Block 8 Brain Science 2 - Marcus

Left MCA Stroke -Cortical

Clinical Findings: 1. *Aphasia* (Broca/Wernicke/Conduction) 2. Right hemiparesis (weakness); FA > L 3. Right hemianesthesia (sensory loss) 4. Right hemianopia (visual loss on the right out of each eye) 5. Deviation of eyes to the left (contralateral; look towards lesion) During a stroke, the FEF is inactive on the left side. The right FEF pushes eyes to the left.

Right MCA Stroke -Cortical

Clinical Findings: 1. *Neglect* (right parietal lobe) 2. Left hemiparesis (weakness); FA > L 3. Left hemianesthesia (sensory loss) 4. Left hemianopia (visual loss on the left out of each eye) 5. Deviation of eyes to the right (contralateral; look towards lesion) During a stroke, the FEF is inactive on the right side. The left FEF pushes eyes to the right.

Advanced Sleep Phase Syndrome

Common in elderly patients Tx: Evening light to phase *delay* (makes your sleep cycle *later*)

Delayed Sleep Phase Syndrome

Common in mid-20s and younger. -Freshman in college (stay up till 4am, sleep until 2pm) Tx: use morning light to phase *advance* (make your sleep cycle *earlier*).

Complete Spinal Cord Injury

Complete loss of movement and sensation below the level of injury. *Initial Symptoms:* opposite of expected UMN 1. Hypotension (spinal shock) 2. Areflexia (spinal shock) 3. Erect penis (spinal shock) 4. Incontinent forever Reminder: CNS lesion *Spinal shock = initial onset of LMN signs before UMN signs*

*Diffuse Axonal Injury (DAI)* -Associated with *motor vehicle accidents* (rotational acceleration/deceleration) -The "miracle" stories of people waking up from 10 year comas is resultant from slow axonal regeneration

DAI is usually the result of a *rotational mechanical force* from *off-center trauma* that causes *shearing force on white matter*. This causes *axonal degeneration with secondary demyelination*, resulting in slowed conduction of nerve impulses and a *comatose* or *persistent vegetative state*. *Imaging:* 1. CT may be normal 2. MRI may show small *petechial hemorrhages* due to the shearing of axons *Graded on 3 point scale (3 is bad):* *1.* gray-white junction (greatest density difference; greatest injury) *2.* 1 + corpus callosum *3.* 1 + 2 + brainstem

Meningeal Tumor at the Falx Cerebri causes...

Damage to the *leg areas* on the medial surface of the cerebral hemispheres (think of the homunculus). Both legs could be weak (paraparesis) or paralyzed (paraplegia). This can also result from midline lesions or lesions affecting both ACAs, but it's more commonly a thoracic or lumbar pathology.

Additional brain volume from a mass/edema/hydrocephalus leads to....

Decreased blood and CSF in the brain to accommodate *↑ICP*.

*Storage Diseases* (Autosomal Recessive)

Decreased function of a particular enzyme leads to *accumulation of the immediate precursor* in the reaction that the affected enzyme would ordinarily catalyze, which leads to swollen, puffy neurons. 1. *Tay-Sachs:* deficiency of hexosaminadase A (swelling of neuronal cytoplasm) -More common in Ashkenazi Jews heritage -Presents with zebra bodies on electron microscopy and a *cherry-red spot*. 2. *Niemann-Pick:* deficiency of sphingomyelinase 3. *Gaucher's disease:* deficiency of glucocerebrosidase

Hematoma Volume on CT =

(*A***B***C*)/2 *Measurements on CT:* A= Greatest hemorrhage diameter B= Greatest diameter 90 degrees to A C = # of 10mm transverse slices with hemorrhage present (along neuraxis)

*Direct Pathway* of Basal Ganglia -Facilitates movement -*Excites thalamus* and cortex -*Inhibition of GPi*, which disinhibits thalamus

*"Go" Pathway:* 1. Input from cortex to Striatum (activated) 2. *Striatum inhibits GPi* (which normally inhibits Thalamus) (inhibition of inhibition = disinhibition) 3. Thalamus is activated and sends output to cortex (excitatory loop) Two negatives (inhibitory interneurons) in pathway = Excitatory

*Indirect Pathway* of Basal Ganglia -Inhibits movement -*Inhibits thalamus* and cortex -*Activation of GPi*, which inhibits thalamus

*"No Go" Pathway:* 1. Input from cortex to Striatum 2. Striatum inhibits GPe, which reduces inhibition on the STN (sub-thalamic nucleus) 3. *STN activates GPi* which inhibits Thalamus 4. Thalamus output to cortex (less excitation due to inhibition) Three negatives (inhibitory interneurons) in pathway = inhibitory

*Hyper-Direct Pathway* (slows down impulses) -Skips striatum and GPe (directly to STN) -*Activation of GPi*, which *inhibits thalamus* (and cortex)

*"No Go"* Pathway (skips striatum and GPe) 1. Cortex excites STN (directly) 2. *STN excites GPi* 3. GPi inhibits Thalamus 4. Reduced thalamus output to cortex One negative = inhibitory *Thought to slow down otherwise impulsive actions when there are conflicting choices.* Remember that the basal ganglia is involved in reinforcement learning (via dopamine).

Sympathetic Pathway (Pupil Dilation)

*1st order:* Hypothalamus (diencephalon) → upper thoracic spinal cord *2nd order:* Upper thoracic spinal cord (T1) → sympathetic trunk → superior cervical ganglion *3rd order:* Superior cervical ganglion → carotid artery → CN V1 → long ciliary nerve → pupillodilator muscles of the iris

Parasympathetic Pathway (Pupil Constriction)

*1st order:* Retina → optic nerve → optic tract → pretectal nucleus (midbrain) *2nd order:* Pretectal nucleus → posterior commissure → bilateral EW of CN III *3rd order:* EW → CN III → ciliary ganglion *4th order:* Ciliary ganglion → short ciliary nerves → pupillocontrictor muscles of the iris

Loss of cerebral blood flow below ________ leads to loss of function and cell death/injury *Reference:* Normal = 54cc/100g/min.

*20cc blood/100g brain tissue/min.* *Between 20cc/100g/min and 54cc/100g/min (normal), the brain is able to compensate by extracting cerebral O2 more efficiently to compensate for decreased flow.* *Below 20cc/100g/min:* 1. Function fails 2. Cell function and structure (membranes) fail 3. Cell necrosis 4. Irreversible infarction (secondary injury)

*Cluster Headache* -Primary Headache (neuropathic) -*Treatment:* triptans and high flow O2

*30-60 min of sharp, stabbing periorbital pain.* Often "seasonal" or occur in predictable patterns (clusters). *Disease Characteristics:* 1. Tears 2. Nasal congestion 3. Rhinorrhea 4. Injected sclera 5. Ptosis (dropping eyelid) *Treatment:* 1. Prophylactic therapy (see migraine list below) 2. *Triptans* (e.g., sumatriptan; serotonin receptor agonist) 3. *High flow inhaled O2*

Hematoma Growth is Bad

*5% higher risk of death with each 10% expansion of the hematoma* (Monroe-Kelli Doctrine: ↑V ,↑↑ICP, ↓outcome).

Pediatric Brain Tumors

*70% occur in the posterior fossa* (so hydrocephalus is common). -Cerebellar (pilocytic astrocytoma: posterior fossa, Rosenthal fibers) -Brain stem astrocytoma (pontine glioma) -Medulloblastoma (Homer-Wright Rosettes) -Ependymoma (perivascular pseudorosettes) 30% occur supratentorial

Trigeminal Hypothesis (not on exam)

*A theory for primary headaches/migraine:* 1. Trigeminal fibers innervate blood vessels in meninges, extracranial arteries, and the circle of Willis 2. Nerve endings contain peptide neurotransmitters → triggers release of neuropeptides → produce an *inflammatory response around the innervated blood vessels*. a. *Neurokinin A or substance P*: promote release of plasma proteins and fluid from meningeal blood vessels b. *CGRP:* potent vasodilator 3. The trigeminal nerve becomes secondarily activated by these events, transmitting pain impulses to the trigeminal nucleus caudalis which relays pain impulses to higher centers in the brain.

Neuropathological Grading of Astrocytoma (WHO)

*AMEN:* *A*typia (nucleus hyperchromatic, pleiomorphic) *M*itoses (active cell divisions) *E*ndothelial proliferation (neovascularization) *N*ecrosis (tumors outgrow blood supply) *Grade 1:* no AMEN (pilocytic astrocytoma: posterior fossa, Rosenthal fibers) *Grade 2:* A (diffuse infiltrating glioma, *low grade*) -Treatment: surgery or observation ± radiation -Survival: 5-10+ year -Gd MRI enhancement: *never* *Grade 3:* AM (anaplastic astrocytoma) -Treatment: surgery (as much as possible), radiation, chemo -Survival: 3-4 years -Gd MRI enhancement: often *Grade 4:* AMEN (glioblastoma multiforme, GBM) -Treatment: surgery (as much as possible), radiation, chemo -Survival: 1-2 years -Gd MRI enhancement: *always*

*Bacterial* Meningitis (Summary)

*Abbreviated Pathophysiology:* 1. Subarachnoid space inflammation (MØ: IL-1b, TNF-a, IL-6 loosens tight junctions) 2. Increased BBB permeability 3. Cerebral Edema (↑ICP) 4. Altered cerebral blood flow (↓O2) → secondary injury (Ca2+) 5. Neuronal injury due to ROS generated *Clinical Findings:* 1. *Fever* (inflammation) 2. *Headache* (↑ ICP) 3. *Meningismus* (inflammation → *neck stiffness*) 4. *Altered sensorium* (due to brain swelling) 5. Brudzinski's and Kernig's Signs 6. Lumbar puncture (↑neutrophils, ↑protein, ↓glucose)

Duchenne Muscular Dystrophy (exam)

*Absence of dystrophin* results in pathology -Dystrophin glycoprotein anchors the muscle fiber to the ECM via merosin (which *stabilizes the muscle membrane during contraction*) -X-Linked inheritance (mainly affects men) -Unfavorable X-skewing allows for female carriers to have mild symptoms -*Becker Muscular Dystrophy:* reduced dystrophin, but not gone (milder phenotype) *Clinical Findings:* 1. Progressive *proximal muscle weakness* 2. *Gower's Sign:* difficulty standing up; need arm support 3. *Calf pseudo-hypertrophy:* fat / fibrous tissue displace dead muscle tissue 4. Cardiac, GI, and cognitive abnormalities are also possible *Treatment:* mainly supportive -Corticosteroids can prolong walking and slow the rate of muscle strength decline if given appropriately

Acute vs Chronic Meningitis Etiology

*Acute* - Viruses/Bacteria (onset: hours to days) *Chronic* - Spirochetes, *Mycobacteria*, Fungi (onset: weeks to months)

Guillain-Barré Syndrome (GBS) (exam) -aka *Acute* Inflammatory Demyelinating Polyradiculoneuropathy (AIDP)

*Acute* ascending weakness often preceded by a gastrointestinal infection (e.g., *Campylobacter jejuni*). -Symptoms reach peak within 4 weeks (and then usually get better). Cause: *Auto-immune attack of PNS myelin* (due to molecular mimicry) Clinical Findings: 1. *Ascending weakness* (starts in distal legs and feet) 2. Acute flaccid paralysis: weakness or paralysis and reduced muscle tone without other obvious cause 3. Loss of reflexes 4. *Autonomic symptoms* (bloating, urinary dysfunction, lightheadedness, abnormal sweating) 5. *Respiratory involvement* (diaphragm) *Diagnosis:* 1. History/Physical Exam: acute, ascending weakness 2. CSF: *↑protein; normal cell count* (*albuminocytological dissociation*) 3. MRI: nerve root enhancement (poly*radiculo*neuropathy) *Treatment:* IV immunoglobulin (IVIg) or plasma exchange (plasmapheresis)

Damage to Brodmann 6 (PMA and SMA) or the posterior parietal cortex results in...

*Apraxia:* impairment in the ability to perform learned motor actions without the loss of basic motor or sensory function *Motor:* inability to comb one's hair or brush one's teeth, even though each tools purpose was understood. *Sensory:* cannot draw a picture of a clock (lack the sensory or perceptual ability)

Damage to Broadmann 6 (premotor/supplementary motor) results in...

*Apraxia:* impairments in the ability to perform learned motor actions without the loss of basic motor or sensory function. CST intact (motor function), but can't process and plan the tasks to act.

Forebrain Abnormalities

*Arrhinencephaly:* ("no nose brain") failure of *olfactory* development (CN I) often associated with Kallman's syndrome. Mildest form of *holoprosencephaly*, where the cerebral hemispheres fail to separate. As a consequence, a giant midline cystic space is left in the brain (so-called "alobar" holoprosencephaly). Failure of brain diverticulation correlates well abnormalities in facial features, such as a single nostril or cyclopia.

Ataxia Components

*Ataxia:* disordered, clumsy movement caused by impaired coordination, without weakness (cardinal sign of cerebellar dysfunction) 1. Dysmetria: overshooting, past-pointing in reaching tasks (finger-nose-finger) 2. Dysdiadokokinesia: inability to perform rapid alternating movements 3. Drunken gait (truncal ataxia) 4. Explosive, stoccato, "scanning" speech (non-rhythmic) 5. Megalographia: writing is large to compensate for loss of coordination 6. Decomposition of movement (jerky, broken movement) A patient with dorsal column disease may also show an ataxic gait, but dorsal column ataxia is made worse by closing the eyes, whereas cerebellar ataxia is not (tested by Romberg's sign). Cerebellar lesions cause *no deficit in conscious sensation* and patients can report proprioceptive information with their eyes closed.

Myasthenia Gravis (exam)

*Autoantibodies attack ACh receptors on post-synaptic membrane* → reduced ACh molecules binding receptors -*Decreases likelihood of muscle fiber reaching threshold* (for depolarization and contraction). Clinical Findings: *fatiguable eye/pharyngeal muscles* -Dysphagia (difficulty swallowing) -Dysarthria (difficulty speaking) -Opthalmoparesis (trouble moving eyes) -Diplopia -Nasal speech -Ptosis -Respiratory Weakness *Diagnosis Confirmation:* 1. Antibody testing (blood test) 2. *Edrophonium test (short acting ACh-ase inhibitor)* or ice pack test. -Allow for ACh to bind receptors on the post-synaptic membrane. *Treatment:* 1. Pyridostigmine (mestinon) 2. Corticosteroids 3. IVIg 4. Steroid-sparing immunosuppressant agents (if steroids are not an option)

Lambert-Eaton Myasthenic Syndrome (NMJ Disease) (exam)

*Autoimmune* attack on *pre-synaptic* voltage-gated *Ca2+ channels*, impairing release of ACh. Most cases are associated with an underlying malignancy, like *lung cancer*. *Clinical Findings:* 1. Limb-weakness and difficulty walking 2. *Symptoms improve with continued exercise (build-up of Ca2+ in nerve)*; unlike fatiguable muscles in Myasthenia Gravis 3. *Sparing of ocular and bulbar (neck) muscles* unlike in Myasthenia Gravis 4. Reduced reflexes *Treatment:* 1. Screen for malignancy and treat underlying cancer

*Clinical Features of Huntington's Disease* -Median survival is 15 years after onset

*Autosomal dominant* trinucleotide (CAG)n repeat expansion in the *hunt*ingtin (HTT) gene on *chromosome 4* (4 letters). *Symptoms manifest between ages 20 and 50:* CAADD 1. Chorea (hyperkinesia initially) → hypokinesia (Parkinsonism later) 2. Athetosis (slow, writhing/serpentine movements) 3. Aggression 4. Depression 5. Dementia (sometimes initially mistaken for substance abuse) *Paternal anticipation* results from expansion of CAG (polyglutamine) repeats (age of onset inversely related to number of repeats), which *destroys the caudate* and putamen (striatum). *Neurotransmitter Changes:* *C*audate loses *A*Ch *G*ABA (*CAG*) 1. *↑dopamine* (SNc) (chorea) 2. *↓ACh* (basal nucleus of Meynert) (↓memory) 3. *↓GABA* (nucleus accumbens) (less inhibition = aggression) *Treatment:* No cure -Treat symptoms using *dopamine receptor antagonists* or *decrease dopamine production*

Stages of Sleep

*Awake:* 1. Eyes open → beta waves (12.5-30 Hz). 2. Eyes closed → alpha waves (8-13 Hz). *Sleep:* As one goes into deeper stages of sleep, these waves slow down. 1. *Stage 1* → theta waves (3-7 Hz) (presleep, or nodding off). 2. *Stage 2* → sleep spindles (most prominent form; accounts for ≈ 50% of sleep during the night); K-complexes (slow, triphasic waves) evoked upon sound. 3. *Stage 3-4* → delta waves (this is the stage where sleep walking and night terrors occur; deepest sleep). This is also where we don't remember if we woke up or not. 4. *Rapid eye movement (REM)* → beta (sawtooth) waves (EEG looks as if the patient were awake, but *muscles are paralyzed* (activated brain, paralyzed body)). REM sleep is when *dreams* occur. Disrupted REM sleep is thought to be the cause of sleep paralysis).

Acute Pyogenic *Bacterial* Meningitis

*Bacterial* meningitis confined to the subarachnoid space, grossly seen as *pus on the surface of the brain*. *Common Causes:* 1. S. pneumonia (adults) 2. N. meningitidis (young adults) 3. H. influenza (infants) 4. E. coli (neonates) *CSF profile:* 1. ↑ protein 2. *↓ glucose* 3. *Neutrophil* predominance 4. ↑ pressure

*Tension Type Headaches* -Primary Headache

*Band-like* squeezing pain at temples, forehead, base of skull. Think *"muscle tension".* Treatment: *NSAIDS (for neck muscles)*

Prediction Errors and Subsequent Dopamine Effects

*Baseline:* There is slight bias towards "Go" (direct pathway) because *D2 receptors are selectively occupied*, resulting in less activity of D2-carrying indirect-pathway striatal neurons, resulting in less activity of this net-inhibitory pathway (= slight disinhibition). *Positive Prediction Error:* High dopamine *activates the direct pathway* via D1 receptors and *inhibits the inhibitory indirect pathway* via D2 receptors, resulting in overall high level of thalamic and cortical activity via the synergistic influence of both pathways. *Negative Prediction Error:* Do not drive the direct pathway and do not inhibit the indirect pathway (D1 and D2 receptors both unoccupied), so the *indirect pathway is allowed to inhibit thalamic-cortical output*.

Brainstem Stroke Findings -Crossed signs

*CN Palsies* 1. *CN III* (midbrain syndrome) -Weber's Syndrome (medial midbrain; PCA perforators) -Contralateral hemiparesis (cerebral peduncle) -Ipsilateral CN III palsy -Impaired ipsilateral pupillary reflex and dilated pupil 2. *CN VI and VII* (pontine syndrome)

UMN Signs

*CNS Problem:* everything is *up* 1. Weakness (paresis) or paralysis (plegia) 2. Spasticity (hypertonia, hyperreflexia, clonus) 3. Babinski Sign (+): up-going toes

*Signs of UMN damage* -Long motor tracts (corticospinal and brainstem pathways)

*CNS Problem:* everything is *up* 1. Weakness (paresis) or paralysis (plegia) 2. Spasticity (hypertonia, hyperreflexia, clonus) → although initially patients experience hypotonia and hyporeflexia 3. Babinski Sign (+): up-going toes (pathognomonic for CNS damage)

Cerebral Perfusion Pressure (CPP)

*CPP = Mean Arterial Pressure (MAP) - Intracranial Pressure (ICP)* The net pressure gradient causing cerebral blood flow to the brain (brain perfusion). *Normal cerebral blood flow is 54 ml-blood/100gm-brain/min* If CPP is 0, there is no cerebral perfusion → brain death

*Acute* Evaluation of ICH on Imaging

*CT/A* is sensitive for seeing *acute* blood (CT) and vessels (angiography). -CT is very fast and easy to read (acute blood appears *bright white*; black edema surrounds). -Can reveal hydrocephalus, edema, mass effect, and (potentially) tumor *MRI* good for seeing *chronic, older* blood (more sensitive; especially Gd-contrast). -Gives a more detailed look for other causes of ICH (e.g., parenchymal tumors).

*Gold standard* for detecting aneurysm is...

*Catheter angiography* (helpful at finding small aneurisms missed by CT/A imaging).

*Subarachnoid Hemorrhage* (from Crush)

*Cause:* 1. *Rupture of a cerebral aneurysm* at bifurcations in the Circle of Willis (especially *berry aneurysms* in Marfan's syndrome, Ehlers-Danlos syndrome, and polycystic kidney disease (PCKD) with breakdowns in the internal elastic lamina) 2. *Arteriovenous malformation (AVM):* *arteriolization of veins* due to arterial blood pressure being communicated directly to the veins caused by abnormal anastomoses between arteries and veins without intervening capillary beds to dampen arterial pressure. *Intervening gliotic brain parenchyma* exists between abnormal blood vessels. 3. *Cavernous Angioma:* back-to-back proliferative vessels *without intervening brain parenchyma* that an cause ICH 4. *Trauma* *Locations:* Circle of Willis (85% of aneurysms occur in anterior circulation) *Presentation:* Patients generally complain of sudden onset of the *"worst headache of my life"* or may present beforehand with warning leaks as general headaches. Other symptoms include nausea and vomiting (due to ↑ICP), neck stiffness (blood irritates meninges), and LOC (compressed ARAS). *Diagnosis:* Most SAHs are *detected on CT after the onset of bleeding*, which shows *blood in the cisterns* and filling of blood along the sulci and fissures. If a CT scan is negative, a *lumbar puncture* is performed and *CSF* collected, which may show *elevated blood cells* equally in all tubes collected, or the *CSF may appear yellow (xanthochromic) because of the bilirubin* (breakdown of heme from red blood cells). *Treatment:* 1. Prevent rebleeding (surgical clipping or *coiling* aneurysms) 2. Prevent seizures 3. Prevent *vasospasm:* accounts for 50% of all deaths from SAH patients (treat with Ca2+ channel blocker *nimodipine*) 4. Prevent hydrocephalus (ICP management)

Surgery for Cerebellar ICH

*Cerebellar hemorrhage* with *neurological deterioration* or *brainstem compression* and/or *hydrocephalus* are indicative of surgical intervention. The *posterior fossa is an enclosed space*, and pressure pushing on the brainstem can lead to death. *Supratentorial hematoma evacuation* can be life-saving, but patients may be left with significant disability.

If ICH is caused by ___ , it must be Lobar and not Deep ICH.

*Cerebral Amyloid Angiopathy (CAA)* affecting the terminal branches of the MCA, which receive an "end wave" of blood (pressure) from the ICA

The cerebellar hemispheres (output targets)

*Cerebro-cerebellum:* lateral lobes 1. The *dentate nucleus* sends outputs to the *VL nucleus of the thalamus* (ultimately motor cortex). 2. The cerebro-cerebellum appears to be involved in *high-level movement coordination* of signals of motor cortical origin.

Deep Hypertensive ICH Pathology

*Charcot-Bouchard Microaneurysms:* hypertensive hemorrhages 1. Associated with *chronic hypertension* 2. Affects *small vessels* (e.g., lenticulostriate arteries in basal ganglia, thalamus) and can cause *lacunar strokes* *Mechanism:* *Fibrinoid necrosis causes weakness in the walls of subendothelium → vessel rupture.* *Location:* 1. Cerebral lobes (lobar; 25%) 1. *Basal ganglia (putamen; 35%)* 2. Cerebellum (8%) 3. Thalamus (20%) 4. Pons (7%) *Resolution of ICH:* *Day 1:* acute hematoma white on CT *Month 1:* ICH resolves to black (density decreases by ~1 HU/day)

Subdural Hematoma -More diffuse that epidural (the dura and arachnoid are not adhered)

*Classic Stories*: 1. 88 year old involved in a fender bender (2 weeks ago) 2. 88 year old with scalp ecchymoses; reduced consciousness -*Location:* between the meningeal dura and arachnoid mater (which sit next to each other due to CSF pressure from subarachnoid space) -*Source:* *bridging veins* beneath the dura mater that drain the cerebral cortex into venous circulation (these veins are not reinforced by trabecular cells); *slower* to occur due to venous nature; this can compress lateral ventricles -*Cause:* rapid changes in velocity (acceleration or deceleration in whiplash or shaking); in the elderly, the brain atrophies (10%), providing more subdural space for veins to travel, making shearing forces more potentially damaging -*CT Scan:* crescent-shaped moon pattern (of blood) that crosses suture lines, but cannot pass dural reflections; ipsilateral lateral ventricle compressed

Epidural Hematoma

*Classic Story*: 1. Line drive hits boy in the side of the head 2. Loses consciousness, but up again in under a minute 3. Loses consciousness 20 min later and *breathes rapidly* 4. *Enlarged pupil* (*ipsilateral* blown due to CN III compression) -Location: between the endostium and inside of skull (in the dura) -Source: *middle meningeal a. (superficial/epidural)* in the dura breaks, resulting in a midline shift (the skull doesn't provide space for blood). Can cause transtentorial herniation. -Treatment: bore hole to relieve pressure -CT Scan: biconvex lens that *does not cross suture lines* (dural attachment points), but can cross the falx and tentorium (dural reflections)

Herpes Encephalitis (imaging)

*Clinical Signs:* 1. Rapid onset of fever 2. Headache 3. Seizure 4. Focal neurologic signs 5. Impaired consciousness *Mechanism:* Brain invasion via *CN V3* or *olfactory tract* after *primary oropharyngeal infection* or reactivation of latent HSV1. *Diagnosis:* 1. HSV1 DNA in CSF (by PCR) 2. *Neuroimaging* a. Bilateral but NOT symmetric b. Especially in temporal, limbic, and orbitofrontal lobes *Treatment:* empiric *acyclovir* ASAP

*Cauda Equina Syndrome* -Asymmetric -*Hyporeflexia* -Radicular Pain: L2 and below (affects a larger region than conus medullaris) -*Late sphnicter dysfunction* (cauda equina after conus medullaris on descent)

*Compression of spinal roots L2 and below*, often due to *intervertebral disc herniation or tumor* (motor and sensory deficits). Unilateral (*asymmetric*) radicular pain with LMN deficits. *LMN Motor deficits:* 1. *Hyporeflexia* (ankle/knee) 2. *Sphincter dysfunction* occurs *late* (bladder and anus). 3. *Saddle anesthesia* 4. Lower extremity weakness *Treatment:* emergent surgery and steroids. *Asymmetric:* think you're falling off the horse on one side. Conus medullaris is *symmetric* because the base of the spinal cord is mesial.

Brudzinski and Kernig Signs

*Confirms diagnosis*, but absence does not exclude diagnosis. *Brudzinski's Sign* 1. Flex at neck 2. Reflex of knee (upon neck flexure) *Kernig's Sign* 1. Flex leg to 90° 2. Hyperextend the knee (pain?)

*Status Epilepticus* -Treatment: *benzodiazepines*

*Continuous (≥ 5 min) or recurring seizures* (without interval recovery to neurologic baseline) that may result in brain injury. *Treatment:* 1. Fast acting IV-AEDs: *benzodiazepines* (↑frequency of GABA channels, ↑Cl-) 2. First-line IV AEDs: phenytoin 3. Second-line IV AEDs: barbiturates 4. Sedatives: Phenobarbital (if patient is allergic, can give Valproic Acid)

Tectospinal Tract

*Coordinates head movement in response to visual/auditory stimuli.* *Pathway:* 1. Begins in colliculi 2. Decussates in midbrain 3. Travels down through spinal cord (ventromedial) 4. Synapses at spinal level

*Cortical Stroke Symptoms* -Large arteries -Cortical strokes spread to the surface of the brain

*Cortical* usually *large artery, embolic* stroke -FA>L or L>FA (information from homunculus) *CVA (cerebrovascular accident)?* Quick, get in the *VAN!* *Mneumonic:* VAN 1. *Vision* (hemianopia) 2. *Aphasia (L frontal lobe):* loss of ability to understand or express speech, caused by brain damage (dominant) 3. *Neglect (R parietal lobe):* after damage to one hemisphere of the brain is sustained, a deficit in attention to and awareness of one side of the field of vision is observed (contralateral); note: the right hemisphere controls more than half of the brains "intentional spheres"

D1 vs D2 receptors Dopamine effects: 1. *Excites* direct (D1) (↑Go) 2. *Inhibits* indirect (D2) (↓No-Go)

*D1 Pathway:* relatively insensitive to Dopamine 1. Activate Gs (stimulating G protein) 2. ↑cAMP 3. Activates the "Go" pathway (excitation back to the cortex) *D2 Pathway:* very sensitive to Dopamine 1. Activate Gi (inhibitory G protein) 2. ↓cAMP 3. Inactivates the "No-Go" pathway (excitation back to the cortex)

Why do we image meningitis?

*DO NOT image for diagnosis.* We image for: 1. *Cause:* otitis media or otomastoiditis, paranasal sinusitis, dental infection 2. *Complications:* empyema (pus) or brain abscess, hydrocephalus, ischemic infarction

Right Occipital Ischemic Stroke Over Time on CT

*Day 1:* Cytotoxic edema (water *within* cells) (mild hypodensity/mass effect) *Day 6:* Cytotoxic edema (larger hypodensity and occipital horn *compression* due to mass effect) *Day 300:* Encephalomalacia (parenchymal softening): marked hypodensity; occipital horn *enlargement* due to *negative* mass effect

In an acute stroke, water diffusion is....

*Decreased*, making edema more dense on DWI (hyperintense due to lack of diffusion). Note: DWI demonstrates the random motion of *water in tissues*.

*Subacute Combined Degeneration* (spinal cord) Combined: 1. *DC-ML* 2. *CST* -Dentists use N2O → *B12 deficiency* -B12 is required for the methylation of myelin

*Deficiency of vitamin B12 causes axonal degeneration and demyelination of the dorsolateral spinal cord.* *Affected:* 1. *Dorsal columns* (pressure, vibration, fine touch, proprioception) 2. *Lateral CST* (voluntary motor) 3. *Spinocerebellar tracts* (proprioceptive information from Golgi tendon organs and muscle spindles) → hemiataxia and dysmetria (like in Claude's Syndrome) *Spared:* 1. Anterior columns (e.g., AL pathway: can feel pain and temperature) *Clinical Findings:* 1. Ataxic gait (spinocerebellar) 2. Paresthesia (CST) 3. Impaired position/vibration sense (DC-ML) *Comparison to ALS:* 1. Both diseases affect the CST 2. However, ALS affects LMN (anterior horn cells) and SCD affects the dorsal columns (DC-ML).

*Progressive Multifocal Leukoencephalopathy (PML)* -*JC virus*-induced demyelination (*destroys oligodendrocytes*) -Bizarre astrocytes -Immunocompromised patients

*Demyelination of CNS due to destruction of oligodendrocytes* (2° to reactivation of latent *John Cunningham virus* (JCV; papovaviridae) infection from tonsils or GI tract). Seen in 2-4% of patients with AIDS (*immunocompromised patients*). *Pathology:* 1. Oligodendroglial nuclear inclusions (ground glass) 2. Reduced oligodendrocyte counts (JCV destruction) 3. Bizarre astrocytes *Rapidly progressive*, usually fatal. Predominantly involves parietal and occipital areas (visual symptoms are common).

Tissue Window vs. Time Window (Rapid MRI)

*Diffusion-Weighted MRI:* infarct *core* (irreversibly infarcted tissue is indicated by decreased water diffusion = dead brain) *Perfusion-Weighted MRI:* ischemic *penumbra* (brain at-risk for infarction but potentially salvageable with flow restoration) *MISMATCH:* If the mismatch is large (small core, large penumbra), the benefit of thrombolysis may outweigh the risk of hemorrhage (and vice-versa).

*Migraine Headache* -Primary Headache (neuropathic)

*Disease Characteristics:* 1. Gradual onset 2. Throbbing pain 3. Unilateral (more common than bilateral) 4. Last hours to days (3-72 hours) 5. Better with dark quiet room 6. Nausea 7. Worse with exertion or bending over 8. Familial in 70-80% of cases (e.g., CACNA1A Ca2+ channel gene is affected in familial hemiplegic migraine) 9. Motion sickness can often be a predictor *Mechanism:* 1. Cortical spreading depression (ion channels, and alteration of cerebral blood flow) 2. Trigeminal nerves activated (Calcitonin Gene-Related Peptide, CGRP) 3. Trigeminal vascular system involved in pain transmission. *Treatment:* 1. NSAIDs 2. Triptans (serotonin receptor agonists) 3. Ergots (dihydroergotamine: nonselective receptor agonists)

Narcolepsy

*Do not enter sleep through slow-wave, restorative sleep first; go directly to REM*. *Tetrad:* 1. Excessive daytime sleepiness (EDS) (intrusion of REM into wakefulness) 2. Cataplexy (paralysis brought on by emotion) 3. Hypnogogic hallucinations (vivid dreams that occur at sleep onset) 4. Sleep paralysis 5. (Disrupted nocturnal sleep) *Diagnosis:* occurs in a sleep lab with the Multiple Sleep Latency Test (MSLT) -Consists of 4-5, 20min naps, 2 hours apart following overnight polysomnography (sleep monitoring) -Measures latency to sleep onset (stage 1) and REM latency *Sleep Latency Scale:* 1. >10 min = normal 2. 5-10 min = gray zone 3. <5 min = pathological sleepiness *Treatment:* -Sleep hygiene -Prophylactic napping *Medication:* 1. Excessive daytime sleepiness → stimulants 2. REM-associated phenomena → TCAs/SSRIs 3. Excessive daytime sleepiness AND *cataplexy* → *sodium oxybate (Xyrem)* *Sodium Oxybate:* a GHB salt (Rufies) 1. *Increases slow wave sleep (SWS):* stages 1-3 2. Give 2 doses: 1x before bed; 1x 2-3 hours after 3. DO NOT use with CNS depressants

Dysarthria vs Dysphasia lesion

*Dysarthria is M1* lesion affecting mouth area *Dysphasia is SMA* lesion affecting *Broca's area* *Dysarthria:* disorder of *motor speech* (muscular control); inability to articulate words due to weakness of the necessary muscles *Dysphasia:* disorder of *language* -Receptive dysphasia is difficulty in comprehension -Expressive dysphasia (Broca's) is difficulty in putting words together (formulate a word *plan* to make meaning)

*Capsule Formation in Brain Abscess* *Process:* 1. Focal, intracerebral infection (cerebritis) 2. Encapsulated, well-vascularized pus

*Early Capsule:* 1. Decrease in size of the necrotic center (fibroblasts and MØ try to contain the lesion) 2. Development of collagenous capsule (fibroblasts) (ring enhancement) 3. Regression of cerebral edema *Late Capsule:* 1. Increase in density and thickness of collagen capsule 2. Eventually the capsule ruptures into the ventricles

*Early vs. Late Cerebritis* in Brain Abscess Evolution

*Early Cerebritis (Days 1-3):* 1. Acute inflammatory infiltrate 2. Visible bacteria 3. Marked edema *Late Cerebritis (Days 4-6):* 1. Necrotic center of lesion 2. Fibroblasts and macrophages form a capsule at the periphery of the lesion to contain the lesion Ring-enhancement may also be observed in cerebral hemorrhages (bleeding) and some brain tumors. However, *in the presence of the rapidly progressive course with fever, focal neurologic findings (hemiparesis, aphasia, etc.) and signs of ↑ICP*, the most likely diagnosis should be the *brain abscess*.

*Pseudotumor Cerebri* (Idiopathic Intracranial Hypertension, IIH) -Secondary Headache *Risk Factors:* female TOAD -Tetracyclines (antibiotics) -Obesity -A (vitamin A) excess (acne meds) -Danazol (steroid for endometriosis) Treatment: *carbonic anhydrase inhibitors and weight loss*

*Elevated ICP* with *no mass* present on imaging. If untreated, could cause loss of vision. *Disease Characteristics:* 1. *Papilledema (↑ICP)* with no apparent cause 2. Positional headache (worse when lying) 3. Diplopia with lateral gaze (*CN VI palsy*) 4. No change in mental status 5. *Enlarged blind spot* and peripheral constriction *Risk Factors:* female TOAD -*T*etracyclines (antibiotics) -*O*besity -*A* (vitamin A) excess (acne meds) -*D*anazol (steroid that treats endometriosis) *Treatment:* 1. *Weight loss* 2. *Carbonic anhydrase inhibitor* (acetazolamide and *topiramate*): *↓CSF* 3. CSF shunt placement 4. Optic nerve sheath fenestration surgery (for visual loss)

Neural Tube Defects

*Elevated α-fetoprotein (α-FP)* in maternal serum should make one suspicious of a *neural tube defect* in the fetus. Folic acid (B9) supplementation has been shown to reduce the incidence of neural tube defects. The three most commonly encountered defects: 1. *Anencephaly:* the failure of development of the brain due to lack of closure at the anterior neuropore 2. *Encephalocele:* an outpouching of epithelium-enclosed brain tissue through a cranial defect 3. *Spina Bifida:* failure of closure at the posterior neuropore

EEG Abnormalities in Epilepsy (associated with risk of seizure)

*Epileptiform Abnormalities:* spikes, sharp waves, spike-wave complexes, polyspikes are "fleeting blips" (small changes in EEG tracing). *Absence Seizures (3 Hz spike-and-wave discharges):* petit mal -Bilateral, primary generalized -No response to cues (large waves) -EEG normalizes to "flat-line" and patient can respond

Diagnosis of Multiple Sclerosis

*Evaluation:* 1. Recurrent neurological symptoms 2. Focal findings on exam 3. *Lesions on MRI (plaques detected with high sensitivity)* -*Gd-contrast MRI* demonstrates acute, *periventricular plaques* (areas of oligodendrocyte loss and reactive gliosis/scarring) 4. Abnormal CSF (mild lymphocytosis, elevated protein, *elevated IgG*, *myelin basic protein*) 5. Multiple *white matter lesions* disseminated in *space and time*.

Spinal Epidural Abscess and Metastases

*Extra-Axial* and arises in the *epidural space* (due to infection in the vertebral body or disc). Destruction of the vertebrae is called *vertebral osteomyelitis*. *Classic Presentation:* 1. Fever 2. Spine pain 3. Neurologic deficits *Progression:* due to compression of the spinal cord 1. Back pain (almost always initial symptom) 2. Radicular pain 3. Weakness, sensory changes, and bladder dysfunction (present in 75% of cases 4. Paralysis 5. Sensory loss (50% of case) (thoracic level → paraparesis; cervical level → quadriparesis) 6. Autonomic dysfunction (urinary urgency and incontinence, fecal incontinence, impotence) *MRI:* Rim-enhancing, lenticular *epidural* mass *Pathophysiology:* often in immunocompromised patients 1. S. aureus is common for hematogenous spread 2. Direct extension for contiguous vertebral osteomyelitis or paraspinal infection 3. Direct inoculation (complication of spinal surgery) *Myelopathy:* due to compressed spinal cord or ischemia due to thrombosis of veins or arteries *Treatment:* 1. Aggressive surgical resection (remove as much as possible and stabilize the spine) 2. Radiation 3. Combination of approaches does not lengthen survival, but can improve quality of life.

Intrafusal vs. Extrafusal Muscle Fibers (in parallel)

*Extrafusal fibers:* innervated by *alpha* motor neurons -Larger, power-generating fibers lying outside the spindle (non-spindle) -Generate force and create movement (contraction) *Intrafusal fibers:* innervated by *gamma* motor neurons -Small muscle fibers of the muscle spindle that cause the *contractile poles of the intramural fibers to shorten* -Contraction does not contribute directly to the force developed by contraction of a muscle, but *keeps sensory receptors in the spindle sensitive to stretch* (tightens up the slack after alpha motor neurons contract muscle)

Feedback error correction (WITHOUT cerebellum)

*Feedback error correction* (oscillations) (e.g., too hot, too cold, and so on... because the corrections happen only after the error is detected.) i. A motor command is issued by motor cortex ii. Sensory feedback iii. Feedback signal produces *corrective movement* to compensate for the *experienced error*.

Feedforward error correction (WITH cerebellum)

*Feedforward error correction* reduces oscillations by *compensating for expected error*. i. A motor command is issued by motor cortex (along with efference copy) ii. Sensory feedback (→ cerebellum → cortex) iii. This feedforward single modifies the next motor command to reduce the expected error.

*Hepatic Encephalopathy* -*Alzheimer Type II Astrocytes* -Cirrhosis → portosystemic shunts → ↓NH3 metabolism → neuropsychiatric dysfunction (impaired oxidative metabolism due to *↑NH3*)

*Findings:* 1. Diffuse edema (white matter swelling) 2. Proliferation of so-called *Alzheimer Type II astrocytes*, characterized by a *central clearing of their nucleus and a red, spotty nucleolus*. *Triggers:* 1. *↑NH3 production* and absorption (due to dietary protein, GI bleed, constipation, infection). 2. ↓NH3 removal (due to renal failure, diuretics, bypassed hepatic blood flow). *Treatment:* 1. Lactulose (↑NH4+ generation) 2. Rifaximin or neomycin (↓NH3-producing gut bacteria)

First Generation vs. Second Generation

*First Generation:* Pros: cheap, known efficacy, known long term risks Cons: serious side effects, drug-drug interactions, routine drug level monitoring needed, narrow therapeutic window *Second Generation:* Pros: fewer drug interactions, fewer side effects, broad spectrum, need less blood monitoring, lower risk of birth defects Cons: costly, unclear long-term risks, most are PO Side effects at supra-therapeutic levels of all AEDs: dizziness, ataxia, slurred speech (dysarthria), nystagmus. *Most affected by Na+ blockers like phenytoin and carbamazepine.* Phenytoin, Carbamazepine, and Lamotrigine are also implicated in Stevens-Johnson Syndrome.

Inputs to the Basal Ganglia

*Frontal Cortex* 1. *Motor/Premotor → putamen* (sensory-motor loop) 2. Lateral Prefrontal → caudate (cognitive loop) 3. Orbitofrontal/Medial → nucleus accumbens (limbic loop)

Cerebral Lobes and Function

*Frontal lobe:* motor and pre-motor cortex -Motor planning is localized here. -Both Initiative and Inhibitory regulation of behavior occur here. -The LEFT frontal lobe also contains Broca's area (expressive language). *Parietal lobe:* primary somatosensory cortex and somatosensory association areas -The RIGHT parietal lobe is important for spatial recognition and manipulation (if damaged → neglect). *Temporal lobe:* primary and secondary associative auditory cortex -The LEFT temporal lobe contains Wernicke's area (fluent language). -MEDIAL: *limbic system/hippocampi:* behavior, emotions and memory *Occipital lobes:* primary visual cortex and secondary visual association areas

Astrocytes

*Functions:* 1. Biochemical support of endothelial cells that form the *blood-brain barrier* 2. Provision of nutrients to the nervous tissue 3. Maintenance of extracellular ion balance 4. Repair and scarring process of the brain and spinal cord following traumatic injuries.

If *hematoma doesn't resolve in 4-6 weeks* from imaging on CT, do this imaging to check for tumor

*Gd-contrast MRI* (checks for acute breach to the blood-brain barrier vs. long term blood) This checks for an underlying *neoplasm.* A thick, fibrous ring (like one that forms around a tumor, should not be present in hematoma.

Types of Seizures

*Generalized (diffuse; affect both hemispheres)* -*Absence (petit mal):* 3 Hz spike-and-wave discharges, no postictal confusion, blank stare -*Tonic-Clonic (grand mal):* alternating stiffening and movement (convulsive) -*Tonic* (stiff: arms up and out) -*Clonic* (shake) -*Atonic* ("drop" seizures (falls to floor); commonly mistaken for fainting) -*Myoclonic* (quick, repetitive jerks) *Focal/Partial (affect a single area of the brain)* -Commonly originates in the medial temporal lobe of left brain -*Look away from seizure at onset* (FEF activated; pushes eyes to contralateral side) -*Simple (no LOC):* motor, sensory, autonomic, psychic -*Complex (LOC):* impaired consciousness, automatisms -Motor (jerking), visual (flashing lights), sensory (tingling/altered sensation), limbic (déjà vu)?

Etiology of Multiple Sclerosis

*Genetic component:* 1. Fraternal twins have a 2% and identical twins have a 25-30% risk of developing MS. 2. Strong association between *HLA antigens* (HLA A3, B7, DR2, DQ1). *Environmental or viral origin:* 1. Geographic distribution 2. If you move from high risk area to a low risk area (or vice versa), you maintain the risk of the area in which you spent your early years. 3. *Hygiene Hypothesis:* ↑Th2 (worms) abroad, ↑Treg protects from autoimmune disease 4. Lack of vitamin D? Smoking? *Evidence for autoimmunity as cause (primary theory):* 1. Female predominance 2. Age of onset (early) 3. Relapsing and remitting nature of the disease 4. Presence of triggering events 5. Protective effect of pregnancy 6. Association with MHC 7. Immunosuppressant drugs which have been shown to benefit patients with MS.

Glasgow Coma Scale

*Goes from 3 to 15 (15 is normal)*

*Oligodendrogliomas* -Common in the frontal lobes

*Grade II: low grade* -Radiologically similar to astrocytomas -More likely to be calcified -*Commonly present with seizure* -Better survival than astrocytoma (10-16 years) *Grade III/IV: anaplastic* -Prognosis better than anaplastic astrocytoma (III) -Chemo: procarazine, CCNU, vincristine, *temozolomide*

Muscle Spindle Sensory Axon Fiber Types

*Group Ia (equatorial region)* - rate of length change (respond to *dynamic* change in length) *Group II* - length (respond when there is *absolute* change in length)

*Brown-Séquard Syndrome (review)* -Spinal cord hemisection

*Hemisection of spinal cord.* Consequences of AL decussation in spinal cord: 1. Loss of AL tract *contralateral* 2. Loss of DCML tract *ipsilateral* 3. Loss of CST tract *ipsilateral* (weakness) 4. UMN (hypertonia, hyperreflexia, Babinski)

*Type II Chiari Malformation* -Posterior fossa lesion

*Herniation* of low-lying cerebellar vermis and tonsils (*2* structures) through foramen magnum with aqueductal stenosis → non-communicating hydrocephalus. Type I = just tonsils (1 structure). 1. To accommodate ↑CSF, the normal six-layered cortex (pseudo-) tries to form more, smaller gyri (*pseudomicropolygyria*). 2. Flattens the pons 3. Elongates the 4th ventricle 4. "Breaks" the tectum (midbrain) 5. S-shaped kink in the spinal cord 6. Lumbar meningomyelocele (dura+spinal tissue)

Most common cause for *Viral Encephalitis*

*Herpes Simplex Virus (HSV):* temporal inflammation *Electroencephalography (EEG):* In 80% of encephalitis cases with HSV, there is an asymmetric *temporal focus with periodic materializing epileptiform discharges (PLED)*

Highest and lowest teratogenic risk AEDs

*Highest Risk:* Valproic Acid (but broad spectrum) *Lowest Risk:* Lamtorigine, Leviteracetam (LL=least risk)

*Prion Diseases* (spongiform encephalopathy)

*Histology:* parenchymal vacuolization (*Champagne bubbles* = prion protein aggregates). *Prion diseases are caused by the conversion of a normal (predominantly α-helical) protein termed prion protein (PrPc) to a β-pleated form (PrPsc)*, which is transmissible via CNS-related tissue (CJD) or food contaminated by BSE-infected animal products (variant CJD = mad cow). *PrPsc resists protease degradation and facilitates the conversion of still more PrPc to PrPsc.* PrPsc is resistant to standard sterilizing procedures, including autoclaving. Accumulation of PrPsc results in spongiform encephalopathy and dementia, ataxia, and death. *Prion Diseases:* 1. *Creutzfeldt-Jakob:* rapidly progressive dementia, typically sporadic (some familial forms) 2. *Bovine Spongiform Encephalopathy:* also known as "mad cow disease" 3. *Kuru:* acquired prion disease noted in tribal populations practicing human cannibalism

SAH Classification

*Hunt and Hess Scale* *Grades:* *1:* Asymptomatic or mild headache (70% survival) *2:* Moderate to severe headache; CN palsy but otherwise normal (60%) *3:* Drowsy but no neuro deficit (50%) *4:* Stuporous, hemiparesis, decerebrate rigidity (20%) *5:* Deep coma, decerebrate (10%)

Narcolepsy may be related to deficiency in ________

*Hypocretin/Orexin.* Decreased hypocretin/orexin (due to a *decrease in the hypothalamic neurons*) promotes REM in many brain regions. Normally, Hypocretin/Orexin promotes wakefulness and suppresses REM (lateral hypothalamus). Absent, there is no suppression on REM.

Reflexes and Nerve roots Roots: 1-2, 3-4 ,5-6, 7 (ascending)

*Hyporeflexia* is seen in radiculopathy (i.e., *reflex arc affected by compressed nerve roots*). Achilles Reflex: S1-S2 nerve root (L5-S1 steppage gait) Patellar Reflex: L3-L4 nerve root (L4-5 lower back pain) Biceps Reflex: C5-C6 nerve root (C6-7 neck pain) Triceps Reflex: C7 nerve root (C6-7 neck pain) Note: L5 has a large root diameter and the foramen is narrow.

*Functional Imaging of Seizure Focus* (Nuclear Medicine) -Ictal (during seizure blood flow is high, SPECT) -Late Post-ictal (post-seizure blood flow is low due to damage during seizure, PET)

*Ictal (during seizure) has ↑ blood flow to focus (SPECT)* -Neurons are rapidly firing during a seizure and need blood -A radiopharmaceutical (99mTc-ehtyl cysteinate dimer) is used to monitor blood flow *Inter/Post-ictal has ↓ blood flow (SPECT)* -Also *↓ glucose metabolism on PET*

AEDs that are CYP450 inducers and inhibitors

*Inducers:* Phenytoin, Phenobarbital, Carbamazepine (PPC) *Inhibitors:* Valproic Acid (V) Note: P450 inducers speed up the catabolism of birth control pills, antibiotics, HIV meds, and chemo + Vitamin D (which can reduce bone mineral density and lead to osteopenia / osteoperosis)

*Poliomyelitis* -Later in life, patients can have worsening weakness (Post-Polio syndrome). -SMA = symmetric weakness -Polio = asymmetric weakness

*Infection of spinal cord by poliovirus* (fecal-oral transmission). -Replicates in the small intestines and oropharynx → spreads to CNS. *LMN disorder:* Infection causes *destruction of anterior horn cells* *Anterior Horn Cell Death Extent:* *Regional:* 1. Hypotonia → *flaccid paralysis* 2. Atrophy (asymmetric) 3. Fasciculations 4. Absent Babinski 5. Hyporeflexia 6. Weakness (asymmetric) *Extensive:* 1. Quadriplegia 2. Respiratory failure (if respiratory muscle is involved) Treatment: *No cure.* Supportive treatment with physical therapy and assistive devices. *Lab Findings:* 1. ↑WBCs (lymphocytic pleocytosis) in CSF 2. ↑protein in CSF 3. No change in CSF glucose (↓only in bacterial infections) 4. Virus recovered from stool or throat

Cervical Plexus

*Innervates neck muscles* Components: *Motor* roots of *C1-C4* Location: Deep to SCM (rarely injured due to location)

Cataplexy

*Intrusion of REM into wakefulness.* -*Emotional onset* (laughter, excitement) -The brain is awake (aroused), but *body is paralyzed (↓muscle tone)* -Sagging of the face, eyelid, or jaw -Dysarthria -Head drop -Diplopia

Role of Neuroimaging in Assessing Stroke

*Ischemic Stroke:* 87% 1. Extent of infarction: CT (candidate for IV-tPA?) 2. Presence of *large vessel occlusion*: CT/A -*Dense MCA sign on CT* (ELVO; treat mechanically) -*Filling defect* or "cut-off" on CT/A (gap in vessel) 3. Collateral blood flow (CT/A) *Hemorrhagic Stroke:* 10% 1. ICH doesn't resolve in 3-4 weeks, MRI with Gd contrast 2. SAH: DSA used to diagnose and treat aneurysm

*Acute CNS lesions* produce ______ (UMN or LMN) signs

*LMN Signs* During spinal shock: 1. More LMN (decreased tone and reflexes) 2. UMN symptoms develop later The anterior horn cell is the cell body of the LMN and is physically in the spinal cord

LMN vs. UMN Signs

*LMN:* HAFAH+W -Hypotonia -Atrophy -Fasciculations -Absent Babinski -Hypo-reflexia -Weakness *UMN:* -Weakness -No atrophy -No fasciculations -Hypertonia (rigid) -Hyper-reflexia -Babinski sign present

*Trigeminal Neuralgia* -Primary Headache (neuropathic) -V3 pain common -*Treatment:* carbamazepine

*Lancinating facial pain (V3>>V2>V1)* caused by an artery compressing the trigeminal nerve. *Disease Characteristics:* 1. Has a trigger point 2. Onset by chewing or talking common over age 40 3. *If <40 look for MS plaque at exiting nerve root of CN V on brain MRI* *Treatment:* 1. Carbamazepine 2. Microsurgery for vascular loop (put a spacer between the vessel and nerve to prevent compression)

*Viral* Encephalitis (imaging)

*Lesion Imaging:* 1. Gray matter predilection (often seen in temporal lobes and basal ganglia) 2. Bilateral (but may be asymmetric) *Clinical Signs:* 1. Altered mental status, behavior, or personality (*encephalopathy*) 2. Speech or movement disorders 3. Motor or sensory deficits *Diagnosis:* CSF profile 1. Lymphocytes > neutrophils (viral > bacterial) 2. ↑ protein 3. Normal glucose

Flexor Posturing (decorticate)

*Lesion above red nucleus* (impaired corticospinal/corticobulbar) 1. Rubrospinal Tract → flexion of the arms 2. Vestibulospinal tract → extension of the legs

Extensor Posturing (decerebrate)

*Lesion below red nucleus* Unopposed vestibulospinal tract → *extension of the arms and legs*

*Relapsing-Remitting MS*

*Lesions appear and disappear*, not all lesions cause disease. -85% of patients start this way -50-80% of these cases will be secondary chronic progressive by 25 years *Old lesions appear as "black-holes" on Gd-contrast MRI.* 5-10 lesions usually leads to symptoms

Scull Fractures

*Linear:* bones of the calvaria are broken, but still held in place by dura -Potential *epidural hematoma* if the fracture crosses the *middle meningeal artery* groove *Depressed:* outer cortex of splintered bone falls inside the inner table of the skull → surgery required to elevate the depressed fragment -The impact of the object leaves a *shockwave* (larger impact as it travels)

Which has a higher risk of recurrence, Deep or Lobar ICH?

*Lobar ICH* are more likely to reoccur to do fewer treatment options. *Deep hemispheric stroke can be prevented with BP medications (↓BP).* Lobar hemispheric strokes (caused by CAA) have no real treatment (just avoiding anti-thrombotic medication).

Glioblastoma (imaging)

*Location:* cerebral white matter (spreads rapidly and diffusely) *Appearance on T2:* "butterfly" glioma (can cross corpus callosum) *Histology:* *pseudopalisading* pleomorphic tumor cells border central areas of necrosis and hemorrhage

Parkinson's Disease and Basal Ganglia

*Loss of dopaminergic input* to striatum *removes a brake on the inhibitory loop* (i.e., no dopamine on D2-indirect pathway to inhibit inhibition), leading to a *constant net inhibitive action on cortex*, resulting in hypertonia. *Drug Therapy:* 1. *L-DOPA* (dopamine precursor): benefits wane after several years 2. *Dopamine agonists:* almost as potent as L-Dopa with no long-term side effects, but there are short term side effects and they cost more. *Surgical Therapy:* 1. *Damage GPi* (pallidotomy) to stop inhibition of the thalamus and reduce bradykinesia and rigidity → now replaced with DBS 2. *DBS on STN* → prevents activation of GPi (resulting in less inhibition on the thalamus; reduces ballismus)

Motor Neuron Diseases

*Lower Motor Neuron (LMN):* wasting/atrophy, low tone (flaccid), reduced reflexes, fasciculations 1. Spinal muscular atrophy (Type 1: Werdnig-Hoffmann disease) 2. Polio *Mixed UMN and LMN:* 1. Amyotrophic Lateral Sclerosis (ALS) *Upper Motor Neuron (UMN):* hypertonia (spasticity), hyperreflexia, Babinski sign 1. Primary lateral sclerosis

For cerebral abscess, best way of imaging is...

*MR-DWI* because the lesion is hyperintense due to pus. Water diffusion is restricted in pus (inflammatory cells and cellular debris) due to the hyperviscoisty of pus as compared to CSF.

Brain Abscess Initiation and Treatment

*Mechanisms of Abscess Formation:* 1. *Contiguous focus of infection* from brain (30-50%) -Otitis media (middle ear), mastoiditis, sinusitis, penetrating trauma 2. *Hematogenous spread* (35%) -Bacteremia from dental infections, endocarditis (infection of the endocardium, which is the inner lining of your heart chambers and heart valves), congenital heart disease 3. *Cryptogenic* (unknown cause) (10-35%) *Imaging:* 1. NO LUMBAR PUNCTURE 2. MRI is preferred; CT for patients unable to undergo MRI (midline shift due to *(+) mass effect*) *Treatment:* 1. Surgical drainage or excision if the mass is large 2. Antimicrobials alone if the abscess is small (<2.5 cm).

Common structural lesions leading to epilepsy

*Mesial Temporal Sclerosis* 1. Pathology in *hippocampus*: neuronal loss and gliosis 2. Risk Factors: prolonged childhood febrile seizure and provoked generalized seizure (associated with meningitis, encephalitis, or brain trauma) 3. One year after surgery: 61% seizure free *Neoplasm* 1. Most are low-grade glial or glioneuronal tumors 2. Involve the cerebral *cortex* (the source of hyperactivity in seizures) 3. One year after surgery: 68% seizure free *Cortical Malformation (from development)* 1. Cytoarchitectural abnormality from abnormal neuronal migration and cell dysplasia (reminder that neuron stem cells start at the ventricles and move out to the cortex) 2. *Focal Cortical Dysplasia* has an earlier ager of seizure onset) and is treated by cutting the corpus callosum to prevent seizures from traveling to the unaffected hemisphere.

What causes seizures?

*Metabolic derangements* (NOT epilepsy): 1. Hyponatremia 2. Hypo- or hyper-glycemia 3. Hypocalcemia 4. Hypomagnesemia *Other causes of seizures by age:* 1. Children: *genetic*, trauma, *infection (febrile)*, metabolic 2. Adults: stroke, tumor, trauma, infection 3. Elderly: *stroke*, *tumor*, trauma, infection, metabolic

Kearns-Sayre Syndrome (myopathy)

*Mitochondrial Disease* *Lack of functional mitochondria (lack of ATP)* → muscle weakness and progressive *external ophthalmoplegia*. *Other Clinical Findings:* 1. Cardiac problems (heart block) 2. Hearing loss 3. Short stature *Pathologic Findings:* 1. *Ragged Red Fibers:* accumulation of abnormal mitochondria below the plasma membrane of the muscle fiber that cause its contour to become irregular 2. *Parking lot inclusion bodies:* accumulation of abnormal and enlarged mitochondria in highly ordered crystal-like inclusions within the intermembrane space of RRF

*Chronic Meningitis* -Associated with *Mtb* -*Obliterative endarteritis*

*Most cases begin with involvement of the base of the brain*, then spread to the hemispheres after an extended course of time. Left unchecked, chronic meningitis can produce an *obliterative endarteritis* (intimal hyperplasia / occlusion of arteries in the *sub-arachnoid space* → infarction.) *Common causes:* 1. *Mycobacterium tuberculosis* 2. Cryptococcus neoformans 3. Candida albicans (pseudohyphae) 4. Aspergillus fumigatus (true hyphae) 5. Mucor species

Lumbosacral Plexus

*Motor and sensory nerves* -Lumbar plexus: L1-L3 and most of L4 -Lumbosacral trunk: L5 (with some L4) -Sacral plexus: lumbosacral trunk plus S1-S4 The lumbar plexus sits within the psoas muscle and anterior to the vertebral processes. The sacral plexus sits between the pelvic fascial layer and the piriformis muscle. Lumbosacral plexus can be easily affected by tumor invasion from adjacent organs.

Acute disseminated (*post-infectious*) encephalomyelitis (*ADEM*)

*Multifocal inflammation and perivascular demyelination after viral infection or vaccination* (especially after measles or chickenpox). Presents with *rapidly progressive*, multifocal neurologic symptoms, and altered mental status with widespread involvement of the CNS. Pathologly: *perivascular (perivenular) inflammation* associated with vasogenic edema

Treatment of Brain Metastases

*Multiple Masses:* palliative intent 1. Fractionated whole brain XRT 2. Gamma knife (focused radio surgery if <6 lesions and <3.5cm in diameter) *Solitary Masses:* surgical resection -Improve survival and improve symptoms, if not cure

Cerebellum Symptoms

*NAIL:* *N*ystagmus (eye movements) *A*taxia (motor coordination of limbs) *I*ntention tremor *L*oss of balance (gait/posture) *Hemispheres* control *ipsilateral limbs* *Vermis* controls *trunk* and *gait/balance*

Degrees of Nerve Trauma and Injury -"Supporting Structures" = epi/peri/endo-neurium

*Neurapraxia:* conduction block *I:* Loss of myelin sheath (demyelination; will regenerate) *Axonotmesis:* Wallerian degeneration *II:* Loss of axons, but not supporting structures (recoverable) *Neurotmesis:* Wallerian degeneration; nerve trunk discontinuity *III:* Loss of axon + *endoneurium* (not as recoverable) *IV:* Loss of axon + *perineurium* (unlikely recovery without surgery) *V:* Loss of axon + *epineurium* (impossible recovery without surgery)

Neuroprogenitor Cells

*Neuroprogenitor cells of the brain persist for life.* As differentiation occurs, these new cells must foster connections with neighboring cells (synapses within the nervous system are formed and remodeled until death). The *differentiation* of progenitor cells into more specialized cell types (e.g., glial cells or ependymal cells) is controlled by *neural growth factors*.

Treatment of Multiple Sclerosis -No cure -*Corticosteroids:* acute relapse -*IFN-β:* reduce relapses in R-R MS

*No cure.* Focus on symptom management. *Early intervention in high-risk patients with possible MS delays or reduces the probability of developing clinically-definite MS.* 1. *Corticosteroids* may hasten recovery from an *acute relapse*, but do not affect the extent of that recovery or influence long term prognosis. 2. *IFN-β therapy* (Avonex, Betaseron, Rebif, Extavia, Plegridy) and glatiramer acetate are used for relapsing-remitting MS to *reduce relapses*. Newer oral agents (*immunosuppressants*) including Fingolomod (Gilenya), Teriflunamide (Aubagio) and Dimetylfumarate (Tecfidera), Alemtuzimab (Lamtrada) and Natalzumab (Tysabri) and Ocrelizumab have shown to be even more effective in *reducing relapses* and *decreasing MRI activity* and are being used increasingly.

Normal and Diseased State CSF Profiles

*Normal CSF Profile:* 1. *Glucose:* 50-80 mg/dL (2/3 of blood) 2. *Protein:* 15-45 mg/dL (elevated in disease due to vasogenic edema) 3. *RBC:* none 4. *WBC:* 0-5 cells/uL (60% *L*, 40% *M*, 0% *N*) 5. *Opening pressure:* 70-180 mmH2O (200+ is abnormal) 6. *Appearance:* clear

*Saccular (Berry) Aneurysm* -Cause of SAH

*Often due to connective tissue disorders (lack of an internal elastic lamina).* *Highest risk of rupture:* 85% in anterior circulation 1. >7mm 2. Anterior communicating (ACom) 3. Posterior communicating (PCom) 4. Posterior circulation (basilar, vertebral, and cerebellar). *Clinical Findings:* 1. *ACom:* compression → *bitemporal hemianopia* (compression of optic chiasm); visual acuity deficits; rupture → ischemia in ACA distribution → contralateral *lower extremity* hemiparesis, sensory deficits. 2. *MCA:* rupture → ischemia in MCA distribution → contralateral *upper extremity and lower facial* hemiparesis, sensory deficits. 3. *PCom:* midbrain compression → ipsilateral *CN III palsy* → mydriasis ("blown pupil") and down-and-out eye; may also see ptosis

Cheyne-Stokes Breathing

*Oscillatory pattern of hyperventilation slowing to apnea* for periods of several seconds and then gradually returning to hyperventilation. *Hyperventilation leads to low CO2, which then leads to reflexive apnea (no need to breathe if CO2 is already low). Apnea, in turn, leads to high CO2, which induces hyperventilation.* This crescendo/decrescendo pattern is due to the short delay in pulmonary blood getting to chemoreceptors, which leads to "overshoot" in both directions. This is the *normal pattern of an intact brainstem, but is usually overridden by intact diencephalon and cerebrum which maintain respiratory drive above apnea at all times*.

*Signs of LMN damage* -Spinal or brainstem motor neurons, ventral roots, motor nerves -Mnemonia: going to HĀFAH's basement (lower) + W

*PNS Problem:* everything is *low* 1. Hypotonia (lower muscle tone; flaccidity) 2. Atrophy (less muscle mass) 3. Fasciculations 4. Absent Babinski (-): down-going toes 5. Hyporeflexia (less reflexes) 6. Weakness

LMN Signs -Mnemonia: going to HĀFAH's basement (lower)

*PNS Problem:* everything is *lowered* 1. Hypotonia (lower muscle tone; flaccidity) 2. Atrophy (less muscle mass) 3. Fasciculations 4. Absent Babinski (-): down-going toes 5. Hyporeflexia (less reflexes) 6. Weakness

Clinical Features Based on Brain Abscess Location

*Parietal Lobe:* 1. Headache 2. Visual field defects *Frontal Lobe:* 1. Headache 2. Drowsiness 3. Inattention 4. Mental function decline 5. Hemiparesis 6. Motor speech disorder (Broca) *Temporal Lobe:* 1. Ipsilateral headache 2. Aphasia (dominant hemisphere) 3. Upper homonymous quadrantonopia (Meyer's lower loop) *Cerebellum:* 1. Vomiting (vermis and hemispheres) 2. Nystagmus (vestibular nucleus in pons/medulla) 3. Ataxia (spinocerebellum (vermis and associated areas near the midline) presents itself with a wide-based "drunken sailor" gait) 4. Dysmetria (cerebellar hemispheres; finger-nose-finger)

Clinical and Pathological Features of Parkinson's Disease

*Parkinson TRAPS your body:* 1. Tremor (pill-rolling tremor at rest; resolves with movement) 2. Rigidity (cog-wheel) 3. Akinesia (or bradykinesia)(masked/statues) 4. Postural instability (stooped) 4. Shuffling gait (festinating) *Pathology:* 1. Dopamine neurons of the substantia nigra pars compacta (SNc) slowly die *(depigmentation)* (50-80%) 2. *Lewy bodies:* α-synuclein aggregates (eosinophilic inclusions) in pigmented nerve cells (SNc)

*Bacterial* Meningitis

*Pathogenesis:* 1. *Mucosal colonization and local invasion* - Nasopharyngeal acquisition of a new organism - Fimbriae: finger-like projections of bacteria that attach to pseudostratified columnar epithelium - Transport: transcellular: attach, travel through cell and into bloodstream 2. *Bacteremia* - Bacterial capsule: inhibits neutrophil phago and resists complement-mediated killing - Host defense mechanisms: virulence factors prevent host defense 3. *Meningeal invasion* *Pathophysiology:* 1. *Bacterial replication in subarachnoid space* - Low Ig and complement in CSF (*inadequate host defenses*) 2. *Release of bacterial virulence components* - Cell wall components (peptidoglycan) - Lipo-oligosaccharide 3. *Cytokine release* by MØ (*IL-1b, TNF-a, IL-6*) causes inflammation in the subarachnoid space and loosens tight junctions (↑BBB permeability) 4. *Cerebral Edema (↑ ICP)* - *Vasogenic* (BBB breakdown): high molecular weight proteins enter; H2O flows via diffusion - *Interstitial:* CSF flow is disrupted and fluid backs up - *Cytotoxic:* toxic substances from WBC → cloudy swelling of the brain parenchyma 5. *Altered cerebral blood flow* - Loss of cerebrovascular autoregulation (preventing normal brain perfusion with altered BP) - *Cerebral vasculitis:* WBC inflammation inflames blood vessels and ↑stroke risk 6. *Neuronal Injury:* - Generation of ROS, RNS, and peroxynitrite (host response causes collateral damage) - Apoptosis

HIV Infection and the Brain

*Pathologically, HIV infection produces:* 1. *Giant cells* (multinucleate mass of MØ that usually wall off granulomas) 2. *Stab cells* (slender, microglial cells) 3. *NO inclusion bodies* *Pathological Presentations:* 1. Acute meningitis or encephalitis 2. Subacute encephalitis 3. Vacuolar myelopathy 4. Peripheral neuropathy HIV predisposes the host to opportunistic infections, including *toxoplasmosis*, which can produce *mulberry-like toxocysts* in the brain parenchyma associated with proliferation of *tachyzoites* within the cystic space.

*Tethered Cord Syndrome*

*Pathology:* 1. Abnormally low-lying conus medullaris (L3 rather than L1) 2. 2° short, thickened filum terminale (descending fibrous tissue from apex of the conus medullaris) or intradural lipoma *Clinical Findings:* 1. Back pain 2. Leg weakness 3. Sensory loss 4. Bowel/bladder dysfunction 5. Cutaneous stigmata (hair over area on back)

*Wernicke's Encephalopathy* -Thiamine (B1) deficiency -Mammillary bodies and hyptothalamus -Confabulation (lying)

*Pathology:* 1. Hemorrhagic lesions of the *mammillary bodies and hypothalamus* (but the lesions are not truly hemorrhagic). 2. Proliferation of small vessels (reticulin stain) 3. Neuronal loss and gliosis of affected areas Damage to the *dorsomedial thalamus* leads to the *confabulation* (make things up that are not true) characteristic of Wernicke-Korsakoff syndrome (often seen in chronic alcoholism due to malnutrition and *B1 deficiency* that impairs neuronal energy utilization).

*Giant Cell / Temporal Arteritis* -Secondary Headache -*Periorbital pain and tenderness* -↑*CRP/ESR* (inflammation) -Damaged internal elastic laminae -Treatment: *high dose steroids*

*Periorbital, throbbing pain often with visual symptoms (e.g., floaters).* 1. *Onset is >50 y.o.* 2. *Tenderness over the temporal arteries; artery stiff to palpation* *Lab Findings:* 1. Elevated CRP (*C-reactive protein*) 2. Elevated ESR (*erthyrocyte sedimentation rate*, measure of inflammation) 3. On pathology, vessels have *damaged internal elastic laminae* (which invokes an inflammatory response of lymphocytes, plasma cells, macrophages, and *giant cells*.) Risk: Stroke and visual loss Treatment: *High dose steroids (Prednisone)*

Oculocephalic Reflex (Doll's Eyes)

*Positive Doll's = Normal.* Eyes deviate opposite to head turn (to maintain fixation on the target). When both the FEF and PPRF are "out" (herniation has reached the pons), Doll's eyes will be present (*negative test*).

*Primary vs Secondary Headaches* *Primary:* neuropathic *Secondary:* nociceptive

*Primary Headache is benign; neuropathic* 1. Migraine 2. Muscle contraction ("tension") headache 3. Cluster headache 4. Headache unassociated with a structural lesion 5. Trigeminal neuralgia *Secondary headache is due to a specific cause; nociceptive* 1. Increased ICP (can be detected via papilledema) (e.g., mass effect stretches dura) 2. Infections and inflammations (e.g., irritating effects on blood vessels or dura) 3. Structural lesions 4. Drugs and toxins

Primary vs. Secondary Injury (TBI)

*Primary Injury:* Damage occurring at the time of impact (contusion, tissue disruption, hemorrhage, axonal injury, penetrating injury) *Secondary Injury:* Edema, ischemia, oxidative injury, neurochemical disruption, and toxicity

Causes of Brain Metastases

*Primary Sites:* 1. Lung cancer (50%) 2. Breast cancer (15-20%) 3. Unknown primary (10%) 4. Melanoma (10%) 5. Colorectal cancer (5%)

Brain Neoplasms (Mass)

*Primary:* tumor from cell of CNS origin (astrocyte, meninges, neuron, germ cell, lymphocyte, etc.) -Usually a single mass, but can be extensive -*Intra-axial* (exception: meningioma) *Secondary:* metastases (via bloodstream) -Usually multiple masses -Brain metastases: intra-axial > extra-axial -Spine metastases: extra-axial > intra-axial

*Cortico-Ponto-Cerebellar Loop* -Affected in essential tremor -Deep Brain Stimulation of VIM interrupts cerebellar output and can remove essential tremor (tremor during movement)

*Provides efference copy of motor commands to cerebellum (that cancels out expected somatosensory sensations).* *Crossed projection:* cerebrum receives spinal (ipsi) and cortical (contra) input concerned with the ipsilateral side of the body *Input:* Corticopontine fibers carrying motor commands from M1 (cerebral cortex) *synapse in pons at the pontine nuclei*, then cross midline and travel through the *middle cerebellar peduncle* on the opposite side of the brainstem (*efference copy*). *Output:* Purkinje cells have an *inhibitory* influence on the dentate nucleus, involved in high-level movement coordination. These axons exit through through superior cerebellar peduncle, decussate, and terminate in the contralateral VL thalamus, where they synapse before traveling back up to M1 (contralateral to the cerebellar hemisphere).

Function of Basal Ganglia -Reinforcement learning with dopamine

*Reinforcement learning (trial-and-error) via dopamine.* The basal ganglia is not just a motor structure, but motor symptoms are the most obvious sign of dysfunction.

Kindling Model (in mice)

*Repeated sub-convulsive stimuli* resulted in electrical after-discharges. Eventually, these sub-convulsive stimuli led to *stimulation-induced clinical seizures*, and later, to *spontaneous seizures (epilepsy)*.

__________ (artery) is especially affected by embolism

*Right ICA* because it has a direct pathway from the left ventricle of the heart where most emboli come from (mural thrombosis in A Fib)

Warning Signs for *Secondary Headache* (*Red Flags*)

*SNOOP:* require immediate neuroimaging (and potential LP) -*S*ystemic symptoms (fever/weight loss) or Secondary Risk Factors (HIV/cancer) -*N*eurological symptoms (confusion, LOC) -*O*nset (sudden, abrupt) -*O*lder (new onset in middle age) -*P*revious headache (change frequency or severity) Other secondary headache symptoms: 1. *Sudden onset* 2. *Worst or First* 3. *Atypical* 4. Pain worsens 5. Neuro signs (focal weakness, *sleepiness*) 6. New Headache over age 50 7. Positional headache (lying/bending over > standing as ICP is higher without gravity) 8. Wakes patient in middle of night 9. Projectile vomiting 10. Altered consciousness (LOC)

How is the STN different from other intrinsic basal ganglia nuclei?

*STN* (sub-thalamic nucleus) is the *only excitatory output* among intrinsic nuclei of the basal ganglia

Microhemmorhages on *MRI/SWI* in CAA -Blood iron from peripheral, petechial hemorrhage

*SWI = susceptibility weighted imaging* Blood *iron* from prior *peripheral microhemmorages* is visualized (black). CAA damage usually occurs at *terminal branches of the MCA*.

*Palisading* of nuclei happens for... -Pseudopalisading = GBM

*Schwannomas.* *Location:* 1. Classically at the cerebellopontine angle involving both CNs VII and VIII, but can be along any peripheral nerve. 2. Often localized to CN VIII in internal acoustic meatus → vestibular schwannoma. *Bilateral vestibular schwannomas found in NF-2.* *Treatment:* Surgical resection is curative

Seizure vs. Syncope

*Seizure:* disrupted cerebral physiology with *hyperexcitable, hypersynchronous neuronal activity* 1. *Prodrome:* None, or typical aura (GI, déjà vu, sensorimotor) 2. *Setting:* Random, often in sleep, may be seated, not situational 3. *Ictus:* Rigid fall, injuries, incontinence, clonus—occ. focal 4. *Confusion:* Prominent, minutes to hours, occasional Todd's paresis *Syncope:* temporary LOC caused by ↓BP 1. *Prodrome:* Nausea, pallor, clammy, visual graying, altered pulse 2. *Setting:* Often situational (pain, emotion, dry), upright, voiding 3. *Ictus:* Flaccid fall, rare injury, brief and generalized jerking 4. *Confusion:* Mild, fleeting, no paresis, "shaken up"

*Anterior Cord Syndrome*

*Sensory loss is "dissociated" (DC-ML intact; AL affected)* 1. Loss of motor function (CST/anterior horns) → paraplegia 2. Loss of pain and temperature (AL / anterior commissure). 3. Maintain position, vibration, and touch (DC-ML) 4. Hyperreflexia

Kleine-Levin Syndrome

*Sleeping Beauty syndrome* -Persistent episodic hypersomnia -Cognitive or mood changes Many patients also experience *hyperphagia and hypersexuality*.

Types of Skeletal Muscles Mneumonic: *1 Slow Red Ox*idative Phosphorylation I. *Slow twitch:* red fibers resulting from ↑mitochondria and myoglobin (↑oxidative phosphorylation) → sustained contraction. Proportion ↑ after endurance training. II. *Fast twitch:* white fibers resulting from ↓mitochondria and myoglobin (↑anaerobic glycolysis). Proportion ↑ after weight/resistance training, sprinting.

*Slow Twitch (I):* posture and endurance (*aerobic* metabolism with *sustained contraction*) (e.g., soleus muscle; postural muscles) -Small motor neurons -Axons conduct slowly -Tonically active during movement -Slow rise and decay in tension (slow twitch) -*High lipid* and oxidative enzymes -Small fibers, few in motor unit -*Little stored glycogen and few glycolytic enzymes* -Many *mitochondria* (aerobic respiration) -Rich capillary supply with high levels of *myoglobin* (high O2) *Fast Twitch (II):* sprinting muscles (*anaerobic* metabolism with *short, powerful contractions*) -Large motor neurons -Axons conduct rapidly -Burst at high frequencies -Fast rise and decay in tension (fast twitch) -Rapid fatigue -Large fibers, many in motor unit -Lots of *stored glycogen* -High levels of glycolytic enzymes (glycolysis) -Few mitochondria -Poor capillary supply *Fast Fatigue-Resistant (IIA):* intermediate (fast and slow type) -e.g., gastrocnemius (mixed uses) *Fast Fatiguable (IIB):* more cross bridges, less ATP -e.g., extra-ocular muscles

*Spasticity* -Loss of net inhibition (CST) -Activation of LMN via 1a afferents in a *positive feedback loops* -*Treatment:* cut dorsal roots to stop unopposed activation of LMN by 1a afferents

*Spasticity ONLY occurs with lesions inside the CNS* (UMN sign). 1. Hyperreflexia (exaggerated tendon reflexes) 2. Hypertonia (increased resistance to passive movement due to ↑tone) 3. Clonus (oscillating muscle spasm) Spasticity occurs as a result of *loss of net inhibitory input from the CST,* which leads to unopposed *activation of alpha motor neurons* receiving input from Type 1A afferents. A surgical treatment for severe spasticity is to cut the dorsal roots (*dorsal rhizotomy*), which stops Type 1A afferent inputs to the alpha motor neuron.

Brain Tumors vs. "Lower Organ" Tumors

*Staging is not defined by the TNM system* 1. T: size and extent of the main tumor 2. N: number of affected nearby lymph nodes 3. M: metastasis There is no CNS lymphatic drainage into lymph nodes, no concept of "margins," and brain tumors very rarely metastasize to lower organs

*Polysynaptic (Crossed) Reflexes* 1. Flexor Reflex 2. Crossed Extensor Reflex

*Stepping on Pin*: activates Aδ fibers from nociceptors (graded: greater intensity; greater reflex) *Reflex:* occurs in spinal cord (loss of this reflex indicates damage to the spinal cord or peripheral nerves) *Stimulated Leg:* withdraws (flexor) 1. Inhibit extension 2. Activates flexion *Opposing Leg:* supports (crossed extensor) 1. Activates extension 2. Inhibits flexion Note: In adults the *crossed extensor reflex* is not normally elicited without strong stimulation but may appear in exaggerated form when there is spasticity due to *cerebral or brainstem damage*.

Basal Ganglia Components

*Striatum* 1. Caudate 2. Putamen 3. Nucleus Accumbens (ventral striatum) *Globus Pallidus* 1. Internal segment (GPi): inhibits thalamus 2. External segment (GPe): inhibits STN (indirect) *Functionally:* 1. *Substantia Nigra* (midbrain) a. Pars compacta (*SNc*): contains *dopaminergic cells* b. Pars reticulata (SNr): motor function 2. *Subthalamic Nucleus* (STN) (diencephalon)

*Subcortical Stroke Symptoms* -Small arteries -Deep, lacunar strokes don't take out a large area of cerebrum -*Small vessel disease due to hypertension*

*Sub-Cortical* usually *small artery, deep lacunar* stroke -F=A=L (descending cortical fibers have come together)

Non-Cortical vs Cortical Stroke Causation

*Sub-Cortical* usually *small artery, lacunar* stroke -F=A=L (descending information has coalesced) *Cortical* usually *large artery, embolic* stroke -FA>L or L>FA (information from homunculus)

Sudden onset of "worst headache of my life" is probably...

*Subarachnoid Hemorrhage* (due to a *ruptured aneurysm*) leaves the entire brain coated in blood. 1. SAH represent 3% of all strokes with a high rate of morbidity and morality (up to 45%). 2. Affects women more than men (1.6:1) and incidence increases with age (peak 40-60). 3. FAMILIAL (greatest risk is with an affected sibling).

*Types of Herniation* 1. *Subfalcine:* ACA compressed 2. *Transtentorial:* CN III palsy, duret hemorrhages (basilar artery ruptures), contralateral hemiplegia (false-localizing) 3. *Cerebellar:* compresses respiratory centers in the pons and medulla

*Subfalcine:* 1. Swelling of the brain causes a mass effect that pushes brain parenchyma underneath the falx cerebri at the midline of the cerebrum. 2. *Compression of the ACA* causes infarction of the medial frontal cortex *Transtentorial/Uncal:* 1. Brain parenchyma is pushed beneath the tentorium cerebelli atop the cerebellum due to a mass lesion. 2. *Compression of CN III* leads to pupillary dilatation, and *compression of the PCA* causes occipital lobe infarction. 3. Brainstem compression leads to necrosis of the contralateral cerebral peduncle, causing *hemiplegia ipsilateral to the mass lesion* (Kernohan's notch phenomenon / false-localizing sign). 4. Brainstem compression can rupture small, penetrating blood vessels (*paramedian basilar artery branches*) in the *midbrain and pons*, leading to *duret hemorrhages* (patient is braindead). *Cerebellar Tonsillar:* 1. *↑↑ICP* in the cerebellum forces parenchyma through the foramen magnum. 2. *Compresses respiratory centers* in the medulla and pons. 3. *Cushing's Triad:* ↑ BP, irregular breathing, and bradycardia.

Circadian Rhythm regulated by.... (EXAM)

*Suprachiasmatic Nucleus (SCN)* (in ventral hypothalamus) = biological clock Circadian rhythms are endogenously-driven physiological oscillations.

*Distal Symmetric Polyneuropathy* -Common: Diabetic Peripheral Neuropathy

*Symmetric stocking-glove distribution* of weakness, numbness, paresthesias (burning/prickling), and pain. Most often caused by diabetes, but can be caused by HIV, alcohol, vitamin deficiencies (B1/B6/B12), and hereditary neuropathies. *Small Fiber Neuropathies:* 1. *Temperature and pain sensation are affected (small fibers)* 2. Vibration, joint position sense, and strength are usually spared (large fibers). Exam Findings: *Normal EMG test and MRI spine.* *Treatment for Neuropathic Pain:* 1. *Anti-depressants:* -Tricyclics (amitriptyline) -SSRIs (duloxetine) 2. *Anti-convulsants:* -Carbamazepine (for trigeminal neuralgia): Na+ channel blocker -Gabapentin (N-type Ca2+ channel blocker) -Pregabalin: Ca2+ channel blocker

Outputs of the Basal Ganglia

*Thalamus (VA and VL)* 1. VLc, ventral lateral nucleus, pars caudalis 2. VLo, ventral lateral nucleus pars oralis 3. VA, ventral anterior nucleus

Ascending Reticular Activating System (ARAS)

*The ARAS is our anatomic "switch" for cortical arousal.* Features: 1. Centered in the paramedian mesopontine tegmentum 3. Receives input from the spinal cord, special senses, and internal stimuli (e..g, circadian rhythm) and then *projects from the brainstem to the thalamic relay nuclei to the cerebral cortex* diffusely.

Mytotatic Reflex Roles

*The neural circuitry of the myotatic reflex can be thought of in 2 ways:* 1. Automatically adjusting muscle force to a changing load (stretch by added load causes increased 1a sensory firing, which increases alpha motor neuron firing, which causes contraction) *or* 2. Active participation in voluntary muscle shortening (by LMN)

*Mechanisms of Ischemic Stroke* (Stopa and Saad)

*Thrombotic:* atherosclerotic narrowing of cerebral vessels (*progressive* process) 1. *Patients experience TIAs before stroke* (not acute) 2. Dead tissue within the infarct undergoes *liquefactive necrosis*, as MØ clear out the debris. 3. Complete *carotid occlusion* (at bifurcation) can lead to loss of brain tissue served by both the ACA and MCA, though collateral blood circulation can help to minimize tissue damage (communicating arteries). 4. *Small arterioles* frequently become *thickened* and narrowed in patients with *hypertension* (arteriolosclerosis). Affected arterioles often have thickened walls that are described as *onion-skinned* (lipohyalinosis). Occlusion of these small vessels results in *lacunar infarcts* (basal ganglia and pons are popular sites). *Embolic:* cardiac mural thrombus (Afib patients) or embolus of carotid plaque 1. *Acute* onset 2. *Antithrombin III and plasmin try to dissolve the clot*, but by the time restored blood flow arrives, it reaches necrotic brain tissue → *"reperfusion hemorrhage"*. 3. Embolic infarcts have a greater tendency to become hemorrhagic than thrombotic infarcts.

L-Dopa

*Treatment for PD* -Crosses blood brain barrier (BBB) and is taken up by the remaining neurons of the SNc and converted into dopamine (making up for some of the dopamine deficit) -Works best, fastest, cheapest -High % of long-term drug-induced movement complications, wearing off, dyskinesias (hyperkinetic movements, including chorea, dystonia, and athetosis)

Headache pain mediated by ....

*Trigeminal (CN V) and C1/C2 afferents* (descend into the upper cervical spinal cord to the trigeminal nucleus in the brainstem). Reminder: Brain parenchyma lacks nociceptors for pain. The scalp, periosteum, meninges, venous sinuses, blood vessels, and muscles around the head and neck have nociceptors.

Damage to Brodmann 4 (primary motor cortex) results in...

*UMN Signs:* long motor track (pyramidal) damage 1. Hemiparesis (weakness) or hemiplegia (paralysis) especially in fine, precision movements (contralateral; above medullary pyramids). 2. Spasticity (hyperreflexia, hypertonia, and clonus) 3. Babinski's sign

*Diffusion Tensor Imaging (DTI)* -Tract "tracing"

*Used to determine location of white matter tracts and fibers in the brain.* Diffusion Tractography (eigenvalues of movement) 1. Cortex or CSF in ventricles: H2O can move in all directions 2. White matter: H2O can only diffuse along a longitudinal axis of the myelinated fibers

MS Plaques on FLAIR and Gd contrast look like? (*dissemination in space*)

*Used to look a MS dissemination in time:* 1. *FLAIR MRI:* white spots for all plaques (old and new) 2. *Gd MRI:* active, acute inflammatory demyelination appears white because these are areas of active inflammation (new plaques) The use of FLAIR/Gd imaging can be used to track MS progression: from preclinical phases, through the relapsing-remitting phase (where quiescence might be seen on Gd = old lesions appear as a "black hole"), and into the secondary-progressive phase.

Vasogenic Edema vs. Gliosis

*Vasogenic Edema:* -Excess of fluid and protein in extracellular space from breakdown of blood-brain barrier -*Positive mass-effect*, i.e., *pushes* *Gliosis:* -Proliferation of neuroglia as a repair process; brain "scarring" -*Negative mass-effect*, i.e., *pulls* *Encephalomalacia:* -Softening or loss of brain tissue as a late manifestation of injury

Brain Neoplasms (Mass Effect)

*Vasogenic Edema:* destruction of the BBB allows protein and water to infiltrate (around mass). Disruption of the BBB (by the presence of vasogenic edema) is a clue for *metastases*. *Presentation:* 1. Compression: effacement of sulci or ventricles (which can cause hydrocephalus and swelling of the ventricles) 2. Herniation: displacement of parenchyma across compartments delimited by falx cerebri or tentorium cerebelli

Midline and Intermediate Vermal Regions (output targets)

*Vermis:* 1. Sends its output via the *fastigial nucleus* 2. Influences *axial muscles* via projections to the *vestibular nuclei* and the *reticular formation* (ventromedial brainstem pathways: vestibulospinal / reticulospinal). *Intermediate/Paravermal Zone:* 1. Sends its output goes by way of the *interposed nucleui* 2. Concerned with *girdle and proximal limb muscles* 3. Has strong connections to the *red nucleus* and the lateral brainstem (rubrospinal) pathway. 4. Adjusts ongoing movements via its extensive sensory input from the spinal cord.

Acute Lymphocytic *Viral* Meningitis

*Viral meningitis* that can cause *glial nodules* (activated microglia around necrotic brain tissue), phagocytosis of dead neurons (*neuronophagia*), and eosinophilic, intranuclear *inclusion bodies* if the disease spreads to the brain parenchyma (*encephalitis*). *Inclusion Bodies:* 1. Cowdry Type A: herpes viruses (HSV) 2. Cowdry Type B: poliovirus 3. "Ground Glass": PML (progressive multifocal leukoencephalopathy) 4. Negri bodies (intracytoplasmic) *CSF profile:* 1. ↑ protein 2. *= glucose* 3. *Mononuclear* predominance (perivascular/periventricular lymphocytes, plasma cells, and MØ)

Neurotransmitters in Sleep

*Wake:* -NE: promotes wakefulness, suppresses REM (locus ceruleus) -Dopamine: promotes alertness and wakefulness (SNc) -Histamine: cortical activation (posterior hypothalamus) -*Hypocretin/Orexin:* promotes wakefulness, *suppresses REM* (lateral hypothalamus); a deficiency in hypocretin/orexin leads to narcolepsy (skip slow wave sleep, and go right into REM) *NREM:* -Serotonin: suppresses REM (Raphé) -GABA: inhibitory; involved in NREM (reminder: GABAergics are sleeping pills) -Adenosine: suppresses excitatory neuronal transmission in the CNS and PNS (caffeine is an adenosine antagonist) *REM:* (EXAM) -*ACETYLCHOLINE (ACh):* works in the *"REM-on"* neurons in the *pons* to *promote REM sleep*. As a result, anti-cholinergic drugs can affect REM sleep. ACh formed in the basal forebrain nucleus of Meynert)

Inclusion Body Myositis (myopathy)

*Weakness and atrophy asymmetric* and can affect both *proximal and distal muscles*. -*Flexor forearm* and *knee extensor* muscles are most affected -Pathology shows ringed vacuoles and inflammation Unlike dermatomyositis and polymyositis, inclusion body myositis *does not respond well to any immunosuppressive treatments*. Support only.

Brainstem (signs) Weakness: *Crossed Signs*

*Weakness:* Ipsilateral face; contralateral arm/leg (long tracts decussate in caudal medulla) *Non-Motor:* CN abnormalities -Midbrain: CN III, IV -Pons: CN V, VI, VII, VIII -Medulla: CN IX, X, XI, XII *General Rule:* 1. Motor pathways and CN motor nuclei tend to be antero-medial. 2. Sensory pathways and CN sensory nuclei tend to be dorso-lateral. *UMN signs*

Nerve Root/Plexus (signs) *Nerve Root:* radiculopathy (dermatome/myotome) *Nerve Plexus:* plexopathy (brachial/lumbosacral)

*Weakness:* One limb, in distribution of root (dermatome/myotome) or plexus (brachial/lumbosaccral) *Non-Motor:* Sensory abnormalities *LMN signs*

Spinal Cord (signs)

*Weakness:* Quadriparesis/Paraparesis *Non-Motor:* Spinal sensory level, sphincter/bladder disturbance *UMN +/- LMN signs*

Muscle (signs) -Proximal

*Weakness:* Symmetrical bilateral; *proximal > distal!* *Non-Motor:* *No non-motor symptoms!* *Neither Sign*

Neuro-Muscular Junction (signs) -Bulbar / EOM

*Weakness:* Symmetrically bilateral, generalzied or *prediliction for bulbar (pharyngeal) and extra-ocular muscles*; *muscles are also fatiguable* *Non-Motor:* No non-motor symptoms *Neither Sign*

Subcortical corticospinal tracts (CST) (signs)

*Weakness:* Usually *equal* contralateral hemiparesis (cortical fibers have come together on descent) *Non-Motor:* Often none; If bilateral, slurred speech, impaired swallowing, pseudo-bulbar palsy (inability to control facial movements (such as chewing and speaking)) *UMN signs*

Cerebral Cortex (signs)

*Weakness:* Usually *unequal* contralateral hemiparesis (structures are spread out on the homunculus, so different structures (FAL) will be affected differently) *Non-Motor:* often none, but the sensory cortex is adjacent to M1; motor language could be affected (Broca's on left). If bilateral, ↓LOC. *UMN signs*

Nerve (signs) -Distal > Proximal -Stocking glove

*Weakness:* distal axons undergo Wallerian Degeneration 1. Polyneuropathy (symmetric bilateral): legs > arms; *distal > proximal*) (*stocking-glove*) 2. Mononeuropathy (in distribution of the nerve only; e.g., median nerve in carpal tunnel) *Non-Motor:* Sensory disturbance (unless pure motor polyneuropathy); *distal > proximal* *LMN signs*

Alternative Treatments of Epilepsy (non-pharmaceutical)

*When standard AEDs fail* (30% of patients), *surgery* is an additional option. *Well-localized cases to non-eloquent cortex.* 1. Lobectomy 2. Lesion-ectomy 3. Laser ablation (LITT) 4. Callostomy (cut corpus callosum) for palliation 5. Vagal nerve stimulation *Non-Surgical Options:* 1. Medical marijuana 2. Ketogenic diet (pediatric)

Most Common Multiple Sclerosis Symptoms

*White matter demyelination:* 1. *Limb weakness* (corticospinal) 2. *Vision* -Central scotomata (optic nerve) -Diplopia (brainstem) 3. *Altered sensation* (DC-ML, AL, spinocerebellar) 4. *Incoordination* (cerebellum/brainstem) 5. Bladder, bowel, and sexual dysfunction (*autonomics*) 6. *Cognitive impairment* (cerebral)

Proven Risk Factor for Brain Tumors

*X-irradiation* most often induces *meningioma*. Exposure: 1. Low-level XRT to scalp for tinia capitis (worms) 2. Prophylactic CNS radiation to children with acute lymphocytic leukemia (ALL)

Chronic Traumatic Encephalopathy

Deleterious effect of *cumulative TBI/concussions* *Symptoms:* -Cognitive impairments -Lower scores on neuropsychological testing -Personality changes -Depression -Parkinsonian features among impact-athletes -Degenerative changes -*Association:* Alzheimer's dementia

Mononeuritis Multiplex (exam)

-*Asymmetric* neuropathy affecting large nerves → occurs *step-wise* -Associated with vasculitis-causing diseases (e.g., RA) -*Motor and sensory nerves* are involved, causing weakness, numbness, paresthesias, and pain

Subarachnoid Hemorrhage -Xanthochromia in CSF

-*Location:* between the arachnoid mater and pia mater -*Source:* typically *burst cerebral aa. aneurysm* (follows the contour of sulci/gyri); results in a *thunderclap headache* -*Finding:* *blood in cisterns* (star shape on CT) and filling along the sulci and fissures (over the convexity of the brain due to subarachnoid space continuance around the cerebrum); *blood cells can be found in CSF via lumbar puncture* (bilirubin in the CSF results in *xanthochromia* -- yellow discoloration).

Ulnar Nerve Entrapment (mononeuropathy)

-Compression of the ulnar nerve as it wraps around the elbow (funny bone) -Numbness in ring finger to pinky extending down on palmar/dorsal hand -Weakness in hand (test with paper hold; thumb bends out to compensate) -Tinel sign at elbow (feel radiating pain?)

Carpal Tunnel Syndrome (mononeuropathy)

-Focal median neuropathy at wrist -Numbness in thumb to half of ring finger with thenar eminence spared -Weakness in thumb movement -Tinel (at wrist) and Phalen sign Treatment: wrist brace at night, pain meds (gabapentin), and/or surgery

Psychogenic Coma

Diagnosis of exclusion (pretty much everything anatomically is normal)

To confirm an aneurysm (acutely) do this imaging

Digital Subtraction Angiography

Symptoms of ICH

1. *Abrupt onset* with gradual evolution over minutes to hours 2. *Thunderclap headache (50%)* - also seen in subarachnoid hemorrhage 3. Neck stiffness (due to irritation of the meninges) 4. Vomitting (due to mass effect) 5. Focal Seizures (10%) 6. Focal symptoms as a function of site of bleed

*Dyskinesias* (extrapyramidal) -Abnormal movement

1. *Akinesia:* unable to initiate movement 2. *Bradykinesia:* slow movement (Parkinsonism) 3. *Chorea:* jerky, involuntary movements (dancing movements of Huntington's disease; *degeneration of caudate*) 4. *Athetosis:* slower, writhing, twisting movements (cerebral palsy and Huntington's) 5. *Ballismus:* rapid, large-amplitude flinging movements (usually contralateral *STN damage*, decreasing excitation of the GPi, which disinhibits the thalamus and grossly exaggerates otherwise normally-skilled movements) 6. *Tic:* rapid, fleeting, stereotyped movement (suppressible with effort; Tourette's syndrome) 7. *Tremor at rest:* pill-rolling tremor of Parkinsonism

Sleep Physiology

1. *Autonomics:* -*NREM:* parasympathetics (pupils constricted, slow heart rate, sweating reduced, genitalia flaccid, gut motility enhanced) -*REM:* sympathetic tone decreases further, parasympathetic dominates, but there are phasic increases in sympathetic outflow (variable heart rate, pupils dilate, thermoregulation disrupted (no hypothalamic regulation during REM); engorged genitalia. 2. *Cardiac:* -*NREM:* slowed heart rate, decreased cardiac output, BP decreases (vasodilation) -*REM:* cardiac output is the same as wake, vasodilation (except striated muscle) 3. *Pulmonary:* -*NREM:* automatic, regular breathing; decrease in O2; increase in CO2 -*REM:* irregular breathing; decreased muscle tone (throat muscles collapse) increase upper airway resistance (2x) 4. *Endocrine* -Growth hormone synthesized (slow wave sleep: 3-4) -Prolactin synthesized in NREM (1-3) -TSH peaks in the evening and declines during sleep -Cortisol and melatonin regulated by circadian rhythm

*Temporal Bone* Basilar Skull Fracture Symptoms

1. *Battles Sign* (mastoid ecchymosis) 2. CSF Otorrhea (CSF drains from ear) 3. Facial Nerve (CNVII) Palsy

To have a coma you have to do one of the following:

1. *Bilateral hemisphere* (or diencephalon) lesions (light bulbs) 2. *Upper brainstem* lesions (primary or secondary, ARAS) (light switch) Coma is NOT due to: 1. Unilateral hemisphere lesion alone (leads to lateralizing findings with intact consciousness) 2. Lower brainstem lesion alone (leads to significant motor and other brainstem findings but intact consciousness, such as locked-in syndrome)

Diagnosis of Brain Tumors

1. *CT (most common)* -Relatively sensitive, *not specific* -Can miss structural lesions (particular in the posterior fossa due to bony anatomy) 2. *MRI* (best for diagnosis of intracranial neoplasms) -*Gd-enhanced* MRI can look for breaches to the BBB (metastases) 3. Histology

Basal Ganglia Dysfunction (*Extrapyramidal motor signs*)

1. *Dyskinesias* (abnormalities of movement) 2. *Dystonias* (abnormalities of resting muscle tone) -*NOT hyperreflexia* (which is seen in CST "pyramidal" spasticity; UMN sign) 3. *Tremor*

*Conus Medullaris Syndrome* -Symmetric -*Hyperreflexia* -Saddle Region anesthesia -*Early sphnicter dysfunction* (conus medullaris comes before cauda equina on descent)

1. *Early* sphincter dysfunction 2. *Saddle* (perineum) anesthesia (S2-4) 3. *Hyperreflexia* (UMN) 4. Dull aching pain over the site of the tumor Conus medullaris is *symmetric* because the base of the spinal cord is mesial. Cauda equina is *asymmetric:* think falling off the horse on one side.

Clinical Features of Encephalitis

1. *Encephalitis:* inflammation of the brain parenchyma with neurologic dysfunction 2. *Encephalopathy:* *Altered consciousness* (confusion, disorientation, behavioral changes, cognitive impairment)* ± inflammation*. *Heterogeneous Etiology:* only determined in 16% of patients -*69% viral* (mononuclear cells in CSF) -20% bacterial -7% prion -3% parasitic -1% fungal

Vegetative State

1. *Eyes open* 2. *NO response to external environment* 3. Sleep-Wake cycle preserved 4. Profound bihemispheric dysfunction

Topographical control of lobes of cerebellum

1. *Flocculonodular lobe and Vermis* (vestibulo/spino-cerebellum) -Influence the trunk and posture via ventromedial brainstem pathways (tectospinal, vestibulospinal, reticulospinal) -Vermis: Fastigial nuclei to axial muscles 2. *Intermediate lobe* (spinocerebellum) -Influences the girdle and proximal limbs (especially arm flexure) via the lateral brainstem pathway (rubrospinal) -Interposed nuclei (emboliform and globus) 3. *Lateral cerebellum* (cerebrocerebellum) -Connected with cortex to influence the CST and fine hand movements -Dentate nuclei to VL thalamus and motor cortex

Oligodendrogliomas (Pathology)

1. *Fried egg* cells (round nuclei with clear cytoplasm, often calcified) 2. *Chicken-wire capillary pattern*

Major Routes of CNS Infection

1. *Hematogenous* 2. Direct inoculation (trauma; e.g., rusty nail) 3. Local extension (e.g., sinuses) 4. Through the PNS (e.g., rhabdovirus, HSV)

*Principles of Motor Control* *Higher Levels:* voluntary *Lower Levels:* automatic (reflex)

1. *Higher level structures* (cortex, cerebellum, basal ganglia) play a greater role in *voluntary actions*, including the *planning phases* of movement 2. *Lower levels* are more directly involved in the actual *execution of movements* and in more *automatic movements* (e.g., postural control, respiration, and reflexes such as the gag or knee jerk reflex).

Pathological Findings in Epilepsy

1. *Hippocampal Sclerosis* (Mesial Temporal Sclerosis: neuronal loss in CA1 region and gliosis = scarring/hardening) 2. *Focal Cortical Dysplasia* (faulty neuronal stem cell migration; "balloon" cells) 3. *Polymicrogyria* or *Pachygyria* (gyral abnormalities)

*Oligodendroglioma* Required Genetic Changes

1. *IDH mutation* 2. Chromosome *1p and 19q* co-deletion (LOH) Note: if MGMT is methylated, *temozolomide* will have a better response.

Seizure Phases

1. *Ictus or Ictal:* the period of the seizure. 2. *Post-ictal:* the period of abnormal behavior that follows the ictus (e.g. confusion, lethargy) 3. *Inter-ictal:* the baseline phase in between seizures 4. *Aura:* The earliest experienced symptoms that predict an imminent larger seizure to follow (early ictal phase). Usually affects a sufficiently small cortical region so that consciousness is unaffected and memory of the aura is generally intact as well. *Déjà vu, olfactory hallucination*

*Decreased Glucose in CSF* is due to ...

1. *Increased anaerobic glycolysis* of leukocytes and bacteria (↓glucose ↑lactate) 2. Increased rate of macrovesicular glucose transport across arachnoid villi 3. *Increase metabolic rate of brain and spinal cord* 4. Inhibition of glucose entry by alteration in membrane carrier systems 5. Cerebral vasculitis and decreased cerebral blood flow

Input and Output of Basal Ganglia Circuitry

1. *Input:* Cortex → *Striatum* (the main input nucleus of the Basal Ganglia) 2. *Output:* *GPi* → Thalamus

Lumbar puncture is contraindicated for....

1. *Mass in Brain* 2. *Brain Abscess* A puncture in the lumbar spine could allow high ICP to push CSF downward, putting the patient at *increased risk for herniation*. Use *MRI* to diagnose brain abscess instead. CT for patients unable to undergo MRI.

CNS Infection Terminology

1. *Meningitis:* Inflammation of the meninges (brain and spinal cord) 2. *Encephalitis:* Inflammation of the brain parenchyma 3. *Meningoencephalitis:* Inflammation of the meninges and brain parenchyma 4. *Myelitis:* Inflammation of the spinal cord 5. *Suppurative space-occupying lesions:* Brain abscess, subdural empyema, epidural abscess *Inflammation is defined by an abnormally high WBC count in CSF.*

Types of Reflexes

1. *Monosynaptic:* single synaptic relax (stretch reflex) (e.g., ulnar or patellar reflex) 2. *Polysynaptic:* more complex circuitry (e.g., withdrawal reflex)

Input fibers of Cerebellum

1. *Mossy fibers* from the spinal cord and vestibular nuclei activate granule cells that each sends a *parallel fiber* to *weakly excite* Purkinje cells. Parallel fibers connect to thousands of Purkinje cells each. 2. *Climbing fibers* from the inferior olive (rubrospinal tract) wrap around and *strongly activates* Purkinje cell dendrites. Interactions between mossy fibers and climbing fibers (cerebellar inputs) lead to *long-term synaptic plasticity* that underlies *learning* and the *refinement of motor control*.

Perinatal Vascular Injury

1. *Multicystic encephalopathy:* accumulation of *small infarcts* due to multiple ischemic insults in development → *liquefactive necrosis* 2. *Hydranencephaly:* complete *occlusion of the carotid arteries* → no brain tissue grows → large sac of watery fluid 3. *Status Marmoratus:* excessive myelination of the gray matter structures of the basal ganglia resultant from ischemia of the region with corresponding death of neurons in the basal ganglia nuclei (*marbling of basal ganglia*). 4. *Periventricular Leukomalacia (PVL):* "white matter atrophy around the ventricles" due to ↓ perfusion at the boundary zone between ventriculopetal and ventriculofugal arteries, where the metabolic requirements of myelinating white matter are high → *cerebral palsy* in survivors. 5. *Syringomyelia:* a *hole in the spinal cord* (anterior commissure of AL pathway; *no pain/temp* in a cape-like distribution) that can be either developmental (*Chiari Malformation I* = tonsillar herniation that results in a fluid filled sac in cord = syrinx) or post-traumatic (spinal injury → liquefactive necrosis → hole in the cord).

Symptoms of a Radiculopathy (nerve root problem)

1. *Pain shooting down arm or leg* 2. Pain and sensory deficits in a *dermatomal* distribution (area of skin in which sensory nerves derive from a single spinal root) 3. Weakness in a *myotomal* distribution (groups of muscles innervated by a single nerve root) 4. *Reduced reflexes (hyporeflexia)* Usually, the intervertebral disc herniates into central canal, *affecting the inferior nerves* (eg, herniation of L3/L4 disc affects L4 spinal nerve, but not L3).

Symptoms of Neuropathy

1. *Positive Symptoms:* reflect spontaneous nerve activity -Motor: cramps, twitching -Sensory: burning pain, piercing pain, buzzing, tingling 2. *Negative Symptoms:* reflect reduced nerve activity -Motor: weakness, fatigue, wasting -Sensory: numbness, poor balance and gait, difficulty distinguishing hot and cold 3. *Autonomic Symptoms:* ACh = parasympathetic -Early satiety -Bloating -Constipation or diarrhea -Impotence -Urinary dysfunction -Abnormal sweating (too much or none) -Lighheadedness

Glioblastoma Findings on Histology

1. *Pseudo-palisading* tumor cells *border central areas of necrosis* 2. Endothelial proliferation ("glomerular" neovasculature) (↑FGF and VEGF)

*Frontal Bone* Basilar Skull Fracture Symptoms

1. *Raccoon Eyes* (peri-orbital ecchymosis) 2. CSF Rhinorrhea Remember: Joanna got hit in the forehead and had raccoon eyes.

*Dystonias* (without hyperreflexia) (extrapyramidal) -Abnormal tone, posture, and position

1. *Rigidity:* increased tone, "cog-wheeling" in Parkinsons (ratchet-like jerks) 2. *Torticollis:* fixed, twisted neck posture 3. *Writer's cramp, muscian's hand:* acquired focal dystonia Note: *hypertonia is NOT accompanied by hyper-reflexia*, unlike hypertonia in spasticity, a pyramidal sign associated with corticospinal dysfunction.

Motor Response Pathway

1. *Rubrospinal* Tract (red nucleus to contralateral *arm* → *flex*) 2. *Vestibulospinal* tract (vestibular nuclei → bilateral *arms and legs* → *extension*)

Spells vs. Seizures

1. *Seizure:* disrupted cerebral physiology with *hyperexcitable, hypersynchronous neuronal activity*. 2. *Spell:* less specific of pathophysiologic mechanism (preferred if cause unknown).

Cranial Nerve VII Lesions

1. *Supranuclear:* affects its descending innervation (forehead spared) 2. *Nuclear:* in the nucleus itself (whole face) 3. *Infranuclear:* somewhere in the nerve between the nucleus and the innervated muscles (whole face) Muscles of the upper face on one side can be made to contract by signals from either motor cortex. In contrast, the part of the facial nucleus representing muscles of the lower face receives only the usual input from the contralateral motor cortex. Thus, a contralateral lesion above the level of the facial nucleus will interrupt all of the corticobulbar input to the muscles of the lower half of the face, while the upper part of the face can still be voluntarily activated by the remaining ipsilateral corticobulbar projection. In contrast, a lesion of the facial nucleus or its axons (as they are exiting the brainstem or in the facial nerve) will lead to paralysis or weakness of the whole face on the same side as the lesion, because the entire ipsilateral facial musculature must pass through that nerve. Thus, a patient with a nuclear or infranuclear lesion affecting the whole nerve would be unable to close the eye, wrinkle the brow, or show the teeth. In contrast, a patient with a supranuclear lesion in, for example, the internal capsule would be able to close the eye and wrinkle the brow, but would be unable to show the teeth. *Preservation of voluntary control of the muscles of the upper face is due to the survival of the supranuclear innervation of the upper part of the facial nucleus from the ipsilateral cerebral cortex.*

*Spinocerebellar Pathways* -Carry *prioceptive information* from the skin, joint, *tendon organ*, and *spindle receptors* -Travel in the (most) lateral funiculus of the cord -*Ipsilateral inputs to the cerebellum*

1. *Ventral Spinocerebellar Tract* -Double decussation (convoluted) -VST begins ipsilateral to the cerebellum, crosses over immediately in the spinal cord, goes up through the medulla, crosses over again, and enters the cerebellum at the *superior cerebellar peduncle*. 2. *Dorsal Spinocerebellar Tract* -No decussation (straightforward) -Inputs from the spinal cord stay on the same side of the body and enter largely via the ipsilateral *inferior peduncle*.

Cerebellar Dysfunction (complex)

1. *Vestibulocerebellum* -Impaired *balance* (postural instability; *negative* Romberg) -Impaired control of *eye movements* (nystagmus) 2. *Spinocerebellum* -Wide-based *"drunken sailor" gait* (truncal ataxia) 3. *Cerebrocerebellum* -*Ataxia:* can't carry out movements by the extremities (dysmetria/appendicular ataxia) -*Intention tremor* (coarse trembling worst at end of movement) -*Peculiar writing abnormalities* (large, unequal letters, irregular underlining) -*Dysarthria* (slurred speech) -*Dysdiadochokinesia:* inability to perform rapidly-alternating movements

Glioblastoma Mutations in Younger vs Older Patients

1. *Younger* Patients (secondary GBM): *p53 mutations* present (± IDH1 mutations) 2. *Older* indicates de novo (primary GMB) with *EGF-R amplification*

Brain Neoplasms (Necrosis) -MR Spectroscopy (lactate) -Gd-enhanced MRI (necrotic core)

1. *↑ lactate* (biomarker for anaerobic glycolysis) 2. Contrast-enhaced MRI (Gd) shows *rim-enhancement* (with *non-enhancing core of necrotic tissue*)

How to Help Avoid Secondary TBI

1. *↑O2 and nutrients to counter loss* -Avoid hypermetabolism in the brain (control fever and seizures) -Sedation reduces brain metabolism 2. *↑blood flow to counter edema, ischemia, or infarction* -Avoid hypotension (low BP) and hypovolemia (low fluids) -↓ICP (osmotic agents: sugar/salt; hyperventilation: blow off CO2) -Ensure MAP is enough for adequate cerebral perfusion and measure continuous ICP if the patient has a poor neural exam

Stroke Risk Factors

1. Age (biggest non-modifiable risk factor) 2. Hypertension (biggest modifiable risk factor) 3. Heavy alcohol use 4. Atrial fibrillation: the heart pumps irregularly and pauses allow for a clot to form (cardioembolic stroke)

*Preventative Migraine Medications* (Prophylactics)

1. Beta blockers (propranolol) 2. Ca2+ channel blockers 3. Antiepileptic drugs (*valproic acid*, *topiramate*, gabapentin) (birth defects; sleepiness) 4. Antidepressant drugs: *TCAs (amitriptyline) and SSRIs/SNRIs* 5. Injections (*botulinum toxin for >15 headache days per month*) 6. Supplements (Mg, Riboflavin) 7. Behavioral treatment: CBT, relaxation, biofeedback (Class A evidence = 30-60% reduction)

Diagnosis of SAH confirmed with

1. CT w/o contrast (NCCT) good for new subarachnoid hemorrhages (acute blood?). 2. Lumbar Puncture will show Xanthochromia (yellowing of CSF). 3. MRI FLAIR and Proton-Density weighted images (for unusual causes of SAH) 4. CT/A for large aneurysms (95-100% sensitive for aneurysms >5mm).

Lesions of the Posterior Fossa

1. Chiari Malformations (II: tonsils and vermis; I: tonsils) 2. Dandy-Walker malformation (malformation of the vermis)

Muscular Co-contractions

1. Co-contraction of synergists increases force (cooperate to move a joint). 2. Co-contraction of antagonists increases stiffness of a joint. *Example:* *Synergists:* biceps and brachialis (flexion) *Antagonist:* triceps (extension)

Circadian Rhythm Findings

1. Core temperature goes down, then rises 2. Melatonin increases, then falls BMAL1/CLOCK (heterodimer TF) build up PER1-3 and CRY1,2 during activity and catabolism (SCN active). When PER1-3 and CRY1,2 are at higher levels, they un-dimerize BMAL1/CLOCK TF (SCN neurons inactive).

*Non-Motor Symptoms of Parkinson's Disease* -Can be present before diagnosis

1. Decreased olfaction (smell) 2. Constipation 3. Anxiety and Depression 4. *Sleep changes* (REM sleep disorder) 5. Fatigue

Risk Factors for Parkinson's Disease

1. Family history (1:100 → 3:100 risk) 2. Not smoking cigarettes

EEG Diagnosis of Epilepsy

1. Graphical depiction of cortical electrical activity. 2. Records voltage differences from points on the scalp. 3. Relates to *synchronous activation of apical dendrites of pyramidal neurons in upper neocortical laminae by excitatory afferent inputs*. The electric field (dipole) generated by similarly oriented pyramidal cells in cortex (layer 5) is detected by scalp electrodes.

Clinical Signs and Symptoms of Cerebral Edema

1. Headache 2. Nausea 3. Emesis (vomiting) 4. Papilledema 5. Focal signs 6. Seizures Leads to flattened out gyri, narrowed sulci, and compression of ventricular cavities. Swelling compresses venous outflow channels, leading to widespread vascular congestion, which can raise ICP and potentially result in herniation.

*Intracerebral Hemorrhage Pathophysiology* (within hours)

1. Hematoma formation 2. Hematoma growth (early expansion) 3. Increased intracranial pressure (↑ICP); mass-effect (Monroe-Kellie) 4. Tissue shear/disruption 5. Toxic effects of blood products / oxidative effects (brain normally not exposed to blood) 6. Inflammatory effects 7. Edema

Clinical Evaluation of PNS Pathology

1. History 2. Physical Exam -Motor: bulk, tone -Reflexes: hypo/hyper-reflexia -Sensory: light touch, temperature, proprioception 3. Laboratory Studies -CPK for muscle breakdown -Diabetes for neuropathy 4. Imaging -MRI for radiculopathy/herniated disc -Ultrasounds for compression neuropathies (carpal tunnel) 5. Nerve conduction study (NCS): electrical stimulation of the nerves to evaluate APs 6. Electromyography (EMG): specialized needs record electrical activity from selected muscles

History that helps diagnose ICH

1. History of trauma 2. Hematologic abnormality 3. Anti-coagulant/anti-thrombotic use 4. Symapthomimetic drug abuse (e.g., cocaine ↑BP) 5. Dementia (cerebral amyloid antipathy, CAA)

Early ischemic changes on NCCT (of ischemic stroke)

1. Hypodensity of infarcted brain due to edema -Due to cytotoxic edema (water in the brain) -If hypodensity of MCA is large → futile infarction (poor outcome despite reperfusion; more likely to hemorrhage after reperfusion) 2. Effacement of sulci due to mass effect 3. Loss of difference between gray and white matter 4. Dense MCA → thrombus is denser than unclotted blood (due to proteins)

Multiple Sclerosis Onset

1. In a genetically predisposed individual, a viral infection or other inciting factor - promotes *entry of T cells and antibodies into CNS* 2. This leads to increased expression of cell adhesion molecules (CAMs), matrix metalloproteinases (MMPs), and *proinflammatory* cytokines. 3. These attract additional immune cells which break down extracellular matrix to aid migration. 4. An *autoimmune response* is activated against antigens. 5. *Immune attack on myelin denudes axons*, which slows nerve conduction and leads to neurologic symptoms. 6. Patches of scar tissue (plaques) form over the affected areas in the cerebral white matter, cerebellum, brainstem, spinal cord and optic nerves (Multiple Sclerosis).

Lumbar puncture findings for *Viral* Encephalitis (CSF)

1. Increased WBC (>5 mononuclear cells/ml) 2. Normal glucose 3. Elevated protein 4. Normal opening pressure

Neurological Exam for Determining Consciousness

1. Level of consciousness (LOC) 2. Pupillary responses 3. Extraocular movements (EOM) 4. Motor responses 5. Respiration

Neuroimaging Signs of Neoplasm

1. Mass 2. Mass effect 3. Hypercellularity 4. Neovascularity 5. Necrosis

PNS Pathologies

1. Motor neuron → motor neuron disorder 2. Nerve roots → radiculopathy 3. Nerve plexus → plexopathy 4. Peripheral nerve → neuropathy 5. Neuromuscular junction (NMJ) → NMJ disorder 6. Muscle → myopathy

Muscle tone in NREM vs REM sleep

1. NREM: tone decreased 2. REM: tone absent (paralysis except EOMs and respiration muscles) REM and NREM sleep alternate every 90 min (rhythmic, cyclic process).

Schumacher's Criteria for Diagnosing Multiple Sclerosis

1. Objectively defined CNS lesions/abnormalities 2. *Two or more focal lesions in white matter separated in both space and time* 3. Slow and steady *stepwise progression* of disease 4. Onset usually between 10 and 50 years of age 5. *Absence of alternative diagnoses* that fit the clinical picture

A person is not a candidate for IV-tPA if...

1. On CT, hypodensity area is greater than 1/3 of MCA territory (large infarction) -- reperfusion therapy would most likely cause harm 2. On CT/A, there is an absence of collateral vessels 3. The patient is acutely bleeding

Treatment for Radiculopathy

1. Oral or topical pain medication 2. Epidural steroid injections 3. Physical Therapy 4. Surgery (when indicated)

Spinal Cord Injuries (location)

1. Paraparesis (thoracic cord and below) 2. Quadriparesis (cervical cord)

Clinical Presentation (brain tumor)

1. Subacute presentation of focal neurologic deficit (slow onset) 2. *Seizure* (1/3 of brain tumor patients, and most likely with tumors that *invade or compress cerebral cortex* compared to subcortical tumors) 3. Non-focal symptoms (headache-↑ICP; dementia, personality change-orbitofrontal; gait disorder-cerebellum)

Classifications of Coma

1. Supratentorial 2. Infratentorial 3. Diffuse 4. Psychogenic

*Respiration* and Coma

1. The *respiratory center (located in the pons and medulla)* is modulated by both metabolism and behavior. 2. *Pons and medulla modulate breathing based upon input from CO2, O2, and other receptors* 3. Prefrontal cortex and hypothalamus generate behavioral and emotional control

Sleep Onset

1. Wakefulness: low voltage, mixed frequency EEG -*Alpha rhythm (8-13 Hz) predominates when relaxed, awake, and with eyes closed* 2. At sleep onset, alpha waves disappear, and low-voltage theta rhythm appears (3-7 Hz) Eyes: slow, rolling movements Muscles: gradual diminution

Questions to ask in seizure focus imaging for epilepsy

1. Where is the seizure focus (zone of seizure origin)? -Anatomic Imaging: MRI -Functional Imaging: SPECT (↑ ictal blood flow) or PET (↓glucose metabolism post-ictal) -MRI + magnetoencephalography: localizes epileptic focus by dipole source modeling 2. Is there a structural lesion? Is it resectable? -Where is the epileptic zone (cortex that must be resected or disconnected to alleviate seizures)? -Common: mesial temporal sclerosis (hippocampal neuron loss and gliosis due to ongoing seizures), focal cortical dysplasia (faulty neuronal stem cell migration), and low-grade tumors (involving cerebral cortex) 3. What brain areas should be spared? -Eloquent cortex (Motor, Language or Memory functional areas to be spared) -Determined via fMRI and DTI (diffusion tensor imaging/tractography)

Lumbar puncture findings for *bacterial* meningitis

1. ↑ Opening Pressure (70-180 mmH2O is normal; 200-500 mmH2O is diseased) 2. ↑ WBC (neutrophils) (0-5/ml mononuclear is normal; 1000-5000/ml neuts is diseased) 3. ↑ Protein (vasogenic edema: large proteins crossing BBB) 4. ↓ Glucose (50-80 mg/dL is normal; <40 mg/dL is diseased) *Abnormal CSF looks white and milky* (due to neutrophil infiltrate).

For patients on oral anti-coagulants with ICH, what is first step?

1. ↓INR (1.1 is normal) by *administering Vitamin K*. 2. Provide fresh frozen plasma 3. *Provide prothrombin* complex concentrates (PCCs): give back Factors to *stop Coumadin and reduce anticoagulation*. 4. ↓BP *Factor VIIa is NOT recommended* because it does not replenish other Vitamin K-dependent factors and can increase the risk of thrombic events. *Reminders from Block 5:* 1. Vitamin K epoxide reductase is an enzyme that reduces vitamin K after it has been oxidized in the carboxylation of glutamic acid residues of blood coagulation enzymes (II, VII, IX, X). 2. INR = prothrombin time = extrinsic pathway and measures Factors I (fibrinogen), II (prothrombin), V, VII, and X.

Infratentorial Coma

Direct lesion destroys the brainstem (e.g., basilar stroke). Characteristics: 1. Prior brainstem signs or *sudden coma* 2. Early abnormal respiration 3. Abnormal CN exam

Multiple Sclerosis Disability

Disability resulting from the first 4 years tend to predict the level of disability in 15-20 years. About half of patients are at least somewhat disabled 10 years after onset, but this increases to 80% at 25 years.

Peripheral Nerve Pathology (neuropathy)

Diseases that affect the peripheral nerve can damage the myelin, axon, or both *Peripheral nerves are surrounded by connective tissue:* 1. *Endoneurium:* surrounds axon 2. *Perineurium:* surrounds fascicle 3. *Epineurium:* surrounds peripheral nerve and vasculature Trauma to the peripheral nerves can be graded in severity depending on which of these structures are damaged.

Neuronal Migration Disorders

Disorders of neuronal migration occur because of *inappropriate or defective migration of neurons formed in the germinal matrix*. Three types are most significant: 1. *Lissencephaly:* complete *absence of gyri* of the brain caused by an early defect in neuronal migration must occur *early in development*. 2. *Pachygyria:* a disturbance of neuronal migration that *occurs later* (i.e., after the process is underway), resulting in *flattened and enlarged gyri*. -The cortical migration of neurons is often impaired, resulting in *four layers* rather than six. 3. *Micropolygyria:* defects in neuronal migration that *occur even later* than would produce pachygyria (pseudomicropolygyria is the result of a Chiari malformation) -A *four-layered cortex* is still seen, but the *gyri are small* rather than enlarged

Phenobarbital (barbiturate)

1st gen Mechanism: *GABA Agonist* (increases inhibition); prolonged opening of Cl- channels Administration: IV and PO Side effects: Sedation, mood, dependence Clinical uses: Tonic-clonic, partial seizures, status epilepticus, *tremor* *1st line in neonates* ("pheno*baby*tal")

Valproic Acid

1st gen Mechanism: *Increased GABA* (blocks Ca2+/Na+ channels and glutamate receptors) Administration: IV and PO Side effects: Tremor, weight gain, *most teratogenic* Clinical uses: *Broad spectrum*, 1st line tonic-clonic, partial seizures, absence, myoclonic, *bipolar*

*Benzodiazepines* (lorazepam, diazepam, clonazepam) -Treat *acute* seizures (IV load) and *status epilepticus*

1st gen Mechanism: *Increases GABA binding affinity* Administration: IV and PO Side effects: Sedation, lethargy, dependence Clinical uses: *1st line status epilupticus* (also for *anxiety*)

Phenytoin

1st gen Mechanism: *Na+ channel blocker* Administration: IV and PO Side effects: Gum hyperplasia, coarse features, Stevens-Johnson rash, cerebellar toxicity Clinical uses: 1st line Tonic-clonic, partial seizures, status epilepticus *CAN WORSEN ABSENCE SEIZURES*

Carbamazepine

1st gen Mechanism: *Na+ channel blocker* Administration: PO Side effects: Ataxia, diplopia, hepatotoxicity, aplastic-anemia, leukopenia Clinical uses: 1st line partial seizures and tonic-clonic, also for *trigeminal neuralgia* *CAN WORSEN ABSENCE SEIZURES*

Ethosuximide

1st gen Mechanism: *T-Type Ca2+ channel blocker* (thalamocortical) Administration: PO Side effects: EFGHIJ—Ethosuximide causes Fatigue, GI distress, Headache, Itching (and urticaria), and Stevens-Johnson syndrome Clinical uses: Only *absence* seizure. *DO. NOT USE ON FOCAL SEIZURES.*

Patterns of Brain Metastases -Usually *epithelial* (i.e., carcinomas)

2/3 are parenchymal and *prefer the cerebrum* 8x to the cerebellum → multiple enhancing lesions of variable size associated with *mass effect from vasogenic edema*. Prefer the cerebral *gray-white matter junction* and cerebellum (due to *↑vasculature*).

Lamotrigine

2nd gen Mechanism: *Na+ channel blocker* Administration: PO Side effects: *Stevens-Johnson syndrome rash*, *LEAST teratogenic* (LL=least) Clinical uses: Tonic-clonic, partial seizure, also for *bipolar*

*Topiramate (Topamax)* -Topamax → "Dop"amax (sedation) = good for *migraine*

2nd gen Mechanism: *Na+ channel blocker* Administration: PO Side effects: Sedation, cognitive slowing, renal stones Clinical uses: Broad spectrum, partial seizures, tonic-clonic, Lennox-Gastaut syndrome, also for *migraine prevention* and for *pseudotumor cerebri (IIH)* (i.e., for female TOAD: Tricyclics, Obesity, Vitamin A, Danazol (steroid for endometriosis)

*Gabapentin* -*N*-type Ca2+ channels = *n*europathic pain

2nd gen Mechanism: Inhibits voltage gated *N-Type Calcium channels* Administration: PO Side effects: Sedation, dizziness, fatigue, weight gain, peripheral edema Clinical uses: Partial seizures (adjunctive only) (useful for *peripheral neuropathy* and chronic pain)

Levetiracetam -*NO PROTEIN BINDING (no drug interactions)* -Good for a patient on *warfarin*

2nd gen Mechanism: Unknown Administration: IV and PO Side effects: Anxiety, mood, one of the *least teratogenic* (LL=least) Clinical uses: Broad spectrum, partial seizures, tonic-clonic

Dopamine and Basal Ganglia Dopamine effects: 1. *Excites* direct (D1) via Gs 2. *Inhibits* indirect (D2) via Gi

Dopamine allows a shift in which pathway is more active by using: 1. D1 Receptors (direct: "Go") 2. D2 Receptors (indirect: "No-Go") *Positive Predictive Error:* Dopamine turns up D1 (direct pathway) and turns down D2 (indirect pathway). The basal ganglia output is high. At *baseline*, more *sensitive D2 receptors* are preferentially occupied by the low level of available dopamine, and this serves to *inhibit* striatal neurons of the *indirect pathway* on which they reside. Inhibiting the inhibitory (indirect) pathway results in net disinhibition of downstream structures (thalamus then cortex).

Spinal Cord Demyelination

50-90% of patients with MS have cord demyelination. The cervical cord is more affected than the thoracic cord due to more white matter per unit area.

Demyelination vs. Dysmyelination

Dysmyelinating diseases are those in which *myelin is improperly formed* (leukodystrophies), not those in which it is destroyed (demyelination).

All MS patients test positive for....

EBV (molecular mimicry: DNA is similar to myelin)

Absent time cues, circadian rhythms free-run.

Each circadian cycle is ~24.1-24.2 hours. Dark/light cycles usually keep the "24" hour clock in check, but in constant darkness, the biological clock pushes the cycle forward (melatonin onset is later, decline is also later). *Go to bed later, wake up later.* *Circadian rhythms interact with the homeostatic drive for sleep to produce sleepiness.* The longer you're awake, the more sleepy you become. When you're at your least aroused (circadian), your homeostatic drive to sleep is greatest.

*Contusion* -Damage to is visible on imaging

A bruise to the brain resulting from direct, focal injury to the CNS tissue (caused by multiple microhemorrhages from small blood vessel leaks). Typically in *orbitofrontal cortex* or *temporal poles* (petrous areas with bumps). *Example:* coup-contrecoup injury 1. *Coup injury* occurs at the site of impact (bruising of tissue immediately beneath injury) 2. *Contrecoup injury* occurs on the side opposite the impact, where the brain is forced against the skull (usually petrous areas). This injury is usually larger. Evidence of *old contusions* remains grossly as a *plaque jaune* (depressed, yellow patches that affect gyri), which may be a source of subsequent seizure activity (*epileptogenic*).

Multiple Sclerosis Pathology

A disease of myelin and/or oligodendrocytes, *not intrinsic axonal injury* (only myelin affected; not axons). Multiple sclerosis is characterized by a *sharp distinction between lesioned and normal white matter*. This is due to MØ eating the myelin at perivenous regions.

Charcot Marie Tooth Disease (exam)

A group of *hereditary, progressive peripheral nerve disorders.* Defective production of protein involved in structure and function of peripheral nerves or their myelin sheath. Can be *demyelinating* (most common, *Type I*, due to PMP22 deletion) or axonal. PMP = peripheral myelin protein (produced by Schwann cells). *Clinical Findings:* 1. Lower extremity *weakness and sensory deficits* (neuropathy; foot drop) 2. *Hammer toes* 3. *Pes Cavus* (high foot arch) 4. Inverted *"champagne bottle" leg*

Contralateral *arm and leg* damage indicate....

A lesion of the internal capsule, brainstem or upper spinal cord, where the axons destined for the cervical and lumbosacral cord are gathered together. Cortical damage would need to be widespread to affect both the contralateral arm and the leg, which are represented at opposite ends of M1.

Extra-Axial Mass

A mass that arises in the meninges (brain or cod) or bone (calvaria or vertebrae), has a *broad dural base*, and displaces the brain or cord.

Intra-Axial Mass

A mass that arises within the brain or spinal cord, replaces or infiltrates, and has *no or minimal dural contact*.

Electromyogram (EMG)

A recording of the action potentials of a single muscle fiber reflects the activity of a single motor neuron unless pathology is present.

Twitch and Tetany

A single action potential in a motor neuron produces a brief increase in tension in the muscle (twitch). Action potentials that are close together in time will produce twitches that summate (temporal summation). At the fusion frequency (40/sec), the muscle fiber no longer twitches with each impulse but exerts *sustained tension* (*tetany*). *Tension increases* as the firing rate of the motor neuron increases *beyond the fusion frequency* (LMN can fire at over 800/sec). The y-axis of the image can be thought of as: 1. Force 2. Number of active cross bridges 3. Intracellular Ca2+ concentration

Astrocytomas

Account for 80% of all brain tumors and peak in middle age and late life. *Histology:* 1. Subtle *↑astrocytes*, which tend to crowd one another due to *loss of contact inhibition* 2. Astrocytes surround neurons (*satellitosis*)

*Dermato*myositis (myopathy) (exam) - Polymyositis (endomysial, CD4+) *with rash*"

Acquired, inflammatory muscle disorder (*perimysial inflammation and atrophy* by CD4+ cells). *Classically presents with:* 1. Symmetric, *proximal muscle weakness* (thighs, hip girdle, neck, shoulder girdle) 2. Myalgias and muscle cramps 3. *No sensory symptoms* (no numbness or tingling) 4. *Malar skin rash* (*shawl*, on *hands*, around eyes, etc.) 5. *Difficulty rising from a low position, raising arms over head* (proximal muscle weakness) *Associated with:* -Increased risk of malignancy and lung disease -Perifascicular atrophy (atrophy and degeneration of myofibers at the periphery of fascicles caused by ischemia from *loss of the endomysial capillary bed*) *Treatment:* corticosteroids (to fight inflammation)

*Polymyositis* (myopathy) -Endomysial, *CD8+*

Acquired, inflammatory myopathy. Similar to dermatomyositis but *without skin rash* -No perifascicular atrophy -Endomysial, *CD8+*

*Pituitary Adenoma* -Bitemporal hemianopia -*Prolactinoma:* galactorrhea, amenorrhea, ↓bone density

Adenoma may be nonfunctioning (silent) or hyperfunctioning (hormone producing). Most commonly presents as hyperplasia of lactotrophs (prolactinoma) → *hyperprolactinemia*. Prolactinoma in women classically presents as galactorrhea, amenorrhea, and ↓ bone density due to suppression of estrogen. Nonfunctional tumors (macro-adenomas) present with mass effect (*bitemporal hemianopia*, hypopituitarism, headache). *Treatment:* 1. Dopamine agonists (prolactinomas) 2. Transsphenoidal resection (surgery)

Motor Neuron Pool

All alpha motor neurons (LMNs) in one location of the anterior horn that *innervate the same muscle*.

Spinal Cord Localization

All functions are ipsilateral (but pain and temp). Motor (ventral) (CST) Pain/Temp (ventral) (AL) Vibration/Proprioception (dorsal) (DC-ML) Somatotopic representation (mesial=axial; lateral=extremties)

*Alexander's Disease* -Rosenthal fibers on pathology

Also known as *fibrinoid leukodystrophy*, Alexander's Disease is a *progressive and fatal neurodegenerative disease*. It is a rare genetic disorder and *mostly affects infants and children*, causing developmental delay and changes in physical characteristics. *Pathological Finding:* *Rosenthal fibers:* deposits in astroglial cells, which support and nourish other cells in the brain and spinal cord.

*Cerebral Amyloid Angiopathy* (Congophilic) -*Imaging:* T2-*GRE*: gradient recalled echo detects micro hemorrhages in amyloid-β affected vessels

Amyloid-β peptide is deposited in *small arterial vessels* causes degeneration of vessels (vascular fragility). This shows up *"apple-green"* when stained with *congo red*. Common cause of ICH in the elderly (>70 years old). *Demented, usually normotensive.* On imaging (T2-GRE, sensitive to blood), *micro-hemorrhages* are seen in vessels affected by *Amyloid-β* (particularly at *gray-white junctions*). Acute lobar hematoma is also seen (common in elderly patients with CAA). Note: In Alzheimers, amyloid-β is deposited in the brain parenchyma rather than vessels.

If sub-arachnoid hemorrhage is located in basal cisterns, it means it is a...

An aneurysm

*Devic's Disease* (Neuromyelitis Optica, NMO)

An autoimmune inflammatory disease primarily targeting the *optic nerves and spinal cord* due to a *mutation in aquaporin-P4*.

Meningioma (imaging)

An extra-axial benign mass originating from *arachnoid cap cells* that is biologically malignant. *Location:* located along meninges (broad dural base) *Affects women 2-4x more than men.*

Encephalocele

An outpouching of epithelium-enclosed brain tissue through a cranial defect (*herniation of the meninges (and brain)*). In the East, *anterior encephaloceles* tend to present most often, with the outpouching pushing through a defect in the *cribriform plate*. In the West, *posterior (occipital)* cranial defects are more common. Overall, occipital encephaloceles are most common (75%).

If patient has focal seizures, treat with...

Anything except ethosuximide. DO NOT USE ETHOSUXIMIDE.

Brodmann's Areas 4 and 6

Area 4 is Primary Motor Strip (M1): execution of movements Area 6 is SMA (supplementary motor area) and PMA (premotor cortex): planning movements, generating intent to move, and converting plan to action (strategy) Area 6 is "upstream" (imagine movements) of area 4 (perform movements) in processing motor commands.

Brain Abscesses

Associated with acute *bacterial endocarditis* (infection of the inner heart layer), cyanotic congenial heart disease, and chronic pulmonary *sepsis*. Develop as a *fibrous capsule* (fibroblasts) composed of reticulin and collagen to *wall off a focal area of cerebritis* (localized infection / inflammation). On histology, the cavity that is formed is filled with *pus*. Even when the pus is drained, the fibrous capsule (reticulin/collagen) remains and can be a *potential seizure focus*.

*Spinal Muscular Atrophy* (SMA) (exam) -Autosomal Recessive (SMN1 mutation) -SMA = symmetric weakness -Polio = asymmetric weakness

Congenital *degeneration of anterior horns* of spinal cord. *LMN Only:* HAFAH + W 1. Hypotonia (*floppy baby*) 2. Atrophy 3. Fasciculations (*tongue*) 4. Absent Babinski 5. Hyporeflexia 6. Weakness (symmetric) SMA Type 1 (infantile) is the most common and severe. 2-3 Juvenile; 4 Adult. *SMA Type 1: Werdnig-Hoffmann disease* 1. "Floppy Baby": generalized muscle weakness that progresses rapidly 2. Typically infants die after 1-2 years (due to *respiratory failure*)

Inferior Cerebellar Peduncle

Connected to *Medulla* Mostly INPUT but has some OUTPUT for cerebellum

Superior Cerebellar Peduncle

Connected to *Midbrain* Main OUTPUT for cerebellum

Middle Cerebellar Peduncle

Connected to *Pons* Main INPUT for cerebellum

Consciousness vs. Arousal

Consciousness is the state of full awareness of one's self and one's relationship to the environment. It consists of both degree of arousal (level of consciousness) and content of thought. One cannot comment on content unless there is intact arousal. If someone is asleep (not dreaming), one cannot say his or her thought lacks content because he or she has an altered state of arousal (physiological). *Coma is a pathological state of altered arousal, which is in some ways similar to deep sleep.*

*Dandy Walker Syndrome* -Posterior fossa lesion

Consists of *partial or complete absence of the cerebellar vermis* (hypoplasia), *enlargement of the fourth ventricle*, and cyst formation near the internal base of the skull, causing an enlarged posterior cranial fossa. Treatment: shunting to relieve hydrocephalus

*Guillain-Barré Syndrome* -AKA Acute Inflammatory Demyelinating Polyradiculoneuropathy (AIDP)

Autoimmune condition that often presents after *gastrointestinal infections* (commonly implicated: *Campylobacter jejuni*). *Mechanism:* 1. Destroys Schwann cells by inflammation and demyelination of peripheral nerves (including CN III-XII) 2. Destroys motor fibers due to molecular mimicry, inoculations, and stress, but no definitive link to pathogens. Characterized clinically by *ascending paralysis and PNS demyelination*. *Facial paralysis* (usually bilateral) and *respiratory failure* are common. May see *autonomic dysregulation* (e.g., cardiac irregularities, hypertension, hypotension) or sensory abnormalities. *Almost all patients survive* with a majority recovering completely after weeks to months with respiratory support, plasmapheresis, and IV immunoglobulins (IVIg).

Multiple Sclerosis (MS) Overview

Autoimmune inflammation and *demyelination of CNS* (brain and spinal cord) with subsequent axonal damage. Can present with: 1. *Acute optic neuritis* (painful, unilateral visual loss associated with *Marcus Gunn pupil*) 2. *Brainstem/cerebellar syndromes* (e.g., diplopia, ataxia, scanning speech, intention tremor, nystagmus/INO (MLF syndrome) (bilateral > unilateral) 3. *Pyramidal tract weakness* (corticospinal demyelination) 4. *Spinal cord syndromes* (e.g., electric shock-like sensation along spine on neck flexion [Lhermitte phenomenon], neurogenic bladder, paraparesis, sensory manifestations affecting the trunk or one or more extremity) Symptoms may exacerbate with increased body temperature (eg, hot bath, exercise). *Relapsing and remitting is most common clinical course.* *Most often affects women* (3x more than men) in their *20s and 30s* More common in *Caucasians living farther from equator*.

*Blood Supply to the Motor System*

Because of its distributed nature, the motor system can be compromised by pathology in almost any of the blood vessels serving the CNS. 1. *ACA:* foot and lower leg 2. *MCA:* face, arm, and hand area. Penetrating branches of the MCA supply the internal capsule and basal ganglia. 3. The *cerebral peduncle* and midbrain tegmentum are supplied by a plexus from the *basilar*, posterior cerebral, and posterior communicating arteries. 4. *Pontine* motor structures and parts of the cerebellum are supplied by branches of the *basilar* artery (Locked-In Syndrome). 5. *Medullary* motor structures and parts of the *cerebellum* are supplied by the branches of the *vertebral and basilar arteries*. 6. Motor pathways in the *spinal cord* are supplied by branches of the *anterior and posterior spinal arteries* which receive blood from the *vertebral arteries* and various branches of the aorta. -*Cervical* spine: *vertebral* supply -*Thoracic and lumbar* spine: *radicular* arteries from aorta

Functional MRI (fMRI) (not on exam)

Blood-O2 level-dependent contrast. Neural Activity = Blood Flow

Impaired Level of Consciousness (alertness)

Both hemispheres (less likely), or brainstem (ARAS), or both. ARAS = ascending reticular activating system

Crossed Signs

Brainstem

Bilateral symptoms generally indicate...

Brainstem or spinal cord pathology (subcortical; unless the disease is multifocal with multiple lesions). Massive involvement of the motor cortex on both sides to affect all limbs is far less likely (think broad homunculus).

Upper Motor Neuron Symptoms

CNS

Are the motor symptoms lateralized (all left or all right)?

Contralateral Hemisphere

First line treatments for epilepsy

Carbamazepine and Phenytoin (grand mal; tonic-clonic). Valproic Acid for generalized seizures (broad spectrum AED that can help migraines and bipolar disorder)

Locked-In Syndrome (coma)

Cause: *anterior pons infarction* (basilar artery disease and tumors that lead to bilateral ventral pontine lesions) *Findings:* 1. *Normal LOC (dorsal reticular formation spared)*; arousable 2. Total paralysis, but *can blink and move eyes vertically* (CN III) (*quadriparesis* due to corticospinal/corticobulbar damage in ventral pons) 3. *Central Pontine Myelinolysis* (can occur with overly rapid correction of hyponatremia; osmotic demyelination)

Locked-In Syndrome

Caused by *basilar artery disease and tumors that lead to bilateral ventral pontine lesions*. Findings: 1. *Quadraplegia* (paralysis in all 4 limbs) due to *bilateral transection of corticospinal tract* 2. Unable to speak (CN IX, X, XII), move face (CN VII), or move eyes horizontally (CN VI) due to *destroyed corticobulbar fibers* 3. Patient can still do *vertical eye movements* (*CN III intact above the pons*) 4. Patient *remains conscious* (no LOC) Overall: 1. *Paralysis of ALL voluntary movement, except vertical eyes* 2. Sensation intact 3. No LOC

*Decorticate (Flexor) Posture* -Rubrospinal takes over (disinhibited) → arm flexure

Caused by large scale, acute lesions of the cerebral cortex (tumors or strokes) that occur *above the red nucleus* and *removes inhibitory input to the red nucleus* (allowing flexion). *Findings:* 1. Net activation of flexors (*tonic arm flexion*) 2. Leg extension due to descending input of the vestibulospinal tract. Early *uncal herniation* can disinhibit the red nucleus, causing flexor posturing. In uncal herniation (transtentorial herniation), the innermost part of the temporal lobe, the uncus, can be squeezed so much that it moves towards the tentorium and puts pressure on the brainstem, most notably the midbrain (where the red nucleus resides).

MS plaques especially seen in which parts of brain

Corpus Callosum (periventricular) Middle Cerebral Peduncle Subcortical white matter Temporal and Occipital white matter

Central Lesion Locations

Cortical Grey Matter Cortical White Matter Subcortical Grey/White Matter (basal ganglia, thalamus, etc...) Cerebellum Brainstem Spinal Cord white matter

Clinical Signs of Cerebellar Dysfunction

Cerebellar disease or damage results in a *decrease in the quality of movement* rather than a change in the amount of moment). *"NAIL"* 1. Nystagmus 2. Ataxia 3. Intention tremor 4. Loss of balance Note: The amplitude of an intention tremor increases as an extremity approaches the endpoint of deliberate and visually guided movement

*Cerebral Vasospasm* (detected by CT/A) -Treat with oral *nimodipine* (Ca2+ blocker that prevents vasospasm) -Monitor blood flow velocity with *transcranial dopler*

Cerebral vasospasm is the *prolonged, intense vasoconstriction of the larger conducting arteries in the subarachnoid space which is initially surrounded by a clot*. Significant narrowing develops gradually over the first few days after the aneurysmal rupture, and can lead to *tissue ischemia and death (necrosis)*. This spasm usually is maximal in about a week's time following hemorrhage. Vasospasm is a major contributor to post-operative stroke and death especially after aneurysmal SAH. Vasospasm typically appears 4 to 10 days after SAH.

Conduction Aphasia

Characterized by intact auditory comprehension, fluent (yet paraphasic) speech production, but *poor speech repetition*. The classical explanation for conduction aphasia is that of a disconnection between the brain areas responsible for speech comprehension (Wernicke's area) and speech production (Broca's area), due specifically to damage to the *arcuate fasciculus*, a deep white matter tract.

Anencephaly

Characterized by the complete replacement of brain tissue with fibrous tissue. Anencephaly often presents with complete *absence of structures above the diencephalon* (*open brain and lack of skull vault*).

Polysomnogrpahy (sleep study)

Electroencephalography: Brain Activity Electrooculography: Eye Movements Electromyography: Muscle Activity (tone)

Brain Abscess

Encapsulated (ring-enhancing) poly-microbial infection. 1. Strep, Staph, gram-negative, anaerobes, TB 2. Fungus; toxoplasmosis *FLAIR MRI:* vasogenic edema (white) around mass is free to diffuse (not restricted like cytotoxic edema). *DWI MR:* bright white mass due to pus

Ring enhancement on contrast MRI from...

Endothelial proliferation

Focal neuropathies (dysfunction of a single peripheral nerve) due to compression usually caused by....

Entrapment or *compression neuropathies* are typically *demyelinating*.

What causes epilepsy?

Epilepsy is a disorder of *unprovoked, recurrent seizures* (febrile seizures are not epilepsy). This is the result of *excessive neuronal excitability (hyper-synchronized cortical neurons)* and *loss of inhibitory neurons* → often genetic causes with mutations in channels and receptors. *Causes:* 1. Focal CNS injuries (trauma, tumor, hemorrhage, infection, ischemia, inflammation) → epileptogenesis (conversion of a normal neuronal network into a hyperexcitable network) 2. Neurodegenerative illnesses 3. CNS developmental abnormalities (focal cortical dysplasia, lissencephalies (gyri malformations)) 4. Genetics

AED that only treats absence seizures

Etho*sux*imide (Sucks to have Silent (absence) Seizures)

Vestibulo-Ocular Reflex (VOR)

Eyes deviate toward the cold (brave the cold, escape the heat). Direction of quick nystagmus: COWS (cold-opposite; warm-same)

*Voluntary rapid eye movements* (saccades) are mediated by the....

FEF *pushes* gaze. "Look towards lesion." Right FEF controls the left PPRF (contralateral to eye in control)

Spina Bifida

Failure of closure at the posterior neuropore and presents as one of three types: 1. *Spina bifida occulta:* bony defect, often in the vertebral column, *without involvement of the dura mater*. In many patients, a small tuft of hair can be seen overlying the defect. 2. *Meningocele:* occurs if the dura herniates through the bony defect (filled with CSF) 3. *Meningomyelocele:* formed if the dura and spinal cord tissue herniate through the defect 4. *Rachischisis:* occurs if the spinal cord is directly open to the air without overlying meninges or connective tissue.

Firing of Alpha Motor Neurons

Firing of alpha motor neurons is controlled by inputs from 4 general sources: 1. Sensory input from muscle spindles (Ia, Ib axons, skin afferents) 2. Same and nearby spinal segments (spinal interneurons) 3. Propriospinal inputs (running up and down cord, intersegmentally) 4. Supraspinal control (e.g., UMN in brain via CST)

*Phase-Advance* Circadian Rhythm

Fly to Europe: Go to bed earlier, wake up earlier. You need to feel sleepy before the clock says you should. Melatonin onset becomes earlier over time, and declines earlier on.

*Phase-Delay* Circadian Rhythm

Fly to Hawaii: Go to bed later, wake up later. Force yourself to stay awake longer than you would in Boston. Melatonin onset becomes later over time, and declines later on.

Golgi Tendon Organ

Formed by the endings of *Group Ib* axons, which are *sensitive to mechanical deformation* and are interwoven among the strands of the tendon near its junction with the muscle. Because the Golgi tendon organs lie in the tendon that is mechanically in series with the muscle, they are *deformed whenever the attached muscle develops force against a load and produces tension in the tendon*. The *1b fiber* sends a signal to the spinal cord related to the *amount of force being developed* by the muscle. When there is less tension, there are more gaps between collagen fibers. When there is more tension, the fibers become more parallel, interact with 1b fibers, and increase firing of 1b afferents.

PNS Sensory Axons (recap from Block 7) *Large:* touch and position *Small:* pain and temperature

From most myelinated to least (fast to slow): 1. *Aα:* proprioceptors of skeletal muscle (fast) (DCML) 2. *Aβ:* skin mechanoreceptors: fine touch, pressure, vibration, proprioception (DCML) 3. *Aδ:* sharp pain, cold temperature, crude touch (AL spinothalamic) 4. *C:* slow dull pain, warm temperature, itch, referred pain (AL spinothalamic) Note: Aδ and C fibers terminate peripherally as free (not encapsulated) nerve endings. Aα and Aβ fibers terminate in encapsulated nerve endings.

*Gamma Motor Neuron Loop* -Helps determine muscle tone

Gamma motor neuron activation alone can increase the discharge rate of the Ia fiber by shortening the two poles of the intrafusal fiber and stretching the equatorial pole. The Ia afferent fiber makes a monosynaptic excitatory connection with alpha motor neurons to the muscle from which it arises. *Gamma Loop Reflex:* 1. Gamma neuron activation 2. Intrafusal shortening 3. Ia fiber activation (rate of length change) 4. Alpha motor neuron activation 5. Extrafusal contraction *UMN Sign:* spasticity 1. Abnormally *high levels of gamma motor neuron activity* could be characterized by increased resting muscle tone (*hypertonia*) 2. Increased sensitivity of the gamma loop to muscle stretch (*hyperreflexia*)

tPA (acute treatment of stroke) -53% positive, 37% disability; 10% death

Given up to *4.5 hours* from when last known well *Absolute contraindication is active bleeding* -- CT helps determine eligibility. *Eligible for tPA if:* 1. Hemorrhage is absent (not bleeding) 2. Infarction is not "too large" (hypodensity is less than 1/3 volume of MCA territory). *Mechanism:* tPA activates plasminogen → plasmin from to degrade clots into FDPs *DO NOT treat patients:* 1. Age >80 2. History of prior stroke and diabetes 3. Taking oral anticoagulant 4. Active bleeding

*IDH Mutations* in Gliomas -Astrocytomas -Oligodendrogliomas

Glioblastomas with a *wild-type IDH1* gene have a median overall survival of *only 1 year*, whereas *IDH1-mutated* glioblastoma patients have a median overall survival of *over 2 years* (better prognosis. (i.e., IDH-1 mutants have better prognosis.) IDH = isocitrate dehydrogenase (IDH1, IDH2) Reaction: α-ketoglutarate (αKG) → *D-2-hydroxyglutarate (D2HG)*, an *oncometabolite* implicated in the development of glioma. Oncogenesis: 1. D2HG inhibits αKG-dependent enzymes 2. This leads to impaired histone demethylation 3. This leads to epigenetic changes and provides a mechanism for tumorigenesis

*Amyotrophic Lateral Sclerosis* (ALS) (exam) -*Pseudo-bulbar effect:* dysregulation of motor output of emotion (emotional incontinence)

Gradual degeneration of *both LMN and UMN* that can be caused by defect in *superoxide dismutase 1 (SOD1)*. *Amyotrophic:* muscle atrophy *Lateral:* lateral location of the CST in spinal cord *Sclerosis:* scarring of the spinal cord where the motor neurons deteriorate. UMN: corticobulbal (CN) / *corticospinal* LMN: medullary and spinal cord (*ventral horn*) Mixed UMN and LMN signs: *MOTOR ONLY* *LMN Deficits* 1. Dysarthria (bulbar) 2. Dysphagia (bulbar) 3. Asymmetric limb weakness (limb) → *foot drop* 4. Fasciculations (limb) 5. *Atrophy* (*medial to lateral hand*; "split hand"; intrinsic hand muscles) (limb) *UMN Deficits:* -*Spasticity (hyperreflexia and hypertonia)* *Diagnosis:* 1. Exam consistent with UMN and LMN 2. EMG/NCS suggest *motor* neuron disorder 3. No Ab against muscle, no spine issue on imagine. Treatment: *No Cure* (2-5 years of life after diagnosis). Symptomatic treatment. 1. *Riluzole:* provides 2-3 months of survival 2. Edaravone: IV infuse prolongs period of decline before wheelchair 3. Nudexta (dextromethorphan)

With the exception of ________ cells, all cerebellar cortex cells are inhibitory

Granule cells, which send (+) signals via parallel fibers to Purkinje cells

*Ventromedial Brainstem Pathway(s)* -Extension

Has a net *extensor effect* for postural (axial) muscles (trunk, girdle, and *proximal limbs*), promoting an *upright posture*. Also important in balance and orienting movements using axial musculature. *A collection of brainstem projections arising from:* 1. Midbrain tectum (superior colliculus) (*tecto*spinal): reflexive movement in response to visual and auditory stimuli; coordinates eye (*express saccades* via CN III, IV, VI) and reflexive head movements (via neck muscles) 2. Vestibular nuclei of medulla (*vestibulo*spinal): extension to keep body upright 3. Reticular formation of pons/medulla (*reticulo*spinal) These pathways run in the ventromedial part of the white matter of the spinal cord, and synapse onto interneurons at spinal level ventral horns.

Brown-Séquard Syndrome

Hemisection of spinal cord. Consequences of AL decussation in spinal cord: 1. Loss of AL tract *contralateral* 2. Loss of DCML tract *ipsilateral* 3. *Ipsilateral* paresis (weakness; CST) and UMN (hypertonia, hyperreflexia, Babinski)

Desynchronized EEG

High frequency, low amplitude (neurons firing randomly). REM sleep predominates the final 1/3 of the night.

Rebleeding Risk Factors after SAH

Highest risk on first day Long interval from SAH to treatment Higher BP Worse neuro state

*Cytotoxic Edema* (Intracellular) -Occurs mainly in gray matter -*Cloudy-swelling* -Cell membrane injury due to ischemia or toxic exposure (DNP or isoniazid)

In *acute stroke (ischemia)*, there is *decreased water diffusion* as Na/K ATPase and other cell-membrane ionic pumps fail as *ATP is depleted* (due to *anoxia*). This causes an osmotic gradient across cell membranes and a shift of water from extra- to intra-cellular space. ↑ increased viscosity and tortuosity (breakdown of cytoskeleton and organelles) ↓ in extracellular space (cell swelling) ↑ extracellular space tortuosity

Neuromuscular Junction (synapse)

In mammalian muscle, each muscle fiber receives innervation from only one alpha motor neuron. Safety factor: *Every action potential in the motor neuron releases enough ACh to ensure that all the muscle fibers in the motor unit also fire action potentials.*

Brain Neoplasms (Neoangiogenesis) -MR-Perfusion Imaging

In order for neoplasms to grow, vessels must form to support that growth. New vessels are formed from *neoplastic stem cells*. *MR-Perfusion Imaging:* 1.↑relative cerebral blood volume (rCBV) 2. Biomarker of capillary and malignant neovessel number → neoplasms grow so fast that they outgrow their blood supply

*Balo's Concentric Sclerosis* -Concentric, lamellar lesions (in white matter)

In the Far East, Balo's Concentric Sclerosis is commonly seen as *concentric, lamellar lesions* in the cerebral white matter.

Cerebellar and Basal Ganglia Loops

In the left hand loop, the sensory-motor cortex exerts control over the primary motor cortex via a projection to the pons → cerebellum → VL thalamus → back to M1. Note the key position of the VL thalamic nuclei in both the cerebellar and basal ganglia control loops. By way of this projection through VL, cortical cells projecting into the corticospinal / corticobulbar tract are subject to cerebellar feedback.

Spasticity and Segmental Spinal Reflexes

Increased resting tone in extrafusal fibers is observed in many disease states. *Increased alpha motor neuron firing may be due to:* 1. Increased descending input (CST) to the alpha motor neuron 2. Abnormally high gamma activity 3. Both *Interruption of descending motor paths (CST) commonly produces spasticity*: 1. Increase in resting muscle tone (hypertonia; stiff, don't want to move) 2. Increase in reflex excitability (hyperreflexia). Spasticity in a limb can be eliminated by cutting the dorsal roots (1a sensory afferents). This shows that heightened activity in the gamma loop is a major contributor to the problem, because *cutting the dorsal roots deprives the alpha motor neurons of their 1a input*, but does not interrupt descending influences.

*Decerebrate (Extensor) Posture* -Vestibulospinal takes over → extension

Indicates a lesion *between red nucleus and vestibular nucleus* (in the midbrain or upper pons), leading to a net activation of *extensors*. *The spinal cord and lower brainstem are essentially deprived of descending input from forebrain and upper midbrain.* These lesions serve to *shut-down the red nucleus directly* (e.g., due to pressure from progressing, late-stage uncal herniation) or disrupt its descending output. *Findings:* 1. *Arm and leg extension* are observed, due to the relative *overactivity* of the *vestibulospinal tract*, which is still intact below the lesion Note: the vestibulospinal tract normally serves to generate extension in order to oppose gravity and keep the body upright.

Neurocysticercosis

Infection caused by *pork tapeworm, taenia solium* (ingesting eggs in feces-contaminated food and water). *Characteristics:* 1. Common cause of epilepsy in endemic areas (American SW, Central & South America, eastern Europe, Africa, Asia) 2. *Symptoms develop 5-7 years after infection* (range, 1-30 years) 3. Multiple, 1-2cm cysts with visible larva

Golgi tendon organs tend to provide ..... feedback

Inhibitory; regulates force

Brachial Plexus and *Erb's Palsy*

Innervates *arm and most of shoulder* (extends from the cervical roots through the neck below the clavicle, and into the axilla). Components: *Motor and sensory* roots of *C5-T1* *More susceptible to trauma and disease from adjacent structures* (large size, superficial, position between mobile structures). *Erb's Palsy* injures the *upper trunk* section of the brachial plexus (C5-C6 nerve roots). -Can occur due to trauma of the neck and shoulder (*upper trunk*) at birth -"Waiter's Tip" posture (arm internally rotated at the shoulder, extended elbow, and pronated forearm)

Cerebellar Circuitry

Input fibers bring in information (proprioception via spinocerebellar, motor commands via cortico-ponto-cerebellar projections) to cerebellar cortex (purkinje fibers) and to deep cerebellar nuclei. Input info (actual motor state) is compared to motor intention (as perceived through various forms of sensation), and *deep nuclei output (correction signal)* is sent to the cortex. *Cerebellar Nuclei:* DEGF D: limbs (high level movement) E: girdle and proximal limbs G: girdle and proximal limbs F: axial muscles

Reflexes

Involuntary coordinated muscle patterns (contraction and relaxation) elicited by peripheral stimuli. Key Features: 1. Local sign: reflexes pertain to nearby points of the spinal column 2. Graded in intensity 3. Simple, but contribute to complex behaviors 4. Adaptable to circumstances

*Central Cord Syndrome* -Small lesion: shawl (pain and temp loss) -Large lesion: entire body but genitalia (loss of motor, pain and temp, vibration and position)

Lesion grows from middle of spinal cord. *Clinical Findings:* 1. *Suspended sensory level for pain and temperature at lesion level* (*block in anterior white commissure (AL)*) 2. Normal 2 point discrimination (DC-ML) 3. LMN weakness at lesion level (anterior horn cell damage) 4. UMN symptoms below lesion level (if the corticospinal tracts become involved) 5. Hyperreflexia 6. *Arm > Leg weakness (especially hands)*

*Weber's Syndrome* (midbrain peduncle stroke) *Brainstem = crossed signs*

Lesion in *anterior midbrain peduncle* (blocks corticospinal, corticobulbar, and corticopontine tracts as well as CN III) *Vascular Supply:* PCA perforators *Cause:* stroke *Ipsilateral Findings:* CN III (EW and occulomotor) 1. CN III palsy (down and out; dilated; no pupillary reflex) *Contralateral Findings:* peduncles, CN VII, XII 1. Hemiparesis (corticospinal) 2. Lower facial muscle and tongue paralysis (CN VII and XII) (corticobulbar) 3. Parkinsonism (rigid, tremor) (SNc; no dopaminergic output) Parkinsonism: review *TRAPS:* tremor, rigidity, akinesia, postural instability, shuffling gait

Hierarchical Approach to Lesion Localization

Lesion in Nervous System? Central or Peripheral? Above or below the neck? Above or below the tentorium? Right/Left/Both hemisphere?

Cognition Deficit

Lesion in brain

Chronic Inflammatory Demyelinating Polyradiculoneuropathy (CIDP)

Like Guillan-Barre (inflammatory, demyelinating) but more chronic and *can relapse.* *Treatment:* IV immunoglobulin (IVIg) or *steroids* (which don't help GBS)

Minimally Conscious State

Limited, but clear awareness of environment: 1. Follows *simple commands* 2. Answers *yes/no questions* (may or may not answer correctly) 3. Verbalizes 4. Purposeful behavior (smile, cry, reach, hold)

*Millard-Gubler Syndrome* (ventral pons) -Contralateral corticospinal (hemiplegia) -Ipsilateral CN VI and VII -Paralyzed eye looks toward the hemiplegia

Localization: *ventral pons* (unilateral) Vascular supply: *basilar artery perforators* Findings: 1. Ipsilateral *CN VII Palsy* (full face droop and ptosis) 2. Ipsilateral *CN VI Palsy* (abducens paralysis) 3. Contralateral hemiparesis (corticospinal tract) Similar to Weber, but CN VI and VII are affected (ventral pons), rather than ventral midbrain (CN III).

*Claude's Syndrome* (red nucleus) -Ipsilateral CN III -Contralateral hemiataxia/dysmetric (post superior cerebellar peduncle) -Contralateral tremor

Localization: central midbrain (tegmentum) Vascular supply: *PCA Perforators* Findings: 1. Ipsilateral CN III palsy (down and out; dilated; no pupillary reflex) 2. Contralateral hemiataxia and dysmetria (loss of *cerebellothalamic pathway*) 3. *Contralateral tremor (red nucleus)* Similar to Weber, but instead of weakness (cerebellar peduncles) and Parkinsonism (SNc) contralaterally, Claude's affects the red nucleus (hemiataxia/dysmetria).

*Weber's Syndrome* (midbrain cerebral peduncle) -Contralateral corticospinal -Ipsilateral CN III

Localization: medial, ventral midbrain Vascular supply: *PCA perforators* Findings: 1. Contralateral hemiparesis (cerebral peduncle = corticospinal tract) 2. Ipsilateral CN III palsy (down and out; dilated; no pupillary reflex) 3. Contralateral Parkinsonism (SNc)

Gamma Motor Neurons

Located around muscle spindles to *contract intrafusual stretch receptors* during contraction. *Gamma Motor Neurons:* 1. *Take up slack during contractions (causes the contractile poles of the intramural fibers to shorten to put tension on 1a fibers at the equator)* 2. Maintain proper tension on sensory endings of intramural fibers in the spindle throughout the range of extrafusal muscle contraction. 3. *Alpha-gamma coactivation permits 1a fibers to report length changes despite shortening of extrafusal fibers upon contraction.* 4. This shortening allows the spindle to function as a sensing device at all lengths of the muscle as it shortens during normal movements) 5. Overall, this establishes new set point for muscle length i.e., *spindles are stretch receptors and need gamma innervation to maintain their ability to report on muscle length during an active contraction*.

*Alcoholic Cerebellar Degeneration* -Absent Purkinje cells (cerebellum)

Long term use of alcohol (or phenytoin) has detrimental effects on the cerebellum characterized by *loss of vermal tissue* (atrophy) which spreads to the anterior cerebellar hemispheres. *Pathology:* 1. *Purkinje cells are absent* (EtOH destroys them) and there is marked atrophy of the molecular (outermost) layer. *Manifestations:* 1. *Wide-based gait* 2. Incoordination in the legs

Synchronized EEG

Low frequency, high amplitude (neurons firing in synchrony) (slow wave; NREM = non-REM) Slow wave sleep predominates the first 1/3 of the night.

With a small hematoma, as ICP rises, MAP ___ and CPP ___.

MAP↑ and CPP stays the same. Increases to maintain cerebral perfusion pressure, which stays the same. The brain can accommodate increased ICP to some extent.

With a large hematoma, as ICP rises, MAP ___ and CPP ___

MAP↑ and CPP↓ ICP is so high that CPP decreases substantially. Eventually herniation will ensue.

fMRI and DTI are used for...

Mapping eloquent cortex prior to seizure-surgery (e.g., determining the location of the arcuate fasciculus via DTI and looking at Broca's and Wernicke's areas via fMRI while someone is producing speach). This *reduces neurologic deficits* by minimizing injury to eloquent cortex.

Supratentorial Coma

Mass lesion compresses or displaces diencephalon or brainstem (e.g., hemorrhage, cerebral infarction, tumor, abscess). Characteristics: 1. Focal (lateralizing) signs early 2. *Rostral → caudal progression* (herniation) 3. Signs identify one level at a time 4. Motor asymmetry

*Central Pontine Myelinolysis* -AKA osmotic demyelination syndrome

Massive axonal demyelination in pontine white matter secondary to rapid osmotic changes (*overly rapid correction of hyponatremia*) *Clinical Findings:* 1. Acute paralysis (corticospinal) 2. Dysarthria 3. Dysphagia 4. Diplopia 4. Loss of consciousness (ARAS) Can cause *"locked-in syndrome."* Correcting serum Na+ too fast: *"From low to high, your pons will die"* (osmotic demyelination syndrome). "From high to low, your brains will blow" (cerebral edema/herniation).

Most common x-irradiation induced brain tumor is...

Meningioma

*Meningioma* -Usually occurs in the orbitofrontal lobe = "good angel" -Can lead to erratic changes in behavior -*Psammoma bodies* (calcifications)

Meningiomas arise from the *arachnoid cap cells* and affect *women* more than men (hormone-responsive = increase in size during pregnancy). The vast majority are grade I and low-grade (grade II when the meningioma invades brain parenchyma). *Treatment:* 1. Total surgical resection 2. Chemo not very effective *Pathology:* *tumor tail* extension into dura mater 1. *Whirled pattern* (spindle cells concentrically arranged) 2. *Psammoma bodies* (laminated calcifications)

Metastases (imaging)

Metastases form intercellular gap junctions with astrocytes and pirate cytokines that promote growth (Seed and Soil). *Distribution:* 1. 85% supratentorial (cerebral); 15% infratentorial (cerebellar) 2. Watershed distribution at gray-white junctions (increased vascularity) 3. Exception: *GI metastases are more common in the posterior fossa* *Imaging:* Hyperdense on FLAIR due to vasogenic edema (breakdown of BBB)

*Concussion* -No definite structural injury to the brain

Mild TBI (diffuse, primary) ± LOC. -Presents with clinical deficits but *no definite structural injury to the brain* *Best indicators:* -Vacant stare -Delayed reaction time (verbal or motor) -Immediate confusion/disorientation -Impaired verbal learning/memory *Also Common:* -Headache/dizziness -Nausea -Blurred/double vision -Photo/phonophobia *Mechanism:* -May include axonal disruption -May include mechanisms of secondary injury Premature return of a concussed athlete can increase the risk of *"Second Impact Syndrome"* (rapidly progressing cerebral edema leading to secondary injury) and re-concussion. Glasgow: 13-15 (very good to normal)

Juvenile Myoclonic Epilepsy

Mixed type seizures beginning in childhood/early adolescence, often activated by light stimulation

Dopamine and Prediction Errors

Models of reinforcement-learning evoke a *prediction error* that is tied to *unexpected* outcomes: 1. *Increased* dopamine signal for *unexpectedly positive* events 2. *Decreased* dopamine signal for *unexpectedly negative* events 3. *No change* if events transpire as *expected*

*Craniopharyngioma* (pediatric) -Rathke's pouch remnants (ectoderm; supratentorial) -"Motor oil" fluid in tumor -Wet keratin (calcification)

Most common *childhood supratentorial tumor*. May be confused with pituitary adenoma (both cause *bitemporal hemianopia*). Locally invasive and difficult to treat. *Derived from remnants of Rathke pouch (ectoderm).* Calcification is common. *Pathology:* 1. Stellate, squamoid-type epithelium 2. Calcification is common (*wet keratin*) 3. *Cholesterol crystals found in "motor oil"-like fluid within tumor.*

Migraines and Auras

Most common is migraine without aura (common migraine). People with migraines with aura (classic migraine) usually experience focal neurological symptoms, usually *positive visual phenomena* (visual > sensory). *Complex migraines* are usually familial and can include periodic attacks of ophthalmoplegia, hemiplegia, confusion, or ataxia. Aura is neuronal; travels out from a specific area.

*Medulloblastoma* (pediatric) -Homer-Wright rosettes (SRBCT) -Usually involves the vermis (compresses the 4th ventricle) → hydrocephalus

Most common malignant brain tumor in childhood. Commonly involves the *cerebellar vermis* and can *compress 4th ventricle*, causing *noncommunicating hydrocephalus* → headaches, papilledema (↑ICP). The tumor tends to spread into CSF pathways, sending *drop metastases* to the spinal cord. *Pathology:* 1. *Homer-Wright rosettes* (neuropil at center) 2. Small round blue cell tumor (SRBCT): primitive cells *Treatment:* 1. Radiation of the entire neuraxis (including spinal cord)

*Pilocytic Astrocytoma* (pediatric) -Rosenthal Fibers in astrocyte foot processes (Stage 1 astrocytoma)

Most common primary brain tumor in children that usually presents with *hydrocephalus* or mass effect. Treatment: *surgical resection* *Pathology:* 1. Astrocytes with piloid (hair-like) projections 2. *Rosenthal fibers* (eosinophilic, corkscrew fibers) in astrocyte foot processes 3. Tend to be cystic and slow growing

*Hemangioblastoma* -Associated with vHL syndrome -Foamy cells with high vascularity

Most often *cerebellar*. Associated with *von Hippel-Lindau* syndrome when found with retinal angiomas. Can produce erythropoietin 2° polycythemia (↑RBC in hematocrit). *Origin:* Blood vessels. Closely arranged, thin-walled capillaries with minimal intervening parenchyma *Pathology:* Foamy cells with high vascularity. Reminder: vHL protein (a ubiquitin ligase hydroxylated in O2-rich conditions) inhibits angiogenesis by blocking HIF-1α (TF) from activating VEGF, thus preventing an angiogenic switch.

Motor Neuron Somatotopy

Motor neurons innervating *axial (trunk) and proximal limb muscles* are located *medially*, while *distal (hand) muscles* are located *laterally*. This is similar to the dorsal columns.

Muscle Movement

Muscles can only pull, they cannot push. They exert forces by contracting, pulling against tendons, which pull bones.

Demyelination

Myelination increases electrical conduction velocity: 1. Decreases capacitance 2. Increases diameter 3. Prevents electrical current from escaping from the axon into the extracellular space Diseases that affect the myelin sheath result in leakage of electrical current and termination of the action potential.

Brain Neoplasms (Hypercellularity) -MR Spectroscopy -*↑↑ Choline : NAA ratio* -↑ mitoses

Neoplasms contain many more cells per unit area than normal brain parenchyma (more mitoses occurring). Appears *hyperdense* on non-contrast CT (NCCT) because they are hypercellular (more dense)! MR Spectroscopy: *↑↑ Choline : NAA ratio* 1. ↑ Choline (more cells/unit area; makes up phospholipid bilayer) 2. ↓ N-Acetyl Aspartate (sign of normal neuronal function)

*Safety Factor in NMJ* -NMJ is where the nerve communicates with the muscle

Nerve terminal will normally release enough ACh to induce a summated potential that is greater than threshold to ensure transmission is successful. When *safety factor is reduced* there is failure of transmission → *NMJ disease*.

Cerebro-Pontine Angle

Neurofibromatosis type 2 is a disorder characterized by the growth of noncancerous tumors (vestibular schwannomas with palisading, pleomorphic tumor cells) in the nervous system, especially at the cerebro-pontine angle. Autosomal dominant mutation in *NF2* tumor suppressor gene on *chromosome 22*. Findings: -*Bilateral acoustic schwannomas (2 ears)* -Juvenile cataracts (2 eyes) -Meningiomas and ependymomas (2 parts of the brain)

Intra-Arterial Mechanical Thrombectomy

Neurointervention to remove clot. *Locations:* 1. *ICA:* angioplasty (balloon) and stent 2. *MCA:* thrombectomy *Criteria:* 1. Moderate-to-severe deficit (NIHSS score >6) 2. Within 24 hours of stroke-onset 3. Infarct < 1/3 MCA territory (core) and large volume of ischemic tissue at risk (penumbra) 4. Documented emergent large vessel occlusion (ELVO)

Vestibulocerebellum

Nodule and Flocculus; connected to the *vestibular nuclei* Actions: 1. *Balance and gait* 2. Postural maintainance 3. Eye movements

If person comes in with possible stroke or hemorrhage, first imaging is

Non-Contrast CT (NCCT): takes only 10 min

Servo-assisted Movement

Normally, alpha and gamma motor neurons increase their firing rates together in order to contract a muscle. *If muscle contraction doesn't meet expectations, spindles (1a) give immediate corrective feedback (servo-assisted movement).* *Intense activation of the gamma motor neurons* allows the *gamma loop* (via 1a afferents) to *assist in depolarizing the alpha motor neurons* (along with the descending corticospinal tract) acting on the contracting muscle, boosting input to the muscles.

Secondary Injury (TBI) *Process:* 1.↓O2 2.↓ATP (anaerobic glycolysis) 3.↓glutamate uptake by glial cells 4. ↑Ca2+ uptake by neurons (NDMA-R) 5a. Activated lipases → Lipid peroxidation (membrane failure) 5b. Mitochondrial swelling 6. ↓↓ATP ( due to↓OXPHOS) 7. Cytochrome C released 8. ROS produced 9. Caspases → Apoptosis

Occurs following primary injury (seconds to weeks). *Mechanical insult → Cell injury.* *If you lose CPP when ICP is elevated, you lose Cerebral Blood Flow (O2 and nutrients).* *Loss of flow below 20cc/100g/min means loss of cells over time.* *Process:* 1. Trauma, failure of nutrient delivery, and ischemia promote *anaerobic glycolysis* 2. This results in decreased ATP 3. Energy (ATP)-dependent glutamate uptake on glial cells and neuronal processes slows → *glutamate excitotoxicity* 4. Increased glutamate means increased Ca2+ uptake by the neuron via NDMA-R 5. Increased intracellular Ca2+ (from uptake and organelle dysfunction) leads to mitochondrial swelling, and then *uncoupling of oxidative phosphorylation*, further decrease of ATP production, opening of the mitochondrial permeability transition pore (mPTP), release of *Cytochrome-C*, production of *ROS*, activation of caspases, and *cell death*. The best place to interrupt this TBI cycle is before it happens (prevention). There are no proven drugs or treatments to prevent any steps of this process.

Peroneal Nerve Entrapment (mononeuropathy)

Occurs when patients cross legs. 1. Peroneal nerve entrapment occurs at the fibular head 2. *Weakness of foot dorsiflexion (foot drop)* and *eversion* 3. Numbness on lateral lower leg and top of foot 4. Tinel sign at fibular head

On CT, intracerebral hemorrhage stroke looks _____________

On CT, intracerebral hemorrhage stroke looks *hyperdense* due to blood/fluid. Either deep (basal ganglia or thalamus) or lobar. 10% of all strokes.

On CT, ischemic stroke looks _____________

On CT, ischemic stroke looks *hypodense* (no blood). 87% of all strokes.

On T1 MRI and FLAIR, what does MS look like? T1: gray matter gray, white matter white, CSF bright white FLAIR: gray matter white, white matter gray, CSF black

On T1 MRI, MS looks like *"black holes"* (a marker of chronic axonal injury). Reminder that on T1, white matter looks "white." On FLAIR MRI, MS looks like *white spots* and plaques can show up in periventricular white matter, perpendicular to the long axis of the lateral ventricles (*Dawson's Fingers*). *Perivenular demyelination* explains perpendicular orientation relative to the long axis of ventricles.

Motor Unit

One motor neuron and all the muscle fibers it innervates. The smallest unit of muscle that can be manipulated by the CNS. The fewer muscle fibers alpha motor neurons innervate, the finer the neural control over that muscle. The muscle fibers innervated by one alpha motor neuron are scattered within a muscle, an arrangement that contributes to smooth action of the muscle because the *force of contraction develops over a short period of time* instead of instantaneously. This also means that loss of a single motor unit (as in early stages of motor neuron disease or with aging) will not seriously affect control of a particular muscle.

For an MS *Diagnosis*, MS must be *disseminated in space*

One or more FLAIR/T2-lesion in at least two of four areas (multifocal): 1. Periventricular (touching ventricle) 2. Juxtacortical (touching cortex) 3. Infratentorial (around aqueduct/4th ventricle) 4. Spinal Cord

Optic Neuritis

Optic neuritis is a demyelinating inflammation of the optic nerve. It is most often associated with multiple sclerosis, and it may lead to complete or partial loss of vision in one or both eyes 50-70% of patients with isolated optic neuritis will have brain lesions consistent with demyelination. 70% of these patients with one or more brain lesion will develop MS.

Choroid Plexus Papilloma

Overgrowths of choroid plexus tissue. *Findings:* 1. Well-differentiated (capable of producing CSF). 2. Tend to appear in lateral ventricles of kids 3. May produce (communicating) hydrocephalus

Muscle Structure Review

Overview: 1. Muscle is composed of fascicles, which contain many muscle fibers: 2. Muscle fibers are composed of many muscle fibrils (myofibrils) 3. Actin, myosin, and other proteins make up the sarcomeres Muscle disorders can occur due to pathology at different levels of the fiber/fibril structure: 1. Muscle fiber ion channels 2. Muscle structure 3. Muscle metabolism 4. Inflammatory processes

Lower Motor Neuron Symptoms

PNS

*Conjugate horizontal eye movements* are mediated by the ___

PPRF (ipsilateral); PPRF *pulls* the gaze *Left PPRF pulls eyes to the left* 1. Left PPRF activates left CN VI 2. Left CN VI abducts the left eye 3. Left CN VI activates right CN III via MLF 4. Right CN III adducts the right eye

AEDs that come as IV (can be loaded)

PPV+B: Phenytoin, Phenobarbital, Valproic Acid, Benzodiazepines

Stretch receptors are arranged in _________ to muscle and golgi tendon organs arranged in __________ to muscle.

Parallel - Stretch (sense length) (1a afferent) Series - Golgi (sense force) (1b afferent)

Migraines and Vascular Disease

Patients with migraines and migraines with aura are at *higher risk of cerebrovascular / cardiovascular disease* -- and are also more likely to have an asymmetrical or anomalous Circle of Willis. Women with migraines with aura should *AVOID estrogen-based contraceptives* as it increases risk of stroke.

Poor Prognosis Sign in Coma

Persistent abnormal brainstem signs (especially pupils) are indicative of poor prognosis.

Basilar Skull Fractures usually involve the ...

Petrous part of temporal bone or the orbital part of frontal bone

Purkinje cells

Primary *output neurons* of the cerebellum, with an *inhibitory influence* on the deep nuclei (GABA).

Chemotherapy Treatment of Brain Tumors

Prognosis for astrocytoma/glioblastoma and oligodendrogliomas is *better if MGMT is methylated*. MGMT is a DNA-repair protein for alkylating damage. If MGMT is *methylated* (*inactive*), alkylating chemotherapy (*temozolomide*) will be more effective. Active MGMT can prevent the drug from working.

Extraocular Movements (Transtentorial Herniation)

Progressive findings assume *transtentorial herniation*: *Diencephalon:* brisk OCR/VOR (*cortical control by the FEF has been removed*) *Midbrain:* may be diminished, dysconjugate *Pons:* absent (no PPRF to pull gaze) *Medulla:* absent (no PPRF to pull gaze) PPRF: paramedian pontine reticular formation *Need intact cortex for nystagmus.*

Levels of Consciousness (Transtentorial Herniation)

Progressive findings assume *transtentorial herniation*: *Diencephalon:* progressive deterioration *Midbrain:* coma (ARAS) *Pons:* coma (ARAS) *Medulla:* coma

Motor Response (Transtentorial Herniation)

Progressive findings assume *transtentorial herniation*: *Diencephalon:* semi-purposeful to flexor *Midbrain:* flexor to extensor posturing *Pons:* extensor to flaccid posturing *Medulla:* flaccid (below the vestibular nuclei that run until caudal medulla; analogous to high cervical spine injury)

Respiration Response (Transtentorial Herniation)

Progressive findings assume *transtentorial herniation*: *Diencephalon:* sighs, yawns, Cheyne-Stokes *Midbrain:* central neurologenic hyperventilation *Pons:* end-inspiratory pauses (apneusis) or eupnea (normal but not reactive to stimuli) *Medulla:* ataxic or apneic

Pupils (Transtentorial Herniation)

Progressive findings assume *transtentorial herniation*: *Diencephalon:* small, reactive (unopposed parasympathetic outflow; *sympathetic disturbed* as *hypothalamus is diencephalic*) *Midbrain:* midsize fixed (loss of both parasympathetic (EW) and sympathetic) (*blown if CN III is directly involved* and nothing is disrupting the hypothalamus, e.g., uncal herniation) *Pons:* midsize fixed (*direct pontine damage/hemorrhage→pinpoint*; sympathetics traverse brainstem and are out; parasympathetics not inhibited) *Medulla:* midsize fixed

Waking/Arousal controlled in ....

Reticular Formation of Midbrain (ARAS): upper brainstem nuclei and the reticular formation ARAS = Ascending Reticular Activating System

Epilepsy Pharmaceuticals

Search for phenobarbital. Reminder: time = brain

Herniated Disk (radiculopathy)

Separating vertebral bodies are intervertebral discs composed of a central gelatinous nucleus pulposus and surrounding annulus fibrosus. Causes: 1. Nucleus pulposus herniates through the annulus fibrosus into the central canal, *compressing the nerve root*. 2. Infection, tumor, or trauma

Deep ICH caused mainly by....

Small arterioles frequently become thickened and narrowed in patients with *hypertension* (arteriolosclerosis). Affected vessels often have thickened walls that are described as *onion-skinned* (lipohyalinosis). Occlusion of these small lenticulostriate vessels results in *lacunar infarcts* (basal ganglia and pons are popular sites). Other causes: 1. Anticoagulants 2. Vascular malformations (arteriovenous)/aneurysms 3. Tumors 4. Infarction with hemorrhagic transformation 5. Venous sinus thrombosis 6. Drug use (stimulants, sympathomimetics)

Bilateral weakness sparing face

Spinal Cord

Peripheral Lesion Locations

Spinal Cord grey matter Root Plexus Nerve Neuromuscular Junction Muscle

Fasciculations (synchronous) -Wave-like twitching across muscle

Spontaneous firing of individual diseased alpha motor neurons causing a *synchronous contraction* of the fascicle of muscle fibers forming their motor units.

*Rubrospinal Tract* -aka Lateral Brainstem Pathway -*Arm Flexure*

Strong effect on *arm flexors* (role in decorticate posturing). Receives input from the cortex (as well as some from the cerebellum and brainstem). Originates in the *Red Nucleus* of midbrain, runs in lateral funiculus (brief), decussates in the midbrain, runs in lateral brainstem (next to lateral pyramidal pathway), and synapses at spinal level. *Tract ends at cervical enlargement of the anterior horn,* which indicates its major role in controlling the *proximal arm* muscles (potentially in reaching and steering the arms).

Prefrontal cortex lesions usually lead to...

Subtle changes in attention, planning, and emotional regulation. *Patient Findings:* "bad angel" 1. Inattentive 2. Disinhibited (*impulsive*, unable to act based on longer-term planning) 3. Stimulus-locked (simple, immediate responses to environmental cues) 4. Abulic (lacking in motivation, even for simple tasks)

This imaging is sensitive for hypodensity of hemorrhage

T2 weighted gradient

In low hygiene environments, immune system develops more....

TReg cells

Diagnostic Tests for Nerve and Muscle Function

Tests that look at abnormalities in the PNS: 1. NCS: nerve conduction studies 2. EMG: electromyography

Deep Cerebral Structures

The *deep white matter tracts* (optic radiations, corona radiate, etc.) become very compact in projecting information upon descent → hemi-body syndrome (not just FA or L). The *deep gray structures* include the thalamus and basal ganglia. The *thalamus receives all sensory input from incoming sensory pathways* and projects that information to the sensory cortex. It is also a relay station for many intracerebral connections (e.g., GPi or STN) and sensorimotor control loops (e.g, dentate nucleus). The *basal ganglia* play a major role in the control of *posture and movement* (and reinforcement learning via dopamine).

At 10 weeks, the neural tube gives rise to...

The *germinal matrix* (which remains present until week 34). *Neurons and glia* populating the cerebral hemispheres arise mostly from the germinal matrix (*primitive blue cells*), which lies adjacent to the caudate nucleus. The layers of the cerebral cortex are populated in descending numerical order. As the neuroblasts (neuronal precursors), arising from the stem cells of the germinal matrix, migrate away from the ventricular border (ependymal zone), they move outward toward the external border (pia), then are pushed back in (deeper) by the next stem cell migration. The cortex develops in an *inside-out* manner, with layers populated in descending numerical order (1 outer; 6 inner). The germinal matrix *vasculature has poor structural integrity*, but because of its immensely important role, it is richly supplied with blood. This combination means that the germinal matrix is *extremely vulnerable to hemorrhage*, causing *obstructive, non-communicating hydrocephalus.*

*Guillan-Molleret Triangle* -Rubrospinal tract and Cerebellum connection -4 decussations

The *rubrospinal* tract is *crossed* in sending fibers to the cerebellum: 1. Red nucleus fibers double-decussate and go to *ipsilateral inferior olive*. 2. *Climbing* fibers from inferior olive *cross* to the contralateral cerebellar cortex through the *inferior cerebellar peduncle* (climbing the olive tree). 3. Purkinje cells send *inhibitory* afferents to dentate nucleus. 4. *Afferent fibers from dendate nucleus* travel via superior cerebellar peduncle to *contralateral red nucleus*. *Lesions (particularly in the inferior olive) cause palatal myoclonus.* Reminder: The rubrospinal tract (proximal arm flexure) runs in the lateral funiculus (next to the lateral corticospinal tract), decussates in the midbrain, runs in the lateral brainstem, and then descends in the anterior-medial portion of the lateral spinal tract.

CNS Embryogenesis

The CNS is an *ectoderm-derived* structure. In early embryogenesis, ectoderm gives rise to the neural tube through a process of continued neurulation, elongation, and differentiation. *Diverticulation:* with continued differentiation, the cerebral hemispheres are formed (symmetrically). *Two Hemispheres:* *Left:* language and mathematical ability *Right:* spatial perception, the emotional tone of language, and artistic/muscial talent.

Muscular Contraction Force

The CNS must vary the activity of motor units to *grade the force of muscular contraction*. The CNS increases the force developed by the gross muscle by: 1. *Increasing the firing rate of a neuron* (correlated with the force of contraction) 2. *Recruitment* (increasing the number of active motor neurons in a pool)

Mean Arterial Pressure

The average pressure in a patient's arteries during one cardiac cycle.

*Intracranial Pressure* -↓BP (MAP) or ↑ICP leads to ↓CPP

The body regulates the amount of blood going into the brain. Even when the heart is pumping faster, the brain shrinks its blood vessel size to regulate. When the intracranial pressure begins to rise *(↑ICP), the body raises the Mean Arterial Pressure to keep the cerebral perfusion pressure the same* (must push blood harder to get it into the brain). Only when the ICP becomes overwhelmingly large (*↑↑ICP*) due to TBI is there a *decrease in cerebral perfusion (CPP)* pressure (not enough blood gets to the brain due to ↑ICP). *Overall: ↓BP or ↑ICP leads to ↓CPP*

Cerebellum and Efferent Copy

The cerebellum is a parallel motor control system. It receives an *efference* copy (*mossy fibers*) of motor commands, and uses this to *cancel out unexpected somatosensory sensations*. Efference copy is an internal copy or signal the the brain sends, informing itself of an efferent (outgoing) movement-producing signal. Since efference signals can only be created with our own movements (and not with someone else's), when we try to tickle ourselves, we send an efference copy and know that we are trying to tickle ourselves. This cancels out the expected tickling (somatosensory sensation).

The flocculonodular lobe (vestibulo-cerebellum) (motor outputs)

The flocculonodular lobe is tucked up under the cerebellum and is *related primarily to the vestibular system.* To some degree, it is distinct from the rest of the cerebellum because of its unusual connections. 1. It *receives* some direct projections from *Scarpa's ganglion* (primary vestibular afferent fibers that have not synapsed in the medullary vestibular nuclei). 2. Unlike most cells in the cerebellar cortex, some *Purkinje cells of the flocculonodular lobe project directly to the vestibular nuclei*, without a relay in the deep cerebellar nuclei (which is why the vestibular nuclei might be considered displaced deep nuclei, circuit-wise).

Inputs to the Motor Cortex (areas 4 and 6)

The more complicated and distant a goal, the greater the involvement of the more anterior regions of the prefrontal cortex. *Inputs:* 1. *Motor control:* Basal Ganglia and Cerebellum via VL Thalamus 2. *Ascending somatosensory pathways* via VP Thalamus (DC-ML: state of muscles and outgoing motor actions) 3. *Sensory Association Cortex (visual, auditory info)* via superior longitudinal fasciculus (from parietal lobe) and uncinate fasciculus (from temporal lobe) (e.g., see green light (visual), push on pedal (M1 output)) 4. Diffuse inputs from *subcortical structures* (via *neurohormones*; e.g., NE (locus ceruleus), serotonin (Raphé), ACh (basal forebrain, Nucleus of Maynert) input)

Action Planning

The more immediate and specific the action, the further back in the frontal cortex is the area of the brain that is responsible for it. The more abstract the motor plan, the more anterior areas come into play.

Corticobulbar Tract

The muscles of the face, head and neck are controlled by the corticobulbar system, which terminates on motor neurons within brainstem motor nuclei. Corticobulbar fibers generally decussate when they reach the level of the non-oculomotor cranial nerve nuclei that they innervate.

M-Response and H-Reflex

The myotatic reflex may be studied clinically by electrically stimulating the muscle nerve transcutaneously and recording the EMG of the muscle of interest with surface or intramuscular electrodes. The electrical stimulus sets up volleys in both sensory (1a) and motor (LMN) fibers, so the *muscle contracts first (M-wave)* due to the volley of impulses in the motor neurons, and again later due to the orthodromic volley relayed from Ia fibers onto alpha motor neurons (H-wave). This test bypasses the muscle spindle. *Findings:* 1. *Normal M wave, Absent H reflex:* suggests normal neuromuscular transmission, but abnormal sensory fibers or *problems with the synaptic relay from Ia to alpha motor neuron* in the affected spinal cord segment. 2. *Reduced M wave:* suggests a *problem in the motor fibers* to the muscle, in the *NMJ*, or in the *muscle* (the efferent loop).

Monosynaptic (Stretch) Reflex

The myotatic reflex proper results from *monosynaptic input from Ia spindle (stretch receptor) afferents* onto alpha motor neurons of the same muscle (the homonymous muscle). Through *reciprocal innervation* via an inhibitory interneuron, the Ia input *inhibits* the motor neurons of *antagonist*, or opposing, muscles (heteronymous). No gamma motor neurons are excited monosynaptically by 1a afferents. However, using *Jendrassik's maneuver* (clasp hands together, try to pull apart), one can *activate gamma motor neurons* by a different input that alters the spindle's sensitivity to stretch. This exaggerates the myotatic reflex by making the *spindle more sensitive to stretch* (by pulling on spindle endings).

Infratentorial Tumors

The position of the cerebellum beneath the tentorium means that it may be affected by infratentorial tumors and other space-occupying lesions of the posterior cranial fossa. The *cerebello-pontine angle* is a common site for tumors that may involve cranial nerves (such as CN V, VII and VIII of pons), as well as the cerebellum. Large tumors will involve more cranial nerves, including the upper (midbrain) and lower (medullary) ones. The cerebellar tonsils are protuberances of the cerebellum that lie against the medulla. When there is tumor or hemorrhage in the posterior cranial fossa (or ICP), the *tonsils may herniate through the foramen magnum, compressing the medulla resulting in weakness, obstructive hydrocephalus, and ultimately death*.

*Corticospinal Tract* -aka Pyramidal Tract

The primary motor cortex contribution to the corticospinal tract is to mediate voluntary, non-reflexive movements, particularly *fine, precise, delicate actions* of the torso and upper and lower limbs. Originates in cortex (60% frontal or 40% parietal lobes) and *descends internal capsule to midbrain cerebral peduncles, ventral pontine nuclei, and medullary pyramids.* *LATERAL CST (limbs)* provides descending voluntary motor information to the *contralateral limbs* (decussates in caudal medulla (pyramids) and travels down *lateral funiculus of spinal cord*). *ANTERIOR CST (axial)* does not decussate at medulla but does so at spinal level instead. This tract innervates *ipsilateral muscles that help to orient you to the contralateral world (e.g., SCM)*. Additionally, the anterior CST controls the movements of axial muscles (of the trunk). Both synapse at spinal level in ventral horn (95% onto interneurons in gray matter; 5% directly onto alpha motor neurons). Of note, the sensory axons (40% of CST) project to sensory relay structures (e.g., dorsal horn, dorsal column nuclei, and intermediate gray matter of the spinal cord), where they control and modify the sensory information that reaches cortex. Think: pain regulation on gate-keeper interneurons in the spinal cord.

Motor Unit Size and Function

The size of a muscle's motor units determines how finely the muscle can be controlled. Larger motor neurons innervate many large muscle fibers; small motor neurons innervate a few small muscle fibers. The muscle fibers innervated by one motor neuron are all the same type (there are fast and slow motor units, just as there are fast and slow muscle fibers). When motor nerves to different muscle types are switched (cross-innervation experiments), the muscle fibers take on characteristics dictated by the innervating neurons, but this conversion is never complete.

Size Principle of Motor Neuron Recruitment

The tension added by recruiting a larger number of motor units is determined in part by the size of the activated units: *small motor units, which produce weak forces, are recruited first; larger motor units, which produce larger forces (because they engage the largest muscle fibers), are recruited last*. *Small motor neurons are activated first because it takes less synaptic current to drive them*, compared to larger motor neurons. As larger units come in, they are added to an ever-increasing baseline of force. Thus, the percentage increase in force is kept relatively constant. When a large motor neuron fires, the impulse does not reach all the muscle fibers simultaneously because these are scattered and the conduction distances vary. *The stereotyped recruitment order from small to large motor units helps to grade the force of contraction smoothly rather than abruptly.* Notice how your control of movement is precise at low force and becomes jerky and less precise when you are holding a very heavy weight.

Warfarin (Coumadin)

The treatment of choice for *secondary stroke prevention in patients with Atrial Fibrillation and stroke*. Used to prevent clot formation (inhibits vitamin k-dependent pathway of clotting factor γ-carboxylation).

Tongue deviation for LMN/UMN lesion

Tongue deviates *towards LMN lesion* (CN XII lesion) and away from UMN lesion (cortical lesion). UMN decussates onto CN XII nucleus in the medulla. Additionally, in LMN lesion, there may be fasciculations.

Dopamine Levels in Movement Disorders

Too little → Parkinsonism (akinesia and rigidity) Too much → Chorea *Thus, drugs that treat chorea reduce dopamine. Drugs that treat Parkinsonism may induce chorea by increasing dopamine.*

What are four tubes for Lumbar Puncture (L3-L4)

Tube 1: Cell count Tube 2: Glucose, Protein Tube 3: Culture Tube 4: Cell Count Tube 4 is usually a better cell count measure as Tube 1 could have RBC from a "traumatic tap." *Adjusted WBC in CSF* = Actual WBC in CSF - [(WBC in blood)*(RBC in CSF)] / RBC in blood This ratio is just a proportion of WBC/RBC (blood vs. CSF) → essentially, it stands for the *expected WBC in CSF*. *Adjusted = Actual - Expected*

Neoplastic Lumbosacral Plexopathy

Tumor invasion of the lumbosacral plexus region (near pelvic organs). Symptoms: 1. Subacute onset of *pain in lower back, buttox, hip, and/or thigh* 2. Weakness 3. Reduced reflexes (radiculopathy) 4. Sensory disturbances in the leg Diagnosed by MRI

*Ependymomas* -Perivascular pseudo-rosettes

Tumors arising from *over-proliferation of cells lining the CSF system*. 1. Tend to occur in younger patients 2. Most commonly found in the *4th ventricle* (can cause non-communicating hydrocephalus) → poor prognosis *Pathology:* 1. Histology: *Perivascular pseudo-rosettes* (tumor cells cluster around a central vessel) 2. Gross: fleshy, cauliflower-like mass *Prognosis:* 1. Depends on extent of surgical resection (want to be aggressive; tumors are well-circumscribed) 2. Radiation and chemo are not as effective

*1a Spindle Axon Regulation* (equatorial region)

Two ways to make a *Ia spindle axon* fire more strongly and report dynamic change in intrafusal length (i.e., *stretched equatorial region*): 1. Stretch, no gamma firing (origin and insertion of muscle are father apart) 2. No stretch, gamma firing (same length of muscle)

Type of muscle is determined by...

Type of alpha motor neuron

UMN vs. LMN

UMN are located in the motor cortex and give rise to the corticospinal tract. LMN are the alpha motor neurons located in the anterior horn of the spinal cord (and in the brainstem for CN nuclei). The functional unit of the anterior horn cells is the motor unit (an anterior horn cell and all the muscle fibers it innervates). *Fasciculations represent the spontaneous discharge of a motor unit.*

Glasgow Coma Scale Categories

Used as a trauma scoring system to determine severity of ICH. *Evaluation (and possible points):* Eye Opening (4 points = spontaneously) Verbal (5 points = oriented) Motor (6 points = obeys commands) Best: 15 Concussion: 13-15 *Coma: ≤8* Totally unresponsive: 3

Endovascular Therapy (clot removal > tPA) -ELVO? → endovascular, mechanical fix

Used for treatment of ischemic stroke associated with *emergent large vessel occlusion (ELVO)* within 6 hours. *Large Vessels:* endovascular clot removal → doubled likelihood of recanalization and "good outcomes" 1. Proximal MCA 2. Intracranial ICA (terminus) *Other Locations:* 1. Basilar 2. ACA 3. PCA

Diffuse Coma

Usually metabolic or post cardiac arrest. Characteristics: 1. Early abnormal level of consciousness 2. Symmetrical motor signs later 3. Pupils reactive (often small) 4. Asterixis, myoclonus, tremor, seizure 5. Slow EEG

If patient has tonic, atonic seizures, treat with...

Valproic Acid

If patient has myoclonic seizures, treat with....

Valproic Acid, Leviteracetam, Benzodiazepines

*Vasogenic Edema* (extracellular) -Occurs mainly in white matter -↑vascular permeability due to trauma, tumor, abscess, infarct, meningitis, encephalitis

Vasogenic edema occurs due to a *breakdown* of the *tight endothelial junctions* that make up the *blood-brain barrier*. This allows intravascular proteins and fluid to penetrate into the parenchymal extracellular space.

In general ventromedial pathways control __________ of body and limbs and lateral pathways control ______ of body and limbs

Ventromedial - Extensors (tend to innervate proximal muscles) Lateral - Flexors (tend to innervate distal muscles)

Spinocerebellum (vermis)

Vermis = uvula + pyramid. Actions: 1. Coordinates adjustment of limb musculature. 2. *Comparator between intended and actual movements*.

Who should get a *carotid endarterectomy*?

Vessel is *70-99% occluded* within 2 weeks of TIA or minor stroke. 16% risk reduction. DO NOT perform if vessel is <50% occluded or 100% occluded. A *transient ischemic attack (TIA)* is a brief episode of neurological dysfunction caused by *loss of blood flow* (ischemia) in the brain, spinal cord, or retina, *without tissue death* (infarction).

Hypnogogic Hallucinations

Vivid, "waking" dreams that occur during transitions between sleep and wakefulness. -Hypnogogic: occurs at sleep onset -Hypnopompic: occurs at awakening

Common Stroke Symptoms

Weakness (motor) Numbness (sensory) Dysarthria (facial motor; speech) Face Droop (facial motor)

Axonal Damage

When a nerve fiber is damaged, the distal portion loses contact with the cell body: 1. *Building blocks needed for maintaining the axon cannot reach the distal stump → failure of axoplasmic transport* 2. *Distal* portion will undergo *Wallerian degeneration* 3. Proximal portion undergoes minor changes as well and retains ability to regenerate (sprouting)

Fibrillations (asynchronous)

When motor neurons die or their axons are interrupted, the *individual muscle fibers are denervated* and become *hypersensitive to acetylcholine* and to other chemical stimuli. The resulting small, *asynchronous contraction* of the muscle fibers is called fibrillation, which is not typically detected by visual inspection.

Brain Death

• Brain death equals death, despite the beating heart • Known irreversible cause • Not overdose/hypothermia (potentially reversible) • Observation period varies *Three components:* 1. Absent cerebral function (*no response above the neck*) 2. Absent brainstem function (*no reflexes:* pupillary light reflex, corneal reflexes, VOR, cough, gag) 3. Apnea (no breathing during apnea challenge)

Akinetic Mutism / Abulia

• Eyes open, rare or very slow response to external environment • Severe bifrontal dysfunction *Possible etiologies:* 1. Bifrontal trauma (pre-frontal lobe) 2. Nonconvulsive status epilepticus 3. Depression/catatonia 4. Parkinsonism (akinesia/rigidity)

Delirium

• Impaired arousal, commonly associated with agitation • Increased pulse, temp, blood pressure, sweating, tremor • Alcohol withdrawal, ICU delirium