1NEUROPATHOLOGY1. Normal cell types in CNS/PNS

a. CNS (origin neuroectoderm)i. Neurons: parenchymal cells generated before birth, post-mitotic, use ox metab, high degree of specializationii. Astrocytes: provide structure, react to injury, forms BBB, synthesizes GFAPiii. Oligodendrocytes: myelinate many axons; remyelination is poor if myelin lostiv. Ependymal cells: line ventricles, cilia move CSFv. Choroid plexus: synthesizes CSF, forms blood/CSF barriervi. Microglia: immune cells of monocyte lineage

b. PNS (origin neural crest)i. Schwann cells: myelinate one axon, ability to regenerate myelin if myelin lost

2. Meningesa. Pachymeninges (dura)

i. Forms potential spaces: epidural and subduralii. Forms dural folds: tentorium (b/w cerebrum/cerebellum) and falx (b/w cerebral hemispheres)

b. Leptomeninges (arachnoid/pia)i. Forms real and potential spaces: subarachnoid (w/ CSF) and intraparenchymal

3. CSF production and circulationa. Produced by choroid plexus from blood plasma (0.5L/d independent of ventricular pressure)b. Lateral V 3rd V via foramen of Monro 4th V via cerebral aqueduct subarachnoid via foramen of Magendie

(med)/Lushka (lat)c. Reabsorbed by arachnoid granulations to venous system of braind. Normally little protein, few leukocytes

i. Xanthochromia = yellow color due to degeneration of RBCs/proteinii. Cloudiness usually due to ↑ WBCs/protein

4. Hydrocephalus (enlargement of ventricles)a. Obstructive: blockage of CSF flow w/in the ventricles (↑ICP)b. Non-Obstructive (communicating): impaired flow/resorption outside the ventricle (↑ICP)c. Ex Vacuo: compensation for brain atrophy, especially in elderly (Alzheimers), normal ICPd. Normal Pressure Hydrocephalus: rare syndrome w/ normal ICP but dementia, urinary incontinence, disordered gait

5. Blood-brain barrier (tight junctions b/w capillary endothelium and perivascular astrocytes)a. Many drugs cannot pass intact BBB b/c they are large or chargedb. Breakdown (seen as ring enhancement on CT w/ contrast) due to inflammation vasogenic edemac. Matures late in gestation (kernicterus = damage to basal ganglia due to bilirubin accumulation)

6. Brain edemaa. Vasogenic: damage to BBB (inflammation, infarct, tumor) causes leakage, mainly in white matterb. Cytotoxic: ion pump dysfunction (hypoxia/stroke, toxins) causes cell swelling, mainly affects gray matterc. Interstitial: ↑ intraventricular pressure (obst. hydroceph) pushes fluid out into periventricular white matter

7. Increased ICPa. B/c of rigid skull, anything that ↑ volume (tumor, abscess, edema, hemorrhage) can ↑ ICP

(Monro-Kellie hypothesis)b. Sx: headache, projectile vomiting, papilledema, decline in LOC (level of consciousness), cardio-

respiratory changes (bradycardia, HTN, irreg respirations), focal signs such as effects on pupil dilation

8. Herniation: brain structures are pushed through anatomic openings due to ↑ ICPa. Cingulate: cingulate gyrus under falx cerebri ACA compression foot/leg homunculus lossb. Uncal: UNILAT uncus under tentorial incisure midbrain/CNIII compression coma,

anisocoria (1 pupil dilated), duret hemorr c. Central: BILAT dienceph/med temporal under tentorial incisure midbrain/thal compression

coma, hydroceph, posturingd. Tonsillar: cerebellar tonsils/medulla thru foramen magnum medulla compression loss of

consciousness, apnea9. Define

a. Astrocytosis: acute hyperplasia/hypertrophyb. Gliosis: chronic proliferation of astrocyte processes glial scar, common in MS c. Cavitation: occurs w/ significant neuron/glia loss; cavity filled w/ interstitial fluid and lined by gliotic brain tissued. Metabolic Astrocytosis (aka Alzheimers type 2): proliferation/enlargement of gray matter astrocytes in response to

metabolic injury such as may occur 2° to liver or kidney failuree. Selective vulnerability: certain neurons are susceptible to certain dz (ex) B1 (thiamine) defcy Wernicke’s encephalopathyf. Wallerian degeneration: degradation of axon distal to site of lesion (Schwann cell tunnel may persist for re-growth)g. Trans-synaptic degeneration: degeneration of neuron across a synapse due to signaling disruption

i. Anterograde = loss of neuron loss of target cell b/c it has no inputii. Retrograde = loss of target cell loss of neuron stimulating it

h. Demyelination:i. 1° is a disease that destroys myelin but spares axon (ex) MS (CNS) or Guillain-Barre (PNS)ii. 2° is breakdown of myelin following axon degeneration (ex) Wallerian degeneration

i. Dysmyelination: abnormal myelin (ex) leukodystrophiesj. Mass lesion: any pathologic process producing an increased volume, thus increased ICPk. Respirator brain: ICP > arterial P ischemia/brain death diffuse brain autolysis IF pt is kept alive by respirator l. Radiculopathy = damage to spinal rootm. Plexopathy = damage to nerve plexusn. Causalgia = burning pain sensation

NEUROANATOMY1. Important areas: primary motor (4; precentral gyrus), primary somatosensory (3/1/2; postcentral gyrus), auditory (41/42), Broca’s

area (44/45), Wernicke’s area (39/40), visual (17)

2a. Premotor cortex (6) and frontal eye field (8) data → primary motor cortex (4) → corticospinal tracts → corona radiata /

internal capsule → cerebral peduncles/basis pontis/pyramids where form lateral (crossed) and anterior (uncrossed) corticospinal tracts → terminate in ventral horn of spinal cord → axon out via ventral root to muscle

b. Discriminitive touch/vibration and positional sense info to DRG → dorsal columns (fasciculus gracilis (lower) and cuneatus (upper)) → synapse in nuclei gracilis and cuneatus → 2° axon decussation in lower medulla → medial lemniscus → synapses in VPL nucleus of thalamus → 3rd axon projects to primary sensory cortex (3/1/2)

c. Pain and temperature info to DRG → synapses in substantia gelatinosa → decussation at spinal level of entry → ascends in lateral spinothalamic tract to synapse in VPL nucleus of thalamus → 3rd axon projects to primary sensory cortex (3/1/2)

d. Light touch same as pain and temp except that axons ascend in anterior spinothalamic tracte. Vision info from retinal axons thru CNII → optic chiasm (medial half decussate) → optic tracts to synapse in LGN (lateral

geniculate nucleus) →optic radiations → calcarine/visual cortex (17)f. Coordinated gaze involves FEFs/MLF (medial longitudinal fasciculus)/PPRF (paramedian pontine reticular formation)g. Hearing info from cochlea through CNVIII synapse in cochlear nucleus → bilateral projections via superior olivary nucleus

and lateral lemniscus to synapse in inferior colliculus → axons to MGN (medial geniculate nucleus) → projections via auditory radiation to auditory cortex (41/42)

2. Limbic system consists of hippocampus (HC), fornix, mammillary bodies, cingulate gyrus (CG), parahippocampal gyrus (PHCG) and Circuit of Papez (see below)

MTT fornix cinguluma. CG → ant nucleus of thalamus → mammillary body → HC → PHCG → CG

3. Cranial nerve exit locations:a. Midbrain = CN III / IVb. Pons = CN V / VI and CN VII / VIII at junction w/ medullac. Medulla = CN IX / X / XI / XII

4. Upper motor neurons (from primary motor cortex Betz cells to synapse on LMNs in ant horn and CN motor nuclei)a. Lesions spastic paralysis (greater weakness in extensors), hyperreflexia, Babinskib. Contralateral if above decussation (90% in medulla), ipsilateral if below

5. Lower motor neurons a. Lesions flaccid paralysis, hyporeflexia, muscle atrophy, fasciculations (indicates denervation)b. Always ipsilateral

6. Cerebelluma. Lesions ataxia, dysmetria, intention tremor, dysdiadochokinesia (inability to perform rapid alternating mvmt)

7. Basal ganglia (caudate, globus pallidus, putamen, substantia nigra)a. Lesions dyskinesias, rigidity, resting tremor, chorea, athetosis, dystonia

8. Brainstema. Decerebrate posturing = upper/lower extremity extension (lesion b/w red and vestibular nuclei)b. Decorticate posturing = upper flexion, lower extension (supratentorial lesion)

9. Spinal corda. Acute transaction (“spinal shock”) complete paralysis/anesthesia/areflexia below lesionb. Chronic transection complete paralysis/anesthesia but hyperreflexia below lesionc. Central cord syndrome

i. Bilateral loss of pain/temp (spinothalamic) at level of lesion, since decussates at level it enters SCii. UMN paralysis of upper ˃ lower limbs (corticospinal)

d. Anterior cord syndrome (usually due to ischemic injury to ant spinal artery)i. Bilateral loss of pain/temp below lesion (already decussated) ii. Bilateral UMN loss below lesioniii. Relative sparing of proprioception/discriminative touch below lesion

e. Brown-Sequard syndrome (hemisection; usually due to trauma, MS or tumor) i. Contralateral loss of pain/temp below lesion ii. Ipsilateral UMN/LMN/proprioceptive loss/cutaneous anesthesia below lesion

f. Cauda equina syndrome (saddle distribution w/ LMN paralysis below lesion)10. Visual pathways

a. R optic nerve lesion total blindness in R eyeb. Optic chiasm lesion bitemporal hemianopiac. R optic tract lesion L homonymous hemianopiad. R Meyers loop lesion (MCA stroke) L homonymous superior quadranopiae. R occipital lobe lesion L homonymous hemianopia w/ macular sparingf. Pupillary light reflex aff = CNII, eff = CNIII (constriction is PS)

11. Extraocular movementsa. CNIII: sup rectus, inf rectus, med rectus, inf oblique, levator palpebrae

i. Internuclear opthalmoplegia due to MLF lesion (no adduction w/ lat gaze)b. CNIV: sup oblique (intorsion/depression) and CNVI: lat rectus

12. Terms:a. Anopia = complete blindnessb. Scotoma = focal defect in visual fieldc. Cortical blindness = asymmetric vision loss w/o afferent pupillary defectd. Conductive hearing loss = dampening of ossicle mvmte. Sensorineural hearing loss = damage to ipsi CNVIII systemf. Tinnitus = ringing in ears; Hyperacusis = impaired feedback to tensor tympani via

CNVIIIg. Tinel sign = paresthesias provoked by tapping over median nerve in wristh. Phalen test = paresthesia provoked by holding wrists flexed

13. Vestibulo-Ocular Reflex to maintain fixed gaze w/ any head mvmta. Head turns R = activate R/inhibit L CNVIII L lat rectus + R medial rectus

stimulated eyes turn L fixed gaze14. Example syndromes from lecture

a. Wallenbergs syndrome = medullary lesion

3i. Ipsi: ataxia (cerebellum), loss of face pain/temp (CNV), palate paralysis (CNX), Horners (CNIII-SS), nystagmus

(CNVIII)ii. Contra: loss of body pain/temp (spinothalamic)

b. Saturday Night palsy (radial n lesion) → LMN symptoms w/ wrist dropc. Posterior occipital lobe infarct (PCA lesion)

i. Affects visual cortex contralateral homonymous hemianopia d. Motor stroke (internal capsule lesion)

i. NO sensory fibers are affected (they are thalamic) and it is pii. Contralateral UMN syndrome

e. MCA lesioni. Contralateral motor/sensory loss (esp. face/arms), homonymous hemianopia, horizontal gaze palsy, language

deficitsf. Weber’s syndrome = infart in ventral midbrain

i. Ipsi CNIII palsyii. Contralateral hemiparesis

g. Foville’s syndrome – infarct in pons (basilar art) affecting PPRF, CNs VI/VII, corticospinal tract, ML, MLFi. Ipsi horizontal gaze palsy and CNVII palsyii. Contra hemiparesis, sensory loss, intranuclear opthalmoplegia

h. Millard-Gubler syndrome = pons infarct affecting CNs VI/VII, corticospinal tract (smaller infarct than Foville)i. Ipsi CN VI/VII palsyii. Contra hemiparesis

NEURODEVELOPMENT1. Any disturbance in motor/cognitive/language/social skill acquisition can cause developmental delay in child (MR=mental retardation)

a. MR = subaverage intellect (IQ ˃2 SDs below mean) w/ concurrent deficits in adaptive behavior w/ onset ˂18mo ageb. Cerebral Palsy = disordered motor fxn evident in early infancy due to Δ in muscle tone, involuntary mvmts, ataxia

2. PREnatal errorsa. Malformations

i. Dorsal induction (3-4w) neural tube defect (dysraphic state), -fetoprotein ↑ in amniotic fluid w/ open defect1. Failure of neural tube closure

a. anencephaly: NO ant neuropore closure degen of brainb. myelomeningocele: NO post neuropore closure SC/meninges thru vertebral defect

2. Failure of mesodermal development (neural tube is closed)a. encephalocele: brain/meninges thru skull defect, usually occipital, assoc w/ Meckel-Gruberb. meningocele: meninges thru skull or verterbral defect, assoc w/ Arnold-Chiari defect

(herniation of cerebellum thru foramen magnum)c. spina bifida: mild lumbar vertebral defect but intact skin

ii. Ventral induction (5-6w) holoprosencephaly (failure to develop cerebral hemispheres), often w/ no corp. callos.1. Assoc w/ mid-facial deformities – cyclopia, cleft lip/palate, no nose2. Causes: trisomy 13/18, maternal DM, infxn, EtOH

iii. Neuron proliferation (2-4mo) microcephaly (genetic/teratogens/infxn) or macrocephaly (failure of apoptosis)1. Neurons normally arise from germinal matrix

iv. Neuron migration (3-5mo) agyria (migrational arrest in white matter lissencephaly) 1. Neurons migrate out along radial glia or along surfaces (tangential route)2. Manifests as dev. delay (NOT progressive, just never there in the first place)

v. Synaptogenesis/myelination (6mo-yrs postnatal) trisomy 21, leukodystrophies1. CNS normally myelinated by birth, progresses post to ant (sight then speech)2. Dysmyelination is abnormal myelin compound

a. Pelizaeus-Mersbacher Disease: nystagmus, spasticityb. MLD: confluent white matter, vision problems, spasticityc. Aquaduct stenosis: huge 3rd ventricle, sunsetting

b. Maternal conditionsi. Fetal Alcohol Syndrome: most common preventable form of MR

1. Assoc w/ growth defcy, microcephaly, MR, facies (flat face, thin upper lip, short palpebral fissures)

ii. Toxins: cocaine, anticonvulsants, lead, radiation, Retin Aiii. Infxns: TORCH organisms (Toxoplasma, Rubella, CMV, Herpes)

c. Genetic dzi. Trisomy 21: autosomal recessive, risk increases w/ maternal age

1. Assoc w/ MR, hypotonia, microcephaly, facies/simian crease, congenital heart defectsii. Fragile X syndrome: ˃200 CGG repeats, males (most common cause of MR in males)

1. Assoc w/ MR, macrocephaly, long face/big ears, macro-orchidismiii. Prader-Willi: 15q12 mutation (missing paternal), males

1. Assoc w/ hypotonic baby, short stature, hypogonadism, voracious appetiteiv. Angelman: 15q12 mutation (missing maternal), females

1. Assoc w/ MR, inappropriate laughter/smiling, seizuresv. Rett syndrome: MEPC2 mutation, females

1. Assoc w/ MR, hand wringing, regressivevi. Neurocutaneous dz

1. Tuberous Sclerosis: autosomal dominant, TSC mutation (chr 9/16)a. Assoc w/ MR, seizures, variety of tumors, shagreen (velvety) patches, ashleaf spots

2. Neurofibromatosis I: autosomal dominant, NFI mutation (chr 17/22)a. Assoc w/ café au lait spots, neurofibromas, axillary freckles, optic gliomas, Lisch nodules

3. Sturge Weber syndrome: actually not genetic (sporadic)a. Assoc w/ MR, facial angiomas, seizures, hemiparesis

3. PERInatal errorsa. Hypoxic-ischemic encephalopathy: necrosis of vulnerable gray/white matter permanent focal deficits

4i. Significant cause (but one of many) of cerebral palsy

b. Cerebral palsy: static dz w/ varying degrees of MR, language/social deficits, and motor dysfxni. Assoc w/ germinal matrix bleeds, periventricular leukomalacia (holes in white matter), thin CCii. Spastic (hemi/quad/diplegic) or extrapyramidal (non-spastic, choreic) typesiii. RF = young mother, male baby, premature, infxns, 3rd trimester bleeds

4. POSTnatal errors (not evident until after birth)a. Inborn errors of metabolism manifest as irritability, abnormal muscle tone, seizure, unusual odor, vomiting/refusal to eat

i. Acidopathies: (ex) Maple Syrup Urine dz, buildup of branched chain amino acidsii. Lysosomal storage dz: (ex) Hurlers/Hunters, buildup of MPSiii. Glycogen storage dz: (ex) Pompe’s Disease, lack of acid maltase cardiac probs and death w/o tx

5. Patterns of Brain Injurya. Premature Infants

i. Periventricular necrosis: ischemia focal necrosis in deep cerebral white matter (not watershed like adults)ii. Germinal matrix bleed: even small bleeds cognitive dysfxn, increased risk of cerebral palsy

1. Grade 1 confined to germinal matrix2. Grade 2 confined to ventricle3. Grade 3 dilates ventricle4. Grade 4 ruptures ventricle into parenchyma

b. Perinatal i. NOT usually periventricular ii. Hypoxic/ischemic encephalopathy (difficult labor/delivery, respiratory distress syndrome)iii. TORCH infxns can be transmitted during birth (ex) periventricular Ca + hydrocephalus w/ CMV

c. Postnatal i. Child abuse/neglect (subdural bleed as a sign of trauma, think shaken baby syndrome)

6. Assesing development: hx (maternal, delivery, milestones), PE (wt/ht/head circum/skin/fontanelles), non-invasive neuro, labs

AGE DEGREE OF DEVELOPMENTNeonate Fetal position/head lag/reflex grasp, responds to light, cries2 mo No head lag/reflex grasp, follows with eyes, vocalizes, smiles6 mo Sits unsupported/reaches for & grasps objects, responds to sounds, babbles, stranger anxiety10 mo Crawls/pincer grasp, mama/dada, peekaboo, separation anxiety1 yr Stands/walks, single words, tries to feed self2 yr Steps/hand dominance, short sentences, organized play, toilet trained

REFLEX ONSET DISAPPEARANCEGalant (suspend face down, turn toward stroked side) Birth 1-2 moRooting (baby turns mouth toward mothers nipple) Birth 3 moMoro (if startled, aBduct then aDduct arms) Birth 6 moPalmar Grasp (baby grips things put in hand) Birth 6 moTonic Neck (arm/leg extend on side face turned to) Birth 6 moPlantar Grasp (same as Babinski) Birth 9 moLandau (arch back/raise head when on stomach) 3-5 mo 2 yrParachute (put out arms to brace fall) 6-9 mo persists

Porencephaly = cavity in wall of cerebrum communicating w/ both ventricle and brain surfaceHydranencephaly = extreme ventricle expansion w/ squishing of parenchyma to thin membraneUlegyria = selective loss of cortex in depths of sulciMulticystic Encephalomalacia = severe destruction w/ multiple cavitationsStatus Marmoratus = neuronal loss and glial scars followed by abnormal myelination in BG/thalamus

NEURORADIOLOGY1. Primarily use CT/MRI

a. CT: Xrays show differences in tissue densitiesi. Density expressed in Hounsfield units based on how much xray beam disruptedii. HI density (white) = bone, calcification, blood, tumoriii. LO density (dark) = CSF, edema, fat, air

b. MRI: magnetic field and applied radiofrequency pulses show difference in signal intensityi. T1 = CSF/edema dark, WM light/GM darkii. T2 = CSF/edema bright, WM dark/GM lightiii. FLAIR → dark CSF but WM dark/GM light

5iv. DWI used for acute stroke

c. Contrast enhancement: leaky BBB allows contrast to leak from intravascular to extracellular

i. CT uses iodine/MRI uses gadoliniumii. Diff dx for ring enhancing mass

MAGIC DR (LT)1. Metastasis2. Abscess/Aneurysm3. Glioma (HI grade) or Granuloma4. Infarct (subacute)5. Cysticercosis (T.solium worm infxn)6. Demyelination/MS plaque7. Resorbing hematoma8. Lymphoma/Toxoplasmosis in AIDS

2. Edemaa. Vasogenic: follows white matter tracts in “finger-like pattern,” assoc w/ BBB breakdown (infxn, mets)b. Cytotoxic: intracellular edema (Na/K pump disrupted) that involves both gray & white matter, assoc with acute strokec. Interstitial: CSF escape from ventricles into periventricular areas, assoc w/ hydrocephalus

3. Herniationa. Subfalcine = displacement of cingulated gyrus beneath falx

i. Ipsi ventricle compressed/contra ventricle may enlargeii. ACA displaced/compressed which may lead to infarct

b. Uncal (aka descending transtentorial) = uncus and PHCG displaced medially and descend through tentorial notchi. Brainstem and CNIII displaced/compressedii. PCA may be displaced/compressed leading to infarct

4. Tumorsa. Astrocytoma (cerebral hemisphere) most common primary brain tumors (esp. glioblastoma multiforme)

i. Features (HI grade): thick, irregular rim around necrotic core, enhance intensely, vasogenic edemaii. Features (LO grade): focal, homogenous, NO enhance

b. Oligodendriglioma (superficial cerebral hemisphere)c. Ependyoma (4th ventricle)

i. Features: in region of cerebellum, assoc obstructive hydrocephalusii. Choroid plexus tumor (children = lateral ventricle ; adults = 4th ventricle)

d. Meningioma (extra-axial)i. Features: well circumscribed, enhance homogenously/intensely, CT best

e. Metastasis (anywhere, look for multiple!) account for 50% brain tumorsi. Features: enhance homogenously/ring, vasogenic edemaii. Commonly from breast/lung/melanomaiii. 80% occur at gray/white jxn of cerebrum

5. Infectionsa. Encephalitis: affects temporal lobes, think HSVb. Meningitis: enhancing sulci due to pus accumulatingc. Cerebritis: often at corticomedullary junction, ring enhancing w/ lots of edema

i. Early (3-5d): focal infxn, mass of PMNs, edema, hemorrhage, necrosisii. Late (5d-2wk): necrotic foci coalesce, vascular proliferation edemaiii. Early capsule (2wk): well-formed collagen capsule w/ necrotic coreiv. Late capsule (wks-mos): central cavity shrinks and wall thickens

d. HIV associatedi. HIV encephalopathy: atrophyii. Toxoplasmosis: ring enhancing “target” appearanceiii. Lymphoma: ring enhancing, cannot distinguish this from toxo w/ imagingiv. PML: very bright w/ T2 due to demyelinationv. Crypto: cystic appearing lesion in deep cortex

6. Multiple sclerosis: asymmetrical periventricular plaques (active will enhance, thus ring-enhancing), MRI more sensitive7. Spinal cord

a. Degenerative dz: disc bulge, disc herniation (will see cord compression), spondylosis (spurs)b. Trauma: use CT for fracture (e.g. compressed vertebrae), MRI for complications (e.g. edema, blood)c. Syrinx: pathological cavity in SC, looks like segmented dark areas on T1/light areas on T2d. Infxn: osteomyelitis (heterogenous look to bone/disk narrowing), sarcoid/TB lesions (multiple plaques)e. Tumors

i. Extradural: most likely a met, +enhancementii. Intradural/extramedullary: inside dura but outside SC, +enhancementiii. Intradural/intramedullary: inside SC, +enhancement, SC enlargement

PATHOLOGY OF STROKE1. Cerebral vasculature

a. Internal carotid a ACA/MCAi. ACA: medial cerebrum ii. MCA: lateral cerebrum, basal ganglia, Brocas/Wernickes

b. Vertebral a basilar/PCAi. PCA: inferior temporal lobes

c. Penetrate as perforators = end arteries, thus watershed areas (ischemic penumbra)d. Poor collateral circulation due to perforating arteries being end arteriese. Causes of CVD: atherosclerosis, HTN, DM, aneurysms, amyloid angiopathy, vasculitis, malformations, thrombo-emboli

2. Strokea. Acute neurological dysfunction due to a vascular process that persists >24h (if ˂24h is transient ischemic attack)

i. 5% of those experiencing TIAs have stroke w/in 2d; 11% have stroke w/in 90d

Blue: normalGreen: bulgeRed: herniation

Non contrast CT w/ vasogenic edema

T1 MRI w/ ring enhancing lesion

T2 MRI w/ hydrocephalus

6b. Many pts die a few days later due to inflammatory edema increased ICP herniationc. Ischemic stroke (infarct) – usually due to atherosclerosis and/or thromboembolus

i. Ischemia rapid onset of neurologic deficit1. Focal deficits due to reduced flow in one vessel2. Global deficits due to systemic failure (hypoxia, severe hypoglycemia, hypoTN)

ii. Central infarcted dead tissue with potentially viable “stunned” penumbra iii. Damage from hypoxia, glutamate excitotoxicity, Ca/Na influx, inflammation, apopotosisiv. Affects neurons>oligodendrocytes>astrocytesv. Irreversible damage occurs after ~5minvi. Reperfusion may cause more neuronal injury (from ROS damage) or hemorrhagic infarctvii. Causes

1. Idiopathic2. AS of large vessels stenosis, sudden occlusion, distal embolization3. AS of small vessels lacunar infarcts (˂1cm), normally seen w/ chronic HTN4. Elderly/A-fib cardiac emboli which go to brain

viii. Pathology1. 12-24h: red neurons (necrosis; see to right) + acute inflamm2. 1-5d: liquefaction (encephalomalacia) + MΦ; peak edema3. 1w: astrocyte proliferation4. 1mo: gliosis + cavitation5. Late Δs: wallerian degen, atrophy, compensatory hydrocephalus

ix. Hemorrhagic stroke 1. Spontaneous rupture of blood vessel subarachnoid or intraparenchymal bleeds2. Trauma usually results in epidural or subdural hemorrhages3. Intra-axial (aka intraparenchymal)

a. Ganglionic : basal ganglia (putamen/thalamus/pons/deep cerebellum) bleed, due to HTN vascular dz, assoc w/ Charcot-Bouchard micro-aneurysms

b. Lobar : superficial lobe bleed, due to small vessel dz4. Extra-axial

a. Epidural : more likely due to trauma, esp MMA, “silent” interval of 6-12hb. Subdural : more likely due to trauma, esp shearing of bridging veins to superior sagittal sinus

i. Can cross suture lines and have up to 90% mortalityii. Acute = clotted bloodiii. Subacute = clotted and liquefying bloodiv. Chronic = liquid bloodv. Hygroma = CSF-like fluid rather than blood

c. Subarachnoid : base of brain, due to Berry aneurysm rupture (larger arteries) → arterial vasospasm, thunderclap headache

x. Causes1. Hypertensive vascular disease (most common) Berry aneurysm (which can also be congenital!)

a. Berry aneurysms occur at branch points and may be assoc w/ PKD2. Amyloid angiopathy (think elderly w/ Alz) weakening of vessel walls that predisposes to hemorrhage

xi. Pathology1. Acute hemorrhage will show a mass of blood mass effect2. Resorbed hematoma cavitation lined w/ wall of gliotic hemosiderin-stained tissue

3. Diffuse hypoxic/ischemic encephalopathya. Global cerebral ischemia due to profound systemic hypoTN (ex) cardiac arrestb. Damage is usually symmetrical and affects vulnerable cell populations

i. Sommer’s Sector (CA1) of hippocampus ii. Middle cortex (see laminar necrosis)iii. Watershed zonesiv. Purkinje cells of cerebellum

c. Severe irreversible damage persistent vegetative state, brain death, or respirator brain (autolysis)

4. Blunt Head Injurya. Skull fracture (bone broken but parenchyma not necessarily injured)

i. Types1. Linear = radiates from site of impact2. Basal = involves base of skull bones3. Depressed = bone pushed into cranial cavity4. Diastatic = separation along suture lines5. Comminuted = bones fragmented6. Contrecoup = fracture removed from site of impact7. Open = fracture associated w/ laceration of dura8. Compound = fracture associated w/ laceration of scalp9. Consequences: intracranial hematoma, CSF leakage out through nose/ear, ingress of air

(pneumocephalus) or infectious agents, cranial nerve damageb. Contusion = hemorrhage w/in superficial brain tissue w/o disruption of pia-arachnoid at surface

i. Usually at crests of gyriii. Coup (under impact site) or contrecoup (opposite from impact site)iii. May be asymptomatic until glial scarring occurs (can cause seizure)

7c. Laceration = traumatic disruption of brain surface w/ hemorrhaged. Diffuse axonal injury = disruption of axons (esp. long tracts of midbrain, corpus callosum, deep cerebral white matter)

i. Associated w/ severe rotation/acceleration injuries (ex) whiplashii. See perivascular microhemorrhage w/ swollen axons late accumulate β-APPiii. May result in persistent vegetative state

CLINICAL STROKE1. Types of stroke

a. Ischemic, due to vessel obstructionb. Hemorrhagic stroke, due to vessel rupturec. Transient ischemic attack

i. Focal neurologic deficit with complete resolution of all neuro sx w/in 24 hoursii. Common in elderly iii. Often results in stroke in w/in next few days

2. Risk factorsa. Non-modifiable: age, gender, previous stroke, family hx of stroke, sickle cell dzb. Modifiable: HTN (BP directly related to risk), DM, high LDL, smoking, obesity, sedentary lifestyle

3. Sx a. Sudden onset (w/in 10 seconds)b. Weakness/numbness/incoordination on one side of bodyc. Sudden headache/confusion/change in speech/diplopia/vision loss

4. Evaluationa. Focused neuro exam: LOC, language, eye mvmts, strength, coordination, sensationb. Presence of carotid bruitsc. CT head w/o constrast to differentiate hemorrhage vs ischemic stroke (which H&P cannot)

5. Tx (acute stroke) a. Door to tx in 1hb. ONLY give t-PA if <3h since pt was last seen normal (otherwise ASA)

i. Must be >18yr old, CT shows ischemic stroke, exam shows measurable deficitii. NEVER use in hemorrhagic stroke as would only exacerbate the bleeding

c. Lower BP if >220/110, even then must slowly lowerd. Complications: seizures, MI, aspiration pneumonia (impaired swallowing), DVT/PE (bedrest), depression/confusion

6. Long term managementa. DOC is ASA, easy/safe/cheap/effectiveb. Warfarin w/ high risk A-fib pts

i. HI risk: previous stroke/TIA, +CHF, +HTN, older than 75ii. LO risk: no previous stroke, no HTN, younger than 65 – JUST ASA!iii. MED risk: no previous stroke, +HTN, 65-75 – clinical decision

c. Statins to lower LDL cholesterold. Diuretics/ACEI to lower BPe. Lifestyle modificationsf. Surgery

i. Carotid endarterectomy (CEA): removes plaques from vesselsii. Carotid stenting: increasingly used, but only FDA approved for HI risk pts w/ sx stenosis

g. Primary prevention (no sx) = antiplts + RF management + CEA if stenosis 80-99%h. Secondary prevention (sx) = antiplts + RF management + CEA if stenosis 50-99%

PATHOLOGY OF BRAIN TUMORS1. Can’t classify as benign/malignant (as a benign tumor in an important spot = really bad), thus Px based on location/resectability

a. Assign as HIGH grade 3-4 (rapid growth, poor px) or LOW grade 1-2 (easily resectable, slow-growing, good px)2. Sx due to mass effect (increase ICP HA, papilledema, projectile vomiting, herniation) or local damage (focal deficits, seizures)3. Age/etiology

a. Childreni. Posterior fossa (cerebellum/brainstem)ii. Mainly 4th ventricle ependyomas, cerebellar astrocytoma/medulloblastoma

b. Adultsi. Cerebral hemispheresii. Mainly cerebral astrocytoma/glioblastoma, metastasis, meningioma

4. Primary: tumors whose cell type is a normal component of the nervous systema. Neuroectodermal origin

i. Gliomas (differentiated)1. Diffuse astrocytoma : infiltrative, aggressive (grade 2-4), enhancing (vessel prolif+necrosis destroys BBB)

a. Grade 4 is glioblastoma multiforme w/ pseudopalisading cells (rim of nuclei around necrosis)2. Pilocytic astrocytoma : children, grade 1, solid/cystic, Rosenthal fibers (GFAP in astrocyte processes)3. Oligodendroglioma : 30yo, grade 2-3, infiltrative w/ fried-egg cells + calcifications seizures4. Ependymoma : grade 1-3, solid tumors that grow into ventricles obstructive hydroceph/mass effect5. Choroid plexus tumor : occurs w/in ventricles obstructive hydroceph/mass effect + CSF overproduction

8ii. Primitive Neuroectodermal Tumors (PNET; undifferentiated, common in kids, aggressive)

1. Medulloblastoma : grade 4, typically in kids, occurs in cerebellum and blocks 4th obstructive hydroceph/mass effect, disseminates to CSF, Homer-Wright rosettes

b. Tumors of non-ectodermal origini. Meningioma : common in elderly, solid/extra-axial (attached to dura), whorls/psammoma bodies ↑ ICPii. Primary CNS lymphoma : despite no lymphatics in brain can get HI grade B cell lymphoma in elderly, AIDS w/EBViii. Neurofibroma : one of the few attributed to a genetic syndrome, assoc w/ nerve sheath tumors

5. Secondary: metastases, most commonly from lung, breast, GI, skin (met of a primary CNS tumor is rare)a. 20-30% of all brain tumors, common in elderly and often first presenting signb. Solid w/ central necrosis, well-circumscribed, assoc vasogenic edemac. Leptomeningeal carcinomatosis: tumor cell spread through CSF ptwys hydrocephalus + multiple CN/spinal nerve

probs + high CSF protein

PATHOLOGY OF INFECTION1. Compartments

a. Skull/vertebrae osteomyelitisb. Meninges epidura/subdural empyema or meningitisc. Parenchyma cerebritis (aka abscess), encephalitis, spongiform encephalopathy (prions, technically neurodegen)

i. Meningoencephalitis – diffuse meningeal and parenchymal processii. Encephalomyelitis – diffuse parenchymal and SC process (usual viral or immune-mediated)iii. Myelitis – localized to SC, immune-mediated

2. Routes of infxn: hematogenous (most common), direct implantation (trauma/surgery), axonal transport (herpes)3. Consequences: direct tissue damage (liquefactive necrosis), edema ( mass effect), neoplastic transformation (EBV assoc w/ HIV)4. Types

a. Acute purulent meningitis (subarachnoid space)i. Orgs: listeria/G- rods/haemophilus (kids), strep/staph (adults), neisseria (both)ii. Clinical: infxn hematogenously disseminates nuchal rigidity (+ Kernig (hurts to extend knee)/Brudzkinski

(lifting head causes hip/knee flexion) signs), fever, headache (HA), N/V, photophobia, ΔLOC, seizureiii. Pathology: inflamm/edema ↑ ICP/herniation + pus in subarachnoid space sepsis/parenchymal infiltrationiv. CSF: markedly HI opening pressure (>200), HI protein (>50), LO glucose (<40), neutrophils

b. Aseptic meningitis (subarachnoid space)i. Orgs: common viruses, cancer cells (leptomeningeal carcinomatosis), chemicalsii. Clinical: self-limiting/milder than bacterial form, sx similar but no ΔLOCiii. CSF: mild ↑ protein, normal glucose, lymphocytes

c. Chronic meningitis (subarachnoid space)i. Orgs: persistent agents like TB/syphilis, sarcoidosisii. Clinical: non-specific/non-localizing sx makes it hard to dx, sx include seizures/cognitive dysfxn/low feveriii. Pathology: chronic inflamm fibrosis, non-obstructive hydroceph ↑ ICP/mass effect, 1° base of brainiv. CSF: HI opening pressure (due to obstructive hydroceph), markedly HI protein (>100), lymphocytes/monocytes

d. Abscess/Cerebritis (intraparenchymal) / empyema (epi/subdural)i. Orgs: varietyii. Clinical: sx include fever, HA, seizures, focal deficits, sepsis, predisposed if immunosuppressed/other infxnsiii. Pathology: focal destructive lesions w/ inflamm edema mass effect herniation and/or sepsisiv. CSF: HI opening pressure (rest fairly normal if lesion has not extended into CSF pathways)

e. Acute viral encephalitis (intraparenchymal)i. Orgs: tissue tropism, i.e. viruses seek out particular type of cell to infect

1. poliovirus ant horn cell destruction w/ LMN paralysis2. varicella-zoster trigeminal/dorsal root ganglia w/ dermatomal vesicular rash3. herpes simplex I medial temporal lobes w/ hemorrhagic necrosis/Cowdry inclusions4. CMV periventricular white matter if immunocompromised5. rabies brainstem w/ lethal consequences

ii. Clinical: fever/HA/acute focal sx (seizures, deficits, ΔLOC)iii. Pathology: tissue necrosisiv. CSF: normal protein, normal glucose, lymphocytes

f. Chronic viral encephalitis (intraparenchymal)i. Orgs: HIV ( immunocomprimise + AIDS dementia), JC virus ( PML (progressive multifocal leukoencephalopathy)

due to destruction of oligos/demyelination)ii. Clinical: insidious onset slowly progressive dementia

AUTOIMMUNE1. Compromised BBB formation of Ab (sometimes pathogenic) to the normally “hidden” nervous system Ag OR cross-rxn b/w

systemic Ab & nervous system Ag (molecular mimicry)2. Plasmapheresis uses filtration by molecular wt to remove Ab/immune complexes/complement/etc from blood vs IVIg (pooled

human Ig) which suppress endogenous Ab production by over-loading the pt’s immune system3. Koch-Witebsky postulates determine if dz is truly autoimmune

a. Serum Ab present & titers proportional to dz activityb. Passive transfer of Ab produces dzc. Active transfer (immunization) of Ag produces dz

4. Myasthenia Gravis: weakness due to anti-AChR Aba. Sx: muscle fatigability (eyes usually affected first), diurnal variation, reflexes/sensation unaffectedb. Dx: arm aBduction time <5mn +tensilon test (strength improves w/ edrophonium injection), +anti AchR Ab, decrement w/

repetitive stimulation on EMG/jitter on SF (single fiber) EMG, thymoma (or penicillamine) may be cause of anti-AChR Absc. Tx: pyridostigmine (anti-AChE), plasmapheresis or IVIg, steroids, thymectomy

5. Lambert-Eaton: weakness due to anti-VGCC Ab (interfere w/ voltage-gated Ca channels needed for ACh release)a. Sx: muscle fatigability (less bulbar/resp m than MG), affected gait, depressed reflexes, autonomic dysfxnb. Dx: +anti-VGCC Ab, increment w/ repetitive stimuation (due to Ca accumulation), concurrent small cell lung carcinomac. Tx: pyridostigmine, plasmapheresis/IVIg, steroids, tx of lung tumor

96. Polymyositis/Dermatomyositis: most common inflammatory myopathies (PM: inflamm in endomysium, DM: inflamm in perimysium)

a. PM is autoinvasive Tc cells that attack myocytes; DM is immune complex-mediated microangiopathy w/2° myocyte damageb. Sx: erythema of neck, trunk, & ext surfaces of PIP/MCP/elbow/knee, nailbed infarcts, periorbital edema, “eyeshadow”c. Dx: progressive symmetric weakness of neck flexors, dysphagia, erythemad. Tx: plasmapheresis, IVIg, steroids

7. Guillain-Barre syndromes, which include…a. AIDP: acute inflamm demyelinating polyneuropathy

i. Sx: both sensory (ataxia) & motor (loss of reflexes) affected, older adultsii. Dx: multifocal/asymmetric “ascending” neuropathy, recent febrile illness (molecular mimicry), no WBC in CSF but

protein elevatediii. Nerve conduction study (EMG): prolonged distal latency, slowed conduction, prolonged F-wavesiv. Tx: plasmapheresis, IVIg (steroids NOT helpful)

1. Tx should not be started more than 3wk after onset unless there is clear progression2. Start tx asap in pts that can’t walk unassisted

b. Fisher syndrome = anti-ganglioside GQ1b Abs affect oculomotor fibers/sensory gangliai. Ataxia, areflexia, ophthalmoplegia and unreactive pupils

c. AMAN: acute motor axonal neuropathy, resembles AIDP but only motor n affected (see esp. in Japan, China, Mexico)i. Sx: loss of reflexesii. Dx: low amplitude on EMG (indicates axonal drop-out) but conduction not slowediii. Assoc w/ Campylobacter infxn→ molecular mimicry to LPSiv. Recovery often rapid and complete

d. AMSAN: acute motor-sensory axonal neuropathy, resembles AIDP but axonal drop-out rather than demyelinationi. Sx: ataxia, loss of reflexesii. Dx: low amplitude on EMG (indicates axonal drop-out) but conduction not slowediii. Assoc w/ Campylobacter infxn→ molecular mimicry to LPSiv. Recovery is slow and less complete than AMAN

8. CIDP: chronic inflamm demyelinating polyneuropathy, resembles AIDP but slower onset (˃8wk) and relapsing/remitting coursea. Sx: as above (but no clear antecedent illness)b. Dx: prolonged distal lateny/F-waves on EMG (indicates slowed conduction)c. Tx: plasmapheresis, IVIg, steroids

9. CIDP-MGUS: CIDP w/ monoclonal gammopathy of unknown significance, like CIDP but more sensory involvement so may not respond to usual CIDP tx

10. Anti-MAG (myelin assoc glycoprot) and GALOP (gait ataxia late-onset polyneuropathy): myelin wide-spacing11. MMN: multifocal motor neuropathy, resembles ALS but no UMN sx

a. Sx: slowly progressive weakness w/ atrophy/fasciculations beginning in armsb. Dx: focal slowing and conduction block on EMG, anti-GM1 ganglioside Abc. Tx: IVIg (not plasmapheresis or steroids)

12. Myeloma +/- osteosclerosisa. +osteo: common demyelinating neuropathy/POEMS that improves w/ tx of myelomab. –osteo: rare axonal neuropathy that does not improve w/ tx of myeloma

13. Paraneoplastic syndromesa. PCD: paraneoplastic cerebellar degen, Ab bind Purkinje cells, assoc w/ ovarian/uterine/breast carcinomas (anti-Yo Ab)b. POM: paraneoplastic opsoclonus-myoclonus, dancing eyes/feet, assoc w/ child neuroblastoma/adult breast cancer (anti-Ri)c. PESN: paraneoplastic encephalitis and sensory neuronopathy, assoc w/ small cell lung cancer (anti-Hu)

14. Stiffman (stiff person) syndrome: anti-glutamic acid decarboxylase Ab (enzyme in GABA synthesis)15. Neuromyelitis optica (NMO or Devic’s dz): inflamm demyelinating dz of optic n/SC, NMO-Ig Ab is marker to distinguish from MS16. PANDAS: pediatric autoimmune neuropsychiatric disorder assoc w/ streptococcus, tics or OCD, anti-basal ganglia Ab17. Multiple Sclerosis: discussed below

PATHOLOGY OF MULTIPLE SCLEROSIS1. Myelinopathies

a. Primary: direct damage to myelin or myelin-producing cells (ex) MSb. Secondary: damage to axon results in damage to myelin (ex) Wallerian degenerationc. Patterns include plaques (MS), punctuate lesions (ADEM), diffuse (leukodystrophy)

i. MS: chronic/progressive dz assoc w/ random discrete areas of demyelinationii. ADEM: acute disseminating encephalomyelitis due to viral infxn assoc w/ tiny perivascular foci of demyelinationiii. Leukodystrophy: autoR dz steady progressive decline thru-out childhood w/ diffuse, symmetric demyelination

d. Central pontine myelinolysis: acute destructive dz due to over-rapid correction of hypoNai. See rapidly developing quadriplegia due to bilateral corticospinal tract damage (to myelin)

2. MS plaquesa. Plaques are foci of complete demyelination (looks grey in the white matter)

i. ACUTE: myelin breakdown w/ inflammationii. EVOLUTION: MΦ infiltration, astrocyte proliferationiii. CHRONIC: possible remyelination

b. Axons are not necessarily destroyed, just demyelinated/remyelinatedc. Common in periventricular white matter and subpial white matter, esp. SC & optic pathways3. Dx reflects pathology

a. Multiple CNS lesions in time and spaceb. CSF shows mild lymphocytic pleocytosis/oligoclonal bands/elevated myelin basic protein/(-) Lyme titer c. T1 MRI shows ring enhancing lesion (assoc inflamm of an active plaque weakens BBB)

CLINICAL MULTIPLE SCLEROSIS1. Epidemiology: 15-50y w/ peak in 20s, F>M, ↑latitude (temperate climate) before age 15, assoc HLA (ch6; MHC class II HLA-DR2

haplotype DR15/DQ6), white N. Europeans 2. Sx

a. Vision: optic neuritis ( vision loss), nystagmus, diplopliab. Motor: limb weakness, cerebellar ataxia

10c. Sensory: paresthesias, L’Hermitte’s sign (electric shocks w/ neck mvmt)

3. Dx (current is Poser criteria which only uses hx/sx, no imaging/CSF)a. Multiple CNS lesions in time and spaceb. Mild lymphocytic pleocytosis/oligoclonal bands/elevated MBP in CSFc. T1 MRI shows ring enhancing lesion (as opposed to more destructive PML)d. NO specific Ab have been identified (but still considered autoimmune)

i. Assoc w/ increased titers to various viral Agii. Assoc w/ oligoclonal Ab bands but no identifiable Ag

4. Txa. High-dose methyprednisolone may shorten course of acute exacerbations but most immunosuppression ineffectiveb. Beta-interferons reduce severity and freq of exacerbations (block IFN)c. Glatiramer (mixture of amino acids) inhibits immune response to MBP (myelin basic protein)d. Mitoxantrone slows progression but is cardiotoxice. Natalizumab (anti-4 integrin Ig) reduces freq of exacerbations (keeps inflamm cells from x BBB)

i. Can reactivate latent JC virus (causes fatal PML)f. Mitoxantrone (antibiotic class anti-neoplastic) slows progression

PATHOLOGY OF NEUROMUSCULAR DISEASE1. Neuromuscular components

a. Skeletal muscle structurei. Myocytes: composed of myofibrils (chains of sarcomeres), eccentric nucleiii. Connective tissue wrappings include endomysium, perimysium, epimysiumiii. NMJ between motor axon/muscle cell, ACh secreted by motor end plate

b. Skeletal muscle physiologyi. Innervated by myelinated motor neurons from anterior horn cell in spinal cordii. Motor unit = motor neuron + all the skeletal muscle cells innervated by itiii. Nerves have trophic effect on muscle (thus denervation leads to atrophy)iv. Two fiber types intermixed checkerboard appearance (see right)

Type 1 Type 2Red (myoglobin) White (glycogen)

Sustained work (not fatigable) Sporadic work (fatigable)Slow twitch Fast twitch

Smaller fibers Larger fibersOxidative metabolism (mitochondria) Glycolytic metabolism

High capillary density Low capillary density

c. Peripheral nerve structurei. Bundles of myelinated/unmyelinated motor and sensory fibers

1. α fibers extrafusal muscle (larger myelinated)2. γ fibers intrafusal muscle (stretch reflex; smaller myelinated)3. Aα/Aβ/Aδ/C fibers are sensory

ii. Connective tissue wrappings include endoneurium, perineurium, epineuriumiii. Schwann cells myelinate ONE axon, internodes w/ saltatory conduction

d. Peripheral nerve physiologyi. Denervation LMN syndrome = flaccid paralysis, hyporeflexia, atrophy

2. Neuropathy skeletal m dysfxn due to loss of innervation (see ALS, autoimmune lecture)a. Pathology: Wallerian degen, dying back degen, segmental demyelination (onion bulbs in CIDP due to progressive

episodes of demyelination/remyelination)

113. Myopathy skeletal m dysfxn due to direct myocyte injury

a. Pathology: myofiber necrosis, ragged red fibers (increased mitochondria), basophilic fibers (regen), inflamm, fibrosis

CLINICAL NEUROMUSCULAR DISEASE1. Sensory loss requires nerve involvement but weakness may be due to either neuro- or myo-pathy2. Distal weakness > proximal + sensory loss + hyporeflexia → think neuropathy3. Proximal weakness > distal + myalgias (w/ myositis) + intact sensation/reflexes → think myopathy 4. Neuropathy

a. Acquired: asymmetric i. Autoimmune neuropathies (see autoimmune lecture)ii. Diabetic neuropathy (most common)iii. Endocrine neuropathyiv. Infections (HIV, HepC, Lyme)v. Toxic neuropathy (meds, EtOH, Pb)vi. Nutritional neuropathy (B vits)

b. Hereditary: symmetric w/ all limbs involved, slowly progressing, assoc w/ connexin-32, Po, GDA P1i. Demyelinating: Charcot Marie Tooth I, III, IVii. Axonal: CMT II, V, VI + hereditary sensory neuropathies (HSN) I-V

c. Neuropathy Evaluation: genetic testing, labs, EMG/NCS for demyelination & F-waves, nerve biopsy4. Myopathy (direct myocyte injury)

a. Endocrine: common in Cushing’s (selective atrophy of type 2 fibers)b. Metabolic: GSDs (McArdle’s/Pompe’s) & mito disorders (see elevations in serum lactate due to anaerobic metabolism)c. Toxic

i. Myopathy w/ neuropathy: statins, amiodarone, organophosphates, vincristineii. Myopathy w/cardiomyopathy + neuropathy: colchicine (gout), EtOH, chloroquine, clofibrate, doxorubicin

d. Periodic paralysis is due to problems w/ voltage-gated ion channelsi. HyperK periodic paralysis due to Na channel mutationsii. HypoK periodic paralysis due to Ca channel mutationsiii. Myotonia (inability to relax following voluntary contraction)

e. Myositis: inflamm of muscle progressive weakness w/ pain + elevated CK (creatinine phosphkinase)i. Due to infxn, drugs, auto-immune (PM/DM, see autoimmune lecture)

f. Dystrophies: genetic, progressive myopathiesi. Duchennes: X-linked mutation lack of dystrophin difficulty standing, wheelchair by 12, death by 30

1. Beckers is a decrease in dystrophin w/ similar but less severe clinical pictureii. Facioscapulohumeral: autosomal dominant (ch4) weakness in shoulder girdle/face in 20siii. Oculopharyngeal: autosomal dominant (ch14) dysphagia/ptosis in 50s, common in French Canadiansiv. Myotonic (most common adult form): autoD CTG repeat myotonia, hatchet face, arrhythmias (may need

pacemaker), cataract, hypogonadism, frontal balding, EKG changes, often assoc w/ neuropathy

AMYOTROPHIC LATERAL SCLEROSIS1. General

a. Idiopathic, lethal, asymmetric neurodegenerative dz affecting both UMN/LMN progressive atrophy and weaknessi. Eye mvmt and sphincter tone spared until late in courseii. Rare familial form assoc w/ SOD1 mutation (ch21)

b. Most common form of adult motor neuron diseasec. Affects men/women equally, age of onset peaks in 6th decaded. Spinal Muscle Atrophy (SMA) is autosomal recessive ALS-like dz in children, assoc w/ loss of SMN1 gene (ch5), see

symmetrical weakness due to degeneration of ant horn cellsi. SMA1: infantile, aka Werdnig-Hoffmanii. SMA2: intermediate formiii. SMA3: juvenile, aka Wohlfart-Kugelberg-Welander

2. Clinical a. UMN sx: hypertonia (despite weakness), hyperreflexia, +Babinski

i. MRI is normal, which rules out SC/brain lesionsb. LMN sx: muscle atrophy/weakness, fasiculations

i. Nerve conduction shows…1. Reduced amplitude (indicates motor axonal loss)2. Normal velocity (no demylination), normal F-wave (not root prob), normal latency (not sensory prob)

ii. Needle EMG shows…1. Fasciculations at rest (indicates denervation)2. Polyphasic w/ movement (indicates devervation followed by some reinnervation)

c. NO cognitive, sensory, cranial nerve, or sphincter problems3. Pathology

a. UMN loss degeneration of pyrimidal tracts, corticospinal tracts, Betz cells of primary motor cortexi. Assoc w/ gliosis (GFAP stain), Bunina bodies (eosinophilic inclusions),

b. LMN loss degeneration of anterior horn cells/ventral root, neurogenic atrophy of muscle i. Early Δs: myofiber atrophy (variable diameters) + EMG fibrillationsii. Mid Δs: fiber type grouping (lose checkerboard) + ↑ EMG amplitude (re-inn by surviving= ↑ size motor unit)iii. Late Δs: fibrofatty atrophy + ↓ EMG amplitude (group atrophy= ↓ # motor units)

4. Txa. Riluzole slightly improves life expectancy (4-6mo) and QOL b. W/o tracheostomy or ventilation support, life expectancy is <2 years after bulbar involvementc. With predominantly spinal involvement, 5 year survival is <20%

Fiber type grouping

12

COGNITIVE DYSFXN1. Definitions

a. Aphasia: inability to understand and use languageb. Anomia: inability to name (word finding difficulty)c. Agraphia: inability to writed. Alexia: inability to reade. Acalcula: inability to calculatef. Agnosia: failure to recognize perceived stimulig. Anosagnosia: failure to recognize illness (unaware of deficits)h. Prosopagnosia: inability to recognize faces (can recognize parts of faces, ID people by voice)i. Achromatopsia: loss of color vision (inferior parietal/occipital lobe lesion)j. Apraxia: impairment of skilled mvmtk. Aprosodia: loss of control of voice intonation/emphasis (usually R side of brain)l. Neglect: ignoring one side of the environmentm. Disconnection: inability to transmit info from one area of cortex to another (callostomy R/L hand disconnected)

APHASIA TYPES SPEECH COMPREHENSION REPETITION OTHERBroca’s Poor Intact Poor Damage to 22Wernicke’s Fluent Poor Poor Damage to 44/45Global Poor Poor PoorConduction Intact Intact PoorTranscortical Motor Poor Intact Intact Damage anterior to Brocas Transcortical Sensory

Intact Poor Intact Damage posterior to Wernickes

Echolalia Poor Poor Intact

2. Gerstmann’s syndrome: dominant parietal lobe lesion tetrad of sxa. Finger agnosia: cannot name fingers or indicate a finger named for themb. L-R disorientation: cannot indicate which hand/foot is L vs Rc. Acalculia: inability to carry out calculations, often due to pt mistaking the #sd. Agraphia: inability to write

3. Alexia can be +/- agraphiaa. w/ agraphia is worse, due to lesion in dominant parietal lobb. w/o agraphia still allows for writing, spelling, comprehension, due to posterior dominant/occipital lobe + splenium of CC

4. Amnesiaa. Types of memory: registration (attention span), short-term, long-termb. Anterograde: can’t form new memories, occurs in Korsakoff’s syndrome

13c. Retrograde: can’t remember preformed memories (Ribot’s law – most recent memories are lost first)d. Amnestic syndrome

i. Usually bilateral limbic system lesions + mix antero/retrogradeii. Common after traumatic brain injury

e. Transient global amnesia (think transient ischemia attack)i. Benign but acute onset of profound transient anterograde amnesiaii. Full recovery of anterograde memory but leaves a permanent memory gap

5. Visiona. Cortical blindness: pupillary response preserved but no visionb. Anton’s syndrome: cortical blindness w/ anosagnosiac. Balint’s syndrome: oculomotor apraxia, optic ataxia, visual inattention, visuospatial issues

DEMENTIA1. Mild cognitive impairment: simple memory complaint (corroborated by someone) w/ intact ADLs + normal cognitive fxn2. Dementia: memory impairment + one of the following w/o delirium

a. Language, judgment, abstract thinking, praxis, constructional abilities, visual recognitionb. Multiple etiologies – Alzheimers is most common (covered below), also due to…

i. Diffuse Lewy body dz1. Clinical: dementia + motor sx of PD (bradykinesia, cogwheel rigidity, shuffling gait), visual halluc.2. Pathology: widespread Lewy bodies (α-synuclein inclusions) atrophy

ii. Vascular dementia1. Clinical: dementia + step-wise decline in fxn following each vascular event2. Pathology: multiple infarcts (large or lacunar) cavitations

iii. Frontotemporal dementia (think Pick’s dz)iv. Rapidly progressing dementias (covered in prion lecture)

3. Evaluationa. Labs: CBC & chem7, glucose, BUN/creatine, B12, LFTs, thyroid (Δs in any can cause cognitive impairment)b. Mini-mental status examc. Depression screening (often hard to distinguish)

ALZHEIMERS DISEASE (AZ)1. Epidemiology

a. Most common type of dementia; affects hippocampus especiallyb. 90% sporadic, 10% familial (earlier onset + faster progression)c. Risk increases w/ age, insulin resistance, hypercholesteremia

2. Clinical featuresa. Gradual progression (10yrs) vs stepwise in multiple infarct dementia or undulating in DLBD

i. Early sx: impaired recent memory, depressionii. Late sx: impaired remote memory, poor speech, agitationiii. End-stage sx: complete amnesia, mute

b. Definitive dx is via autopsy, but imaging can complement evaluationi. MRI: marked reduction in brain volume (frontal & parietal) + hydrocephalus ex vacuoii. fPET: impaired glucose utilization in posterior cingulate gyrus & parietal cortex (DLBD is anterior)

3. Pathologic featuresa. Δs that correlate best w/ cognitive fxn are:

i. Severe loss of neurons gliosis + low brain wt + hydroceph ex vacuo1. 1˚ hippocampus, entorhinal cortex, parietal/frontal cortex

ii. Neurofibrillary tangles: intracell inclusions of hyperphosphorylated tau proteins iii. Senile plaques: accumulation of β-amyloid in neuropil

b. Other Δs: hirano bodies (inclusions), amyloid angiopathy (β-amyloid in vessel walls)c. Pallor of locus ceruleus (AD is defcy of ACh)d. Dx criteria: #plaques/HI power field, # needed to dx increases w/ age (>76y=15+)

4. Geneticsa. Trisomy 21 (3 copies of APP gene) early onset AZb. Mutated APP gene assoc w/ familial AZc. APO E4 allele assoc w/ sporadic AZd. Presenilin 1/2 increase Aβ-amyloid

5. Pathophysiologya. Beta/gamma secretases abnormally splice APP into β-amyloids I-40 (vessels)/I-42 (neurons) = non-fxnal and toxicb. Β-amyloids activate caspases that lead to hyperP of tau (tangles)

i. HyperP is also indirectly caused by insulin resistance via disinhibition of GSK36. Tx

a. Acetylchoinesterase inhibitors (donepezil, galantamine, rivastigmine) slow progession more than relieve sxb. NMDA receptor antagonist (memantine)c. Vit E may slow progressiond. Do not use estrogen for tx

PRION DISEASE1. Caused by mutations/conformational changes of the prion protein PrPc to PrPsc or to glycated prion prot

a. Normally PrPc to PrPsc are in equilibrium unknown trigger catalytic conversion to pathological form

b. PrPSC beta sheet conformation, which forms insoluble plaques and causes dz2. Pathology

14a. Spongiform degeneration formation of cytoplasmic vacuoles that are filled PrPSC proteinb. Various types of amyloid plaques of prion proteinc. Gliosis excessive for degree of neuronal loss

3. Typesa. Sporadic CJD: most common, onset 65y, rapid progress (<1y), defined by mutation of codon 129 (Met/Val) of prion gene

i. M/M type 1: occipital/parietal cortexii. M/M type 2: cerebral cortex (most common)iii. M/V type 2: cerebellum, ataxia precedes dementia, Kuru plaques iv. V/V type 2: thalamus

b. Familial CJD: AD inheritancec. Gerstmann-Straussler-Scheinker: slower progression than other forms of prion diseases (3-5y)d. Human BSE: mad cow dz

CLINICAL HEADACHE1. Most due to VD of intracranial b-vessels stimulation of surrounding trigeminal nerves (or via increase/decrease ICP, inflamm)

a. There is release of CGRP (CNV stimulation) which ↑ pain2. Primary types (F˃M except cluster)

a. Migraine : neurovascular dz w/ recurring unilateral HA, pulsating quality, assoc w/ N/V, photo/phonophobia, family hxi. Without aura

1. Must have 5+ attacks lasting 4-72h that meet above criteriaii. With aura = visual/sensory sx that develop gradually before HA onset (must have 2+ attacks)

1. Aura sx do NOT last more than 1h2. Aura sx are reversible3. HA follows aura w/ free interval ˂1h

iii. With typical aura = homonymous visual disturbance, unilateral paresthesias/numbness/weakness, aphasic speechb. Tension : diffuse bilateral squeezing sensation, can become chronic w/ chronic NSAID use (aka medication misuse HA)

i. Rarely see photophobia, phonophobia, N/Vc. Cluster : M>>F, excruciating non-throbbing “hot poker” pain behind one eye assoc w/ ptosis/miosis/lacrimation/nasal

congestion, attacks last 45min, have ~3 attacks/dy (often nocturnal) during cluster, cluster ~2mo and occur every 1-2yr3. Secondary types

a. Pseudotumor Cerebri or Benign Intracranial HTN: 30y obese F, sx of ↑ ICP w/o hydrocephalus (see papilledema, HA, transient/intermittent vision Δs, and small slit-like ventricles), tx wt loss, acetazolamide (carbonic anhydrase inhibitor), optic nerve sheath fenestration if progressive vision loss

b. Trigeminal Neuralgia or Tic Doloreux: ˃40y, brief, severe unilateral lancinating pain in distribution of 1+ CNV branches elicited by touch/chewing/talking, tx carbamezapine (anticonvulsant)

c. Temporal Arteritis : >60y, temporal HA, vision Δs, fever/wt loss, elevated ESR, vasculitis on biopsy, tx oral prednisone4. Common associations

a. “Thunderclap” first & worst HA = SAH, get a CT/LPb. Warning sign of increased ICP is HA that awakens pt (b/c hypoventilate when sleeping ↑ CO2 & compensatory VD)c. Palpable tender temporal arteries w/ vision changes = giant cell (temporal) arteritis, get an ESRd. Cherry-red w/ HA in wintertime = CO poisoninge. ALL headaches can cause N/Vf. Photopsia = see flashes of light

HEADACHE PHARMACOLOGY1. Primary headache: tension, migraine, cluster (=CDH or chronic daily HA if >15/mo for tension/migraine)2. Neurovascular hypothesis: belief is that HA is due to vasodilation – trigeminal n innervates cranial blood vessels, sensitization of

vessels (due to stress, noise, etc) release of inflammatory mediators (CGRP/substance P) which cause paina. 5HT agonists VC via 5HT-1B receptors on cranial vessels + inhibition of nociception/pain via 5HT-1D receptors on CNV

3. HA assoc with N/V and decreased GI emptying will impact drug absorption4. Acute vs prophylactic tx

a. Use acute during the HA, the sooner the betteri. Tension: acetaminophen, NSAIDSii. Migraine: triptansiii. Cluster: O2 (ipsi nostril)

b. Use prophylaxis when HA are frequent (>2/wk), severe, or have contra to acute drugsi. Tension: amitriptyline (TCA)ii. Migraine: beta-blockers, topiramate (anti-convulsant)iii. Cluster: prednisone, verapamil, lithium

5. Drug-induced (medication misuse) headachea. CDH due to overuse of HA meds hyperalgesia (↑pain sensitivity) due to suppression of natural opioids, usually due to

OTC analgesics (tylenol, caffeine, ASA), tx is d/c drug6. Headaches in women

a. Menstruation HA due to fluctuation of E2 levels, thus tx w/ birth control or NSAID mini-prophylaxis (just before period)b. In pregnancy, NO triptans/ergots

ACUTE TREATMENTDRUG MOA SIDE EFFECTS

Ergot Alkaloids 5HT-1/DA R agonist VCPoor oral bioavailability

Peripheral VC numbness/tingling, muscle pain, gangreneDA activation N/V (may combo w/ metoclopramide)Contra: vascular dz, pregnancy, liver/kidney dz, concomitant triptans/cyp3A4s

Triptans Sumatriptan

5HT-1B/D R agonist VCGood for migraine/cluster

Well tolerated/less nausea than ergot due to 5HT receptor selectivity “triptan sx” (tingling, lethargy, chest tightening)Contra: vascular dz, pregnancy, concomitant use w/ ergots or MAOI

Acetaminophen Not an NSAID, but close Safest of all tx

15NSAIDS/ASA (-) prostaglandins Safe but can cause GI bleedingCaffeine VC Safe, can caffeineism, assoc w/ withdrawal Has (tx is reintroduction)Midrin Combo of isometheptene (like epi) +

dichloralphenazone (sedative) + acetaminophen

SE are numbness/dizzinessContra: MAOI (excessive catechol release), antidepressants

Metoclopramide Anti-emetic via DA antag Safe, DOC for nausea in migraine, given in combo to ↑ gut motility

Opiods Abuse potential

PROPHYLACTIC TREATMENTDRUG MOA SIDE EFFECTS

Tricyclics amitriptyline

Unknown DOC for tension HA prophylaxisAnticholinergic SE (drying, constipation)Contra: pregnancy, glaucoma, urinary retention, concomitant MAOIs

B-blockers propranalol

Unknown DOC for migraine HA prophylaxis, double dip w/ heart dzAntiadrenergic SE (fatigue, bradycardia, hypoTN)Contra: asthma, DM

Topiramate Not given Migraine HA prophylaxisCan cause cognitive dysfxn, wt loss

Verapamil Ca channel blocker DOC for cluster + migraine HA prophylaxis (takes 3-8wk), double dip w/ heart dzValproic acid Not given Cluster and migraine HA prophylaxis, double dip w/ seizures or bipolar disorderLithium Enhances 5HT

transmissionDOC for chronic cluster HA prophylaxis, double dip w/ bipolar disorderContra: pregnancy, kidney dz, plus it sucks to take it

NEUROPATHIC PAIN 1. Pathophysiology

a. Nociceptive pain is via damage to tissue (protective)i. Quality is “aching” or “throbbing,” responds to NSAIDS/opiodsii. Normally:

1. Painful stimuli (substance P, TNF, prostaglandins) via nociceptors to DRG2. Impulse carried to spinothalamic tract to cortex3. Cortex releases NE/5HT/GABA to inhibit excitatory pain impulses → dampens the sensation of pain

b. Neuropathic pain is via direct neuronal injury (no purpose) pathologic change in the nerve to promote paini. Quality is “burning” or “electric”, refractory to conventional analgesics, both +/- sx (cold, numb, asleep, crawling)ii. Most types have both both central/peripheral pain due to hyper-excitability of neurons

1. Central: loss of inhibitory GABA OR enhanced glutamate excitation of NMDA Rs promote sensation of paina. Includes pain assoc w/ stroke, MS, Parkinson’s, spinal cord injury

2. Peripheral: over-sensitization of peripheral nerves due to ↑ # Na channels/adrenergic Rs promotes paina. Includes pain assoc w/ diabetic neuropathy, post-herpetic or trigeminal neuralgia, phantom limb

2. Typesa. Diabetic peripheral neuropathy

i. Burning, tingling bilateral sensation in extremities loss of sensation foot ulcers/amputationii. Tight glucose control has shown efficacy in preventing microvascular complications (may be due to sorbital)iii. DOC: pregabalin, gabapentin, duloxetine, tramadol, TCA, opiods

b. Post-herpetic neuralgia (pain lasting 1-3mo post healing of shingles)i. Complication of shingles (herpes zoster) most common in elderlyii. Promising vaccineiii. DOC: gabapentin, pregabalin, tramadol, lidocaine patch, opiods

c. Trigeminal neuralgia (Tic Doloreux)i. Compression & demyelination of 5th cranial nerve unilaterally, most common in MSii. DOC: carbamezapine (or oxacarbazepine)

d. Drug-induced peripheral neuropathyi. Blood-nerve barrier is weaker than BBB, thus drugs can cross easier & cause toxicity

1. Cancer chemotherapy (80% of pts) disrupts axonal transport/decrease myelin2. Antiretrovirals + HIV itself causes neuropathy3. Isoniazid (can be prevented w/ supplemental B6)

ii. Distal axons affected first, followed by Wallerian degen, obvi not helpfuliii. DOC: gabapentin, lidocaine, opioids, TCAs

3. Strategies to treat neuropathic paina. Start low, go slowb. Everyone is different, choice is specific to patient and should account for DDI, co-morbities, SE, etc

DRUG MOA INDICATION ADVERSE EFFECTSGabapentin Ca channel blocker All Dizziness, drowsiness, wt gain, edema, cog dysfxnPregabalin Ca channel blocker All Dizziness, drowsiness, wt gain, cog dysfxn, dry mouthCarbamazepineOxcarbazepine

Na channel blocker Trigeminal neuralgia Inducer, SIADH, rash (SJS), aplastic anemiaOxy not metab to 10-11 epox intermediate = less SE

Lidocaine Na channel blocker Post-herpetic Only for post herpes, never put on open lesionAmitriptyline (TCA)

SNRI Diabetic, drug-induced

DO NOT use if arrhythmias, seizures, MAOIs

Duloxetine SNRI All DO NOT use if MAOIOpiods Unknown (for NP) All Constipation (stool softener/stimulant), resp depression

16Topiramate Na channel blocker 3rd line option Wt loss, kidney stonesValproic Acid Unknown (for NP) 3rd line option Inhibitor, THBpenia, hepatotox, wt gain, alopeciaTramadol SNRI Diabetic neuropathy DO NOT use if seizuresCapsaicin substance P depletion Only in combination Don’t smear all over your hands and then rub your eyes

SEIZURES1. Interntnl Classification of Epileptic Seizures: recurrent unprovoked seizures due to transient hypersynchronous electrical activity

a. Automatisms: stereotypic repetitive/automatic motor or vocal behaviors (ex) rubbing, squeezing, picking, lip-smackingi. Most common in complex partial and absence seizures

b. Aura: sensation experienced by some pt before an impending complex partial seizure, essentially a simple partial seizurec. Most important is the correct classification, since tx can differ

i. (ex) Phenytoin/Carbamezapine are 1st line for tonic-clonic but will make absence/myotonic/atonic worse2. Partial seizures (may progress to a secondarily generalized seizure)

a. Simple: consciousness intacti. Sx: contralateral motor/sensory (+/- march), autonomic (aura, sweating, pallor), psychic (déjà vu, intense fear)

b. Complex: consciousness impaired, assoc w/ automatisms & aura, ictal amnesia + post-ictal confusioni. Sx: above + able to respond in a limited way (ex: doesn’t recognize name when called, but turns toward noise)

3. Generalized seizuresa. Simple Absence (petit mal): momentary LOC (spontaneously becomes “absent”), transient spike/wave EEG activity, NO

post-ictal confusion, usually begins before pubertyb. Atypical Absence: EEG spike/wave activity more heterogeneous, may have automatisms and worse sxc. Tonic-Clonic (grand mal): LOC + convulsions, profound post-ictal confusion

i. Tonic phase first - all muscles contract, fall to ground, arms/legs extended & rigid, bites tongue, no breathingii. Clonic phase follows - rhythmic jerking

d. Myoclonic: consciousness appears preserved + sudden shock-like contraction of head/UL, <1s long, common w/ awakeninge. Atonic: brief impairment of consciousness + sudden loss of tone in postural muscles fall, no post-ictal (hop right up)

i. Frequent falls can result in injury, think young kids in helmet4. Status Epilecticus: 2+ seizures w/o regaining consciousness, life-threatening if seizures are tonic-clonic

a. Tx: emergent tonic-clonic gets iv push of fosphenytoin and lorazepam and may require medical sedation5. Etiology

a. Childhood (0-10y): perinatal injury, congenital defectsb. Adolescence (10-18y): idiopathicc. Early adulthood (18-35y): trauma, idiopathic, drugs/EtOHd. Late adulthood (35+y): brain tumor, vascular diseases, degenerative diseases (like AD)

6. Txa. Goal is to maintain normal lifestyle with complete seizure control and no side effects (possible in 65% of pts)b. Always initiate w/ single drug (preferably non-sedating), monotherapy is the rule!

i. Valproic acid, carbamazepine, phenytoin, lamotrigine are 1st line for partial and tonic-clonic seizuresii. Valproic acid, lamotrigine, ethosuximide are 1st line for absence, myoclonic, and atonic seizures

SEIZURE PHARM1. Goal is to reduce seizure spread (spread of abnormal activity to normal tissue) via tx that:

a. Block Na/Ca channels, which keeps cells refractory to AP by preventing Na/Ca influxb. Enhance inhibitory (GABA) via ↑synthesis or R agonist (which hyperpolarizes cell due to Cl influx)c. Decreasing excitatory (NMDA) via R antagonists

2. Traditional drugs (PHT, CBZ, VPA, PHB, BZO, ETH) tend to have more side effects, but also more dataa. Serious SE include teratogenesis, blood dyscrasias (check baseline), osteoporosis/malacia

3. Clinical pearlsa. MAJOR inducers: phenytoin, carbamazepine, phenobarb

i. Inducers will decrease [] of those drugs metab by CYP, this happens slowlyii. CBZ also induces own metabolism = initially therapeutic but then levels drop off due to autoinduction ↑ dose

b. MAJOR inhibitors: valproic acidi. Inhibitors will increase the [] of those drugs metab by CYP, this happens immediately

c. PHT undergoes non-linear metab (ex of hot dog line @ halftime) so increase dose slowlyd. PHT is 90% protein bound so only free [] is clinically useful

i. Δs in protein binding (renal/hepatic dz, preg, burns, trauma, inflamm) Δs in free []

17e. All in table below except topiramate/zonisamide (hepatic/renal) have hepatic metabolismf. Best scenario is to d/c AED if pregnant, otherwise monotherapy, and always give folate

DRUG MOA ADVERSE EFFECTSPhenytoin Na channel blocker acne, hirsuitism, diplopia/ataxia/nystagmus, gingival hyperplasia, ↓OC efficacyCarbamazepine

Na channel blocker SIADH, rash, hirsuitism, ↓OC efficacy

Valproic Acid Na/Ca block, +GABA rash (can Stevens-Johnson syndrome!), THBcytopenia, hepatotox, wt gain, alopeciaPhenobarbital +GABA Rash, sedation, cognitive dysfxn, ↓OC efficacyBenzodiazepine

+GABA

Ethosuximide Ca channel blockerLamotrigine Na channel blocker rash (can also Stevens-Johnson Syndrome, NEVER use w/ VPA!!), aplastic anemiaOxcarbazepine Na channel blocker SIADH, ↓OC efficacyTopiramate Na, +GABA, -NMDA wt loss, kidney stones, cognitive dysfxn, ↓OC efficacyZonisamide Na/Ca blocker kidney stonesSIADH = syndrome of inappropriate ANH release and OC = oral contraceptive

EYE MOVEMENTS/DIZZINESS1. 3 types of neurologic dizziness

a. Vertigo: illusion of mvmt when stationary (rotation, translation, or tilt)b. Dysequilibrium: imbalance when standing/walkingc. Presyncope: lightheadedness, graying vision

2. 3 types of psychologic dizzinessa. Confusion: poor concentration, agitationb. Giddiness: excitement/elationc. Derealization: depersonalization, detachment, déjà vu

3. Goal is to always keep object centered on fovea, thus there are many reflexes to maintain thisa. Vestibular: holds images steady during brief mvmt (ex) driving on bumpy roadb. Nystagmus: quick phase is normal, as it resets the eye back toward visual cuec. Vestibulo-ocular: involves CNVIII, CNVI, CNIII, MLF to keep eyes fixed when head rotates

i. Oscillopsia = loss of VOR4. Bedside tests

a. Calorics (Barany’s): COWS CUWD is normal, lack of nystagmus indicates problem w/ vestibular systemi. So, cold water in one ear = slow same/fast opposite while warm = slow opposite/fast same (COWS)ii. So, cold water in both ears = slow down/fast up while warm = slow up/fast down (CUWD)

b. Hallpike Dix Maneuver: provokes nystagmus in BPPV (benign paroxysmal positional vertigo) by stirring up endolymph in semi-circular canals

i. Rotate head 45˚ and extend neck, quickly move pt from sitting to supine (watch) and back (watch)ii. +HD will cause vertical nystagmus w/ gaze away from lower ear, torsional w/ gaze toward

CENTRAL (brainstem/vestibular n) PERIPHERAL (CNVIII, canals)Nystagmus direction

Single direction Both horizontal and vertical

Fixation Does NOT suppress nystagmus Suppresses nystagmusGaze No change Nystagmus increases w/ gaze toward quick phase sideCalorics Increases nystagmus Little changeBalance Severe problem, unable to tandem, +Romberg Mild problem, poor tandem, -Romberg Other No hearing loss/tinnitus Assoc hearing loss/tinnitus

5. Intranuclear opthalmoplegia: diploplia/vertigo due to non-conjugate lateral gazea. Due to destruction of MLF (tract from abducens nuclei to contralateral oculomotor nuclei)b. inability to adduct affected eye + physiologic nystagmus in unaffected eyec. Ex: loss of R MLF no R adduction + nystagmus in L eye due to diploplia (shown in picture at right)

6. Episodic Dizziness <1min = BPPVa. Loose otoconia affect endolymph flow dizziness, often in posterior canalb. Dx: nystagmus w/ Hallpike-Dix maneuverc. Tx: Epley or Semont maneuver to get junk out

7. Dizziness <1h = TIAs, migraine, panic attacks8. Dizziness >1d = Meniere’s dz

a. Episodic increase in endolymph pressure fluctuating low frequency sensorineural hearing loss + tinnitus9. Acute vertigo (1-3d) tx w/ vestibular suppressant (diazepam/droperidol) + antiemetic (promethazine/prochlorperazine) + bed rest

a. If >3d (subacute) stop vestibular suppressants

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COMA1. Total lack of consciousness – no response to sound/light/pain, no sleep/wake cycles, no voluntary movements

a. Arousal = state of alertness; mediated by RAS (core of brainstem from rostral midbrain to caudal medulla) and post. HMSb. Content = higher cortical fxn

2. Etiology: damage to RAS, hemorrhage/infarct, hypoxia, trauma (1° causes), herniation (2° cause), metabolic (aka diffuse damage)3. Clinical signs

a. Respirationsi. Lesions at various levels of brainstem are characterized by different pathological breathing patternsii. Cheyne-Stokes: crescendo-decrescendo (episodes of apnea and tachypnea)

b. Pupilsi. Pinpoint fixed = ponsii. Large fixed = dorsal midbrain (tectum)iii. Unilateral dilated w/ third n palsy = compressed CNIII, often due to uncal herniationiv. Mid-position fixed pupils = ventral midbrainv. Small pupils w/ Horner’s syndrome = lesion in sympathetic pathway (HMS, C8-T1, etc)vi. Pupillary light reflex is intact w/ metabolic coma, thus most impt sign distinguishing it from structural coma

c. Vestibular reflexesi. +VOR (not conscious to fix on object but eyes do anyways), aka “doll’s eyes”ii. Fast phase of nystagmus via cerebrum (so absent in coma) eyes move tonically toward (cold) or away (warm)

from ear stimulated but there will be no nystagmus back in other direction1. If both phases are absent, then brainstem (bilateral MLFs) also damaged = very poor px

d. Persistent vegetative state: “worsening” of coma but NOT brain death as brainstem is still alivei. Sleep-wake cycles presentii. No purposeful response to stimuli, bowel/bladder incontinenceiii. May open eyes, track mvmts, cry, grunt, etc (this is spontaneous)iv. PVS pt is kept alive by their fxn’ing brainstem, a brain dead pt is kept alive strictly by life support

e. Uncal Herniationi. Respiration: normal to Cheyne-Stokesii. Pupils lack direct reflex, dilated on affected sideiii. Oculocephalics: Doll’s eyesiv. Calorics: 3rd nerve paralysis prevents contralateral adduction (eye won’t cross midline)v. Response to pain: reflexive only on ipsilateral sidevi. Babinski: + contralaterally

4. GCS (Glasgow Coma Scale): objective way of recording pts conscious state based on eye/verbal/motor responses a. 3=brain death (esp. if pupils fixed and vestibulo-ocular reflexes absent)b. <8=severe comac. 15=normal

5. Pseudocoma Statesa. Psychogenic unresponsiveness – pt avoids hitting themselves when arm dropped toward face and resists attempts to

open/close eyelidsb. Locked-in syndrome – pt is completely paralyzed but is awakec. Abulia (akinetic mutism) – pt is completely apathetic w/ lack of initiative due to lesion in premotor cortex

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SLEEP6. Sleep stages

a. Stage 2: spindles & K-complexesb. Stage 3 & 4: delta (slow-wave) sleep

7. Waking areas = reticular formation, posterior hypothalamus vs sleep-inducing areas = preoptic nuclei, anterior hypothalamus8. Narcolepsy = excessive daytime sleepiness (EDS) regardless of sufficient nocturnal sleep

a. Assoc with ↓ hypocretins 1 and 2 (important HMS proteins assoc w/ arousal) + HLA DQB1*0602 genotypei. Measure hypocretin-1 in CSF: normal ~300 pg/ml, narcoleptic w/ cataplexy usually has ˂100 pg/ml

b. Sxi. Excessive daytime sleepiness: daytime napping may be physically irresistibleii. Cataplexy: REM related phenomenon, lose muscle tone but not consciousness, triggered by emotionsiii. Sleep paralysis, fragmented sleep, hypnogogic (sleep onset) and hypnopompic (at waking) hallucinations common

c. Dxi. Epworth Sleepiness Scale (ESS) evaluates pt tendency to fall asleep in various situations over past 1mo

1. 24 is maximum2. Narcoleptics tend to score 16+3. 10+ is sleepy4. Normal is 5 or less

ii. Polysomnography (PSG) to look at REM latency (normal is 90-120min, narcoleptics may be ≤15 min→SOREMPs)iii. Multiple Sleep Latency Test (MLST) is series of 5 nap opportunities 2h apart (must ave ≤8min for narcolepsy)iv. Maintenance of wakefulness test (MWT) tests ability to stay awake (often used on truck drivers)v. Clincally dx when:

1. EDS >3mo + cataplexy OR2. Complaint of EDS + assoc sx (part iii above) + sleep latency <10min + other causes ruled out

d. Txi. EDS: structured nighttime sleep/naps, stimulants

1. DA agonists = amphetamines, methylphenidate2. Non-DA agonists = modafinil, which activates hypocretin region of hypothalamus

ii. Cataplexy: TCAs (nortriptyline), SSRIs (fluoxetine), SNRI (venlafaxine), gammahydroxybutyrateiii. Sleep fragmentation: good sleep hygiene

9. REM Behavior Disordera. Atonia during REM sleep (except diaphragm and eyes) facilitated by tegmentoreticular tract (dorsolateral pons)b. PSG will show excessive tonic chin EMG activity and/or phasic muscle twitchesc. Often have rhythmic jerking of legs (sometimes arms) every 5-90sd. Must r/o panic, PTSD, somnambulism (sleep walking), night terror, nocturnal epilepsye. Tx w/ clonazepam

10. Restless Leg Syndrome (RLS)a. Urge to move due to unpleasant sensations in legs that worsen w/ rest/inactivity, esp. at night, and are relieved by mvmtb. More common in women and assoc w/ iron deficiency, family hx, dopaminec. Tx w/ D2 agonists (ropinirole/pramipexole) most helpful, give ferrous sulfate if ferritin ˂ 45 mcg/L

i. Can also tx w/ L-dopa but w/ lots SE including augmentation: sx come on earlier and are more severe

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BASAL GANGLIA (diencephalon)1. BG circuit involves direct & indirect pathway

a. Input to striatum is via a motor plan from the prefrontal motor cortexi. Bereitschafts potential: “readiness,” precedes muscular activity

b. Output to primary motor cortex for execution of mvmt is via thalamusi. At rest, thalamus tonically inhibited by GABA from GPi/SNpr

c. BG optimizes the motor program but has no role in the motor decisiond. The ONLY things that release GLU (i.e. are excitatory) are

cortex/STN/thalamuse. GPe and GPi are tonically active unless actively inhibited

2. Disinhibition (two (-) synapses in a row) is how the BG initiates movementa. Yellow highlighted pair results in disinhibition of the thalamusb. Green highlighted pair results in disinhibition of STN

3. Direct (which cause mvmt) and indirect pathways (which inhibit mvmt)4. Cortex signal (glutamate) causes GABA release to GPi and GPe but normally the direct pathway trumps the indirect and the

STN is tonically inhibited

5. Dopamine receptorsa. Dopamine selectively excites the direct pathway and inhibits the indirect pathwayb. D1 family (D1/D5): acts to excite the striatum

i. DA from SNpc binds striatal D1 excitation/release of GABA to GPi inhibition of tonically active GPic. D2 family (D2/D3/D4): acts to inhibit the striatum

i. DA from SNpc binds striatal D2 inhibition/NO release of GABA to GPe tonically active GPe6. Structure of striatum

a. Striatum = caudate, putamen, globus pallidus (interna/externa) and nucleus accumbensb. Input to striatum is mostly cortex (also important is SNpc via dopamine) + somatotopically organized

i. Motor/sensory homunculi of cortex are projected onto lateral putamen (feet dorsal, face ventral)ii. Caudate active during saccadic eye mvmt; input from frontal/supplementary eye fields

c. Striosomes (axons go to D1 R and project to GPi)i. Substance P and dynorphinii. Limbic function

d. Matriosome (axons go to D2 R and project to GPe)i. Enkephalinii. Sensorimotor system

e. Medium Spiny Neurons (90-95% of striatum)i. Abundant spines due to immense amount of input they receiveii. GABAergic (silent at rest)iii. 3 types based on DA R type

1. D1 R type have substance P and dynorphin and project to GPi/SNr; primarily striosomal2. D2 R type have enkephalins and project to GPe; primarily matrisomal3. D3 R type have uncertain function

7. Convergence= connections from many neurons to fewer neurons8. Parallelism= parallel circuits that never interact

a. Removing DA generates ↑communication b/w parallel circuits so leads to more convergence9. Hypokinetic disorders

a. Parkinsons: progressive degeneration of the DA neurons from the SNpc means the striatal nuclei fxn w/o DA inputi. Loss of DA on D1 R NO release of GABA from striatum GPi no longer inhibited, so it (-) thalamus = NO mvmtii. Loss of DA on D2 R release of GABA from striatum GPe now inhibited, so STN able to excite GPi further iii. In other words, the direct pathway is silenced/indirect pathway is hyperactive (both ↓ mvmt)

10. Hyperkinetic disorders (disrupted indirect ptwy)a. Hemiballismus

i. STN is destroyed NO indirect pathway NO activation of the GPi/SNr “brake” and hyperactive thalamusb. Huntingtons

i. Connection b/w striatum/GPe is destroyed NO indirect pathway same as above

Cortex (+) Glut Striatum (-) GABA GPi ↓↑(-) GABA Thalamus ↑↓(+) Glut Cortex

(-) GABA (+) Glut

GPe STN ↓(-) GABA

Direct

Indirect

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CLINICAL MOVEMENT DISORDERS1. Most mvmt disorders involve the basal ganglia and the other cmpts of extra-pyramidal motor system (thalamus, STN, SN, Red n)2. Ballismus: loss of STN (usually unilateral) = no stimulation of GPe/SNpr = no inhibition of thalamus sudden flinging of entire limb3. Chorea (distal brisk mvmt) & athetosis (proximal writhing): loss of indirect pathway nearly continuous mvmt of 1+ limbs / trunk

a. Huntingtons: auto dominant, >30 CAG repeats on ch4 loss of D2 output and sx above (caudate degenerates early)b. Sydenhams: post-infxnc. Toxic: most common is from over-medicated PD but can be CO poisoning

4. Dystonia: genetic/idiopathic continuous involuntary contraction of muscle groups abnormal posturea. Wilsons disease can cause a pediatric generalized dystonia

i. Always check Cu levels in pt aged 6-40 w/ new mvmt disorder (serum ceruloplasmin, urine Cu, K-F rings)b. Cervical: most common form in adults, idiopathic (torticollis)c. Toxic: caused by neuroleptic drugs/levodopa tardive dyskinesiad. Blepherospam: involuntary closing of eyee. Writing dystonia: occurs only when writingf. Tx: L-dopa (kids), botulinum injections (adults, focal), anti-cholinergics (adults, generalized)

5. Parkinsons Dz (bradykinesia)a. Loss of SNpc = loss of DA at both D1/D2 R in striatum depressed direct/hyperactive indirect hypokinesiab. Sx: unilateral bradykinesia, cogwheel rigidity, resting pill-rolling tremor (4-6 Hz), postural instability, festination (involuntary

quickening of gait w/ shorter strides), supranuclear palsy, ANS dysfxn (constipation/nocturia/dysphagia/etc)i. Progressive dz w/ onset 60y, also assoc w/ cognitive changes/depression

c. Path: SNpc degeneration w/ pallor (DA neurons have melanin in them), gliosis, Lewy bodiesd. Etiology: both environmental (toxins) + familial, tho twin studies show little evidence for genetics

i. -synuclein mutation (ch4): autoD, early onset (40s) + fast progression + Lewy bodiesii. Parkin gene (ch6): autoR, early onset (20s) + slow progression + NO Lewy bodiesiii. Dysfunction of proteosomal degradation function (via ubiquitin) may damage SNciv. LRRK-2 (leucine-rich repeat kinase 2): autoD (most common cause of inherited PD)v. PINK-1 (PTEN-induced kinase 1): loss of fxn leads to PD

e. Tx: L-dopa is most efficacious but has many motor SE (see below); DBS (deep brain stimulation) to STN or GPf. Parkinson’s Plus syndromes

i. MSA (multiple system atrophies)1. Shy-Drager syndrome: parkinsonism/ataxia/ANS dysfxn2. Olivopontocerebellar atrophy (OPCA): parkinsonism/cerebellar dysfxn3. Striatonigral degeneration

ii. PSP (progressive supranuclear palsy): parkinsonism/impaired eye mvmt/cervical dystoniaiii. CBD (corticobasal degeneration): parkinsonism/apraxia/alien hand syndrome

6. Tremor: regular rhythmic mvmts, classified as fast/slow, pill rolling/flex & ext, postural/resting/intentiona. Essential tremor: fast (8-12 Hz) postural, bilateral, increases w/ age, tx w/ primidone or thalamic DBSb. Can be induced by drugs, adrenaline, etc

7. Tics: repetitive but irregular (ex) Tourettes = both motor/vocal tics that start when ˂21 yr old8. Myoconus: sudden, focal but irregular9. Fasiculations: involve motor units, NOT whole muscle (that would be myoclonus)10. Ataxia: sensory/cerebellar lesion dyscoordination, dysmetria, dysdiadochokinesis11. Asterixis: intermittent lapses in postural tone

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PARKINSON’S PHARM1. Goal is to restore balance of dopamine and ACh w/in the CNS, thus main drugs = DA agonists + muscarinic ACh antagonists2. Tx is symptomatic only, it does not alter the course of the dz3. DA cannot x BBB but L-dopa (DA precursor) can, once in nerve terminal its DA by enzyme DDC (also converted peripherally)

a. To prevent periph conversion before L-dopa even gets to brain, admin w/ carbidopa, a DDC inhibitor which can’t x BBB4. Levo/carbidopa is gold std w/ dramatic improvement initially but severe SE after about 5 yrs

a. On-off effect: unpredictable switch from mobility to hypokinesic PD state w/ no relationship to timing of dosei. Tx is apomorphine injections, DA agonist (switching to sustained-release L-dopa doesn’t help)

b. Wearing-off: loss of effect near end of dosing interval, relates to plasma [ ], occurs sooner w/ progression of dzi. Tx is increasing dosing frequency, DA agonist

c. Dyskinesias: involuntary chorea-like mvmts in nearly all pts w/ long-term L-dopa use (tx: smaller more frequent doses)d. Delayed gastric emptying causes delayed onset response, so best to take on empty stomach (unless controlled-release)e. B/c of all the unavoidable SE, L-dopa is NOT an initial tx, it should be thought of as a drug of last resortf. Some evidence that L-dopa might actually worsen progression due to production of ROS that damage nerve terminalsg. May cause visual hallucinations (animals/insects/people); may need to tx w/ clozapine or quetiapineh. May cause hedonistic homeostatic dysregulation w/ excessive gambling/sexuality/appetite/etc

5. DA agonists do not depend on fxnal presynaptic neurons, do not generate ROS, cause less motor sx, but will eventually need L-dopa6. IN GENERAL, start pt on anti-chol/amantidine, then add DA agonist, then add levi/carbidopa, then add COMT/MAOIs

DRUG MOA ADVERSE EFFECTSL-dopa/Carbidopa

Sinemet↑DA at nerve terminal SE: motor sx (dyskinesias), psychiatric sx, O-HTN, N/V

Narrowing therapeutic window/duration of action w/ dz progression

CIs: hx of melanoma; w/ MAOIsErgots

BromocriptineNon-Ergots

ApomorphineRopinirole

PramipexoleRotigotine

Direct DA R agonists 2nd best efficacy after levo/carbadopaBromo: D1 antag/D2 agonist; CIs: 3A4(-), CAD/MI

Apo: D1/D2 agonist, triggers “on” in minutes, CIs: sulfite allergyRopin: D2/D3 agonist, efficacious as monotherapy + for “wearing off”Pram: like ropinirole but may also help w/ depressionRotig: transdermal patch

Entacapone COMT(-) less DA breakdown Adjunctive therapy, may cause diarrhea/urine discolorationSelegilineRasagiline

MAO-B(-) less DA breakdown

Selegiline: Adjunctive therapy (probably since such low bioavailability) Oral disintegrating tablet form avoids 1st pass + ↑ benefit Has toxic amphetamine metabolites ↓ L-dopa by 10-30% when starting tx CIs: TCAs, SSRIs (5HT syndrome)Rasaligine: irreversible MAOI w/ no toxic metabolites and ↑ potency

Anti-AChsBenztropine

Trihexyphenidyl

Restores balance, tx tremor but not bradykinesia/posture/gait

SE: dry mouth, constipation/GI stasis, urinary retention, ↑ eye pressureInitial monotherapy if mild or adjunct if severeCIs: BPH, GI obstruction, narrow angle glaucoma

Amantadine ↑ DA synthesis/release↓ synaptic DA reuptakeTx tremor/rigidity/bradykinesia

SE: livedo reticularis, edema, seizure/CNS effectsInitial monotherapy if mild or adjunct if severe

Stalevo = L-dopa/carbidopa/entacapone combo drug

NCS/EMG 1. Nerve conduction studies

a. Distal latency: delay btw nerve stimulation and muscle contraction (= time as AP crosses NMJ)i. Prolonged latency indicates demylination

b. Conduction velocity: = segment distance/segment latencyi. Slowed velocity indicates demylination

c. Amplitude: reflects # motor units recruitedi. Decreased amplitude indicates axonal loss

d. Repetitive stimulation: assesses amplitude over timei. Abnormal decrement dx of myasthenia gravis

e. H-reflex: assesses proximal n (dorsal root/ant horn)i. Decreased reflex + rest of motor responses are normal indicates proximal slowing

f. F-wave: assesses proximal n (ant horn only) via retrograde conductioni. Prolonged latency/absent F-wave indicates proximal slowing, seen w/ radiculopathies, spinal processes, Guillain

Barre 2. Electromyography (used to distinguish btw neuropathies/myopathies)

a. Fibrillation: pathological, indicates denervation in either caseb. Amplitude:

i. Neuropathy = large, indicates prior denervation + re-innervation 1. Re-innervation - surviving motor units pick up denervated fibers & these extra muscle cells bigger

amplitudeii. Myopathy = small, indicates less recruitment due to loss of muscle cells

23c. Recruitment: first increase frequency, then increase #

i. Neuropathy = normal amplitude but less interference vs myopathy = decreased amplitude but full interferenced. SF jitter: assesses temporal variability of 2 muscle fibers of the same motor unit

i. Not specific for myasthenia gravis but very sensitiveHIGH YIELDRed neurons Necrotic neurons following ischemia, e.g. strokeCyclopia/cleft lip Holoprosencephaly i.e. problem w/ ventral inductionDark CSF + dark WM/light GM FLAIR MRIProlonged F-wave Prox slowing in anterior hornAlpha-synuclein Accumulates and forms Lewy bodies in PDL’Hermitte’s sign, Dawson’s fingers, oligoclonal bands Multiple SclerosisCowdry-type inclusions HSV encephalitisKernig/Brudzinski signs Condordant leg/neck mvmt seen in meningitisPseudopalisading cells GlioblastomaSoap-bubbly/cystic appearance HIV assoc Cryptococcus encephalopathySpongiform degeneration CJDOnion bulbs Recurrent de/remyelination in CIDPHeliotrope discoloration of upper eyelids DermatomyositisGower’s sign Muscular dystrophy (how these babies push up to stand)Hatchet face Myotonic dystrophySommers sector Vulnerable area of hippocampus often affected in diffuse hypoxiaAnti GM1 ganglioside Ab MMNMultiple CNS lesions in time/space Multiple sclerosisRagged red fibers Increased mitochondria in myopathiesDiurnal variation of sx Myasthenia gravisVision loss when bending over/papilloedema Pseudotumor cerebriRosenthal fibers Pilocytic astrocytomaFried egg cell OligodenrocyteGingival hyperplasia S/E of phenytoinSOD1 mutation ALS (familial form, most are idiopathic)b-blocker vs b-interferon Migraine prophylaxis vs. MS treatmentRecent Campylobacter infxn AMAN, AMSANHomer-Wright rosettes MedulloblastomaPsammoma bodies, whorls MeningiomaBaby w/ unusual odor Inborn error of metabolismb1 deficiency Loss of anterograde memory in KorsakoffsLow frequency hearing loss Meniere’s diseaseElevated ESR Temporal arteritisDOC for trigeminal neuralgia CarbamezapineInducers Carbamezapine, phenytoin, phenobarbInhibitors Valproic acid+ Hallpike Dix Vertical nsystagmus away from lower ear, torsional toward+ Romberg Central lesion causing nystagmusComa w/ + pupillary light reflex METABOLIC comaDecreased hypocretin NarcolepsyDamage to area 44/45 Brocas aphasia, comprehension intact but speech poorDamage to area 22 Wernickes aphasia, fluent but makes no senseColcichine Gout drug that causes myo/neuro/cardiomyopathySymmetric vs asymmetric neuropathy Hereditary vs acquiredSIADH SE of carbamezapine/oxcarbazepineThunderclap HA, worst HA of life SAHBunina bodies ALS (eoisinophilic inclusions)Natalizumab MS drug that can reactive latent JC virus fatal PMLMarkedly high opening pressure (~200) Bacterial meningitisLesion at corticomedullary jxn Met (or possible absecess, b/c also hemato spread)Imaging for SC trauma CT for fracture, MRI for complicationsDisappearance of reflex grasp 6mo, at this point baby actually reaches for objects and graspsInternal capsule lesion true motor stroke, i.e. no sensory deficits, purely UMN sxAcute vs chronic SC transaction Hyporeflexia vs hyperreflexiaDuret hemorrhage Bleeding in pons, seen in uncal herniation“Repeat” genetic diseases Fragile X, Huntingtons, myotonic dystrophyLacunar infarct Chronic HTNCharcot-Bouchard aneurysms Assoc w/ ganglionic bleedsBilateral limbic system lesion Often due to trauma, amniestic syndrome

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HIGH YIELD IMAGES

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ANSWERS (LR)PolymyositisEdema mass effect/midline shiftDuret hemorrhageMCA infarctHydrocephalus ex vacuoLewy bodiesMeningiomaGanglionic hemorrhagic strokeMedulloblastomaHomer Wright rosettes (medulloblastoma)

28Multiple sclerosis (pale = demyelination)MS plaqueGlioblastomaLacunar infarctBerry aneurysmParkinsons (loss of s. nigra pigment on L)Metastasis at corticomeduallry junctionPallisading (glioblastoma)Psammoma bodies (meningioma)GliomaLissencephalyOsteomyelitisCryptococcus in HIV (characteristic cytstic appearance)Acute PCA ischemic stroke (CT)Abscess w/ marked vasogenic edema (T2 MRI)Numerous metastases (T1 MRI)Subarachnoid hemorrhage (CT)Tonsillar herniation w/ syrinx (T1 MRI)Extradural tumor compressing SC w/ assoc edema (T1 MRI)Intradural/intramedullary tumor (T2 MRI) note the lack of demarcation btw tumor and SCHSV encephalitis in temporal lobe (T2 MRI)Acute purulent meningitis (CT) note the white sulci due to accumulation of pusExample of FLAIR – dark CSF (like T1) but dark WM/light GM (like T2) be able to recognize!!