoplegiaDue to damage to the cranial nerves passing through the orbital fissurePartial/complete paresis of oculomotor nerve (IIIrd cranial nerve), trochlear nerve (IVth cranial nerve), and abducens nerve (VIth cranial nerve)Blindness Loss of sensation to the upper face may occur (see cranial nerve palsies). Cavernous sinus syndrome 3,4,V12,6,Horners EtiologyCavernous sinus thrombosis (e.g., due to sinusitis)Carotid-cavernous fistulaCavernous sinus tumorsCarotid artery aneurysmsTolosa-Hunt syndrome (idiopathic granulomatous inflammation of the cavernous sinus) Clinical featuresSwelling of the conjunctivaProptosisSigns of CN palsy due to compression (CN III, IV, V-1, V-2, and VI pass through the cavernous sinus) Painful ophthalmoplegia: partial/complete paresis of oculomotor nerve (third cranial nerve), trochlear nerve(forth cranial nerve), and abducens nerve (sixth cranial nerve)Absent corneal reflex: paresis of the ophthalmic branch of the trigeminal nerve (V1)Loss of sensation to the upper face may occur due to damage to trigeminal branches V1 and V2 (see cranial nerve disorders).Horner syndrome Cerebellopontine angle syndrome V3,6,8 Etiology: most commonly vestibular schwannomas (acoustic neuroma), although other cerebellopontine angle tumors may result in the same presentation Clinical featuresUnilateral hearing loss TinnitusVertigoHeadacheLoss of facial sensation Diplopia Gradenigo's syndrome 6,V1, otitis media Etiology: complication of otitis media and mastoiditis that spreads to the petrous apex of the temporal bone, can also be tumor growth in the same area Clinical features: typical triadLateral rectus palsy Retro-orbital pain Otorrhea (ear discharge)

Peripheral nerve injuries Peripheral nerve injuries include a variety of conditions in which one or more peripheral nerves are damaged, leading to neurological deficits distal to the level of the lesion. Possible causes include systemic diseases (e.g., diabetes, autoimmune disease) and localized damage (e.g., trauma, compression, tumors). Peripheral nerve injuries may occur as isolated neurological conditions or, more commonly, in association with soft tissue, vascular, and/or skeletal damage. Patients with peripheral nerve injury may present with sensory deficits, loss of motor function, or a combination of both. Diagnosis is based on clinical evaluation, imaging techniques (x-ray, CT/MRI), and electrodiagnostic examination (e.g., nerve conduction study, EMG). Observation and conservative treatment (e.g., activity modification, splinting, electrical stimulation) are indicated in most closed injuries, which have a high rate of spontaneous recovery. Patients with open injuries or long disease courses may require surgical treatment. Recovery from peripheral nerve injury is often incomplete and patients may experience chronic pain.

Types of nerve damage Classification of peripheral nerve injury is useful for determining the prognosis and choosing a treatment strategy. NeuropraxiaCompression injury causing temporary disruption of nerve conductionThe whole nerve remains structurally intact.Good prognosis with complete recovery of nerve function AxonotmesisThe axon is damaged but the perineurium and epineurium remain intact.Leads to central chromatolysisDefinition: the reaction of a neuronal cell body in response to an axonal injuryCharacteristics Swelling of the neuronal bodyDispersion of the Nissl bodiesDisplacement of the nucleus to the peripheryFunction: These changes reflect an increase in protein synthesis in an effort to restore the integrity of the damaged axon.Results in Wallerian degenerationDefinition: an active neuronal degeneration process in response to axonal injuryCharacteristics Initially retained electrical excitability of axonal membrane distal to the injury, lasting up to 36 hoursProgressive degeneration of distal segment cytoskeleton with dissolution of axonal membraneDegradation of residual myelin sheath by macrophages and Schwann cellsThe proximal stump either stays in place or retracts slightly; ultimately, the stump will sprout regenerative nervous fibers that, ideally, reinnervate the distal tissues.Regeneration is significantly more efficient in the peripheral nervous system than in the central nervous system.Function To clear axonal debris and prevent scarringFacilitate targeted reinnervation of tissues previously innervated by that axon before injuryGood chance of at least partial recovery NeurotmesisComplete nerve transectionConnective sheath damage The chances of recovery are very poor without surgical repair. Traumatic neuroma: benign, painful nodular thickening caused by nerve regeneration at the site of different forms of nerve injury Nerve injuries in the upper body Brachial plexus injuries Erb palsy Injury to the upper trunk of the brachial plexus (C5-C6) EtiologyExcessive lateral flexion of the neckTrauma (e.g., falling on the head and shoulder in a motorcycle accident)Birth injury: excessive lateral traction on the neck during delivery and shoulder dystocia Clinical featuresWeakness of muscles in the C5 and C6 myotomes → flexed wrist with an extended forearm and internally rotatedand adducted arm (waiter's tip posture)Weak biceps brachii, brachialis, and brachioradialis → impaired flexion and supination of the forearm; absent biceps reflexWeak infraspinatus → impaired external rotation of the armWeak deltoid and supraspinatus → impaired arm abductionWeak wrist extensors → impaired wrist extensionAsymmetric Moro reflex in infants (absent or impaired on the affected side)Sensory loss in the C5 and C6 dermatomes (thumb and lateral surface of the forearm and arm) TreatmentImmobilization in flexion and external rotation with an abduction bracePhysiotherapySurgery for severe nerve damage or prolonged cases Klumpke palsy Injury to the lower trunk of the brachial plexus (C8-T1) EtiologyHyperabduction of the armTrauma (e.g., breaking a fall by grabbing a branch)Birth injury: excessive traction on the arm during deliveryCompression of the lower trunk of brachial plexus (subacute to chronic onset) Pancoast tumorCervical rib Clinical featuresWeakness of muscles in the C8 and T1 myotomes (intrinsic hand muscles) → total claw hand (persistent flexion of the interphalangeal joints and extension of the metacarpophalangeal joints in the hand)Absent grasp reflex in infantsSensory loss in the C8 and T1 dermatomes (little finger and medial surface of the forearm and arm)Preganglionic Horner syndrome if injury occurs proximal to the white ramus communicansDecreased peripheral pulses if subclavian vessels are compressed by a Pancoast tumor or cervical rib (see thoracic outlet syndrome) TreatmentSplinting the hand to correct the claw handPhysiotherapySurgery for severe nerve damage Injured nerveNerve rootsCommon causesMotor deficitsSensory deficitsAxillary nerve injuryC5-C6Anterior shoulder dislocation Fracture of surgical neck of the humerusIatrogenic (shoulder reconstruction procedures, rotator cuff surgery, osteosynthesis of humeral fractures)Compression due to mass in the axilla (e.g., nodular fasciitis, schwannoma)Paralysis of the deltoid muscle → impaired arm abductionParalysis of the teres minor muscle → impaired external rotation of the armMuscle atrophy: flattened deltoidLateral shoulder (lower half of the deltoid region) Musculocutaneous nerve injuryC5-C7TraumaUpper trunk compression (e.g., Erb palsy) Paralysis of brachialis and coracobrachialis muscles → impaired elbow flexion Paralysis of biceps brachii → impaired forearm supinationLateral forearm, from the elbow to the base of the thumb Median nerve injuryC5-T1Proximal: supracondylar fracture of humerusDistal: carpal tunnel compression, wrist laceration (suicide attempt)Proximal injury: hand of benediction (ulnar deviation upon wrist flexion) Distal injury: median clawBoth injuries: ape handInability to make OK sign(anterior interosseous nerve syndrome) Muscle atrophy: thenar muscles Palmar aspect of thumb, index and middle fingers, lateral ring finger Radial nerve injuryC5-T1Axilla: crutch use, saturday night palsyMid-arm: midshaft fracture of the humerusWrist: radial fracture, wearing tight bracelets or handcuffsAxillary injury: impaired forearm extension at elbow, wrist drop Mid-arm injury: wrist dropDorsal aspect of thumb, index, and middle fingers, lateral ring finger Ulnar nerve injury C7-T1 Proximal: fracture of medial epicondyle of humerus Distal: ulnar tunnel syndrome (cycling, ganglion cyst), hook of hamate fracture Ulnar claw Wartenberg sign Froment sign Palmar and dorsal aspects of lateral half of ring finger, little finger Suprascapular nerve injury Infraspinatus and supraspinatus Compression Entrapment of the nerve within the suprascapular notchParalabral ganglion cystThickening and/or bony ossification of the overlying superior transverse scapular ligament Major or repetitive trauma Limited adduction, abduction, and external rotation of the arm Shoulder instability (due to paralysis of rotator cuffmuscles) Thoracodorsal nerve injury Latissimus dorsi, teres major Surgery in the inferior part of the axilla or on scapular lymph nodes Latissimus dorsi: limited shoulder retraction, impaired adduction and internal rotation of the arm Teres major: limited internal rotation and adduction of the arm Long thoracic nerve injury Serratus anterior Axillary surgery (e.g., lymph node dissection during mastectomy) Stab wounds Carrying a heavy backpack for a long time Medial winging of the scapula, impaired abduction of the arm beyond 90° Dorsal scapular nerve injury Rhomboid major, rhomboid minor, levator scapulae Isolated injury is uncommon; usually accompanies injury to the scalene muscles Lateral winging of the scapula Phrenic nerve injury Diaphragm See phrenic nerve paralysis. Elevation of the diaphragm on the side of the phrenic nerve lesion → ↓ pulmonary and cardiac function Nerve injuries in the lower body Injured nerve Nerve roots Common causes Motor deficits Sensory deficitsSuperior gluteal nerve injuryL4-S1Iatrogenic injury due to intramuscular injections in the superomedial regionParalysis of gluteus medius and minimus, tensor fascia lata → impaired hip abductionPositive Trendelenburg sign: lateralpelvic tilt towards the opposite side None Inferior gluteal nerve injuryL5-S2Posterior hip dislocationParalysis of gluteus maximus → impaired thigh extensionDifficulty standing from a sitting position and climbing stairsBackward lurching gait (an abnormal gait in which the trunk tilts backwards during the heel strike phase in the limb with the weak hip extensor)Forward pelvic tiltNone Femoral nerve injury L2-L4 Direct injury (trauma) Prolonged pressure on the nerve: psoas hematoma, aortic or iliac aneurysms or tumors Iatrogenic: pelvic, abdominal, or spinal surgery; femoral line placement Paralysis of iliopsoas, pectineus, rectus femoris, and sartorius muscles → impaired hip flexion Paralysis of quadriceps femoris muscle→ impaired knee extension and decreased patellar tendon reflex Anterior cutaneous branches: anteromedial thigh Saphenous nerve lesion : medial lower leg, medial edge of the foot Lateral femoral cutaneous nerve injury (meralgia paresthetica)L2-L3Compression at the level of the inguinal ligament, caused by:Increased intra-abdominalpressure (e.g., pregnancy, obesity, ascites)External compression (e.g., tight belts, pants, or compression dressings)Local compression (e.g., tumors, hematomas)NonePain and paresthesias on the lateral surface of the anterior thighCan be improved by wearing looser clothing and/or losing weight Obturator nerve injuryL2-L3Pelvic ring fractures Obturator hernias Paralysis of hip adductors Medial thigh Sciatic nerve injury L4-S3Iatrogenic (misplaced intragluteal injection!)Direct trauma (gun and/or stab wounds)Hip dislocationTotal hip arthroplastyParalysis of hamstring muscles → impaired knee flexionMotor deficits of tibial nerve injury and common peroneal nerve injury Lower leg and foot Tibial nerve injuryTibial fractureTarsal tunnel syndromeParalysis of foot flexors → inability to walk on the toes or balls of the feet; inability to invert foot Sensory loss over sole of the foot (see Morton neuroma) Common peroneal nerve injury L4-S2Fracture of the fibular head Compression: tight casts, sitting cross-legged, Lithotomy positionduring surgeryDeep peroneal nerve: paralysis of foot and toe extensors (dorsiflexors) → foot drop→ high-stepping gaitSuperficial peroneal nerve: paralysis of peroneus longus and peroneus brevis → impaired pronation of the footDeep peroneal nerve: area between the first and second toes (flip-flop zone)Superficial peroneal nerve: lateral surface of the lower leg, dorsum of the feet and toes, except for the space between the first and second toe (deep peroneal nerve) Sural nerve lesion L4-S3Achilles tendon ruptureEntrapment neuropathy (e.g., crural fasciathickening) Ganglion, lipomasNonePosterolateral side of the lower leg, the lateralborder of the foot, and a small area under the heel TIPPED = tibial nerve injury versus peroneal nerve injury: TIP = Tibial → damaged foot Inversion, Plantarflexion; PED = Peroneal → damaged foot, Eversion, Dorsiflexion Diagnostics The diagnosis of peripheral nerve injuries is based on a thorough clinical history, neurological examination, and, in some cases, diagnostic tests (e.g., x-ray if fracture is suspected). ImagingPlain x-ray: detection of compression or transection due to dislocated bone or fracture segmentsCT/MRI: evaluation of causes like nerve tumors, avulsions, and focal soft tissue pathologies Electrodiagnostic studies Nerve conduction study/neurography (analysis of a muscle's electrical activity in response to stimulation of its supplying nerve)Needle electromyography (EMG) Nerve repair Conservative treatment Observation and expectant management in closed injuries of the nerve, which have a high rate of spontaneous recovery Activity modification (e.g., avoid sports or activities that increase likelihood of further nerve injury) Splinting: prevents stiffness and contractures of joints; supports residual nerve functionality and reinnervation Electrical stimulation: supports the regeneration of the proximal axons and reinnervation of the denervated muscles after surgical nerve repair Drug therapy: treatment of chronic neuropathic pain following peripheral nerve injury (e.g., gabapentin); used in combination with surgical treatment to enhance remyelination and motor regeneration (e.g., lithium) Analgesia: infiltration with local anesthetics Surgical repair IndicationsOpen, non-contaminated, sharp injuries; concomitant vascular injuries → immediate surgical exploration and repairOpen, contaminated injuries; postreduction palsy → early surgical exploration and repair (within 3 weeks)Patients without clinical or electromyographic signs of spontaneous recovery → delayed surgical exploration and repair (within 3 months) ProceduresNerve repair (neurorrhaphy): reconstruction of nerve continuity Tendon transfer: A tendon from a sufficiently powerful muscle is redirected towards another tendon in order to restore its motion and function.Nerve transfer: An intact healthy nerve is redirected towards a denervated nerve in order to restore the innervation of its target organ.

Wallenberg syndrome Wallenberg syndrome is a neurological condition caused by a lateral medullary infarction, which results from occlusion of either the posterior inferior cerebellar artery (PICA) or the vertebral artery. For this reason, it is also referred to as lateral medulla syndrome or PICA syndrome. Symptoms include ipsilateral Horner syndrome, palate weakness, hemiataxia, and contralateralsensory disturbances. Management is supportive, and may include swallowing and speech therapy, as well as a feeding tube in some cases.

tiology Ischemic occlusion of the: Posterior inferior cerebellar artery (PICA)Vertebral artery Clinical featuresStructure affectedIpsilateralDysphagia ↓ Gag reflexHoarseness, dysphonia Nucleus ambiguus (motor neuron) Ataxia, dysmetria, dysdiadochokinesiaInferior cerebellar peduncleHorner syndrome Uncontrollable hiccupsSympathetic fibersVertigo (with falling towards the same side of the lesion) → vomitingNystagmus that changes direction with gaze change diplopiaVestibular nucleiLoss of pain and temperature in the faceTrigeminal nucleus and tract (sensory)ContralateralLoss of pain and temperature in the trunk and limbsLateral spinothalamic tract (sensory) Treatment See stroke Additional supportive therapy: speech and swallowing therapy