Neuro #2

Peripheral nerve pathology

Wallerian degeneration dying forward - nerve (axon and myelin) degenerates from the point of axonal damage distally. The cell body undergoes axon reaction/chromatolysis that includes swelling, movement of nucleus to the side, and degradation of Nissl substance (rough ER). Wallerian degeneration causes muscle atrophy. Axonal degeneration dying back - often occurs systemically with axons dying from the most distal site, proximally. Axonal degeneration causes muscle atrophy. Segmental demyelination is focal degeneration of the myelin sheath sparing the axon as well as patches of myelin along the axon. This exposes the axon to damage from the interstitial environment and slows/blocks nerve conduction. Muscle atrophy does not occur.

Glaucoma Drugs

Prostaglandin analogues Latanaprost, travaprost, bimatoprost, unoprostone Decrease intraocular pressure by increasing rate of fluid outflow from the traditional meshwork pathway and uveoscleral pathway between the choroid and sclera. Prostaglandin analogues can be used for all glaucomas (open and closed) except rare inflammatory glaucomas or in those with herpes or keratitis. Prostaglandin analogs can cause ocular irritation and conjunctival injection, increased iris and periocular skin pigmentation with longer, thicker lashes, uveitis, herpes activation, and cystoid macular edema. Beta blockers (eye drops) Non-selective: timolol, carteolol, levobunolol, metipranolol Selective: Betaxolol Beta blockers antagonize beta adrenergic receptors in the ciliary body epithelium to reduce production of aqueous fluid and can be used for all types of glaucoma. Side effects include corneal toxicity, allergic reaction, SOB/Bronchospasm/CHF, decreased libido/impotence, arrhythmias (bradycardia), and depression. Non-selective beta blockers should never be used in those with asthma, COPD, or >1st degree heart block and no beta blockers should be used in those with congestive heart failure. Relative contraindications include sinus bradycardia, hypotension, history of syncope or life threatening depression, brittle (type 1) insulin dependent diabetes, and impotence. Those who use beta blockers can decrease systemic side effects using the nasolacrimal occlusion technique. Carbonic anhydrase inhibitors Topical: dorzolamide, brinzolamide Oral: acetazolamide, methazolamide Inhibit carbonic anhydrase in the ciliary body epithelium, decreasing production of aqueous fluid. Carbonic anhydrases catalyze the conversion of CO2 + H2O to HCO3- + H+ (and vice versa), in parietal cells to make stomach acid, in pancreatic duct cells to make bicarbonate, in red blood cells to convert CO2 from the body into bicarbonate for transport and then back to CO2 in the lungs, and in renal tubule cells to secrete H+ to maintain acid-base and fluid balance. Carbonic anhydrase is also used to make CSF, aqueous fluid (eye), and endolymph and perilymph (semicircular canals). Topical carbonic anhydrase inhibitors (Dorzolamide and Brinzolamide) are used for all glaucomas, and oral CA inhibitors (acetazolamide and methazolamide) are used only to rapidly lower acute increases in intraocular pressure or when a topical forms have not worked or caused side effects. Topical side effects include stinging, burning, redness/dermatitis/conjunctivitis, allergy, transient myopia (nearsightedness), and metallic taste. Oral side effects include paresthesias, frequent urination, metabolic acidosis, and metallic taste. CA inhibitors are structurally similar to sulfonamides so do not use if a patient has a sulfonamide allergy. Never use in those with a sulfonamide allergy, sickle cell disease (acidosis risk), aplastic anemia, or thrombocytopenia. Relative contraindications include adrenal insufficiency, hepatic failure, chronic respiratory acidosis, renal failure, metabolic acidosis, and repeated episodes of kidney stones. Alpha adrenergic agonists Selective (alpha-2 receptors) brimonidine Non-selective (alpha 1 and 2 receptors) Apraclonidine decrease aqueous fluid production and increase rate of fluid outflow from the eye by increasing uveoscleral outflow (space between choroid and sclera). Brimonidine (selective) can be used for all types of glaucomas. Apraclonadine is used for intraocular pressure spikes following laser surgery for glaucoma. Side effects of Brimonidine include dry mouth, fatigue, ocular redness, and ocular irritation. Apraclonidine side effects include severe allergic blepharitis, tachyphylaxis with chronic use, mydriasis (dilation), eyelid retraction, and conjunctival blanching. Do not use alpha adrenergic agonists with MAOIs or in those less than 2yrs. Summary All drugs but oral carbonic anhydrase inhibitors (acetazolamide and methazolamide) and apraclonodine (non-selective alpha adrenergic agonist) can be used for open and closed glaucoma. Prostaglandin analogues, beta blockers, and carbonic anhydrase inhibitors can cause systemic side effects. Alpha agonists don't have many systemic side effects unless used chronically, but can drip into the mouth and make it dry. Beta blockers and carbonic anhydrase inhibitors reduce the amount of aqueous fluid produced. Prostaglandin analogs increase outflow of fluid from the eye. Alpha agonists reduce production and increase outflow.

Diabetic neuropathy

A chronic axonal polyneuropathy seen in 50% of diabetics Distal sensory more than motor symptoms with burning pain, decreased sensation, and less evident motor deficits Loss of pain sensation in feet leads to ulcers that heal poorly due to vascular diabetic changes > amputation 30% of diabetics have autonomic dysfunction from neuropathy, causing postural hypotension with syncope, decreased bladder emptying with recurrent UTIs, postprandial nausea (diabetic gastroparesis), and sexual dysfunction.

Environmental causes of hearing loss

*Aminoglycoside exposure* Those with the A1555G mutation in the 12S rRNA gene causes sensitivity to aminoglycosides (gentamicin), leading to high frequency hearing loss after one normal therapeutic dose. Even with no exposure to ahminoglycosides, they have a predisposition for SNHL, with a mean age of onset of 20yrs, with 50% affected by 40 and 60% by age 70. Congenital CMV infection newborns can get CMV from breast milk, urine, saliva, cervical secretions, ascending (uterine), hematogenous, or placentally. Risk of fetal transmission is much higher during the mom's primary infection and can cause intrauterine growth retardation, retinitis, microcephaly, jaundice, *blueberry muffin rash*, and hepatosplenomegaly. Babies can have permanent mental retardation, SNHL, blindness, or death. Babies who are initially symptomatic have 50% chance of developing SNHL and learning difficulties. 10% of those who appear asymptomatic will develop SNHL by age 7. Other environmental causes: Torch infections - Toxoplasmosis, Rubella, CMV, Herpes Meningitis, LBW/prematurity, hyperbilirubinemia, ventilation.

Poliomyelitis

*Anterior horn cell* disease caused by polio infection (RNA picornavirus). Asymmetric LMN weakness that can be focal or unilateral, affecting bulbar, respiratory, and/or limb muscles. No treatment, care is supportive but often effective in allowing neurons to recover much function.

Amyotrophic Lateral Sclerosis (ALS)

*Anterior horn cell* disease that also affects the lateral corticospinal tracts and motor nuclei of the brain stem. Most common motor neuron disease. Degenerative disease of UMNs and LMNs of brain stem and spinal cord. Cause is unknown (glutamate toxicity and oxidative stress/free radicals), and 5-10% are familial. Symptoms are bilateral and asymmetric, often starting with limb weakness. Bulbar muscle involvement causes trouble swallowing, chewing, speaking, breathing, and coughing. Extraoccular and sphincter muscles are spared (maintain continence). Muscles undergo denervation atrophy. Lateral corticospinal tracts lose axons and myelin and become glottis - which can be seen histologically. Mixed UMN and LMN signs - positive babinski, hyperreflexia, fasciculations. EMG can help confirm diagnosis (distinguishes between neuropathic and myopathic disorders). Progressive and fatal in 3-5 years, with death from pulmonary infection and respiratory failure. Only available treatment is a glutamate blocker - extends life marginally but decreases energy and cognitive function.

Visual anatomy

*Bony orbit foramena* In the bony orbit, there are ethmoidal foramina most medially for the ethmoidal nerves/vessels that go into the front of the nasal cavity. More laterally/posteriorly, there is the optic canal for the optic nerve and ophthalmic artery. At the very back of the orbit is the superior orbital fissure (SOF) for cranial nerves III, IV, V1, VI, and superior ophthalmic veins. The infraorbital nerve branch of V2 traverses the floor of the orbit and exits the infraorbital foramen in the maxilla. The eyeball has an outer, fibrous sclera, a middle vascular choroid, and an inner retina. The sclera is the white fibrous layer (5/6) as well as forms the cornea (1/6), which is transparent. The sclera provides structure and is largely avascular, but the cornea has the highest density of nociceptors in the body. The choroid provides O2 and nutrients to the underlying retina and continues anteriorly as the ciliary body (CNIII), from which zonular fibers attach to the lens and control the shape and thickness (focus/refractive power/accommodation). The ciliary body also connects to the iris, a muscle diaphragm surrounding a central aperture (pupil). The iris consists of 2 smooth muscles - pupillary sphincter muscle that constricts the pupil under parasympathetic control (CNIII) and the pupillary dilator muscle that dilates the pupil under sympathetic control. The retina is the inner sensory layer of the eye, containing ganglion cells whose axons form optic nerves that exit the eye at the optic disc. The fovea is a depression in the macula and the area of highest acuity (highest density of cones). Pupil constriction pathway The optic nerve exits the back of the eye and synapses onto the ipsilateral and contralateral lateral geniculate nucleus (vision pathway) and the ipsilateral pretectal area (constriction pathway). The Ipsilateral pretectal area neurons synapse with the ipsilateral and contralateral Edinger-Westphal nucleus. CNIII neurons from the EW nucleus travel to the ciliary ganglion to synapse with constrictor neurons that travel to innervate the pupillary sphincter muscle in the iris. (Dilation occurs when a neuron in the intermediolateral cell column synapses on a superior cervical ganglion neuron that travels to innervate the pupillary dilator muscle in the iris.) The eyelids contain tarsal plates - bands of dense connective tissue that provide structure and support to the lid. Tarsal glands along the underside of the plates provide lubrication. The eyelids are covered externally by skin and internally by the palpebral conjunctiva, a thin inner membrane that reflects onto the anterior eyeball as the bulbar conjunctiva. The orbital septum, which connects the tarsal plates to the margins of the orbit, helps limit the spread of infection to and from the orbit. *Orbicularis oculi is the sphincter muscle that closes the eyelids and is innervated by CNVII. The levator palpebrae superioris muscle attaches to the superior tarsal plate and opens the eye by lifting the upper lid (CNIII). CNIII opens the eye and CNVII closes the eye.* (and sympathetics help open the eyes a little more) The lacrimal apparatus produces and drains tears that clean and lubricate the eye. the lacrimal gland makes and secretes tears from the upper lateral aspect of the orbit and receives parasympathetic secretomotor nerves from the greater petrosal nerve (CNVII). Blinking sweeps tears toward the superior and inferior lacrimal canaliculi and nasolacrimal sac - the superior dilated portion of the nasolacrimal duct that drains tears into the inferior meatus in the nasal cavity. Most extraoccular muscles arise from a common tendinous ring at the apex of the orbit and insert into the sclera. The inferior oblique arises from the medial aspect of the orbit. The tendon of the superior oblique passes through a trochlea (pulley) and then reflects back to insert on the eyeball. The eyeball/orbit is supplied mainly by the ophthalmic branch of the internal carotid artery, passing through the optic canal alongside the optic nerve to enter the orbit and give rise to many branches. The central retinal artery is one branch that runs within the optic nerve and provides the only arterial supply to the retina (occlusion/thrombosis > ischemia of retina > blindness). Venous drainage is mainly into the cavernous sinus via the superior and inferior ophthalmic veins but can also flow into the facial vein that leads to the internal jugular vein (can flow in either direction because veins in the head/neck don't have valves). *Trigeminal V1 (ophthalmic division) enters orbit through the superior orbital fissure and gives rise to three branches that convey sensation. The lacrimal branch innervates the lacrimal gland, the frontal nerve gives rise to the supraorbital/ supratrochlear nerves that convey sensation from the forehead, and the nasociliary nerve conveys sensation from the the eyeball and cornea (and gives off ethmoidal nerves that innervate the anterior nasal cavity).* The oculomotor nerve (CNIII) innervates many extraoccular muscles and also conveys parasympathetic nerves to the pupillary sphincter muscle (constricts) and the ciliary body/muscle (lens accommodation). Preganglionic parasympathetics synapse in the ciliary ganglion behind the eye and travel via short ciliary nerves to their target. *Sympathetic nerves in the orbit innervate the dilator pupillary muscle and small superior tarsal muscle that help the levator palpebrae superioris (CNIII) elevate the upper lid. The first order neuron travels from the autonomic regulatory nuclei of the hypothalamus to the paravertebral sympathetic chain ganglia at T1-T2. Second order neurons move up the chain to synapse in the superior cervical ganglion, from which 3rd order neurons travel in the carotid plexus to the pupillary dilator muscle. Disruption of these sympathetics can cause Horner's syndrome (meiosis, ptosis, anhydrosis).* Pancoast's tumor - a tumor at the lung apex or superior sulcus - can affect the cervical sympathetic plexus and cause Horner's.

Electromyography/ peripheral nerve conduction velocities

*Nerve conduction study/PNCV - demylinating vs. axonal EMG - neuropathy vs. myopathy* Nerve conduction study stimulating electrodes placed on skin overlying nerve and recording electrodes are placed at a different point along the same nerve or overlaying a muscle innervated by it. Measuring peripheral nerve conduction velocities (PNCV) at multiple points along a nerve can help localize the point of damage. PNCVs can also indicate whether the abnormality is consistent with demyelination (longer delay period) or axonal damage (lower amplitude). PNCVs don't detect abnormalities of the CNS or of small, unmyelinated fibers. CMAPs - Compound motor action potential - summation of all APs of all muscle fibers activated by stimulation of a proximal nerve. CMAPs are compared to a known standard to measure axonal integrity (amplitude/electrical activity that arrives at the recording electrode) and myelin sheath integrity (conduction velocity/distal latency). CMAPs are only used to study muscle innervation. SNAP - sensory nerve action potential - summated electrical activity of a sensory neuron's axons, measured by placing a recording and stimulating electrode along a sensory nerve. EMG - electromyography - electrode inserted directly into a muscle measures activation at rest or during activity. A motor unit potential (MUP) is the AP generated when a motor unit (alpha neuron + innervated muscle fibers) fires. Spontaneous activity at rest (fibrillations/positive waves) indicates denervation of the muscle. A neuropathy caused by loss of nerves/innervation produces a small number of very large motor units (neuropathic motor units) causing larger amplitude APs that are fewer in number (functional nerves adopt muscles that are denervated). A myopathy caused by loss of muscle fibers produces a larger number of tiny motor units (myopathic motor units) causing smaller amplitude APs in greater numbers (more motor units are recruited to accommodate for their small size) EMG can't detect abnormalities secondary to damage of corticospinal tracts proximal to anterior horn cells. EMGs or PNCVs are used for patients with weakness or numbness in which localization and etiology are unclear and treatment would be guided by clarification - compression mononeuropathies, polyneuropathies, ALS, myopathies, myasthenia. EMG should not be done in patients with increased bleeding risk.

Cerebral Palsy

*Permanent* disorders of the development of *movement and posture* causing activity limitation that are attributed to *non-progressive* disturbances that occurred in the developing fetal/infant *brain*. Can be accompanied by disturbances in sensation, perception, cognition, etc. Causes: Periventricular leukomalacia (PVL) - prematurity damages the white matter surrounding the ventricles Hypoxic-ischemic encephalopathy (HIE) - birth complications causing hypoxia Intraventricular hemorrhage (IVH) - prematurity related Cerebral dysgenesis - congenital malformations Spastic cerebral palsy UMN syndrome causing hypertonia, hyperreflexia, extensor plantar responses, and clonus, slow voluntary movements, impaired fine-motor function, difficulty isolating individual movements, and fatiguability. There are also dyskinetic and ataxic types.

Neurocognitive disorders

Acquired cognitive deficits that are the most prominent and defining features of a condition, representing a decline from a previously attained level of functioning and not neurodevelopment deficits. Mild cognitive impairment Memory loss noted by family or patient and testing shows abnormal memory, but there is no functional impairment. Those with MCI are more impaired than normal for their age and are at greater risk for progression to dementia. Static encephalopathy Includes post infectious, post anoxic, and post traumatic (concussion/chronic traumatic encephalopathy) Delirium *Acute* mental status disorder (symptom) characterized by abnormal and *fluctuating attention, with disturbance in level of awareness, confusion,* and reduced ability to direct, focus, sustain, and shift attention (*attentional deficits*). Supportive features include altered level of consciousness (hyper/sleepy fluctuations), illusions and hallucinations, disturbed sleep/wake cycle, altered psychomotor activity, disorientation and memory impairment, and behavioral and emotional abnormalities. Delirium can be caused by any severe medical or surgical illness, which likely causes a release of cytokines and alters NT responses in response to these stresses. The most common causes in the elderly are medication, infection and metabolic disturbance, and drug/alcohol intoxication/withdrawal in young people. Present in 10% of hospital admissions and develops in another 15% during their stay, and is most common in post surgical and ICU settings. To find the cause, first do a general and neuro exam, medication history, electrolytes, renal function, liver function, CBC, thyroid panel, B12, drug levels, urine analysis, ECG, CXR, and pulse ox. If there is no clear diagnosis, then do a head CT. If still no diagnosis, do a lumbar puncture if concerned about meningitis/encephalitis, EEG if worried about seizures, or MRI if worried about stroke. Treat the underlying cause, stop all not critical medications, avoid restraints, foley catheters, and other predisposing factors. Dementia Acquired, persistent, and usually progressive impairment in intellectual function, with compromise in multiple cognitive domains, causing significant functional decline that interferes with work or social life (doesn't affect attention or consciousness as in delirium). Includes degenerative, progressive pathology (alzheimer's, lewy body, frontotemporal); non-degenerative, progressive pathology (vascular, alcoholic, CJD); and potentially reversible pathology (B12 deficiency, hypothyroidism, HIV, syphilis, NPH, and treatable mass).

Opioids

Agonists Heroin, morphine, codeine, oxycodone, hydrocodone, fentanyl, methadone, meperidine, tramadol. Opioid agonists mimic mu receptors and are used for cough suppression, diarrhea, and management of moderate to severe pain. Side effects include nausea/vomiting (stimulates medulla chemoreceptor trigger zone), depressed respiration (decreases responsiveness of brainstem respiratory centers to CO2), *constipation* (decreased motility), exacerbates gall bladder disease (constricts sphincter of Oddi - meperidine is exception), causes euphoria/tranquility (nucleus accumbens), pupillary constriction, depressed cough reflex (cough center in medulla), urinary retention (inhibits urinary voiding reflex and increases external sphincter tone), and *pruritus* (itching, can treat with antihistamines). Opioid agonists cause tolerance and physical dependence - physiological responses not predictors of addiction. Agonists potentiate the effects of phenothiazines, MAOIs, and tricyclic antidepressants (hepatic metabolism) and increase respiratory depression with alcohol and benzodiazepines. Strong agonists Heroin *Morphine* - control of severe pain *Fentanyl* - 100x more potent than morphine, short activation time, rapid termination of effect after small bolus doses, relative CV stability, given IV. Used preoperatively and during surgery to minimize amount of volatile anesthetic needed to keep person unconscious (maintenance). *Methadone* - for chronic pain, opioid abstinence syndromes, and heroin addiction treatment, racemic mix of NMDA receptor antagonist and mu receptor agonist, NMDA antagonism prevents opioid tolerance and adverse effects, given orally. *Meperidine* - rapidly acting synthetic opioid no longer used for pain control because causes seizures, used to be drug for gall-bladder related pain because doesn't constrict sphincter of Oddi Weak to moderate agonists *codeine* - weak-to-moderate agonist prototype, used for analgesia, cough suppression (antitussive), and as antidiarrheal *Hydrocodone* - moderate agonist, opiate most often prescribed in US, usually combined with weaker analgesic (acetaminophen, ibuprofen, aspirin) *Oxycodone* - moderate agonist used for moderate to severe pain *tramadol* - weak agonist, well absorbed orally, lower risk of addiction, can cause seizures and serotonin syndrome Partial agonists Buprenorphine High affinity and low efficacy at the Mu receptor make Buprenophine a partial agonist. It is also a kappa receptor antagonist. It is used for analgesia, opioid abuse deterrence, detoxification, and maintenance therapies. Mixed agonist-antagonists Nalbuphine Mu antagonist and kappa agonist. Used to treat opioid-induced pruritus Antagonists Naloxone, naltrexone Used to reverse the effects of Mu receptor agonists in patients with respiratory depression, increasing respiration in 1-2 minutes and lasting 1-4 hours. Antagonists are used to treat opioid addicts and opioid-induced toxicity (overdose). When given to an addict, it causes an abrupt withdrawal syndrome. Naloxone is used to treat opioid overdose and has a half life of only 1 hour. Naltrexone is used to treat alcoholism and acts for almost 24 hours.

Dementia types

Alzheimer's Progressive, degenerative pathology that is the most common cause of dementia in the elderly and affects 1-2% of those <65yrs. Affects 2x as many women because women live longer. Most cases are sporadic, but they can be familial. Grossly, there is hydrocephaly ex-vacuo from symmetric atrophy of the temporal, parietal, and frontal lobes (occipital lobes can be spared). In those with early onset, the temporal and parietal lobes are most affected. Histologically, you will see extracellular neuritic/senile plaques of amyloid and intracellular neurofibrillary tangles of tau. Frontotemporal dementia (Pick's disease) FTD is a neurodegenerative disorder causing atrophy of the frontal and temporal lobes leading to *personality changes* (apathy, disinhibition, loss of insight and emotional control) and cognitive decline presenting between 45-65yrs and progressing for 2-5 yrs. Grossly, frontal and temporal lobe can be asymmetric. Histologically there are intracytoplasmic Pick bodies made of tau proteins. Lewi body dementia DLB is a neurodegenerative disorder and the second most common cause of dementia (15-30%), causing cognitive impairment, parkinsonism, prominent visual hallucinations, and sleep disorders (REM sleep behavior disorder). Brain is not at atrophic as in Alzheimer's, and histologically you see Lewy bodies made of synuclein in the neocortex, limbic system, and brainstem. Vascular dementia Non-degenerative cause of dementia responsible for 10% of cases. Cerebrovascular disease leads to multiple lacunar infarcts, causing stepwise decline in cognitive function with focal neurologic symptoms. Radiology - absence of signs of cerebrovascular disease argues against vascular dementia but presence of lacunar lesions doesn't prove they are causal (and lesion severity doesn't correlate with dementia severity). Treat HTN to reduce future infarcts and prevent end-organ disease. Anti platelet agents can reduce stroke risk. Alcoholic dementia Non-degenerative dementia caused indirectly by alcohol consumption, which causes Wernicke-Korsakoff syndrome often accompanied by traumatic lesions including chronic subdural hematomas (falls and trauma), vascular disease (co-morbid smoking and HTN), and Alzheimer's pathology (chronic alcohol contributes to Tau and amyloid accumulation). WKS involves degradation of *mammillary bodies,* hypothalamus, thalamus, periaqueductal gray matter, colliculi, and floor of 4th ventricle. caused by thiamine deficiency, causing *confusion, ophthalmoplegia (eye movement paralysis), and gait ataxia*. It can be precipitated in at-risk patient by IV glucose or carbo loading, so always give glucose with thiamine in at risk patients. Treat with thiamine. Korsakoff syndrome follows repeated or chronic encephalopathy that damages the diencephalon and temporal lobes, causing anterograde and retrograde amnesia (with absence of social and cognitive functioning) and confabulation. Creutzfeldt-Jakob Disease CJD is the most common prion disease in humans. Most cases are sporadic (sCJD) affecting middle aged or older people and causing dementia, myoclonus, ataxia, and death within months. EEG shows characteristic periodic sharp wave complexes (PSWC). Other types include familial CJD (fCJD) that is autosomal dominant, variant CJD (vCJD) from consumption of beef, and iatrogenic CJD (iCJD) from exposure to contaminated biomedical products and surgical instruments. CJD causes prominent cortical atrophy and spongiform change histologically. Normal pressure hydrocephalus A potentially reversible cause of dementia caused by conditions that prevent CSF absorption like meningitis or subarachnoid hemorrhage, or idiopathic. Presents with a clinical triad of *dementia, gait instability/apraxia, and urinary incontenance (WWW)* caused by compression of medial frontal lobes affecting the premotor cortex, cortical micturition center, and ventromedial cortex. Diagnose on CT with large lateral ventricles without enlargement of cortical sulci (so not hydrocephalus ex-vacuo). Treat with lumbar puncture or CSF shunt. Concussion A continuum of brain injury ranging from mild (dazed for a few seconds) to severe (loss of consciousness and persistent neurological abnormalities and structural changes). Repeat concussion, especially before symptoms from previous one resolve, have a cumulative effect and cause chronic traumatic encephalopathy (CTE). Trauma causes axonal distortion/stretching (diffuse axonal injury) that allows an efflux of K+ into extracellular space and influx of Ca++ into axons, causing glutamate release that triggers an excitotoxic cascade. Neurons can be reversibly depressed or permanently damaged. This triggers release of tau and beta amyloid in the brain. CTE syndrome begins years after the injuries, with inattention, mood and behavior disturbances, confusion, and memory loss, progressing to dementia and parkinsonism. Grossly CTE causes atrophy, dilation of lateral and 3rd ventricles, and thinning of the corpus callosum. There is neuronal loss and tau deposition in neurons (neurofibrillary tangles) and astrocytes of the cerebral cortex, white matter, deep nuclei, and brainstem. *Tau deposition* (neurofibrillary tangles) is the key cellular change in CTE.

Types of motor lesions

Anterior horn cell Atrophy, weakness, fasciculations, normal sensation, painless ALS, SMA, Polio Corticospinal tract Spacticity, brisk reflexes, weakness bilaterally below a lesion or involving the entire homebody with brain lesions Spinal cord compression, stroke, MS Nerve root (radiculopathy) Pain, paresthesia, myotome weakness, loss of reflex mediated by involved nerve root +/- dermatomal sensory loss compressive radiculopathy (slipped disk), shingles Focal neuropathy Pain, weakness, atrophy of innervated muscle Bell's palsy (CNVII), carpal tunnel Polyneuropathy Paresthesias, distal sensory loss +/- neuropathic pain that can spread proximal, distal weakness, areflexia Acute axonal (rare): arsenic poisoning, porphyria Acute demyelinating (not rare): AIDP (Guillian-Barre) Sub-acute/chronic axonal (very common): diabetic neuropathy, B12 deficiency Sub-acute/chronic demyelinating (not rare): Charcot-Marie Tooth Disease (HPSP), CIDP NMJ Weakness, fatiguability, ptosis, normal sensation, painless Myasthenia Gravis, LEMS, Botulism Myopathy Weakness proximally greater than distally, normal sensation, sometimes muscle pain, elevated CK Polymyositis, dermatomyositis, muscular dystrophies

Ataxia and cerebellar degeneration

Ataxia can be caused by lesions that interrupt sensory input (posterior columns and spinocerebellar) tracts to the cerebellum (spinal or sensory ataxia - tested with Romberg test), pathology of the cerebellar cortex resulting in incorrect execution of cortical signals (cerebellar ataxia), or a combination of both (spinocerebellar ataxia). Friedrich's ataxia (FRDA) Most frequent inherited ataxia. Autosomal recessive ataxia caused by GAA repeats on the frataxin (FXN) gene, which produces a mitochondrial matrix protein involved in iron homeostasis. The mutation causes mitochondrial dysfunction and oxidative stress leading to degeneration of many populations of neurons. Primary pathology is loss of sensory ganglion cells and degeneration of their axons in peripheral nerves, dorsal roots, and posterior columns - depriving the cerebellum of sensory input needed to coordinate movement. Posterior column and spinocerebellar tract demyelinating can always be seen histologically. There is also degeneration of corticospinal tracts, dorsal spinocerebellar tracts, dentate nuclei, and superior cerebellar peduncles. Onset before age 20 of gait ataxia, proprioceptive and superficial sensory loss, weakness of extremities, and spasticity with extensor plantar responses. Most die of cardiomyopathy. Foot deformity (pes cavus) and scoliosis are common, as well as blindness, deafness, and diabetes. Spinocerebellar Ataxia Family of autosomal dominant neurodegenerative disorders characterized by high genetic heterogeneity that causes adult-onset ataxia/cerebellar signs, UMN signs and abnormal reflexes. Cerebellar and sometimes brainstem atrophy is seen grossly. >30 loci/genes - some dominant and some recessive. 11 are caused by oligonucleotide expansion (mostly CAG triplet, but also some penta- and hexa-). Some forms are due to CAG (polyglutamine) repeats, similar to Huntington disease with adult onset and anticipation. Other forms are from intronic repeats, causing foci of RNA (toxic) in Purkinje cell nuclei. Cerebellar ataxias Diverse group of sporadic diseases that cause cerebellar degeneration and degeneration of other anatomical systems. Cerebellar degeneration can be inherited or acquired (prion disease, HIE, nutritional deficiency, autoimmune, alcohol).

Acute back pain

Back pain is a leading reason for all physician visits, with most cases caused by musculo-ligamentous injury or skeletal degenerative changes (compression fracture, herniated disk, spinal stenosis). Other potential causes are infectious (diskitis, epidural abscess, vertebral osteomyelitis), primary malignancy (multiple myeloma, osteoid osteoma), metastasis (pulmonary, prostate, breast), inflammatory/autoimmune (seronegative/ankylosing spondylitis), or visceral disease (expanding aortic aneurysm, retroperitoneal fibrosis, pyelonephritis, ureteral nephrolighiasis, endometriosis). Patients should stay ambulatory and take a high dose of acetaminophen or NSAIDS for 5 days and receive reassurance that the prognosis is excellent. If you suspect a compression fracture, use plain X-ray to confirm. If you suspect a herniated disk (radicular pain), monitor for progressive neurological deficits - if these occur, get an MRI and refer the patient to a specialist. Opioids are not recommended for acute back pain but are often prescribed anyway to offer patients relief when NSAIDs and acetaminophen are not enough. Other therapies for chronic pain management with no strong supportive evidence are braces, traction, spinal manipulation, acupuncture, massage, PT, chronic opioids/NSAIDs/antidepressants/muscle relaxants, topical lidocaine, CBT, and ultrasound. If acute back pain is accompanied by burning electric pain and tingles down a leg, topical lidocaine, anti-depressants (amitriptyline, duloxetine), and/or anti epileptic drugs (AEDs - Gabapentin, pregabalin, carbamazepine).

Vertiginous dizziness

Benign paroxysmal positional vertigo Otoliths/otoconia become dislodged and fall into the posterior semicircular canal, such that turning the head in the plane of the canal moves fluid past the cupula (normal) and creates crystal tumbles (abnormal) that cause imbalance of vestibular input to the brain. This causes recurrent bursts of vertigo lasting seconds to 2 minutes occurring with head movement. Test for BPPV using the Dix -Hallpike maneuver - the patient sits upright with his head turned 45 degrees toward the affected ear and then lies back quickly on the exam table so that the head ends bending backward 20 degrees when lying down. After a short delay, there will be geotropic rotary down-beating nystagmus toward the side of the affected ear (an exception to the general rule that nystagmus beats away). Manage with the epley maneuver, which moves the otoliths back into the utricle. Vestibular neuronitis An unidentified virus causes continuous vertigo that comes on fulmanantly over a few hours and lasts for days. Treat with antiemetics and vestibular suppressants (bentos, antihistamines, and anticholinergics). Meniere's disease Overproduction of fluid inside the vestibular apparatus (hydrops of inner ear) due to disorder in salt homeostasis leads to rupture and leakage, causing vertigo and hearing loss until the hole heals. Vertigo and hearing loss lasts 20 minutes to several hours. Patients will also have spontaneous nystagmus that worsens when gaze turned away from the affected ear, and faked stair step test will turn the patient to the side of the affected ear. Patients must meet 4 criteria for diagnosis: episodic vertigo (2+ lasting >20min), fluctuating hearing loss, tinnitus, and aural pressure (exclude other causes with MRI). Treat with a low salt diet, diuretics, steroids, and valium for spells. Treat severe Meniere's with surgery (craniotomy for vestibular nerve section).

Syndromic hearing loss

Brachio-Oto-Renal syndrome (BOR) Autosomal dominant genetic abnormality causes malformations of the outer, middle and inner ear (lop ear deformity, hypoplasia of ossicles or cochlea); hearing loss; branchial fistulae and cysts, and renal malformations or functional abnormalities. Only 50% with BOR have an identifiable genetic cause, but all identified genes are transcriptional activators for embryonic development expressed in the ear, head mesenchyme, and kidneys. 40% have EYA1, 2% have SIX1, 5% have SIX5. Waardenburg syndrome Is generally autosomal dominant and causes congenital profound to progressive (70%) post-lingual sensorineural hearing loss, pigmentary abnormalities (hypo pigmented hair, heterochromia of iris), and telecanchus (wide distance between eyes). Waardenburg syndrome has 4 phenotypic types and locus heterogeneity (different genes cause same syndrome). The most common genes affected are PAX3 and SOX10, which are transcription factors involved in regulating melanocyte development and neural crust development. Type 1 - hearing loss, pigmentary abnormalities, telecanthus Type 2 - neuro abnormalities without telecanthus Type 3 - musculoskeletal abnormalities in upper limbs Type 4 - associated with Hirschsprung disease BOR and Waardenburg syndrome demonstrate haploinsufficiency - loss of 1/2 of the normal protein activity causes disease.

*DFNB1*

Causes non-syndromic, sensorineural, pre-lingual hearing loss that is usually profound but can vary within families and can occur at high or all frequencies. They present with no vestibular or inner ear abnormalities (so no MRI findings). Most mutations at this location are autosomal recessive, but some can be autosomal dominant (DFNA3). There are two genes at this loci - *GJB2 that encodes connexin 26, and GJB6 that encodes connexin 30*. Connexins are needed to make connexons that form gap junctions between hair cells in the cochlea and CNVIII axons. GJB2 mutations are loss of function (deletion) mutations with founder mutations in Ashkenazi Jews, SE asians, and N. european caucasians. 11% of deaf patients with GJB2 mutations have only 1 identifiable change, and those with a GJB6 mutation (up to 15%) are deaf because their mutation interrupts the promoter gene for nearby GJB2.

Red eye

Causes that are less threatening for irreversible vision loss: Allergy - itching Hordeolum (inflammation around eyelash), chalazion (pimple) - localized lid tenderness Lid, conjunctival, corneal disorders (foreign body, trichiasis/eyelash inversion, dry eye) - scratchiness, burning Causes that are more threatening for irreversible vision loss: Corneal abrasion, scleritis, iritis, acute angle closure glaucoma - deep, intense pain Corneal abrasions, iritis, acute glaucoma - photophobia Corneal edema (acute glaucoma, contact lenses overwear) - halo *Conjunctivitis Bacterial causes will be associated with purulent discharge. Most common pathogens in adults are staph, strep, and H flu. Viral causes will produce clear, watery discharge as well as preauricular lymphadenopathy (may also have sore throat prior to conjunctivitis) (If adenovirus - disinfect with 1% bleach because alcohol won't kill. very contagious). Often one eye will become infected, followed by the other 1-2 days later. Allergic causes produce a stringy, white mucus and tearing in both eyes with swelling of the lids and conjunctiva. Neonatal - chemical/silver nitrate (newborn), gonococcus (2-5 days), or chlamydia (5-14 days)* Corneal infections bacterial keratitis - will see expanding oval, yellow-white dense stream infiltrate and sometimes an ulcer Fungal keratitis - often preceded by ocular trauma with organic matter, causing greyish-white ulcer that may be surrounded by feathery infiltrates and sometimes hypopyon (leukocytes in anterior chamber). Do not treat with topical steroids or fungus will grow more rapidly. Acanthamoeba keratitis - Small, patchy anterior stromal infiltrates, perineural infiltrate, and severe pain. Treat with Chlorhexidine and/or Polyhexamethylene biguanide (PHMB). Contact wearers in hot tubs or lakes are at risk. Herpes simplex epithelial keratitis - dendritic ulcer with terminal bulbs that stains with fluorescent. Do not treat with topical steroids. Gonococcal keratoconjunctivitis (dryness of the conjunctiva and cornea) Causes acute, profuse, purulent discharge, hyperemia (excess blood vessels), and chemosis (swelling of conjunctiva) and can lead to corneal ulceration, perforation, and endophthalmitis (inflammation of internal coats of the eye). Treat with topical gentamicin, bacitracin, or fluoroquinolone; or with IV/IM ceftriaxone or fluoroquinolone. Also treat chlamydia with doxycycline, erythromycin, or azithromycin because many with gonorrhea will have chlamydia. Neonatal Chlamydial conjunctivitis Babies can be colonized with Chlamydia trachomatis during birth, causing purulent discharge from the eyes, swelling, and inflammation a few days to weeks after birth. All newborns receive erythromycin eye drops prophylactically. If Chlamydial conjunctivitis occurs, it *must be treated systemically to prevent pneumonia.* In the 3rd world, adult chlamydial keratoconjunctivitis is a common cause of vision loss (there will be white Trantas dots around the edge of the iris). Treat with topical tetracycline and systemically with tetracycline, azithromycin, or erythromycin. If conjunctivitis develops in a newborn on day 1, it is from silver nitrate. If it develops on days 2-5, it is caused by Neisseria gonorrhea. If it develops between days 5-14, it is chlamydial. Sjogren's syndrome Occurring mainly in women, it's characterized by keratoconjunctivitis sicca (dry eyes), xerostomia (dry mouth), and another connective tissue or autoimmune disease (like RA). It is caused by autoimmune destruction of the lacrimal and salivary glands. Increases lifetime risk for lymphoma. Chemical injury Alkali compounds are more dangerous - lye, learning fluids, fertilizers, pesticides. Acid compounds - battery fluid Treat by diluting the substance with irrigation before going to the ED. Never prescribe topical anesthetics for pain control as they can cause corneal toxicity.

Neurodegenerative disease

Characterized clinically by loss of neurological function (dementia, loss of movement control, paralysis) and pathologically by loss of neurons that are progressive. The most common degenerative disease is Alzheimer's followed by Parkinson's. ALS, Huntington's, and Friedrich's ataxia are other examples. Degenerative diseases are caused by deposition of abnormal proteins in the brain that form intra/extracellular inclusions that interfere with normal function, eventually killing neurons. Alzeheimer's - extracellular neuritic/senile amyloid plaques, intracellular tau neurofibrillary tangles Lewi Body - intracellular alpha synuclein Lewy bodies in neocortex, limbic system, and brainstem Fronto-temporal/Pick's disease - intracellular tau Pick bodies

Electroencephalogram

Electrodes on the scalp surface record weak electrical signals from synchronous activity of millions of neurons emitted through the skull. Waveforms of various frequencies vary with level of alertness. Beta waves are the highest frequency and occur during conscious agitation. Alpha waves are high frequency and occur when realized but aware. Theta waves are lower frequency during somnolence with reduced consciousness. Delta waves are lowest frequency and occur during deep sleep or unconsciousness. EEG is used to evaluate patients for epileptic brain waves or to detect widespread abnormalities in brain function. Some epilepsy syndromes have characteristic abnormalities between or during seizures. EEGs are also used in delirium, coma, and brain death. EEGs are only contraindicated if their findings would not impact management. EEG with diffuse slowing confirms the presence of encephalopathy. Normal EEG does not exclude any diagnosis. Evoked potentials measure brain waves evoked by an electrical stimulus to the limbs and are used for intra-operative monitoring during spine surgery. Polysomnogram uses EEG with other measures to identify sleep disorders.

Dementia drugs

Cholinesterase inhibitors Donepezil, rivastigmine, galantamine Block cholinesterase at nicotinic and muscarinic ACh receptors, prolonging ACh effect at synapses. Primary side effects include nausea, vomiting, diarrhea, and anorexia. Secondary effects include insomnia, vivid dreams, bradycardia, and syncope. Rivastigmine is used to treat mild-moderate Alzheimer's disease and Parkinson's dementia and undergoes non-hepatic metabolism. Galantamine is used to treat mild-moderate Alzheimer's and is metabolized by CYP2D6 and CYP3A4 in the liver. Donepezil is used to treat all stages of Alzheimer's and is metabolized by CYP2D6 and CYP3A4 in the liver. Glutamatergic antagonists Memantine is used to treat moderate to severe Alzheimer's disease. Forming memories through long term potentiation in the hippocampus involves glutamate, which is recycled in glial cells. In Alzheimers, B-amyloid inhibits glutamate recycling, so excess glutamate remains in the synapse and excessively stimulates NMDA receptors, causing Ca++ influx and over-excitation that leads to cytotoxicity. Memantine antagonizes NMDA receptors with mild-moderate affinity. Side effects include headache, constipation, and agitation. Memantine decreases metabolism of bupropion (for depression and smoking cessation) and tryhexylphenidyl. Non-hepatic clearance requires dose adjustment for renal impairment.

Charcot-Marie Tooth (CMT) Hereditary sensory motor neuropathies (HSMN)

Chronic demyelinating polyneuropathy Intrinsic foot muscles lose innervation, causing high arches, hammer toes, motor weakness and orthopedic problems. Calves and ankles are also very thin compared to the thighs. Many are asymptomatic but atrophy and muscle weakness can cause pain and dysfunction/disability. HSMN 1 is caused by a mutation of peripheral myelin protein 22 (PMP22)

Chronic Inflammatory Demyelinating Polyneuropathy (CIDP)

Chronic demyelinating polyneuropathy. Weakness and numbness in arms and legs progressing over several weeks to months, loss of tendon reflexes Slowed nerve conduction velocities, elevated CSF protein. Treat with steroids, plasma exchange, IVIG.

Limbic system

Collection of basal and medial structures controlling basic survival functions, like feelings, behavior, fight or flight, aggression, expressions of emotion and other responses related to sex. Cortical components Limbic cortex - parahippocampal gyrus, circulate gyrus, orbitofrontal cortex Hippocampal formation (memory) Primary olfactory cortex (cortex of the uncus) (Patient HM - parahippocampal gyrus and hippocampal formation removed to treat seizures, causing retrograde amnesia of many years and anterograde amnesia). Diencephalon Hypothalamus (homeostasis, autonomic/neuroendocrine control) - mammillary bodies (Wernicke-Korsakoff's anterograde amnesia from thiamine deficiency). Thalamus - anterior nuclei Basal Ganglia Nucleus accumbens (reward/addiction center at the head of the caudate; fewer dopamine receptors in those who perform compulsive behaviors) Other nuclei Amygdala - (temporal lobe) emotions and drives (high baseline level implicated in anxiety) Basal forebrain - nucleus of Meynert (cholinergic neurons/Alzheimer's) The circuit of Papez a white matter feedback loop through the limbic system. The most important part of the tract itself is the fornix, which connects the hippocampus and the mammillary bodies.

Coma

Coma Absence of consciousness and unarousable unresponsiveness. (Stupor is unresponsiveness with minimal arousal) Causes of coma damage both cerebral hemispheres or the reticular activating system (you need one cerebral hemisphere and the RAS to be conscious). This can be focal lesions or diffuse problems (more common) - high fever, thyroid storm, sepsis, hypoxia, renal failure, etc. *Treatable causes: hypoglycemia, drug intoxication, meningitis, subarachnoid hemorrhage, staticus epilepticus, and increased intracranial pressure (treat with hyperventilation, mannitol, and decompressive surgery). Most common causes of coma: drug poisoning, hypoxia after arrest and resuscitation, trauma, non-traumatic bleeding, and stroke.* *Locked in syndrome (not a coma) Pontine hemorrhage cuts off all motor input to the face and body (cortical spinal and cortical bulbar tracts)*, only allowing for some eye movements (look up and sometimes blink). Person is conscious/arousable. Person is fully conscious (reticular activating system spared) with a normal sleep cycle. Patients can perform baseline breathing (respiratory drive is in medulla) but nothing more, so respiratory infections are common. Glasgow coma scale Patients are given a 3-15 score (worst-best) based on their ability to open their eyes (1=none, 2=pain, 3=speech, 4=spontaneous)), respond verbally (1=none, 2=incomprehensible, 3=inappropriate, 4=confused, 5=oriented), respond motor (1=none, 2=extension to pain, 3=flexion to pain, 4=withdrawal from pain, 5=localize pain, 6=obeys commands). Posturing describes a motor response to pain by someone in a coma. *Decorticate is flexion to pain and indicates lesion in the descending corticospinal tract above the red nucleus. Decerebrate is extension to pain and indicates the lesion is between the red nucleus in the midbrain and the vestibular nucleus in the pons (below red nucleus), eliminating the corticospinal and rubrospinal tract. Pupils Small reactive - opioid intoxication Equal in size but not reactive - midbrain lesion One enlarged, unreactive pupil - CNIII lesion from uncal herniation One small but reactive - Horner's (probably brainstem lesion) Eye deviation Hemispheric lesion affecting the frontal eye field - eyes will deviate toward the lesion, away from the paralysis Pontine lesion affecting the PPRF/abducens nucleus and descending corticospinal tract - eyes will deviate away from lesion, toward paralysis

Eye histology

Cornea The cornea has an outer protective layer of stratified squamous epithelium, a Bowman's membrane deep to that, and then the thick stoma called substantia propria. Deep to that is the thin Descemet's membrane and then a simple squamous epithelium called the endothelium. Iris The iris contains the constrictor (sphincter) pupillae muscle more anteriorly (faces anterior chamber) and the dilator pupillae muscle more posteriorly (faces posterior chamber). The constrictor pupillae are circularly arranged smooth muscles innervated by CNIII that constrict the pupil. The dilator pupillae are radially arranged smooth muscle innervated by sympathetics that dilate the pupil. Ciliary body Contains a double layer of cuboidal epithelium - an unpigmented surface layer and a pigmented deeper layer. The ciliary body suspends the lens, controls its shape for accommodation, and forms aqueous humor. Ciliary smooth muscle innervated by CNIII constricts the ciliary body and relaxes the tension on the lens, allowing it to round and accommodate for near vision. The canal of Schlemm drains aqueous humor into the episcleral venous system (blockage leads to glaucoma). Lens Refracts light due to transparent cells without organelles. It has an outer clear capsule and a simple anterior cuboidal epithelium. The retina Has 10 layers anteriorly to posteriorly: a thin inner limiting layer, optic nerve fibers > ganglion cell layer (cell bodies of optic nerves) > inner plexiform layer (synapses between optic nerve neurons dendrites and bipolar and amacrine cell axons) > inner nuclear layer (bipolar, amacrine, and horizontal cell bodies) > outer plexiform layer (synapses between bipolar, amacrine, and horizontal cell dendrites and photoreceptor cell axons) > cell bodies of rods and cones insulated by Muller cells > thin outer limiting layer > photoreceptor layer with thinner rods and thicker cones > pigment ed epithelium (Melanin, 11 sic-retinol, phagocytic cells to clear debris) sitting on Bruch's membrane on the choroid. Light passes all the way to the photoreceptor layer and signals are carried back up through rod/cone cell bodies > bipolar and amacrine cells > optic nerves. Axons and cell bodies of rods and cones are surrounded by Muller cells.

lesions affecting vision or eye movement and other facial lesions

Lesion of the optic nerve causes blindness in that eye. Pupil will appear normal until light is shone only in the affected eye, producing no direct or consensual response. Lesion sagittally through the optic chiasm causes bitemporal hemianopsia. Lesion in the optic tract causes homonymous hemianopsia on the opposite side. Lesion in Meyer's loop causes homonymous quadrantianopia of the upper visual field on the opposite side. Lesion of the primary visual cortex (PCA stroke) causes homonymous hemianopsia with foveal sparing on the opposite side. Lesion of the medial longitudinal fasciculus (MLF) will prevent the ipsilateral eye from moving medially, will look straight ahead and have a normal pupil. Lesion of CNIII will cause the ipsilateral eye to rotate down and out, with dilated pupil and ptosis (innervation of levator palpubrae) (more prominent in light than dark). Shining light in affected eye will produce a consensual but not a direct response. The inner portion of CNIII houses motor ocular muscles that are more affected by vascular disease (ischemia > down and out gaze, ptosis) and the outer portion carries parasympathetics to the pupil and is more susceptible to compression (eg. berry aneurysm of posterior communicating artery). (Scopolamine used to treat motion sickness causes mydriasis/dilation and cycloplegia/paralysis of ciliary muscles by blocking muscarinic acetylcholine receptors) Lesion of CNVI will cause the ipsilateral eye to be unable to move laterally. Lesion of CNIV will cause hypertropia (misalignment of eyes where visual axis of one is higher, causing diplopia) and extortion (outward rotation of the upper pole of the vertical meridian of the eye). Patients will tilt their head away from the affected side and tuck their chin. Lesion of the PPRF will prevent the eyes from moving to that side. CNVII lesion UMN lesion will cause facial weakness below the eyebrow on the side contralateral to the lesion. LMN lesion will cause facial weakness on the ipsilateral side that includes the forehead (Bell's Palsy or Ramsay-Hunt). The part of the facial nucleus on each side for the forehead is innervated by UMNs from both sides (bilateral innervation). CNVII lesion will also produce a lack of corneal reflex on the affected side (Must protect/close eye to prevent corneal ulceration). Ramsay-Hunt differs from Bells palsy in that there is pain on the affected side and herpes zoster vesicles in the ear canal (reactivation of virus in the geniculate ganglion). Treat Ramsay-Hunt with steroids and antivirals. CNVII palsy can also cause hyperacusis (everything sounds louder in affected ear) because CNVII innervates the muscle that stabilizes the stapes (stapedius). Lesion of CNXII (hypoglossal) will cause the tongue to deviate to the side of the lesion. Lesion of CNIX will cause the uvula to deviate away from the side of the lesion when the palate is elevated (patient says Ahh) and also cause dysphagia and hoarseness. Lesion of CNX would cause a midline uvula with absent gag reflex. Lesion of CN XI can cause ipsilateral shoulder droop, winged scapula, and weakness of shoulder shrug (trapezius) as well as weakness turning the head contra laterally (sternocleidomastoid).

Dystonias

Dystonia - sustained, involuntary muscle contractions that cause twisting or abnormal postures, with symptoms fluctuating and muscles normal between movements. Dystonia can be generalized or focal (more common). Focal dystonias include cervical dystonia (torticollis - neck contractions), blepherospasm (involuntary eye closing), focal hand dystonia (occur when attempting a specific movement - writing), and spasmodic dysphonia (larynx). Most with focal dystonia are effectively treated with botox.

IV general anesthetics

Etomidate, ketamine, propofol, thiopental, Midazolam (anxiolytic and amnesia - used preoperatively before induction) IV agents are given to create a balanced anesthetic and are used for their hypnotic properties (ability to make person lose consciousness). Most act at various sites on GABA receptors to enhance its effect, but ketamine uniquely blocks the NMDA glutamate receptor. IV anesthetics are metabolized in the liver and excreted via the kidneys. IV anesthetics demonstrate multi-compartment pharmacokinetics, with concentrations peaking first in the plasma, then in vessel rich tissues (liver and spleen), and then in muscles and fat. Volume of distribution relates the plasma concentration of a drug to the total amount of drug in the body, calculated using blood levels of the drug in the patient. Context-sensitive half-life refers to the fact that the longer a patient has been on a continuous drip, the longer it takes for the drug plasma concentration to decrease by 50%. Etomidate An induction agent that enhances GABA transmission, it has CV stability but is contraindicated in septic shock. Ketamine A sedative, analgesic, and induction agent, it is a dissociative anesthetic - person appears conscious but is unable to process sensory input. Ketamine antagonizes the NMDA glutamate receptor. Side effects include hallucinations and nightmares, but it is a potent analgesic that causes no respiratory depression (tonically activates SNS). It also causes increased HR and CO. Propofol The most widely used IV general anesthetic. Enhances GABA transmission with rapid onset and rapid recovery. Stops breathing before intubation during induction. Side effects include respiratory depression and bradycardia. Thiopental Good for neurosurgery patients because it enhances GABA transmission and suppresses transmission of excitatory NTs like ACh, decreasing ICP. Side effects include respiratory depression and bradycardia. Thiopental is used in lethal injections for execution.

Perceiving sound

External ear: Pinna/auricle, external acoustic meatus (EAM) aka auditory canal. the lateral 1/3 is cartilaginous and lined with skin that produces cerumen while the medial 2/3 is bony and lined with skin continuous with the tympanic membrane. Tympanic membrane separates external from middle ear Middle ear/tympanic cavity: Contains three ossicles. The handle of the malleus attached to the tympanic membrane and vibrates when sound enters the external auditory canal. The malleus attaches to the incus, which connects to the stapes at the oval window. The tensor tympani (V3 innervation) connected to the malleus lessens damage from loud sounds by tensing the tympanic membrane. The stapedius (CNVII innervation) dampens vibrations of the stapes on the oval window. The pharyngotympanic (eustachian) tube connects the tympanic cavity to the nasopharynx to equalize pressure in the middle ear. Oval window Inner ear: Contains the cochlea/auditory apparatus for hearing and the semicircular canals for balance, encased within the temporal bone. The vibrations of the stapes at the oval window creates waves in the incompressible fluid that fills the cochlea. The waves travel through the perilymph of the scala vestibuli around the 2.5 turns of the cochlea (axis = modiolus, housing nerves and vessels) and then back out through the scala tympani, which causes the round window to bulge out. The scala vestibuli and the scala tympani are part of the bony labyrinth and are continuous at the helicotrema. Inside the cochlear duct (blind ended tube), formed by the vestibular and basillary membranes is endolymph and the organ of corti (the neuroepithelium on the basillar membrane), which houses inner and outer hair cells with stereocillia, a gelatinous tectorial membrane, and many supporting cells. Vibration of the basillar membrane from sound moves the hair cells, which have their stereocillia embedded in the tectorial membrane and connected to one another via tip links linked to ion channels. Movement of the cells mechanically opens and closes ion channels, allowing K+ to enter and depolarize the cell. This opens Ca++ channels in the cell body, causing it to release NTs onto afferent neurons. Hair cells are lined up along the basilar membrane, such that hair cells near the top, wider portion of the cochlea (apex) detect low tones and hair cells at the bottom narrow part (the base) perceive high tones - this is tonotopic organization. The CNS interprets the pattern of hair cell stimulation as a sound of a particular frequency. *CNVIII enters at the medulla* and synapses with the dorsal cochlear nucleus and the ventral cochlear nucleus, decussate in the mid pons, and travel via the lateral lemniscus to the inferior colliculus and then synapse on the *medial geniculate nucleus in the thalamus*. The primary auditory cortex is on the medial face of the lateral fissure in the temporal lobe.

Proposed treatments for genetic muscular dystrophies

Gene therapy Introduction of a gene into a cell through a recombinant viral vector to induce expression of the gene's product. Some genes (like DMD) are too large to fit into the viral vector, so smaller variants are used (not as effective). the vector must also be delivered to the appropriate tissue and induce stable expression - this is difficult for muscular dystrophies involving a large percentage of body mass. Exon skipping Antisense oligonucleotides modulate splicing of precursor mRNA to skip exon containing mutation. 83% of DMD mutations may be amenable to exon skipping, but there is poor cellular uptake, modified protein is truncated (may go from DMD > BMD), and therapy must be highly customized. Read-through of termination codon Aminoglycosides restore protein translation in cellular assays but would have long-term side effects. 15% of DMD variants result in early termination codon. Stem cell transplantation Introduction of donor or genetically-corrected autologous progenitor cells. Difficult to deliver enough cells and distribute them, there's a high mortality rate of transplanted cells, and an immune response against them.

Spinal muscular atrophy (SMA)

Genetic disorder that causes degeneration of the *anterior horn cells* of spinal cord and brain stem. Most common fatal recessive disorder in children after CF. Mutations in spinal motor neuron gene (SMN). SMA is classified based on age of weakness onset, from in-utero to late adolescence. Later onset disease has a better prognosis with slower progression. The most common form present in infancy as a floppy baby with a weak cry and feeding difficulty (unable to swallow) as well as diminished baby reflexes and fasciculation. It is usually fatal within 2 years as LMN loss causes denervation atrophy of muscle, severe hypononia, weakness, and inability to breathe.

Guillian-Barre Syndrome (Acute Inflammatory Demyelinating Polyradiculopathy)

Guillain-Barre is an acute, demyelinating PNS disease characterized by weakness and areflexia beginning in the distal limbs and rapidly advancing proximally (ascending paralysis) and ultimately stopping respiration. (porphyria and heavy metal poisoning can present the same way) Caused by immune mediated inflammation and segmental demyelinating of spinal nerve roots and peripheral nerves, often caused by campylobacter jejuni and proceeded by acute, influenza-like illness. Signs include loss of deep tendon reflexes, slowed nerve conduction velocities, elevated CSF protein (lumbar puncture). EMG/PNCV could also help with diagnosis (EMG to distinguish between neuropathy and myopathy, PNCV measured to distinguish between demyelination and axon degeneration). Supportive care for weeks in ICU with pulmonary and CV support, with plasma exchange and IVIG. 5% die from respiratory failure, autonomic instability, or complications. 20% have some long term disability.

Myopathy

Hereditary myopathies include muscular dystrophies (muscles form normally but slowly break down), metabolic myopathies (Pompe's and McArdle's - exercise intolerance), congenital myopathies (born with muscle problems that do not progress/improve), and mitochondrial myopathies. Acquired myopathies include inflammatory disorders (dermatomyositis, polymyositis, inclusion body myositis), endocrine disorders (Thyroid and cushings), and toxins (steroids, statins) Signs/symptoms of acquired and hereditary myopathies include proximal muscle weakness (Gower's sign), dysphagia and respiratory weakness, and muscle atrophy (and calf hypertrophy for DMD). Acquired myopathies are characterized by acute or subacute (weeks-months) onset while hereditary myopathies present in utero or have insidious onset (months-years). Acquired myopathies usually start in adult years while hereditary myopathies start in infants and children. Progression of acquired myopathies is fast, while it's slow in hereditary myopathies. Skeletal deformities are uncommon in acquired myopathies but scoliosis, hyperlodrosis, pes cavus, and scapula winging can occur with hereditary myopathies. Test for serum creatine kinase and inflammatory markers, genetic testing (defects in muscle cellular proteins - MDPK in myotonic dystrophy and dystrophin in Duchenne's/Becker's), electromyography (EMG), and muscle biopsy. Myopathies on EMG have a recruitment pattern different from loss of nerves - more motor units are recruited to generate the same amount of force (in contrast to neruropathies in which denervated muscle are adopted by surrounding nerves so that fewer motor unit potentials are generated but they are larger in amplitude. Denervation also causes spontaneous activity at rest). Dystrophinopathies: Duchenne's and Becker's Dystrophin stabilizes the muscle membrane glycoprotein complex and protects it from degradation. Absence of the normal complex leads to a leaky membrane with altered Ca++ flow, increased cell death, and chronic inflammation. Mutations are X-linked deletions (60%), point mutations (34%), or partial duplication (6%) in the DMD gene. DMD is a large gene with repetitive sequences in several introns, causing a high mutation rate (mutation produced in a sperm every 10 seconds). Mutations causing Becker's produce a decreased level of dystrophin quantity/activity (rather than absent as with Duchenne) with in-frame deletions, missense variants, and variants that are skipped by alternative splicing. Duchenne's presents at age 2-3 (1 in 3000 males) while Becker's presents at 5-15yrs and is milder. Both can cause cardiomyopathy, calf hypertrophy, and Gower's sign. In Duchenne's, the ability to ambulate is lost early in the 2nd decade and progression to affect the respiratory muscles or heart is the usual cause of death. Carrier females have no clinical symptoms of muscular dystrophy but creatine kinase is elevated in 70% and they have increased cardiomyopathy risk. Women whose other DMD allele is abnormal can have muscular symptoms (skewed X-inactivation, turner syndrome, X;autosome translocation). Corticosteroids are used to postpone decline but can cause weight gain and behavioral problems. Limb-Girdle Muscular Dystrophy Early childhood-adule onset with predominant shoulder and pelvic muscle weakness. Autosomal recessive mutations in sarcoglycans in the cell membrane that contribute to the muscle membrane glycopoprotein complex. LGMD can also be associated with variants of Emerin and lamin A and C proteins in the muscle cell nuclear membrane, with different gene variants associated with different phenotypes (*allelic heterogeneity*). That LGMD can be caused by mutations in different genes is an example of *genetic/locus heterogeneity*. With locus heterogeneity, parents affected with AR LGMD (or another AR disorder) can have an unaffected child because the parents each had mutations at a different locus. Emery-Dreifuss muscular dystrophy Cardiac involvement in the 3rd decade with highly variable severity (can present with sudden cardiac death) Caused by variants in emerin (XLR) or Lamins A or C (AD or AR) in the muscle cell nuclear membrane. myotonic dystrophy The most common form of muscular dystrophy, it is autosomal dominant and has two types: type I (distal) and type 2 (proximal). Causes myotonia (delayed muscle relaxation after contraction), weakness and wasting, frontal balding, temporal wasting, cataract, conduct defects with cardiomyopathy, endocrinopathy, hypersomnia, and low intelligence. Myotonic dystrophy is caused by CTG repeat expansion in the DMPK gene and demonstrates anticipation that requires the mutation passing through a female. RNA builds up in foci in the nucleus, causing reduced protein expression, and RNA binding proteins co-localize with the foci and disrupt expression of other genes. 0-37 repeats is normal, 38-50 repeats is prone to repeat expansion (premutation), 51-100 repeats causes mild, late onset disease (protomutation), 100-1000 causes adult onset of full disease (full mutation), 1000+ repeats causes congenital onset (full mutation). Metabolic myopathies McArdle's - absence of glycogen phosphorylase causes cramps after exercise and rhabdomyolysis with continued exercising. Pompe's - autosomal recessive deficiency of acid alpha-glucosidase (acid maltase) causes glycogen to build up in lysosomes of muscle tissue. Classic infantile-onset Pompe's causes floppy infant with heart failure, hepatomegaly and tongue enlargement that will die in 1 year without treatment. Late-onset Pompe's starts as a child or young adult with progressive muscle weakness and variable progression to respiratory failure. Enzyme replacement therapy (ERT) with recombinant human acid maltase increases survival and functioning but costs $300,000 per year. Inflammatory myopathies Dermatomyositis (DM) - Subacute onset of proximal muscle weakness with very elevated CK (>25x normal), skin rash on face/neck/hands, heliotrope, and malignancy in 25-40% (screen). Treat with IVIG, plasma exchange, or steroids. Polymyositis (PM) - rare condition causing subacute, symmetric proximal muscle weakness that may be associated with pain and is in females more than males. CK is very elevated (>25x normal). PM responds well to IVIG, plasma exchange, and steroids. Inclusion body myositis (IBM) - most common inflammatory myopathy after age 50, more often in females, it selectively involves the finger flexor, quadriceps, and forearm muscles (atrophy) with asymmetric weakness. CK can be normal or mildly elevated (<10x normal).

horizontal eye gaze

Horizontal eye gaze is initiated by input from the frontal eye fields (voluntary) and/or from vestibular nuclei (involuntary). With voluntary control, input is carried via the cortical bulbar tract to the ipsilateral and contralateral parapontine reticular formation, which sends axons to lateral and medial nuclei in the abducens nucleus (CNVI). The lateral nuclei project to the lateral rectus muscles to move the eyes laterally and the medial nuclei project to the contralateral oculomotor nucleus via the medial longitudinal fasciculus. CNIII from the oculomotor nucleus projects to the medial rectus muscles to turn the eyes medially. So to move the eyes to the left, the left abducens nerve from the left abducens nucleus stimulates the left lateral rectus to pull the left eye laterally, and the left abducens nucleus sends another nerve to the contralateral/right oculomotor nucleus so that the right oculomotor nerve stimulates the medial rectus to pull the right eye medially. With involuntary control, nerves from vestibular nuclei not only synapse on the PPRF but also directly onto the abducens nucleus. The vestibular nuclei, inputs from frontal eye fields, PPRF, abducens (CNVI) nucleus, abducens nerve fascicles, and MLF are at the level of the middle cerebellar peduncle in the Pons. The oculomotor nucleus (CNIII), edinger-Westphal nucleus, and occulomotor nerve fibers are at the superior colliculus of the midbrain. Lesion of an abducens nucleus or PPRF will prevent both eyes from looking in that direction. Lesion of one MLF (medial longitudinal fasciculus) is internuclear opthalmoplegia and prevents the ipsilateral eye from looking in the opposite direction (medially), resulting in nystagmus in the other eye when it looks in that direction. Lesion in one MLF as well as the PPRF from the same side causes 1 1/2 syndrome - ipsilateral eye is unable to look in the opposite direction (medially) and the other eye has nystagmus when it looks that way. MS can cause INO as well as 1 1/2 syndrome. Stroke In the first few hours after a stroke, eyes can deviate in one direction from an imbalance between the tonic inputs (each frontal eye field signals eyes to look to the opposite side). *Stroke affecting a frontal eye field will cause the person to look away from the side of paralysis (toward side of stroke). Stroke affecting one side of the pons (PPRF/abducens nucleus and descending corticospinal tract) will cause the eyes to look toward the paralysis, away from the side of the stroke.* Also do deep tendon, gag, and corneal reflex testing, VOR testing (vestibular ocular reflex - caloric testing), and check for papilledema. Perform labs, CT, LP, EEG, and MRI. Stabilize the patient's airway, breathing, and circulation. Give naloxone, glucose, or thiamine if necessary - treat specific causes. Brain death - can be declared if the coma if from a known cause (nothing treatable); there is no hypothermia, drug intoxication, electrolyte disturbance, or acid-base imbalance; absent motor response; absent brainstem reflexes (caloric testing), and apnea (no respiratory drive). Some states require that there are no brain waves on EEG or blood supply to the cerebrum. Persistent vegetative state Similar to coma: no consciousness, communication, or emotion. Different from coma: sleep/wake cycle, withdraws from noxious stimuli and occasional non-purposeful movement, startle response to sound and sight. Minimally conscious state Partial consciousness, reactive vocalization, reactive smiling or crying, sleep/wake cycles, localizes noxious stimuli and reaches for objects, localizes to sound, sustained visual fixation.

Hyperkinetic movement symptoms Tremors

Hyperkinetic movement symptoms Chorea - irregular, semi-directed movements that occur when trying to direct movement Athetosis - continuous writhing movements Ballismus - ballismus - sudden, vigorous, forceful movements of a whole limb Dystonia - sustained contraction of opposing muscle groups, causing twisting movements and abnormal postures Myoclonus - sudden, brief, shock-like movements at rest caused by muscular contraction or inhibition Tremor - oscillatory, usually rhythmical and regular movements Tremor can occur at rest (Parkinson's) or when muscles are active (postural or intention). Parkinsonism tremors are asymmetric, slow, and high amplitude at rest and sometimes during action that worsen with stress and improve with voluntary movement. *Cerebellar tremors are coarse tremors worse at the end of purposeful movements, caused by ipsilateral cerebellar lesions/disease (very rare) and associated with ataxia, dysmetria (undershoot/overshoot), nystagmus, and other cerebellar signs.* Physiologic tremors are low amplitude postural and intention tremors often involving the hands that are caused by stress, fatigue, hypoglycemia, thyroid and adrenal disorders, alcohol withdrawal, and medications and are associated with no other neurologic signs. Essential tremor is a disease process characterized by action tremors that are not part of a broader disease. Action tremors often involve the voice and head movement/posture. Tremors in Wilson disease are postural or intentional wing-beating tremors associated with ascites, jaundice, signs of hepatic disease, Kaiser-Fletcher rings, rigidity, muscle spasm, and mental symptoms. Essential tremors are the most common movement disorder and is familial in 50% (autosomal dominant with variable penetrance). ET causes action tremors worsened with stress and relieved with alcohol consumption. It also differs from PD in that tremors have symmetric rather than unilateral onset, tremor has higher frequency and low amplitude, tremor commonly involves head and voice (rare in PD), and there are no other symptoms besides tremor. *Beta-blockers (propranolol) and mysoline/primidone (anticonvulsant) are used to treat ET.*

Chorea

Hypertonic movement disorders that cause chorea - irregular semi-directed movements when trying to make intentional movement. Examples include Huntington's chorea, anti-parkinson's meds (L-dopa induced dyskinesia), antipsychotics/neuroleptics (tardive dyskinesia), post-strep infection (Syndenham's chorea), lupus associated chorea, and chorea gravidarum (chorea associated with pregnancy) Huntington's disease is a fatal autosomal dominant CAG trinucleotide expansion condition beginning in the 4th-5th decade of life characterized by behavioral changes, chorea, and dementia. Grossly, there is atrophy of the caudate nucleus and dilation of anterior horns of lateral ventricle (ghost eye ventricles), as well as cortex and cerebellar atrophy. Histologically there are neuronal intranuclear inclusions with huntingtin protein from the HTT gene. The CAG repeat is unstable and increases with each generation *via males*, causing earlier presentation and increased severity with earlier onset (anticipation). Those with >36 repeats will develop HD because long stretches of glutamine mis-fold and destroy the function of the protein, which accumulates as a toxic product that causes neuronal degeneration. It has almost complete penetrance.

Parkinson's disease

Hypokinetic movement disorder with 4 cardinal features: tremor at rest (improves with purposeful function), rigidity, bradykinesia, and postural instability Bradykinesia is slowness of movement. Rigidity is stiffness and resistance to movement of a body part (cogwheel rigidity with passive range of motion testing). Associated symptoms include decreased arm swing with walking, decreased facial expression, weak voice. Orthostatic hypotension, constipation, depression, dementia, a speech/swallowing/breathing problems. Affects 1% of those over 55yrs, and 5% are inherited. Dopamine-producing neurons of the substantia nigra lose their pigmentation, which can be seen grossly and histologically. PD is a synucleinopathy - fibrils of insoluble alpha synuclein deposit in neuronal bodies and processes, astrocytes, and oligodendroglial cells, forming Lewy bodies (round lamellated eosinophilic cytoplasmic inclusions) that cause neuronal degeneration and death. Lack of dopamine production by the substantia nigra disinhibits the indirect (inhibitory) pathway of the striatum (D2) and fails to excite the direct (excitatory) pathway (D1). The indirect pathway predominates, with the striatum inhibiting the external globus pallidus that ordinarily inhibits the subthalamic nucleus. This allows the sub thalamic nucleus to excite the internal globus pallidus, which then inhibits the thalamus so that it is unable to excite the cortex. At the same time, the direct pathway is not stimulated so that the striatum does not inhibit the internal globus pallidus, allowing it to inhibit the thalamus.

Aphasia

Inability to produce motor communication, caused by lesions of Brocca's area - motor production of communication, frontal lobe just above sylvan fissure Wernicke's area - language comprehension, dorsal temporal lobe Arcuate fasciculus - white matter connecting Brocca's and Wernicke's that allows for repetition Global aphasia - not fluent or able to comprehend or repeat. Mixed transcortical aphasia - not fluent or able to comprehend, but able to repeat (Arcuate fasciculus spared) Brocca's aphasia - not fluent or able to repeat, but can comprehend. Transcortical motor aphasia - not fluent but able to comprehend and repeat. Wernicke's aphasia - fluent, but not able to comprehend or repeat. Transcortical sensory aphasia - fluent and able to repeat, but not able to comprehend. Conduction aphasia - fluent and able to comprehend but not repeat. Anomic aphasia - fluent, and able to comprehend and repeat but has trouble finding the proper words for things (accessing association cortex).

Ear anatomy

Innervation CNV3 - the trigeminal nerve innervates the part of the ear/face anterior to the canal we well as the front half of the upper ear. CNX - the vagus innervates the central portion of the auricle and the external acoustic meatus (auditory canal). CNVII - the facial nerve has points of innervation at various points on the external ear. Cervical plexus nerves - innervate the posterior portion of the ear and head/neck. Middle ear/tympanic cavity Lateral wall is the tympanic membrane. The medial wall separating the middle ear from the inner ear has a promontory covered by the tympanic nerve plexis (from glossopharyngeal CNIX - sensory to tympanic cavity) as well as the oval window (covered by stapes) and the round window. The thin, bony Tegmen tympani forms the roof of the middle ear and separates it from the cranial fossa. The posterior wall has a small opening called the auditus (inlet) that leads into the mastoid cavity/process. The facial nerve passes through the bony facial canal along the posterior wall. The handle of the malleus is imbedded in the tympanic membrane, the incus connects the malleus and stapes, and the footplate of the stapes fits into the oval window. The chorda tympani nerve (branch of CNVII) passes between the malleus and incus on its way to the oral cavity (taste). Tympanic membrane Normally translucent and pearly gray with a concave outer surface and central depression called the Umbo. the handle of the malleus can usually be seen near the center and the cone of light from the otoscope reflects anteroinferiorly in the healthy ear. The membrane has a thin slack portion superiorly called the pars flaccida and the remainder is thick and taut and called the pars tensa. Inner ear The bony labyrinth is filled with perilymph (similar to extracellular fluid) and made up of the cochlea, vestibule, and semicircular canals encased within temporal bone. The membranous labyrinth is a series of ducts and sacs suspended within the bony labyrinth that are filled with endolymph (similar to intracellular fluid). The membranous labyrinth consists of the cochlear duct within the cochlea, the utricle and saccule within the vestibule, and the semicircular ducts in the semicircular canals. *The utricle and saccule contain specialized sensory epithelium called maculae that are sensitive to horizontal/vertical movements.* At the base of each semicircular duct is a swelling called the ampulla that contains crust that respond to movements of surrounding endolymph during rotational movement.

Parkinson's drugs

Levodopa L-dopa in a dopamine precursor that is able to cross the BBB and is given with carbidopa, which inhibits the enzyme that converts L-dopa to dopamine, minimizing systemic side effects (can't cross BBB) like nausea, vomiting, and orthostatic hypotension. L-dopa is given for parkinson's disease, parkinsonian symptoms (louis body dementia), and restless leg syndrome to improve bradykinesia, tremor, and rigidity (but does not improve postural instability - refractive to treatment). L-dopa acute side effects include nausea, vomiting, orthostatic hypotension, and psychosis. Long term effects (after 3-5 years of use) include dyskinesia - involuntary writhing of face, arms, legs, or trunk. Toxicity when mixed with non-specific MAOIs Dopamine agonists: bromocriptine, pramipexole, ropinirole Bromocriptine is used to treat prolactinoma and some endocrine disorders by suppressing secretion of prolactin from the anterior pituitary (not used for PD because increases risk for cardiac valve fibrosis). Pramipexole and ropinirole are used for restless leg syndrome and PD before L-dopa is necessary and as adjunctive therapy with L-dopa, reducing L-dopa-induced dyskinesias and motor fluctuations. Dopamine agonists cause nausea, vomiting, orthostatic hypotension, and visual hallucinations. Pramipexole and ropinirole can cause sleep attacks as well as compulsive behaviors. Drugs that inhibit CYP1A2 can cause ropinirole toxicity from increased breakdown (Ciprofloxacin for UTIs). MAOb inhibitors: Selegiline and Rasagiline Inhibition of monoamine oxidase prevents breakdown of dopamine, NE, Epi, and serotonin; non-selective MAOIs cause hypertensive crisis when taken with tyramine-containing foods and serotonin syndrome when taken with SSRIs or tricyclic antidepressants. MAOb inhibitors only prevent dopamine breakdown, so they can be taken with tyramine-containing foods and have lower risk of serotonin syndrome with SSRIs and tricyclics (but still don't mix). They are used to treat early Parkinson's and may have a neuroprotective effect. Selegiline and Rasagiline cause nausea and headache, and selegiline can cause confusion and insomnia from its amphetamine metabolites. Amantadine NMDA glutamate antagonist that increases dopamine release and blocks reuptake, used for early tremor-predominant Parkinson's and as adjunctive therapy for late Parkinson's disease to treat dyskinesias or motor fluctuations. Amantadine can cause ankle edema, insomnia, and confusion. COMT inhibitors: Tolcapone and entacapone Used *in combination with L-dopa/carbidopa* to treat L-dopa-associated motor fluctuations and end-of-dose wearing off effects. Carbidopa blocks the primary metabolic pathway for L-dopa outside of the CNS so that a secondary pathway with catecholomethyltransferase becomes more prominent. COMT inhibitors increase the half-life of L-dopa, which can potentiate it's side effects (nausea, orthostatic hypotension, psychosis). They can also cause diarrhea (tolcapone and entacapone) and hepatotoxicity (tolcapone - very limited use). Anticholinergics: Trihexyphenidyl and benztropine Reduced dopamine with PD increases the cholinergic sensitivity in the striatum so that ACh has a greater effect. Anticholinergics improve symptoms (and cholinergic worsen them). Used to treat early tremor-predominant PD in young patients and as adjunctive therapy for those with parkinsonian symptoms secondary to antipsychotics. Not used in the elderly and cognitively impaired because they are at greater risk for memory impairment, confusion, and hallucinations. Other antimuscarinic symptoms include orthostatic hypotension, constipation, nausea, dry mouth, blurred vision, urinary retention, impaired sweating, and tachycardia. Use caution in those with prostatic hypertrophy or closed angle glaucoma. Treatment approach: Start with MAOb inhibitor or amantadine/anticholinergics (young patients with tremor). If ineffective, add L-dopa/carbidopa or a dopamine agonist (not for elderly). If ineffective alone, add the other. For L-dopa peak dose dyskinesia - reduce L-dopa and increase dopamine agonist or add amantadine. To reduce off time - add COMT inhibitor if on L-dopa, add MAOb inhibitor to L-dopa, or decrease L-dopa dosing interval

Other hypokinetic movement disorders

Lewy body dementia - dementia/cognitive decline develop around that same time as parkinsonian features Normal pressure hydrocephalus - presents with triad of ataxia, urinary incontinence, and dementia Medication-induced parkindonism Pugilistic (in boxers, from repeated head trauma) vascular - history of vascular disease and many lacunar infarcts on MRI viral encephalitis multisystem atrophy - autonomic failure progressive supranuclear palsy - vertical gaze palsy (can't look up or down) MPTP toxicity

Cortical components of limbic system

Limbic cortex = parahippocampal gyrus + cingulate gyrus + orbitofrontal cortex/gyrus. The parahippocampal gyrus is lateral to the uncus on the underside of the temporal lobe and encircles the brain stem. Cingulate gyrus runs on the outside of the corpus callosum. Orbitofrontal cortex/gyrus runs on the basal, medial frontal lobes surrounding the olfactory bulbs and tracts. Hippocampal formation On the inner fold of the temporal lobes, deep to the parahippocampal gyrus. It is responsible for forming memories through Long-term potentiation, in which accumulation of Ca++ in postsynaptic neurons after high frequency-activity strengthens synapses to form long term memories (lasting longer than 1 hour). (immediate recall lasts up to 10 minutes, short-term memory lasts up to 1 hour) Primary olfactory cortex Cortex of the uncus (medial aspect of temporal lobe) responsible for interpretation of smell.

Medication induced movement disorders hemiballismus tic disorders

Medication induced movement disorders Antipsychotics, compazine, and metoclopramide can cause acute dystonic reaction, parkinsonism, or tardive dyskinesia. hemiballismus movement disorder affecting one side of the body involving large involuntary jerking and flailing caused by a contralateral lesion involving the subthalamic nucleus - usually a vascular lesion (lacunar infarct/stroke). Tic disorders Tics are rapid, involuntary movements patients can temporarily suppress, but experience anxiety or tension when they do. Tics can be motor or vocal, simple or complex (semi-purposeful). Tics are often seen in a triad of ADHD, OCD, and tics (so be cautious when treating). Families can have a variable penetrance dominant gene related to all three. Tourette's syndrome is a tic syndrome defined by multiple motor tics and at least one vocal tic that occur many times per day almost every day for more than 1 year with onset before age 18 not due to another cause. Most cases are sporadic. Tics are treated only when they are bothersome and cognitive behavioral therapy and medications are used (decrease anxiety that increases tics).

Fragile X syndrome

Most common form of intellectual disability, with boys (homozygous) more severely affected than girls (heterozygous). Causes prominent forehead, narrow face, protruding ears, high-arched palate, strabismus, macro-orchidism, and joint laxity. Caused by expansion of CGG repeat in exon 1 of the FMR1 gene that leads to DNA methylation that transcriptionally silences and decreases protein expression. FMRP is normally responsible for repressing translation of certain mRNAs and localizing them to dendritic spines. Full mutation of over 200 repeats decreases expression of FMRP protein in dendritic spines, allowing for increased levels of protein expression that causes abnormal neurotransmission. Repeat length determines the phenotypic expression: 55-200 causes adult onset Fragile X Tremor Ataxia Syndrome and Premature Ovarian Insufficiency while 200+ causes behavioral and cognitive defects.

Movement disorders

Movement disorders pyramidal syndromes cause spasticity (which can present as incoordination because spasticity makes it hard to move). Cerebellar disorders cause ataxia. Basal Ganglia Disorders cause Hypokinesias (akinesia/bradykinesia, rigidity), hyperkinesias (tremor, dystonia, chorea/athetosis, tics, hemibalismus), or other disorders (obsession/compulsion, mannerisms, akesthisia, restless legs).

NMJ diseases

Myasthenia Gravis Postsynaptic NMJ autoimmune disease Antibodies attack ACh receptors, causing fatiguable weakness, diplopia, ptosis, bulbar and proximal limb weakness. Trouble keeping eyes open and double vision are often the first symptoms. Amplitude of action potentials decreases with repetitive stimulation. Often associated with thymoma. Treat with pyridostigmine (an cholinesterase inhibitor), steroids, and IVIG or plasmapherisis in crisis. Side effects include: Muscarinic - diarrhea, mausea, vomiting, cramps, bronchial and oral secretions, miosis, diaphoresis. Nicotinic - muscle cramps, fasciculations, muscle weakness. Lambert-Eaton syndrome (LES) Presynaptic NMJ autoimmune disease caused by antibodies against V-gated Ca++ channels, causing symmetric proximal muscle weakness affecting mainly the lower limbs, with areflexia or hyporeflexia. Autonomic symptoms include dry eyes, mouth, and sexual dysfunction. LES is associated with small cell lung cancer in 50%. Repetitive nerve stimulation increases strength (amplitude facilitation). Botulism Presynaptic NMJ disorder caused by clostridium bacteria toxin that prevents the release of ACh from their vesicles. This causes descending paralysis and miosis (autonomic effect). Amplitude increases with rapid, repetitive nerve stimulation. Babies that ingest botulism toxin (honey) do not have the gut flora to prevent overgrowth and so can become floppy babies from Clostridium growth and bacteria production. Adults develop acute nausea and vomiting from eating canned food with botulism toxin and some develop neurological symptoms. Clostridium can also live in puncture wounds or abscesses (IV drug users), causing insidious onset of symptoms.

Inhalation general anesthesia

Nitrous oxide, halothane, desflurane, isoflurane, sevoflurane Inhalation agents are used for induction and maintenance of general anesthesia and may act by inhibiting glutamate receptors and enhancing GABA transmission. The effect of inhalation anesthetics depends on the delivery of a therapeutic partial pressure of an agent to the CNS, which is affected by properties of the agents as well as regional blood flow, cardiac output, and ventilation. Drugs undergo uptake (rather than absorption) from alveoli into systemic circulation and are distributed through the body. Minimum Alveolar Concentration (MAC) the concentration of vapor in the lungs needed to prevent movement in 50% of subjects in response to surgical stimulus. (measure of potency) Blood-Gas partition coefficient (BGPC) the solubility of inhaled anesthetics in the blood. The higher the solubility/BGPC, the longer it takes to move into the brain and the longer its duration to onset of action Side effects of inhaled anesthetics include myocardial depression, decreased systemic vascular resistance, decreased systolic blood pressure, increased respiratory rate, decreased tidal volume, hypercarbia, decreased renal blood flow and glomerular filtration rate. They can cause malignant hyperthermia in those with an inherited autosomal dominant hypermetabolic disease caused by mutations in the RYR1 gene. When the mutation is triggered by volatile anesthetics (or succinylcholine - depolarizing paralytic that's fast acting and used during induction for intubation), mutated Ca++ channels in muscles open and allow Ca++ to flood the cells, causing sustained contraction (rigidity) and stimulating glycogen breakdown, glycolysis, and aerobic metabolism, generating excessive heat. The only treatment is dantrolene. Inhaled anesthetics undergo limited biotransformation/ metabolism so recovery/emergence is achieved by lower the concentration in the brain through elimination at the alveolus (rather than excretion), which is affected by ventilation, regional blood flow, and cardiac output. Nitrous Oxide High MAC, low potency - can't achieve surgical anesthesia Halothane Used in developing world (low cost) but not in US because of risk for arrhythmias and immune mediated hepatitis. Desflurane, isoflurane, sevoflurane All have risk for malignant hyperthermia

Sleep disorders

Normal sleep involves the reticular activating system, which includes nuclei that make neurotransmitters that are sent everywhere in the brain to regulate arousal. Hypothalamus - sleep/wake switch Supracyiasmatic nucleus - circadian clock Thalamus - cortical activation, sleep spindle EEG synchronization Pineal gland - secretes melatonin Brainstem - ascending cortical activation, REM/SWS switch Polysomnogram test of sleep cycles and stages though continuous recordings of brain waves (EEGs), electrical muscle activity, eye movements (electrooculogram), breathing rate, BP, blood O2 sat, and heart rhythm. Insomnia difficulty falling or staying asleep, or having non-refreshing sleep for at least 1 month. Can be caused by pain, stress, mood disorders, anxiety, caffeine, poor sleep hygiene, medications, and shift work. Treat with hypnotic drugs, sleep hygiene, stimulus control, and management of contributors (pain, anxiety, etc.). Obstructive sleep apnea obstruction of upper airway during sleep with preservation of respiratory effort, caused by age, obesity, and ethanol use. Symptoms include excessive daytime sleepiness, snoring, cessation of breathing while sleeping, and morning headaches and nonspecific cognitive complaints. Overtime, hypertension and increased cortisol levels (encourages overeating) can develop. Treat with CPAP and weight loss. Narcolepsy sleep regulation disorder in which symptoms of REM sleep occur during wakefulness. Four cardinal features include excessive daytime sleepiness with sleep attacks, cataplexy (sudden loss of tone), sleep paralysis, and hypnagogic hallucinations (dreams when awake). Polysomnogram demonstrates short sleep latency with rem at onset. Treat with stimulants during the day. Restless leg syndrome characterized by an urge to move the legs, usually during periods of rest, typically in the evening. It is associated with iron deficiency anemia and treated with dopamine agonists. REM sleep behavior disorder characterized by loss of normal skeletal muscle atonia during REM sleep, leading people to act out their dreams. It can be associated with Lewy Body Dementia. Night terror sudden unexplained bouts of fear for 10 minutes occurring in stage 3-4 sleep in children, who can't be awakened or consoled. Sleepwalking non-REM parasomnia that is common and more frequent in children, who have no memory and are difficult to arouse. Bruxism non-REM parasomnia characterized by teeth grinding that can lead to dental erosion

Nystagmus

Nystagmus occurs when frontal eye fields send signals in opposition to the part of the brain responsible for pursuing/tracking objects as well as when the vestibular complex (vestibulo-ocular reflex) and the cortical areas send opposing signals. In rotational nystagmus, sustained eye movements causes the VOR compensation to be interrupted by quick eye movements in the opposite direction (in the direction of rotation) to allow the retina to acquire a new image. This allows images to stabilize on the retina for most of the rotation. Direction of nystagmus is named for the fast, cortical eye field mediated phase. Caloric nystagmus occurs when the ear is irrigated with warm or cool water, creating convection currents in the endolymph that cause the vestibular system to perceive the head is rotating in the direction of warm water (excitatory) or away from the cool water (inhibitory). This causes the VOR to move the eyes away from warm water and toward cold water, and the frontal eye fields of the cortex jerk the eyes quickly in the opposite direction. So cold water causes nystagmus in the opposite direction and warm water causes nystagmus in the same direction (COWS). Caloric testing is performed when you cannot move someone's head to check VORs that way or when head turning shows absent VORs but the person is not in a coma (requires vestibular and cortical input). If someone is in a coma, nystagmus does not occur (no cortical input) but deviation from the VOR does. Spontaneous nystagmus is caused by peripheral lesions (labyrinth (Meniere's) or vestibular component of CNVIII) and usually decrease activity on the affected side (cold lesion), causing nystagmus with the fast phase beating away from the affected ear. Benign paroxysmal positional vertigo is an exception (warm lesion) that causes nystagmus beating towards the affected ear because signals from affected labyrinth are too strong rather than diminished. BPPV causes vertigo when the head moves but not when it is still. *Alexander's law states that the amplitude of nystagmus increases when the eye moves in the direction of the fast phase (i.e. away from the affected ear).*

Hemi-neglect

On the cortex, there is a large attention area in the right hemisphere devoted to the left world and somewhat to the right world. The left cortex is consumed by speech areas, so the attention areas only cover the right cortex and not the left. This provides double coverage for attention to the right world but not to the left world. Large lesions in the right parietal or frontal lobes causes patients to neglect the left external world and their left body. Patients often are unaware of profound left-sided deficits (agnosia - inability to recognize things you should).

*Glaucoma*

Optic nerve disease that is one of the leading causes of preventable blindness in the US. Open angle glaucoma Clogging of the trabecular network though which aqueous humor passes to reach the canal of Schlemm elevates eye pressures, causing optic nerve atrophy and decreasing vision. Open angle glaucoma is often not detected until advanced because it is not painful. Treat with systemic beta blockers, topical carbonic anhydrase inhibitors, alpha agonists, and prostaglandin analogs, or with trabeculectomy. Closed angle glaucoma A medical emergency in which the iris gets stuck on the lens, which pushes it anteriorly, closing the angle between the iris and cornea so that the trabecular meshwork is blocked. Aqueous humor builds up in the posterior and anterior chambers, creating a pressure gradient that rapidly damages the optic nerve, causing complete vision loss within hours. Any medication that increases pupil size (sympathetic activation for hypotension) can cause acute angle glaucoma in genetically predisposed people. Symptoms include acute vision loss, acute eye pain, red eye, poorly reactive pupil, seeing halos, increased intraocular pressure, frontal headache, and nausea and vomiting. Signs include cloudy cornea, mid-dilated irregular pupil, and conjunctival hyperemia (excess blood vessels). Treat by reducing pressure with peripheral iridotomy - slit in iris to allow aqueous humor to get to the anterior chamber. Medical treatment includes beta blockers, carbonic anhydrase inhibitors, and pilocarpine (causes pupil constriction to open the angle).

Executive functions Lesions

Orbitofrontal cortex allows us to defer immediate gratification and suppress emotions to obtain long-term benefits - inhibition, perseverance, delayed gratification. Lesion to the orbitofrontal cortex (closed head injury contusions) cause disinhibition, hyper sexuality, compulsion, poor judgement, failure in work/school from lack of perseverance. Lateral prefrontal cortex allows us to assess various alternatives and choose a course of behavior - judgement, planning, rational decision making. Lesions in the lateral prefrontal cortex (not very common, but can deteriorate with old age) cause decreased attention, disorganization, disorientation, and poor decision making. Ventromedial cortex experience emotional wellbeing and motivation to initiate action based on relative importance. Lesions to the ventromedial cortex (bilateral ACA infarcts) cause apathy, decreased spontaneous movement (sometimes akinetic mutism), associated gait disturbance, and associated urinary incontinence.

Vision

Our photoreceptors can detect single photons of light from 400/violet-700/red nm (visible light spectrum) in 10 log units of brightness. Light first passes through the cornea (primary refractive media), the aqueous humor (watery solution of the anterior and posterior chambers), the lens, and the vitreous body. Rods Photoreceptors in the peripheral retina that mediate low acuity vision in darkness. They have an outer segment containing rhodopsin that captures a photon of light and is excited, causing a cascade of reactions that ultimately gate hundreds of ion channels (amplification), leading to release of NT from the pre-synaptic membrane. Cones Photoreceptors located in the central retina that function best in daylight and are responsible for color and high acuity vision. There are three types of cones that are excited by different overlapping ranges of wavelengths: blue cones detect 400-550nm, green detect 500-650nm, red detect 550-700nm. Activation of green and red cones codes for yellows and oranges. The optic disk is where blood vessels and the optic nerve fibers enter, and lies medial to the fovea, the area of highest visual acuity. There are no photoreceptors at the optic disk, creating a blind spot that the brain compensates for using completion. Accommodation To focus on nearby objects, the circular ciliary muscle contracts, decreasing the tension on the elastic fibers and lens and allowing the lens to round. With age, the lens hardens, with loss of accommodation by age 50 called presbyopia. Visual pathway Visual fields map to the opposite hemisphere, with optic nerves from the nasal retina crossing in the optic chiasm. There is retinotopic organization, such that neurons retain their anatomic relationship to one another from the retina to the cortex. After the optic chiasm, optic tracts synapse onto the lateral geniculate nucleus in the thalamus, and second order neurons form optic radiations/Meyer's loop before synapsing on the primary visual cortex at the calcarine sulcus. The most forward bending neurons in Meyer's loop carry information from the upper visual field and synapse in the lingula (more deep/anterior and ventral) and the less bent neurons carrying info from the lower visual field synapse at the cuneus (more external/posterior and dorsal). A large amount of cortex is devoted to the fovea compare to more peripheral fields.

Malignant pain

Pain associated with a disease that will likely kill you. Pain medication should be given on a fixed schedule to manage pain and prevent it from worsening. Patients should also have additional doses of opioids available to take as needed in addition to the schedule doses for break through pain WHO Pain Ladder Step 1(0-3 pain) - non-opioid +/- adjuvant (medication not traditionally considered analgesics like steroids, antidepressants, and anti-emetics). Step 2 (3-6 pain) - opioid for mild to moderate pain (APAP/codeine, APAP/hydrocodone, APAP/oxycodone) +/- non-opioid +/- adjuvant. Step 3 (6-10 pain) - opioid for moderate to severe pain (morphine, hydromorphone, fentanyl, oxycodone) +/- non-opioid +/- adjuvant (benzodiazepine - makes you less bothered by the pain). If opioid tolerance develops, increase the dose or switch to another opioid - this is not the same as addiction, which evokes the reward system and causes cravings. Manage opioid side effects Nausea and vomiting can be addressed by giving a mixed agonist/antagonist or with antiemetics (Zoran/ondansetron). All on chronic opioids should take a stool softener and use laxatives to ensure BM every 48 hours. Antihistamines can be used to manage pruritus.

Other eye pathology

Papilledema sign of increased pressure from hydrocephalus, tumor, or intracranial HTN. Cherry red spot When cell layers over the choroid are infarcted or have accumulation of abnormal metabolic products. The macula is spared because it does not have cellular layers over it and has a different blood supply than the rest of the retina. Causes include central retinal artery occlusion (CRAO), Tay-sachs, and Neiman-Pick (lysosomal storage diseases that cause developmental regression. Neiman-Pick also has hepatosplenomegally). CRAO presents with acute onset painless monocular vision loss and retinal edema with a cherry red spot (endocarditis is a predisposing factor). Causes include cardioembolism, atheroembolism, hypercoagulable state, and *temporal arteritis* (inflammation of extra cranial arteries). Treatment of CRAO involves lower intraocular pressure, and most don't regain useful vision. Optic nerve pallor A sign of chronic optic nerve disease and some retinal pathologies, associated with irreversible vision loss. Relative afferent pupillary defect Asymmetric lesion of CNII so that the light response if more brisk on one side than the other and can be detected using the swinging flashlight test. Benign essential anisocoria The same relative difference in pupil size is present in all lighting, and nothing is pathological - just asymmetric. Light-near dissociation lack of light response but good accommodation. Argyll Robertson Pupil (ARP) is a hallmark of neurosyphilis, and pupils can be small and irregularly shaped. Adie's Tonic Pupil is caused by a lesion in the ciliary ganglion that affects pupillary light response more than accommodation and is usually unilateral (anisocoria) and 3x more common in women. In Adie's tonic pupil, a lesion in the ciliary ganglion causes denervation of the postganglionic nerve supply to the sphincter and ciliary muscle, preventing constriction in response to light. Perinaud's syndrome (dorsal midbrain syndrome) - bilateral light-near dissociation with paralysis of up gaze caused by compression from a pineal tumor pushing on the back of the midbrain. Retinoblastoma The most common primary intraocular malignancy in childhood, it causes leukocoria, strabismus (abnormal alignment), and painful red eye. 70% bilateral, fatal without treatment, and often cause metastases later in life.

Patterns of Weakness

Paresis - weakness -plegia - no movement paralysis - no movement palsy - weakness or no movement Bulbar weakness - weakness from the brain stem - dysarthria, dysphagia, dysphonia, respiratory weakness (sometimes facial weakness is included) Weakness in one semi-bidy > lesion in contralateral cerebrum Weakness on opposite sides of head and body > lesion is in the brain stem on the side of the facial weakness Weakness bilateral below a horizontal line > lesion is in the spinal cord (myelopathy) Weakness in unilateral stripe/myotome > lesion is in a nerve root (radiculopathy) Weakness is unilateral on the face only > lesion is in a cranial nerve (neuropathy) Weakness is an isolated blob > lesion is on a peripheral nerve (neuropathy) Weakness occurs with no apparent pattern in location or timing > diffuse disease of anterior horn cells (specific neuron population degenerates in a disorganized way) Weakness symmetrically affects distally and progresses proximally > diffuse disease of numerous peripheral nerves (neuropathy). Polyneuropathies are usually accompanied by loss of tendon reflexes (not initially with diabetic) and deficits are usually (not always) motor and sensory. Weakness symmetrically affects proximal and bulbar more than distal > diffuse disease of NMJ or muscle (Myopathy)

Neuropathic pain

Presumed to result from disordered function of the peripheral or CNS, with causes including post stroke pain syndrome, spinal cord injury, plexopathy, phantom pain, radiculopathy, mono-neuropathy, and polyneuropathy. Pain is burning, tingling, numbness, shooting, stabbing, or electric-like. Intensity may exceed observable injury. neuropathic pain may respond to opioids, but adjuvant analgesics (tricyclic antidepressants, anticonvulsants, and topical local anesthetics) are the mainstay of treatment.

6 greatest causes of vision loss

Refractive errors Visual acuity improves with the pinhole test. These are corrective errors that cause hyperopia (farsightedness - may notice presbyopia sooner), myopia (nearsightedness), or presbyopia (loss of near vision with age). Refractive errors are reversible with optical correction. With normal vision, the cornea refracts the image directly onto the retina so that the focal point is at infinity and achieves emmetropia. *With myopia, the image falls in front of the retina because the eye is too long or the cornea and lens focus too strongly. Correct with a concave/diverging/minus lens. Hyperopia occurs when the image falls behind the retina because the eye is too short or the cornea and lens refract too weakly. Correct with a convex/converging/plus lens*. Astigmatism is caused by different curvatures on the cornea or lens. Can correct with Photorefractive keratectomy (PRK) where a laser sculpts the cornea with no incisions (flattens for myopia, steepens for hyperopia). Lasik is Laser Assisted In-Situ Keratomileusis in which a microkeratome cuts a thin flap of corneal tissue, an excimer laser reshapes the cornea, and the flap is laid back down. Intralase can be used instead of a microkeratome to create the flap. Glaucoma Leading cause of irreversible vision loss in black americans (old age and family history are also risk factors). Pressure in the eye (sustained >21 or fluctuating IOP) damages the optic nerve and causes visual field loss (first in the periphery). Cupping occurs when increased pressure in the eye pushes into the optic nerve opening and creates a sinkhole (irreversible vision loss). Treat with medications or surgery to lower and stabilize IOP. *Macular degeneration* Age related macular degeneration (ARMD) is the most common cause of irreversible vision loss over age 65. It causes mild to severe loss of central vision, not total blindness. The Amsler grid tests for macular degeneration, which causes metamorphopsia - lines on the grid are wavy or missing. Dry/atrophic macular degeneration is the most common form and may be slowed by vitamins C and E, zinc and copper oxide, and beta-carotene (Age Related Eye Disease Study vitamins). On the fundoycopic exam, you will see drusen - yellow lipid deposits under the retina around the macula. Wet/exudative macular degeneration makes up 10% of ARMD and occurs when abnormal blood vessels under the retina leak fluid, cause scarring, and blur central vision. Treat with injectable anti-VEGF medications. Amblyopia Vision loss that is not correctable by glasses in an otherwise healthy eye that is reversible if detected and treated early (before age 5). More than 1/2 are caused by strabismus (misalignment), and other causes include asymmetric refractive error and deprivation (ptosis). Treat by covering up the good eye so that the other eye gets stronger. Cataract Clouding of the lens that is the leading cause of vision loss worldwide. Causes include aging, diabetes, family history, previous surgery or injury, smoking, and prolonged steroid use. Surgery is used to treat when vision is not clear enough with correction lenses. The cloudy lens is removed and a clear intraocular lens is inserted. Phacoemulsification/ultrasonics involves a phase needle moving back and forth at the same frequency as sound in order to break up the old sense so that it can be sucked out. diabetic retinopathy The leading cause of irreversible vision loss in the US in those under age 65, occurring in 25% of those with diabetes and 90% who are insulin dependent will develop it within 25 yrs after diagnosis. Usually precedes the development of diabetic neuropathy and proteinuria, and 90% of diabetic changes are treatable if detected early. Leaky blood vessels cause hard, yellow exudates to form around the macula, and chronic ischemia leads to neovascularization of the optic disk, eventually leading to diffuse scarring of the retina (proliferative diabetic retinopathy). Diagnose in those <30yrs with an eye exam 5 years after diagnosis followed by yearly eye exams. For those >30yrs when diagnosed, have eye exam yearly. Treatment involves lasering hundreds of light burns in the periphery of the retina to stimulate new vessels to shrink (some peripheral vision loss; PRP - Panretinal photocoagulation), as well as anti-VEGF therapies and vitrectomy (removing bloody vitreous humor). Complications include vitreous hemorrhage, causing sudden vision loss as blood fills the vitreous cavity, as well as macular edema, fibrovascular membrane formation, and traction retinal detachment.

Secondary headaches

Secondary headaches are caused by other illnesses, traumas, or brain disorders - the symptom of another problem. Causes include bleeds, masses/tumors, infection, ocular and sinus disease, carotid/vertebral dissection, intracranial hypertension, intracranial hypotension, temporal arteritis, and analgesic rebound. Red flags that headaches may be secondary to a serious underlying problem include sudden onset (hemorrhage), worsening pattern, systemic illness, focal signs, papilledema, triggered by cough/exertion/valsalva, or if worse in the morning (both suggest increased intracranial pressure). Carotid or vertebral dissection is usually perceived as unilateral neck pain on the side of the dissection (back if a vertebral artery and front if a carotid) after chiropractic manipulation, sports injury, car accidents, etc. Intracranial HTN Occurs with overproduction of CSF, most often in young, obese (pregnant) females because it is associated with higher estrogen states. Rarely it can be caused by toxicity from tetracycline or vitamin A, or Sinus Venous Thrombosis. Papilledema is often the only sign (rarely 6th nerve palsies), but it can cause enlargement of blind spot leading to blindness if left untreated. There will be increased opening pressure on lumbar puncture and normal imaging. Treat with acetazolamide (carbonic anhydrase inhibitor diuretic) or a shunt. Weight loss can also help. Intracranial hypotension Spinal headaches result when CSF is removed during a lumbar puncture or spinal anesthesia or leaks out of a cyst or tear, allowing the brain to press against the bottom of your skull and cause pain. Low pressure/spinal headaches are positional - worse when upright and relieved when lying flat. Treat by laying down, analgesics, caffeine, IV hydration, and if pain persists for 4-5 days, a blood patch (inject patient's blood into CSF where they had the procedure to make a scab over the hole). Temporal arteriris (AKA Giant Cell Arteritis) An inflammatory disease affecting medium to large arteries that causes granulomatous infiltrates to narrow the vessel lumen. It usually occurs in elderly people and causes headache and jaw claudication (cramping). Diagnose with elevated sedimentation rate and temporal artery biopsy. Treat with prednisone. Untreated temporal arteritis can cause blindness. Analgesic rebound headaches are caused by the use of analgesics more than 2-3 times per week on a regular basis. This is the most common cause of chronic daily headache. The most common characteristics of analgesic rebound headaches are daily or near daily headache, tolerance to pain relievers and preventative medications, and nausea, restlessness, anxiety, irritability, insomnia, depression, and difficulty concentrating. The treatment is stopping all analgesics for two weeks, with antiemetics, sedatives, and hydration to tolerate the period.

Epilepsy

Seizure - paroxysmal pathological discharge of neurons resulting in stereotypical behavior or sensation Epilepsy - chronic condition of recurrent unprovoked epileptic seizures Staticus epilepticus - rare emergency of continuous seizures for >30 minutes Focal onset seizures can be simple partial, involving only motor or sensory (or emotional) symptoms, or complex partial, in which memory, cognition, or speech are involved. Generalized onset seizures involve the entire cortex, are usually mediated by the thalamus, and can be caused by high fever, Na+ imbalance, or other systemic problems, and there are often no warning signs leading up to unconsciousness. Examples include absence seizures, tonic-clonic (faint, stiffen, then jerk), infantile spasms (put arms overhead; associated with developmental problems unless managed early), and atonic (rare; lose tone in entire body). Any focal/partial onset seizures can spread and become a secondary generalized tonic clonic seizure. Febrile seizures (not epilepsy) The most common type of seizures, they are provoked by fever in 4% of small children Absence epilepsy Very common, looking like staring spells after which the child returns to normal Lennox-Gasteaus syndrome Primary generalized epilepsy syndrome that includes absence, generalized tonic-clonic, and atonic seizures that present in childhood and is associated with developmental regression *Juvenile Myoclonic epilepsy* Primary generalized epilepsy syndrome that includes generalized seizures as well as small jerky movements representing tiny generalized seizures. Symptoms present in adolescents and they have normal development. Temporal lobe epilepsy Very common form of epilepsy that can include simple partial or complex partial seizures arising in the hippocampus or amygdala (medial temporal lobe). Simple partial seizures consists of de ja vu, transient fear, or unpleasant smell. Complex partial seizures include the above followed by confusion and speech problems for seconds-minutes followed by *amnesia of the event* and mild cognitive changes. Diagnose with an EEG to identify the type (primary partial or generalized). If an EEG doesn't suggest a primary generalized epilepsy syndrome, perform an MRI to look for an underlying cause like a tumor. Treat with anticonvulsants or anti epileptic drugs (or surgery).

*hearing loss*

Sensorineural hearing loss Problems with the inner ear - cochlea, cochlear nerve of CNVIII, and central auditory pathways. In the Weber test, sound will be louder in the good ear. In the Rinne test, the tuning forks sounds louder infront of the ear than when placed against the mastoid, appearing normal. Causes of sensorineural hearing loss include noise exposure (kills hair cells), presbycusis (age related), inner ear infection (rare), and acoustic neuroma. Sudden sensorineural hearing loss is hearing loss of >30dB in 3 contiguous frequencies over less than 3 days, thought to be caused by a virus. Treat urgently with oral or intratympanic steroids to prevent further decline and perform an MRI (5% will have acoustic neuroma). Overall recovery is 50-60%, with vertigo and total hearing loss suggesting worse prognosis. Conductive hearing loss problems with the conduction pathway - outer ear (external auditory canal) and middle ear (tympanic membrane and ossicles - malleus, incus, stapes). In the Weber test, sound will be louder in the bad ear. In the Rinne test, sound will be louder in the bad ear when the tuning fork is on the mastoid than when it is by the ear. Causes of conductive hearing loss include cerumen impaction, swelling of external auditory canal (otitis externa/swimmers ear), tympanic membrane perforation (from infection, trauma, or barotrauma), otitis media, cholesteatoma, or otosclerosis. *Otitis media is an infection, usually from strep. pneumonia, H. influenza, or Moraxella catarrhalis* that is treatable with amoxicillin or tympanoplasty (if >6x/yr). Otitis media with effusion is caused by eustachian tube dysfunction and is not treated unless it persists for month and causes hearing loss leading to problems with speech development - then treat with tympanostomy tubes. Cholesteatoma is a growing blob "pearly tumor" of keratin debris that can be congenital or acquired following repeated infections or trauma. Eustachian tube dysfunction causes negative pressure in the middle ear that retracts the eardrum inward. Keratin debris from retraction pockets of the tympanic membrane builds up in the middle ear and mastoid and destroys surrounding structures, and requires surgical removal (tympano-mastoidectomy). Key symptom is a draining ear that only transiently improves with antibiotic treatment. Otosclerosis is an idiopathic metabolic bone disorder of the temporal bone in which abnormal bone remodeling of the ossicles disrupts their ability to transmit sound from the middle to inner ear because the stapes becomes fixed. This causes conductive hearing loss with a characteristic *Carhartt notch* on the audiogram (air and bone lines come closer together). White, middle aged women are at highest risk. Treat with hearing aid or stapedectomy.

Antiepileptic drugs

Side effects of all AEDs include neurotoxicity (sedation, dizziness, nausea/vomiting, double vision, and ataxia) and systemic toxicity (fetal malformations (all women on AEDs should take folate), bone demineralization, and Stevens-Johnson syndrome). Many AEDs cause bone marrow suppression and hepatotoxicity. neural voltage gated Na+ channel binders: Carbamazepine, Phenytoin, Lamotrigine, valproate, topiramate Bind to inactivated Na+ channels to extend inactivated phase. Carbamazepine - used to treat partial or secondary generalized epilepsy, bipolar disorder, and trigeminal neuralgia. Unique side effects include leukopenia > pancytopenia and hyponatremia. Carbamazepine is a p450 inducer metabolized in the liver. Phenytoin - extends inactivated phase as well as affects resting membrane potential, synaptic transmission, and second messenger systems. Used for partial or secondary generalized epilepsy and staticus epilepticus. Phenytoin is infamous for long term bone demineralization, and unique side effects include hypotension, arrhythmias, and tissue necrosis by IV and gingival hyperplasia with long term phenytoin. p450 inducer metabolized in the liver. Lamotrigine - inactivates Na+ channels and may selectively influence neurons that synthesize excitatory NTs like glutamate. Used for all types of epilepsy and bipolar disorder and has a unique antidepressant effect. Lamotrigine can cause life threatening rashes with very low risk of marrow suppression or hepatotoxicity. It is affected by p450 inducers/inhibitors but does not affect others and is metabolized in the liver. OCPs decrease the efficacy of lamotrigine, causing risk of toxicity when taking placebo pills and lamotrigine levels increase dramatically. Neuronal voltage-gated Ca++ channel binders - ethosuximide, valproate Bind to alpha subunit of T-type Ca+ channels that are heavily expressed in the thalamus, slowing release of NTs. Ethosuximide is used to treat absence epilepsy. GABA agonists Benzodiazepines, barbiturates, valproate, tompiramate Phenobarbital binds to GABA receptors and extends the duration of GABA mediated Cl- channel openings, causing neuronal hyperpolarization. Phenobarbital is used for partial or secondary generalized epilepsy (and staticus epilepticus) and primidone is used for essential tremor. Dose related sedation is very severe and limits use to staticus epileptics, neonatal seizures, and refractory epilepsies. Unique side effects include hyperactivity and addiction. It is a p450 inducer and undergoes hepatic metabolism. Multiple mechanism Valproate - stabilizes inactivated Na+ channels, increases GABA concentrations, and closes T-type Ca++ channels in the thalamus. Used for all types of epilepsy (including staticus epilepticus), bipolar disorder, and migraine prophylaxis. Valproate is a strong teratogen, causing neural tube defects (do not use in women wanting to get pregnant). Thrombocytopenia is common and it is rarely used in children <10yrs because of risk for fulminant hepatic failure. Unique side effects include low amplitude, high frequency tremor, weight gain, and hair loss. Valproate is a p450 inhibitor and undergoes hepatic metabolism. Topiramate - prolongs inactivation of Na+ channels, enhances GABA activity, and antagonizes NMDA glutamate receptors. It is used for all types of epilepsy and migraine prophylaxis. It does not cause marrow suppression or hepatotoxicity but does cause kidney stones, decreased cognition, and weight loss. Topiramate decreases efficacy of OCPs and 30% is metabolized by the liver (70% excreted by kidney). Unknown mechanisms Gabapentin, pregabalin, levetiracetam Gabapentin - may bind to alpha-2 subunit of neuronal V-gated Ca++ channels, inhibiting opening and attenuating release of NTs. Used for partial and secondary generalized epilepsy, chronic pain, and neuropathic pain. Gabapentin does not cause marrow suppression or hepatotoxicity, but does cause peripheral edema and weight gain. it must be taken 2+ hours after antacids and 100% is excreted in the urine (adjust dose for kidney disease). Pregabalin - proposed mechanism is the same as gabapentin. It is used for partial and secondary generalized epilepsy, neuropathic pain, and fibromyalgia. It has the same side effects, metabolism, and drug interactions (antacids) as gabapentin. Levetiracetam - may bind to SV2A protein in presynaptic NT vesicles and also moderate neuronal Ca++ channels. It is used for all types of epilepsy, does not cause marrow suppression or hepatotoxicity, and does cause irritability, depression, and/or behavioral problems. Levetiracetam has no drug interactions and is 100% excreted in the urine (adjust dose for kidney disease). It is very popular because it doesn't require titration and has fast onset, has no significant life-threatening side effects, can be used for generalized and partial onset seizures, and has many forms (IV for emergencies or unable to take pills, liquid for those who can't swallow pills, extended release for once daily dosing). p450 inducers: carbamazepine, phenytoin, phenobarbitol p450 inhibitor: valproate Affect the metabolism of chemotherapies, antivirals, benzodiazepines, corticosteroids, cyclosporine, haloperidol, theophylline, TCAs, OCPs, warfarin, and other AEDs. Valproate increases the toxicity of carbamazepine, phenytoin, phenobarbital, topiramate, and lamotrigine. p450 inducers decrease efficacy of other p450 inducers, topiramate, lamotrigine, and valproate. Don't cause marrow suppression or hepatotoxicity: lamotrigine, topiramate, gabapentin, pregabalin, levetiracetam AED treatment starts after 2 unprovoked seizures. First classify the seizure type(s) and then consider other medications (interactions), hepatic/renal disease, comorbid conditions that could benefit (chronic pain - gabapentin, neuropathic pain - gabapentin, pregabalin, migraine - valproate/topiramate, depression - lamotrigine, bipolar - carbamazepine, valproate, lamotrigine), age, available preparations, and speed of titration. 50% are successful treated with the first AED tried, 25% discontinue because of side effects ad 25% continue to have seizures. If a drug fails, try a second one, which will be effective in 50% of those whose previous failure was from side effects and in 15% of patients whose previous failure was from inefficacy. If the second fails, try another. If the third fails, try combination therapy (another 15% become successful). Overall, 80% of patients are seizure-free. Broad spectrum AEDs for all seizure types include lamotrigine, levetiracetam, topiramate, and valproate. Narrow spectrum AEDs for simple partial, complex partial, and secondary generalized include carbamazepine, gabapentin, pregabalin, phenobarbital, and phenytoin. Ethosuximide for absence seizures. Treat staticus epilepticus within the first 30 minutes (stage 1) with benzodiazepines - IV lorazepam, buccal midazolam, IV or rectal diazepam. Treat stage 2 (30-120 minutes) with IV AEDs - phenytoin, phenobarbital, or valproate. Treat stage 3 (>120minutes) with general anesthetics - propofol, midazolam, or thiopental/phenobarbitol After 24 hours = super-refractory staticus epilepticus

Physiology of pain modulation

Substance P central and peripheral neuropeptide pain mediator that stimulates pain fibers (nociceptors). The signal travels up afferent nerve fibers to synapse in the dorsal horn gray matter and immediately decussate (spinothalamic tract) Substantia gelatenosa One of the lamellae in the dorsal horn in which nociceptive neurons (first order) synapse with second order neurons to make up the spinothalamic tract. (Blocking neurons here with endogenous or exogenous opioids blocks pain signals from reaching the brain). Second order neurons travel to the thalamus to synapse with 3rd order neurons that go to the primary sensory cortex and limbic system (emotional and instinctual centers become upregulated with chronic pain). *Endogenous opiate release is stimulated by the periaqueductal gray matter and occurs from neurons from the reticular formation - gray matter nuclei that project from the brainstem down the spinal cord to synapse in the substantia gelatinosa to block nociceptive input. Opiates bind to receptors at the terminal boutons of afferent pain fibers to keep pain signals from being passed to second order neurons in the spinothalamic tract.*

Syncope

Syncope - transient loss of consciousness and postural tone resulting from brain hypoperfusion lasting only a few seconds. Hypoperfusion can be cardiogenic (MI, arrhythmias, valvular outflow obstruction), orthostatic (autonomic failure from spinal cord injury/diabetic neuropathy/parkinson's plus syndromes, volume depletion, or medications), or vasovagal (most common; a normal variant). Treat orthostatic hypotension by discontinuing HTN medication, eating more salt, hydration Vasovagal/ neurocardiogenic/ neurogenic syncope can be caused by micturition, defecation, cough, carotid sinus hypersensitivity, or noxious stimuli. Pre-syncope - light headedness, visual changes, headache, neck pain, nausea, cognitive slowing, buckling of knees.

Primary headaches

Tension headache Diffuse, mild to moderate pain (rubber band around your head), caused by the trigemini-vascular system (on a continuum with migraine). Muscle straining around the neck and scalp may also play a role. Almost everyone, including children experience them, and they are more common in women. Treatment includes analgesics (NSAIDs), stress reduction, and sleep hygiene. Migraine headache Symptoms include severe, pulsating or throbbing pain that is often unilateral and can last hours to days, causing nausea and vomiting, photophobia and phonophobia, and sometimes auras, light flashes, scooters, or abnormal sensations in the body. Occur in 8% of children, 9% of men, and 17% of women. Genetic abnormalities make the neuromuscular system hyperexcitable, causing antidromic flow of action potentials through sensory trigeminal neurons that trigger nerve terminals to release substance P, neurokinin A (NKA), and calcitonin gene-related peptide (CGRP) onto intracranial blood vessels. This causes vessel dilation and inflammation, which is then perceived by the same trigeminal neurons as pain. Normally innocuous stimuli like pulsations become painful (peripheral sensitization), and this sensitization can spread centrally so that peripherally-acting medications are no longer effective. Prevent pain from escalating by taking 4 ibuprofen and caffeine at the beginning of a migraine. Prophylactic migraine treatment includes beta-blockers, Ca++ channel blockers, tricyclic antidepressants, and anticonvulsants. Acute nonspecific treatments include NSAIDs and Antiemetics. Specific treatments include triptans and dihydroergotamine. They improve with sleep. Migraines can be aggravated by hormones, sleep disturbance, depression, anxiety, medication, caffeine (withdrawal), stress, and certain foods (nitrates, tyramines, chocolate, MSG). Cluster headaches Severe unilateral headaches associated with unilateral ptosis, aniscoria (meiosis/constriction of affected pupil), eye watering, and nose watering. Attacks tend to occur every day at the same time, often waking the person from sleep and last 15 minutes to 3 hours, occurring in clusters everyday for weeks or months. Attacks are exacerbated by any amount of ethanol and improved by inhaling oxygen. They are NOT relieved by rest - patients usually pace around in pain. Treat with migraine medicines and prednisone. Ca++ channel blockers may be best for prophylaxis. Also avoid all alcohol.

Ophthalmology exam

The 8 part eye exam: visual acuity, visual fields, motility (includes alignment), pupils, external exam, ocular surface/slit lamp exam, intraocular pressure, ophthalmoscopy (fundus exam). Acuity Use Snellen Chart near card and have patients wear corrective lenses. If vision too poor, check for finger counting, hand motion, or light perception. Pinhole visual acuity test helps assess if poor visual acuity is from a refractive error. Confrontation visual fields Check visual fields by having the patient count your fingers in the periphery (normal = full to counting fingers FTCF). Use a small white object to look for blind spots by asking the patient to say when it enters their visual field from the periphery and then if it ever disappears. Test macula function using small red object, which will not appear bright red until closer to the center of vision. You can also use the red object to map out the blind spot created by the optic nerve, moving it around slightly to see how large it is. An Amsler grid asess the central 10 degrees of the visual field for early macular pathology (grid lines appear curved). Pupil exam normal = PERRLA (pupils equally round and reactive to light and accommodation) When there is asymmetric vision loss, check for relative afferent pupillary defect with the swinging flashlight test (Marcus Gunn Pupil) that localizes the pathology to the optic nerve or retina. RAPD can be caused by retinal detachment, central retinal arty or ischemic retinal vein occlusion, optic nerve ischemia, optic neuritis, compression, or asymmetric glaucoma. Motility exam Normal alignment = orthophoric test versions (extra ocular function) with the cardinal positions of gaze (H pattern). Medial/horizontal - medial rectus Medial/up - inferior oblique Medial/down - superior oblique Lateral/horizontal - lateral rectus Lateral/up - superior rectus Lateral/down - inferior rectus Hirschberg test - measure deviation using the location of the corneal light reflex. Eso-Deviation causes a more temporal light reflex. Exo-deviation causes a more nasal light reflex. Pseudo deviation is when a prominent nasal fold gives the illusion of an interned eye, but the light reflex (Hirschberg test) shows that it's normally aligned. Cover tests - covering one eye and then uncovering it can be used to detect heterotropia (constant deviation). When one eye is covered, if the exposed eye is deviated, it will move midline and then deviate again when the other eye is uncovered. The cross cover test involves moving the cover back and forth between the eyes and detects heterophoria (latent/some of the time deviation). Eyes will deviate when covered and move back to midline when uncovered, but you can see the drifting back occur when you quickly move the cover. A prism cover test measures total deviation. External exam Look for ptosis, proptosis (eye pushing out), entropion (eyelid and lashes turning in), ectropion (eyelid turning out), eyelid tumors, lid margin disease - blepharitis (inflammation of lid margin), meibomiantis (inflammation of meibomian glands), or styes (painful, acute staph abscess)/chalazia (painless, chronic staph abscess). *Anterior blepharitis is caused by bacterial at the base of lashes, causing inflammation and crusting. Posterior blepharitis is inflammation of the eyelid from clogged meibomian glands. Treat blepharitis with warm compresses, nonirritating shampoo, and antibiotic ointment*. Treat Meibomitis with hot compresses and eyelid massage, and sometimes doxycycline to prevent styes (acute staph abscess). Blepharoptosis - upper eyelid resting lower than normal due to stretching of the levator aponeurosis, CNIII palsy, or Horner's. Ocular surface/slit lamp exam Use a pinlight to assess the conjunctival appearance and possible damage, and to look at corneal clarity and reflex. In the slit lamp exam, a thin beam of light at an angle lets you view a cross section of the layers of the eye: Precorneal tear film, corneal epithelium, corneal stroma, endothelium, anterior chamber, iris, anterior lens capsule, anterior lamella, lens nucleus, posterior lamella, posterior capsule. Cataracts is opacification of the lens. Ocular surface exam involves eversion of the upper eyelids. Intraocular pressure (IOP) Is measured with a tonometer. A goniolens can be used to examine the angle of the cornea to assess for glaucoma. Funduscopic exam Look into the eye at a 15 degree angle temporal to the patient's line of sight. Examine optic disk, retinal blood vessels, retinal background, and macula (look at my light) in that order. The cup to disk ratio (C:D) should be less than .5. Neosynephrine 2.5% (short acting mydriatic) can be used to safely dilate the eye without causing cycloplegia (paralysis of ciliary eye muscles). Don't use in neurosurgical or neurologic patients, those with unstable coronary or cerebrovascular disease, or those with active conjunctivitis.

Cerebellar anatomy

The cerebellum coordinates voluntary movements to produce smooth and balanced muscular activity. Connections of the cerebellum are designed so that it is responsible for the *ipsilateral* body. It's in the posterior cranial fossa, behind the 4th ventricle and below the Tentori cerebelli. It has three lobes - anterior, posterior (includes tonsils), and flocculonodular (inferior surface, between anterior and posterior lobes). The gyri are called folia. Vestibulocerebellum flocculonodular lobe - Responsible for equilibrium/balance and connect with the vestibular system. Deficits there cause loss of balance and ataxic gait on physical exam. Spinocerebellum Anterior lobes and vermis - connect to the spinal cord and are responsible for stereotyped movements. Deficits cause ataxic gait on PE. Cerebrocerebellum Posterior lobes - responsible for coordination/modulation of fine limb movements and connects with motor cortex and red nucleus. Deficits here cause dysmetria, intention tremor, and dysdiadochokinesis (rapid alternating movements). Vermis and flocculonodular are responsible for proximal limb and trunk coordination, balance, and vestibulo-ocular reflexes. Deficits in these regions can be seen on the cerebellar coordination exam. Intermediate hemispheres coordinate distal limb movements. Deficits can be seen on the cerebellar coordination exam. Lateral hemispheres are responsible for motor planning for extremities. Lesions do not cause abnormalities on cerebellar exam but person will be unable to execute complicated, learned movements (dancing, surgery, etc.) Superior cerebellar peduncle - connects to midbrain and carries outputs from deep cerebellar nuclei (4 pairs) to the red nucleus, thalamus, and vestibular nuclei. Middle cerebellar peduncle - connects to pons and carries inputs from the cerebral cortex (corticopontine fibers > pontine fibers) Inferior cerebellar peduncle - connects to medulla and carries inputs from the brainstem and spinal cord (inferior olive vestibular nuclei, ascending tracts with proprioceptive info) Afferents/inputs through the inferior and middle peduncles include climbing fibers from the inferior olive that synapse with purkinje cell dendrites in the cerebellar cortex as well as mossy fibers that synapse with granule cells deeper in the cortex. Purkinje cells in the cortex inhibit the cerebellar nuclei in the cerebellar white matter. Lesion in the left intermediate zone (eg. stroke) will cause left arm and leg ataxia (abnormal nose-finger, heel-shin test), falling to the left, slurred speech, nausea and vomiting. Lesion in the left vermis will cause unsteady gait, falling to the left, trouble maintaining sitting posture, normal finger-nose test, and headache. Lesion affecting the vermis and left intermediate hemisphere will cause left arm and leg ataxia, unsteady gait, falling left, slurred speech, bilateral horizontal nystagmus on lateral gaze and vertical nystagmus on up gaze worse than downgaze, left occipital headache, nausea and vomiting, difficulty concentrating, bilateral papilledema. Lesion affecting the right middle cerebellar peduncle will cause nausea and vomiting, right arm and leg ataxia, mild unsteadiness, inability to perform tandem gait, falling right, nystagmus on horizontal and vertical end gaze, right face cool paresthesias and decreased temperature sensation. Peduncles cause cerebellar and brainstem problems.

Motor systems

The extra-pyramidal system includes the cerebellum and basal ganglia, which modify movement as it happens. Dysfunction in the extra-pyramidal motor systems causes movement disorders. The motor cortex sends info to them and they send info back via the thalamus. Cerebellar output is excitatory (glutaminergic) while basal ganglia output is inhibitory (GABAminergic) - the balance allows for smooth, coordinated movement from proper tone in opposing muscle groups. Brainstem nuclei and associated descending tracts (rubrospinal, vestibulospinal, tectospinal, reticulospinal) control the proximal axial and girdle muscles for posture, balance, head/neck orientation, and automatic gait-related movements. Red Nuclei - descending motor pathways from the red nuclei interact with the cerebellum and contain nerves that descend via alpha motor neurons and deal with posture. The tectum influences tone and posture The vestibular system descends to motor neurons and influences posture The reticular activating system is responsible for arousal, tone, and posture The pyramidal system contains upper motor neurons in the cortex and lower motor neurons in the brain stem (corticobulbar) or spinal cord (corticospinal). Dysfunction in the pyramidal system causes motor disorders. Most of the upper motor neurons decussate in the medulla to form the lateral corticospinal tract, but some remain on the same side in the anterior corticospinal tract. When they each the level of muscle innervation, some of the anterior corticospinal tract neurons decussate to synapse with the lower motor neuron and some do not. This provides bilateral coverage to the trunk area, but only contralateral coverage to the limbs. With the corticobulbar tracts, the forehead has bilateral coverage but below the eyes has contralateral only.

Vestibular system

The vestibular apparatus consists of the vestibule (fluid-filled utricle and saccule - linear head movements, static head position), and three semicircular canals (head rotation), all with hair cells. Within the vestibule (bony labyrinth), the utricle and saccule (membranous labyrinth) each have a swelling called a macula in which hair cells project into a gelatinous layer embedded with calcium carbonate crystals called otoconia/otoliths that given the gel extra mass. When the head moves, gravity pulls on the crystals and inertia of the crystals bends the stereocilia in the opposite direction, opening K+ channels to depolarize the cell, opening Ca++ channels that stimulate NT release onto vestibular nerves. Each semicircular canal is 90 degrees from the other and has an ampulla (swelling) at the end with a cupola inside containing crista attached to nerves making up the vestibulocochlear nerve (CNVIII). In the semicircular canals, the axes of hair cells in the ampulas on either side of the head are mirror images such that turning your head in one direction opens ion channels on that side and closes them on the other so that there is increased firing in CNVIII on the side the head is turning and decreased firing on the opposite side. To reach the CNS, graded potentials created in the hair cells from ion channels opening generate action potentials in afferent neurons of CNVIII (pseudounipolar). Vestibular nerves synapse on vestibular nuclei or enter cerebellum via the inferior cerebellar peduncle. Axons from the vestibular nuclei also enter the cerebellum via the ICP. In the vestibulocerebellum functional control loop, a correction signal is sent from the cerebellum to the lateral vestibular nuclei and reticular formations (bilateral innervation) and motor command output from the vestibular nuclei via the ventral and lateral vestibulospinal tracts is adjusted to axial muscles to maintain posture. The vestibular nuclei also project to the MLF to control eye movements and maintain steady gaze.

Migraine medications

Those with infrequent migraines (<1 per week) use only abortive therapy to treat an attack while those with frequent migraines use prophylaxis medications to prevent them and make them less severe. The most commonly used drugs for prophylaxis are beta blockers (propranolol), tricyclic antidepressants (amitriptyline), and anticonvulsants (valproate and topiramate) (tricyclic antidepressants and anticonvulsants are also used for neuropathic pain) Drugs used to acutely treat migraines are triptans (sumatriptan), dihydroergotamine, analgesics (aspirin, NSAIDs, opioids), and antiemetics (promethazine) Triptans Sumatriptan 5HT-1B and 5HT-1D agonists cause vasoconstriction of cranial arteries and reduced neurogenic inflammation. Self limited side effects include dizziness, tingling, chest discomfort, and non-specific unpleasant sensations. Serious side effects from vasoconstriction include significant temporary elevation of blood pressure, myocardial ischemia with angina or infarction, and stroke. Sumatriptan should not be given in those with history of stroke, transient ischemic attack, or coronary artery disease and should not be given with ergotamines or MAOIs (serotonin syndrome). Dihydroergotamine Serotonin receptor agonist and alpha adrenergic receptor blocker, it stimulates vascular smooth muscle to vasoconstrict. Used when triptans are ineffective. It is given via nasal spray as an outpatient (less effective) and IV or IM in hospital. Self limited side effects include rhinitis (nasal spray), nausea (give with promethazine), and taste disorder (nasal spray). Serious side effects secondary to vasoconstriction include significant temporary elevation in blood pressure, myocardial ischemia with angina or infarction, and stroke. Dihydroergotamine has many category X drug interactions and ergotamines in general are known to cause fibrosis throughout the body.

Trigeminal neuralgia

Trigeminal neuralgia/douloureux is chronic pain condition that affects the trigeminal cranial nerve, usually in the elderly. The pain is excruciating, stabbing, and shock-like and usually involves one side of the lower face and jaw in the V2/V3 distribution. Attacks are exacerbated by sensory stimulation and last seconds to minutes. Trigeminal neuralgia is caused by a blood vessel pressing on the trigeminal nerve as it exist the brainstem. TN symptoms can also occur in those with MS from demyelination of the trigeminothalamic tract. Rarely it can be caused by compression from a tumor. Treatment includes anti convulsive medications. Surgery can be effective if medication does not work.

Causes of hearing loss (genetic)

Up to 1/500 children are pre lingual deaf. Of these, the cause of 25% are idiopathic, 25% are environmental, and 50% are genetic. Of those that are genetic, 70% are non syndromic and 30% are syndromic. Of those that are non-syndromic, 80% are AR, 20% are AD, and 1-2% are X linked. Of those that are AR, 50% are caused by DFNB1 mutations and 50% are caused by other DFNB mutations. There is much locus heterogeneity - multiple genes causing the same phenotype. Loci causing non-syndromic hearing loss are named DFN plus A if AD, B if AR, or no letter if X-linked. A number follows indicating the order in which it was discovered. To assess for syndromic hearing loss, record family history and perform tests that may be indicative of specific syndromes that cause deafness: ECG for arrhythmias, temporal bone imaging for enlarged vestibular aqueducts, ophthalmology, and renal ultrasound. Specific genetic testing is performed when there is a known disorder in the family (targeted mutation analysis), syndromic features suggesting a known genetic disorder (single gene sequencing analysis of genes implicated), and for non-syndromic deafness (connexin 26 gone sequencing, connexin 30 deletion analysis, PCR for CMV on newborn blood spot, A1555G (if exposed to ahminoglycosides), and massively parallel sequencing panels for non-syndromic hearing loss if all testing is negative.

Lesions affecting limbic system

Wernicke-Korsakoff's Degradation of mammillary bodies caused by thiamine deficiency, causing *confusion, ophthalmoplegia (eye movement paralysis), and gait ataxia*. Alzheimer's degredation of basal forebrain cholinergic neurons in the nucleus basalis of Maynert. Bilateral resection of temporal lobe in patient HM (hippocampal formation and parahippocampal gyrus), causing period of retrograde amnesia of many years and anteriograde amnesia. Kluver-Bucy syndrome bilateral temporal lobe lesions affecting the amygdala, most often caused by herpetic encephalitis (which also causes severe anterograde amnesia from hippocampal damage). Kluver-Bucy causes hyperorality (explore objects with mouth), hypersexuality, and personality changes (usually abnormal passivity or docility from loss of fear, loss of ability to recognize emotions in others). Temporal lobe epilepsy The hippocampus and amygdala are the most common sources of seizures, which are usually psychomotor/complex partial seizures involving other parts of the limbic system - olfactory hallucinations, fear, transient memory loss, eating-related mouth movements. Complex partial seizures also involve confusion and speech problems lasting seconds to minutes followed by amnesia and mild cognitive changes.

Basal ganglia

coordinates opposing muscle groups The striatum is composed of the Caudate (medial, superior) and the Putamen (lateral, inferior), which are functionally the same structure. The striatum is excited by the cortex and inhibits the globus pallidus interna (direct pathway) and the globus pallidus externa (indirect pathway). DA stimulates the direct pathway but inhibits the indirect pathway. ACh inside the striatum excites both pathways. The Lenticular nucleus is made of the putamen (lateral) and globus pallidus (medial; interna inhibits the thalamus, externa inhibits the subthalamic nucleus) and is an anatomical structure (the nucleus accumbens is at the head of the caudate and the amygdala is at the tail) In a coronal cross section at the level of the optic chasm, you can see the caudate head on the lateral side of the lateral ventricle as well as the caudate nucleus and putamen inferiorly. A little more posteriorly, you can see the subthalamic nucleus and substantial nigra (also part of the basal ganglia). Direct (excitatory) pathway The cortex excites the striatum (caudate+putamen) with Glutamate, allowing the striatum to inhibit (GABA) the Globus pallidus interna, which ordinarily inhibits the thalamus. This un-inhibits the thalamus, allowing it to excite (glutamate) the cortical motor areas. The striatum direct pathway is excited by DA from the substantia nigra acting on D1 receptors. Indirect (inhibitory) pathway The cortex excites (glutamate) the striatum, which inhibits the globus pallidus externa that inhibits the subthalamic nucleus. This disinhibits the subthalamic nucleus, allowing it to excite the Globus pallidus interna, which inhibits the thalamus, preventing the thalamus from exciting the cortical motor areas. Dopamine from the substantia nigra inhibits the striatum via D2 receptors in the indirect pathway.

Audiometry and tympanometry

frequency = pitch = number of cycles per second (Hz) (low notes = longer wavelengths) Young people can hear from 20-20000 Hz amplitude = loudness = decibels Pure-tone audiometry pure-tone signals are delivered through air and bone conduction. Audiologists present sounds one frequency/pitch at a time (125-8000Hz) and the softest tone at which people can hear it is recorded as the hearing threshold. Audiograms map a series of points for air and bone conduction in each ear, with different symbols for air and bone conduction plotted on the same graph. In a normal audiogram, points for bone and air conduction are relatively the same and located at zero (+/- 10dB) across the measured frequencies because hearing level is a measurement relative to normal. Normal hearing is between 0 and 20dB, mild hearing loss 20-40dB, moderate hearing loss 40-70dB (conversation, phone ringing), severe hearing loss 70-90dB (dog barking), and profound hearing loss is 90-120dB (loud truck, plane taking off). Conductive hearing loss will produce an audiogram with a gap between bone and air conduction, with bone better than air. Sensorineural loss produces an audiogram with bone and air conduction points along the same line, but with the line dropping below normal. Tympanometry differentiates among causes of conductive hearing loss. A tympanometer probe is inserted into the ear canal, and it changes pressure in the ear while generating a pure tone to measure the eardrum's response to the sound at various pressures. The eardrum's response is acoustic energy that is reflected back and expressed as admittance (compliance, flexibility) of the tympanic membrane. Admittance is plotted on the Y axis and air pressure on the X axis, and the peak of the graph reflects resting middle ear pressure (0 daPa). Type A - A normal tympanogram has a steep, symmetrical peak centered at 0 with a peak admittance of 800 mmho. Type B - a flat line with no point of maximum compliance/admittance or change in tympanic membrane vibration based on pressure. This can be caused by a hole in the tympanic membrane or complete lack of mobility of the ossicles from increased pressure due to otitis media with effusion or other space-occupying lesions. Type C - has a peak shifted left toward negative middle-ear pressure values, suggesting the ear drum is retracted from eustachian tube dysfunction.

Reflexes

subconscious stimulus-response mechanisms that are increased in UMN lesions and decreased in LMN lesions. In the patellar reflex, striking the patellar stretches the attached quadriceps and the muscle spindles within it, which send afferent neurons through the dorsal root ganglion and then to the cerebellum/cortex and to other neurons in the anterior horn. Efferent motor neurons flex the quadriceps while interneurons inhibit efferent neurons going to the hamstrings to relax that opposing muscle group. Clonus - rapid succession of flexions and extensions of a group of muscles, usually elicited in the ankle and indicative of UMN lesions Visceral reflexes include the light reflex involving afferent CNII and efferent CNIII, with the midbrain as the center. Another example is the accommodation reflex (pupils constrict when object approaches), with afferent CNII, efferent CNIII, and the occipital cortex as the center. Vestibulo-ocular reflex (VOR) - the reflexive movement of your eyes in the opposite direction of your head turning so that you can maintain a fixed gaze. The vestibular apparatus (semicircular canals) on the side the head it turning towards is excited, sending signals to vestibular nuclei that communicate with the abducens nucleus/PPRF and then CNIII and CNVI to cause the eyes to move in the opposite direction. Activating signals are sent by the vestibular nerve on the side the head is turning toward and inhibitory signals are sent by the vestibular nerve on the opposite side, allowing the eye muscles to pull the eyes in the opposite direction of the head turn and relaxing the opposing muscles. Test for the VOR using oculocephalic testing - turning the person's head side to side and up and down to see if the eyes remain fixed. This works only if the patient is cooperating and fixing on a far point or the patient is in a coma (intact brainstem) with no cortical inputs to interfere with the VORs. Superficial reflexes include the corneal reflex (blinking when something touches eye), with afferent CNV, efferent CNVII, and the pons as the center. the pharyngeal and uvular reflex (gag) involves afferent CNIX, efferent CNX, and the medulla as the center. The plantar reflex involves the afferent and efferent tibial nerves and S1,2 as the center. Babinski/plantar reflex In adults, the toes should curl down (flexion) for a normal plantar response. An extensor plantar response (babinski's sign) is abnormal. Deep tendon reflexes The achilles reflex involves the afferent and efferent tibial nerves with S1,2 as the center. The patellar reflex involves the afferent and efferent femoral nerves with L3,4 as the center. The brachioradialis reflex involves afferent and efferent radial nerves and C5,6 as the center. The biceps reflex involves the afferent and efferent musculocutaneous nerves with C5,6 as the center. The triceps reflex also involves the afferent and efferent radial nerves and has C7,8 as the center. Primitive reflexes Rooting - brush to the cheek makes baby turn head toward it and open mouth. Birth - 4mo. Sucking - something in mouth causes baby to suck. Birth - 4mo. Palmer grasp reflex - birth - 5/6mo. Moro reflex/startle reaction - when babies are leaned backward they open up their arms and legs as if to grab onto something. Birth - 2mo. Tonic neck reflex/fencing posture - turn baby's head to one side and it will extend that arm and draw the other one up by its head. 1mo - 4mo Babinski - birth - 1yr