Download Neurotic Overview

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NEUROPATHOLOGY
1. 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 specialization
ii. Astrocytes: provide structure, react to injury, forms BBB, synthesizes GFAP
iii. Oligodendrocytes: myelinate many axons; remyelination is poor if myelin lost
iv. Ependymal cells: line ventricles, cilia move CSF
v. Choroid plexus: synthesizes CSF, forms blood/CSF barrier
vi. 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. Meninges
a. Pachymeninges (dura)
i. Forms potential spaces: epidural and subdural
ii. 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 circulation
a. 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 brain
d. Normally little protein, few leukocytes
i. Xanthochromia = yellow color due to degeneration of RBCs/protein
ii. 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 ICP
d. 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 charged
b. Breakdown (seen as ring enhancement on CT w/ contrast) due to inflammation  vasogenic edema
c. Matures late in gestation (kernicterus = damage to basal ganglia due to bilirubin accumulation)
6. Brain edema
a. Vasogenic: damage to BBB (inflammation, infarct, tumor) causes leakage, mainly in white matter
b. Cytotoxic: ion pump dysfunction (hypoxia/stroke, toxins) causes cell swelling, mainly affects gray matter
c. Interstitial: ↑ intraventricular pressure (obst. hydroceph) pushes fluid out into periventricular white matter
7. Increased ICP
a. 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 ↑ ICP
a. Cingulate: cingulate gyrus under falx cerebri  ACA compression  foot/leg homunculus loss
b. 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, posturing
d. Tonsillar: cerebellar tonsils/medulla thru foramen magnum  medulla compression  loss of
consciousness, apnea
9. Define
a. Astrocytosis: acute hyperplasia/hypertrophy
b. 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 tissue
d. 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 failure
e. Selective vulnerability: certain neurons are susceptible to certain dz (ex) B1 (thiamine) defcy  Wernicke’s encephalopathy
f.
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 input
ii. 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) leukodystrophies
j.
Mass lesion: any pathologic process producing an increased volume, thus increased ICP
k. Respirator brain: ICP > arterial P  ischemia/brain death  diffuse brain autolysis IF pt is kept alive by respirator
l.
Radiculopathy = damage to spinal root
m. Plexopathy = damage to nerve plexus
n. Causalgia = burning pain sensation
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NEUROANATOMY
1. 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)
a. 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 tract
e. 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
cingulum
a. CG → ant nucleus of thalamus → mammillary body → HC → PHCG → CG
3. Cranial nerve exit locations:
a. Midbrain = CN III / IV
b. Pons = CN V / VI and CN VII / VIII at junction w/ medulla
c. 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,  Babinski
b. 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. Cerebellum
a. 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. Brainstem
a. Decerebrate posturing = upper/lower extremity extension (lesion b/w red and vestibular nuclei)
b. Decorticate posturing = upper flexion, lower extension (supratentorial lesion)
9. Spinal cord
a. Acute transaction (“spinal shock”)  complete paralysis/anesthesia/areflexia below lesion
b. Chronic transection  complete paralysis/anesthesia but hyperreflexia below lesion
c. Central cord syndrome
i. Bilateral loss of pain/temp (spinothalamic) at level of lesion, since decussates at level it enters SC
ii. 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 lesion
iii. 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 eye
b. Optic chiasm lesion  bitemporal hemianopia
c. R optic tract lesion  L homonymous hemianopia
d. R Meyers loop lesion (MCA stroke)  L homonymous superior quadranopia
e. R occipital lobe lesion  L homonymous hemianopia w/ macular sparing
f.
Pupillary light reflex aff = CNII, eff = CNIII (constriction is PS)
11. Extraocular movements
a. 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 blindness
b. Scotoma = focal defect in visual field
c. Cortical blindness = asymmetric vision loss w/o afferent pupillary defect
d. Conductive hearing loss = dampening of ossicle mvmt
e. Sensorineural hearing loss = damage to ipsi CNVIII system
f.
Tinnitus = ringing in ears; Hyperacusis = impaired feedback to tensor tympani via CNVIII
g. Tinel sign = paresthesias provoked by tapping over median nerve in wrist
h. Phalen test = paresthesia provoked by holding wrists flexed
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13. Vestibulo-Ocular Reflex to maintain fixed gaze w/ any head mvmt
a. Head turns R = activate R/inhibit L CNVIII  L lat rectus + R medial rectus
stimulated eyes turn L fixed gaze
14. Example syndromes from lecture
a. Wallenbergs syndrome = medullary lesion
i. 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 drop
c. 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 p
ii. Contralateral UMN syndrome
e. MCA lesion
i. Contralateral motor/sensory loss (esp. face/arms), homonymous
hemianopia, horizontal gaze palsy, language deficits
f.
Weber’s syndrome = infart in ventral midbrain
i. Ipsi CNIII palsy
ii. Contralateral hemiparesis
g. Foville’s syndrome – infarct in pons (basilar art) affecting PPRF, CNs VI/VII, corticospinal tract, ML, MLF
i. Ipsi horizontal gaze palsy and CNVII palsy
ii. 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 palsy
ii. Contra hemiparesis
NEURODEVELOPMENT
1. 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 age
b. Cerebral Palsy = disordered motor fxn evident in early infancy due to Δ in muscle tone, involuntary mvmts, ataxia
2. PREnatal errors
a. Malformations
i. Dorsal induction (3-4w)  neural tube defect (dysraphic state), -fetoprotein ↑ in amniotic fluid w/ open defect
1. Failure of neural tube closure
a. anencephaly: NO ant neuropore closure  degen of brain
b. 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-Gruber
b. 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 nose
2. 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, leukodystrophies
1. CNS normally myelinated by birth, progresses post to ant (sight then speech)
2. Dysmyelination is abnormal myelin compound
a. Pelizaeus-Mersbacher Disease: nystagmus, spasticity
b. MLD: confluent white matter, vision problems, spasticity
c. Aquaduct stenosis: huge 3rd ventricle, sunsetting
b. Maternal conditions
i. 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 A
iii. Infxns: TORCH organisms (Toxoplasma, Rubella, CMV, Herpes)
c. Genetic dz
i. Trisomy 21: autosomal recessive, risk increases w/ maternal age
1. Assoc w/ MR, hypotonia, microcephaly, facies/simian crease, congenital heart defects
ii. Fragile X syndrome: ˃200 CGG repeats, males (most common cause of MR in males)
1. Assoc w/ MR, macrocephaly, long face/big ears, macro-orchidism
iii. Prader-Willi: 15q12 mutation (missing paternal), males
1. Assoc w/ hypotonic baby, short stature, hypogonadism, voracious appetite
iv. Angelman: 15q12 mutation (missing maternal), females
1. Assoc w/ MR, inappropriate laughter/smiling, seizures
v. Rett syndrome: MEPC2 mutation, females
1. Assoc w/ MR, hand wringing, regressive
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vi.
3.
4.
5.
6.
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
PERInatal errors
a. Hypoxic-ischemic encephalopathy: necrosis of vulnerable gray/white matter  permanent focal deficits
i. Significant cause (but one of many) of cerebral palsy
b. Cerebral palsy: static dz w/ varying degrees of MR, language/social deficits, and motor dysfxn
i. Assoc w/ germinal matrix bleeds, periventricular leukomalacia (holes in white matter), thin CC
ii. Spastic (hemi/quad/diplegic) or extrapyramidal (non-spastic, choreic) types
iii. RF = young mother, male baby, premature, infxns, 3rd trimester bleeds
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 acids
ii. Lysosomal storage dz: (ex) Hurlers/Hunters, buildup of MPS
iii. Glycogen storage dz: (ex) Pompe’s Disease, lack of acid maltase  cardiac probs and death w/o tx
Patterns of Brain Injury
a. 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 matrix
2. Grade 2 confined to ventricle
3. Grade 3 dilates ventricle
4. 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)
Assesing development: hx (maternal, delivery, milestones), PE (wt/ht/head circum/skin/fontanelles), non-invasive neuro, labs
AGE
Neonate
2 mo
6 mo
10 mo
1 yr
2 yr
DEGREE OF DEVELOPMENT
Fetal position/head lag/reflex grasp, responds to light, cries
No head lag/reflex grasp, follows with eyes, vocalizes, smiles
Sits unsupported/reaches for & grasps objects, responds to sounds, babbles, stranger anxiety
Crawls/pincer grasp, mama/dada, peekaboo, separation anxiety
Stands/walks, single words, tries to feed self
Steps/hand dominance, short sentences, organized play, toilet trained
REFLEX
Galant (suspend face down, turn toward stroked side)
Rooting (baby turns mouth toward mothers nipple)
Moro (if startled, aBduct then aDduct arms)
Palmar Grasp (baby grips things put in hand)
Tonic Neck (arm/leg extend on side face turned to)
Plantar Grasp (same as Babinski)
Landau (arch back/raise head when on stomach)
Parachute (put out arms to brace fall)
ONSET
Birth
Birth
Birth
Birth
Birth
Birth
3-5 mo
6-9 mo
Porencephaly = cavity in wall of cerebrum communicating w/ both ventricle and brain surface
Hydranencephaly = extreme ventricle expansion w/ squishing of parenchyma to thin membrane
Ulegyria = selective loss of cortex in depths of sulci
Multicystic Encephalomalacia = severe destruction w/ multiple cavitations
Status Marmoratus = neuronal loss and glial scars followed by abnormal myelination in BG/thalamus
DISAPPEARANCE
1-2 mo
3 mo
6 mo
6 mo
6 mo
9 mo
2 yr
persists
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NEURORADIOLOGY
1. Primarily use CT/MRI
a. CT: Xrays show differences in tissue densities
i. Density expressed in Hounsfield units based on how much xray beam disrupted
ii. HI density (white) = bone, calcification, blood, tumor
iii. LO density (dark) = CSF, edema, fat, air
b. MRI: magnetic field and applied radiofrequency pulses show difference in signal intensity
i. T1 = CSF/edema dark, WM light/GM dark
ii. T2 = CSF/edema bright, WM dark/GM light
iii. FLAIR → dark CSF but WM dark/GM light
iv. DWI used for acute stroke
c. Contrast enhancement: leaky BBB allows contrast to
leak from intravascular to extracellular
i. CT uses iodine/MRI uses gadolinium
ii. Diff dx for ring enhancing mass
MAGIC DR (LT)
1. Metastasis
2. Abscess/Aneurysm
3. Glioma (HI grade) or Granuloma
4. Infarct (subacute)
5. Cysticercosis (T.solium worm infxn)
6. Demyelination/MS plaque
Non contrast CT w/
T1 MRI w/ ring
T2 MRI w/
7. Resorbing hematoma
vasogenic edema
enhancing lesion
hydrocephalus
8. Lymphoma/Toxoplasmosis in AIDS
2. Edema
a. 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 stroke
c. Interstitial: CSF escape from ventricles into periventricular areas, assoc w/ hydrocephalus
3.
4.
5.
6.
7.
Herniation
a. Subfalcine = displacement of cingulated gyrus beneath falx
i. Ipsi ventricle compressed/contra ventricle may enlarge
ii. ACA displaced/compressed which may lead to infarct
b. Uncal (aka descending transtentorial) = uncus and PHCG displaced medially and descend through tentorial notch
i. Brainstem and CNIII displaced/compressed
ii. PCA may be displaced/compressed leading to infarct
Tumors
a. Astrocytoma (cerebral hemisphere) most common primary brain tumors (esp. glioblastoma multiforme)
i. Features (HI grade): thick, irregular rim around necrotic core, enhance intensely, vasogenic edema
ii. Features (LO grade): focal, homogenous, NO enhance
b. Oligodendriglioma (superficial cerebral hemisphere)
c. Ependyoma (4th ventricle)
i. Features: in region of cerebellum, assoc obstructive hydrocephalus
ii. 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 tumors
i. Features: enhance homogenously/ring, vasogenic edema
ii. Commonly from breast/lung/melanoma
iii. 80% occur at gray/white jxn of cerebrum
Infections
a. Encephalitis: affects temporal lobes, think HSV
b. Meningitis: enhancing sulci due to pus accumulating
c. Cerebritis: often at corticomedullary junction, ring enhancing w/ lots of edema
Blue: normal
Green: bulge
i. Early (3-5d): focal infxn, mass of PMNs, edema, hemorrhage, necrosis
Red: herniation
ii. Late (5d-2wk): necrotic foci coalesce, vascular proliferation edema
iii. Early capsule (2wk): well-formed collagen capsule w/ necrotic core
iv. Late capsule (wks-mos): central cavity shrinks and wall thickens
d. HIV associated
i. HIV encephalopathy: atrophy
ii. Toxoplasmosis: ring enhancing “target” appearance
iii. Lymphoma: ring enhancing, cannot distinguish this from toxo w/ imaging
iv. PML: very bright w/ T2 due to demyelination
v. Crypto: cystic appearing lesion in deep cortex
Multiple sclerosis: asymmetrical periventricular plaques (active will enhance, thus ring-enhancing), MRI more sensitive
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 T2
d. Infxn: osteomyelitis (heterogenous look to bone/disk narrowing), sarcoid/TB lesions (multiple plaques)
e. Tumors
i. Extradural: most likely a met, +enhancement
ii. Intradural/extramedullary: inside dura but outside SC, +enhancement
iii. Intradural/intramedullary: inside SC, +enhancement, SC enlargement
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PATHOLOGY OF STROKE
1. Cerebral vasculature
a. Internal carotid a  ACA/MCA
i. ACA: medial cerebrum
ii. MCA: lateral cerebrum, basal ganglia, Brocas/Wernickes
b. Vertebral a  basilar/PCA
i. 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 arteries
e. Causes of CVD: atherosclerosis, HTN, DM, aneurysms, amyloid angiopathy, vasculitis, malformations, thrombo-emboli
2. Stroke
a. 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
b. Many pts die a few days later due to inflammatory edema  increased ICP  herniation
c. Ischemic stroke (infarct) – usually due to atherosclerosis and/or thromboembolus
i. Ischemia  rapid onset of neurologic deficit
1. Focal deficits due to reduced flow in one vessel
2. 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, apopotosis
iv. Affects neurons>oligodendrocytes>astrocytes
v. Irreversible damage occurs after ~5min
vi. Reperfusion may cause more neuronal injury (from ROS damage) or hemorrhagic infarct
vii. Causes
1. Idiopathic
2. AS of large vessels  stenosis, sudden occlusion, distal embolization
3. AS of small vessels  lacunar infarcts (˂1cm), normally seen w/ chronic HTN
4. Elderly/A-fib  cardiac emboli which go to brain
viii. Pathology
1. 12-24h: red neurons (necrosis; see to right) + acute inflamm
2. 1-5d: liquefaction (encephalomalacia) + MΦ; peak edema
3. 1w: astrocyte proliferation
4. 1mo: gliosis + cavitation
5. Late Δs: wallerian degen, atrophy, compensatory hydrocephalus
ix. Hemorrhagic stroke
1. Spontaneous rupture of blood vessel  subarachnoid or intraparenchymal bleeds
2. Trauma usually results in epidural or subdural hemorrhages
3. 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 dz
4. Extra-axial
a. Epidural: more likely due to trauma, esp MMA, “silent” interval of 6-12h
b. 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% mortality
ii. Acute = clotted blood
iii. Subacute = clotted and liquefying blood
iv. Chronic = liquid blood
v. Hygroma = CSF-like fluid rather than blood
c. Subarachnoid: base of brain, due to Berry aneurysm rupture (larger arteries) → arterial
vasospasm, thunderclap headache
x. Causes
1. Hypertensive vascular disease (most common)  Berry aneurysm (which can also be congenital!)
a. Berry aneurysms occur at branch points and may be assoc w/ PKD
2. Amyloid angiopathy (think elderly w/ Alz)  weakening of vessel walls that predisposes to hemorrhage
xi. Pathology
1. Acute hemorrhage will show a mass of blood  mass effect
2. Resorbed hematoma  cavitation lined w/ wall of gliotic hemosiderin-stained tissue
3. Diffuse hypoxic/ischemic encephalopathy
a. Global cerebral ischemia due to profound systemic hypoTN (ex) cardiac arrest
b. Damage is usually symmetrical and affects vulnerable cell populations
i. Sommer’s Sector (CA1) of hippocampus
ii. Middle cortex (see laminar necrosis)
iii. Watershed zones
iv. Purkinje cells of cerebellum
c. Severe irreversible damage  persistent vegetative state, brain death, or respirator brain (autolysis)
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4.
Blunt Head Injury
a. Skull fracture (bone broken but parenchyma not necessarily injured)
i. Types
1. Linear = radiates from site of impact
2. Basal = involves base of skull bones
3. Depressed = bone pushed into cranial cavity
4. Diastatic = separation along suture lines
5. Comminuted = bones fragmented
6. Contrecoup = fracture removed from site of impact
7. Open = fracture associated w/ laceration of dura
8. Compound = fracture associated w/ laceration of scalp
9. Consequences: intracranial hematoma, CSF leakage out through nose/ear, ingress of air
(pneumocephalus) or infectious agents, cranial nerve damage
b. Contusion = hemorrhage w/in superficial brain tissue w/o disruption of pia-arachnoid at surface
i. Usually at crests of gyri
ii. Coup (under impact site) or contrecoup (opposite from impact site)
iii. May be asymptomatic until glial scarring occurs (can cause seizure)
c. Laceration = traumatic disruption of brain surface w/ hemorrhage
d. 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) whiplash
ii. See perivascular microhemorrhage w/ swollen axons late accumulate β-APP
iii. May result in persistent vegetative state
CLINICAL STROKE
1. Types of stroke
a. Ischemic, due to vessel obstruction
b. Hemorrhagic stroke, due to vessel rupture
c. Transient ischemic attack
i. Focal neurologic deficit with complete resolution of all neuro sx w/in 24 hours
ii. Common in elderly
iii. Often results in stroke in w/in next few days
2. Risk factors
a. Non-modifiable: age, gender, previous stroke, family hx of stroke, sickle cell dz
b. 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 body
c. Sudden headache/confusion/change in speech/diplopia/vision loss
4. Evaluation
a. Focused neuro exam: LOC, language, eye mvmts, strength, coordination, sensation
b. Presence of carotid bruits
c. CT head w/o constrast to differentiate hemorrhage vs ischemic stroke (which H&P cannot)
5. Tx (acute stroke)
a. Door to tx in 1h
b. 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 deficit
ii. NEVER use in hemorrhagic stroke as would only exacerbate the bleeding
c. Lower BP if >220/110, even then must slowly lower
d. Complications: seizures, MI, aspiration pneumonia (impaired swallowing), DVT/PE (bedrest), depression/confusion
6. Long term management
a. DOC is ASA, easy/safe/cheap/effective
b. Warfarin w/ high risk A-fib pts
i. HI risk: previous stroke/TIA, +CHF, +HTN, older than 75
ii. 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 cholesterol
d. Diuretics/ACEI to lower BP
e. Lifestyle modifications
f.
Surgery
i. Carotid endarterectomy (CEA): removes plaques from vessels
ii. 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%
8
PATHOLOGY OF BRAIN TUMORS
1. 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. Children
i. Posterior fossa (cerebellum/brainstem)
ii. Mainly 4th ventricle ependyomas, cerebellar astrocytoma/medulloblastoma
b. Adults
i. Cerebral hemispheres
ii. Mainly cerebral astrocytoma/glioblastoma, metastasis, meningioma
4. Primary: tumors whose cell type is a normal component of the nervous system
a. 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  seizures
4. Ependymoma: grade 1-3, solid tumors that grow into ventricles  obstructive hydroceph/mass effect
5. Choroid plexus tumor: occurs w/in ventricles  obstructive hydroceph/mass effect + CSF overproduction
ii. 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 origin
i. Meningioma: common in elderly, solid/extra-axial (attached to dura), whorls/psammoma bodies  ↑ ICP
ii. Primary CNS lymphoma: despite no lymphatics in brain can get HI grade B cell lymphoma in elderly, AIDS w/EBV
iii. 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 sign
b. Solid w/ central necrosis, well-circumscribed, assoc vasogenic edema
c. Leptomeningeal carcinomatosis: tumor cell spread through CSF ptwys  hydrocephalus + multiple CN/spinal nerve
probs + high CSF protein
PATHOLOGY OF INFECTION
1. Compartments
a. Skull/vertebrae  osteomyelitis
b. Meninges  epidura/subdural empyema or meningitis
c. Parenchyma  cerebritis (aka abscess), encephalitis, spongiform encephalopathy (prions, technically neurodegen)
i. Meningoencephalitis – diffuse meningeal and parenchymal process
ii. 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, seizure
iii. Pathology: inflamm/edema  ↑ ICP/herniation + pus in subarachnoid space  sepsis/parenchymal infiltration
iv. 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), chemicals
ii. Clinical: self-limiting/milder than bacterial form, sx similar but no ΔLOC
iii. CSF: mild ↑ protein, normal glucose, lymphocytes
c. Chronic meningitis (subarachnoid space)
i. Orgs: persistent agents like TB/syphilis, sarcoidosis
ii. Clinical: non-specific/non-localizing sx makes it hard to dx, sx include seizures/cognitive dysfxn/low fever
iii. Pathology: chronic inflamm  fibrosis, non-obstructive hydroceph  ↑ ICP/mass effect, 1° base of brain
iv. CSF: HI opening pressure (due to obstructive hydroceph), markedly HI protein (>100), lymphocytes/monocytes
d. Abscess/Cerebritis (intraparenchymal) / empyema (epi/subdural)
i. Orgs: variety
ii. Clinical: sx include fever, HA, seizures, focal deficits, sepsis, predisposed if immunosuppressed/other infxns
iii. Pathology: focal destructive lesions w/ inflamm  edema  mass effect  herniation and/or sepsis
iv. 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 paralysis
2. varicella-zoster  trigeminal/dorsal root ganglia w/ dermatomal vesicular rash
3. herpes simplex I  medial temporal lobes w/ hemorrhagic necrosis/Cowdry inclusions
4. CMV  periventricular white matter if immunocompromised
5. rabies  brainstem w/ lethal consequences
ii. Clinical: fever/HA/acute focal sx (seizures, deficits, ΔLOC)
iii. Pathology: tissue necrosis
9
f.
iv. CSF: normal protein, normal glucose, lymphocytes
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
AUTOIMMUNE
1. 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 system
3. Koch-Witebsky postulates determine if dz is truly autoimmune
a. Serum Ab present & titers proportional to dz activity
b. Passive transfer of Ab produces dz
c. Active transfer (immunization) of Ag produces dz
4. Myasthenia Gravis: weakness due to anti-AChR Ab
a. Sx: muscle fatigability (eyes usually affected first), diurnal variation, reflexes/sensation unaffected
b. 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 Abs
c. 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 dysfxn
b. Dx: +anti-VGCC Ab, increment w/ repetitive stimuation (due to Ca accumulation), concurrent small cell lung carcinoma
c. Tx: pyridostigmine, plasmapheresis/IVIg, steroids, tx of lung tumor
6. 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 damage
b. 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, erythema
d. 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 adults
ii. Dx: multifocal/asymmetric “ascending” neuropathy, recent febrile illness (molecular mimicry), no WBC in CSF but
protein elevated
iii. Nerve conduction study (EMG): prolonged distal latency, slowed conduction, prolonged F-waves
iv. Tx: plasmapheresis, IVIg (steroids NOT helpful)
1. Tx should not be started more than 3wk after onset unless there is clear progression
2. Start tx asap in pts that can’t walk unassisted
b. Fisher syndrome = anti-ganglioside GQ1b Abs affect oculomotor fibers/sensory ganglia
i. 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 reflexes
ii. Dx: low amplitude on EMG (indicates axonal drop-out) but conduction not slowed
iii. Assoc w/ Campylobacter infxn→ molecular mimicry to LPS
iv. Recovery often rapid and complete
d. AMSAN: acute motor-sensory axonal neuropathy, resembles AIDP but axonal drop-out rather than demyelination
i. Sx: ataxia, loss of reflexes
ii. Dx: low amplitude on EMG (indicates axonal drop-out) but conduction not slowed
iii. Assoc w/ Campylobacter infxn→ molecular mimicry to LPS
iv. Recovery is slow and less complete than AMAN
8. CIDP: chronic inflamm demyelinating polyneuropathy, resembles AIDP but slower onset (˃8wk) and relapsing/remitting course
a. 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-spacing
11. MMN: multifocal motor neuropathy, resembles ALS but no UMN sx
a. Sx: slowly progressive weakness w/ atrophy/fasciculations beginning in arms
b. Dx: focal slowing and conduction block on EMG, anti-GM1 ganglioside Ab
c. Tx: IVIg (not plasmapheresis or steroids)
12. Myeloma +/- osteosclerosis
a. +osteo: common demyelinating neuropathy/POEMS that improves w/ tx of myeloma
b. –osteo: rare axonal neuropathy that does not improve w/ tx of myeloma
13. Paraneoplastic syndromes
a. 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 MS
16. PANDAS: pediatric autoimmune neuropsychiatric disorder assoc w/ streptococcus, tics or OCD, anti-basal ganglia Ab
17. Multiple Sclerosis: discussed below
10
PATHOLOGY OF MULTIPLE SCLEROSIS
1. Myelinopathies
a. Primary: direct damage to myelin or myelin-producing cells (ex) MS
b. Secondary: damage to axon results in damage to myelin (ex) Wallerian degeneration
c. Patterns include plaques (MS), punctuate lesions (ADEM), diffuse (leukodystrophy)
i. MS: chronic/progressive dz assoc w/ random discrete areas of demyelination
ii. ADEM: acute disseminating encephalomyelitis due to viral infxn assoc w/ tiny perivascular foci of demyelination
iii. 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 hypoNa
i. See rapidly developing quadriplegia due to bilateral corticospinal tract damage (to myelin)
2. MS plaques
a. Plaques are foci of complete demyelination (looks grey in the white matter)
i. ACUTE: myelin breakdown w/ inflammation
ii. EVOLUTION: MΦ infiltration, astrocyte proliferation
iii. CHRONIC: possible remyelination
b. Axons are not necessarily destroyed, just demyelinated/remyelinated
c. Common in periventricular white matter and subpial white matter, esp. SC & optic pathways
3. Dx reflects pathology
a. Multiple CNS lesions in time and space
b. 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 SCLEROSIS
1. 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, diploplia
b. Motor: limb weakness, cerebellar ataxia
c. 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 space
b. Mild lymphocytic pleocytosis/oligoclonal bands/elevated MBP in CSF
c. 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 Ag
ii.
Assoc w/ oligoclonal Ab bands but no identifiable Ag
4.
Tx
a.
b.
c.
d.
e.
f.
High-dose methyprednisolone may shorten course of acute exacerbations but most immunosuppression ineffective
Beta-interferons reduce severity and freq of exacerbations (block IFN)
Glatiramer (mixture of amino acids) inhibits immune response to MBP (myelin basic protein)
Mitoxantrone slows progression but is cardiotoxic
Natalizumab (anti-4 integrin Ig) reduces freq of exacerbations (keeps inflamm cells from x BBB)
i.
Can reactivate latent JC virus (causes fatal PML)
Mitoxantrone (antibiotic class anti-neoplastic) slows progression
11
PATHOLOGY OF NEUROMUSCULAR DISEASE
1. Neuromuscular components
a. Skeletal muscle structure
i. Myocytes: composed of myofibrils (chains of sarcomeres), eccentric nuclei
ii. Connective tissue wrappings include endomysium, perimysium, epimysium
iii. NMJ between motor axon/muscle cell, ACh secreted by motor end plate
b. Skeletal muscle physiology
i. Innervated by myelinated motor neurons from anterior horn cell in spinal cord
ii. Motor unit = motor neuron + all the skeletal muscle cells innervated by it
iii. Nerves have trophic effect on muscle (thus denervation leads to atrophy)
iv. Two fiber types intermixed  checkerboard appearance (see right)
Type 1
Type 2
Red (myoglobin)
White (glycogen)
Sustained work (not fatigable)
Sporadic work (fatigable)
Slow twitch
Fast twitch
Smaller fibers
Larger fibers
Oxidative metabolism (mitochondria)
Glycolytic metabolism
High capillary density
Low capillary density
c.
2.
3.
Peripheral nerve structure
i. 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, epineurium
iii. Schwann cells myelinate ONE axon, internodes w/ saltatory conduction
d. Peripheral nerve physiology
i. Denervation  LMN syndrome = flaccid paralysis, hyporeflexia, atrophy
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)
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 DISEASE
1. Sensory loss requires nerve involvement but weakness may be due to either neuro- or myo-pathy
2. Distal weakness > proximal + sensory loss + hyporeflexia → think neuropathy
3. 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 neuropathy
iv. 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 P1
i. Demyelinating: Charcot Marie Tooth I, III, IV
ii. Axonal: CMT II, V, VI + hereditary sensory neuropathies (HSN) I-V
c. Neuropathy Evaluation: genetic testing, labs, EMG/NCS for demyelination & F-waves, nerve biopsy
4. 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, vincristine
ii. Myopathy w/cardiomyopathy + neuropathy: colchicine (gout), EtOH, chloroquine, clofibrate, doxorubicin
d. Periodic paralysis is due to problems w/ voltage-gated ion channels
i. HyperK periodic paralysis due to Na channel mutations
ii. HypoK periodic paralysis due to Ca channel mutations
iii. 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 myopathies
i. 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 picture
ii. Facioscapulohumeral: autosomal dominant (ch4)  weakness in shoulder girdle/face in 20s
iii. Oculopharyngeal: autosomal dominant (ch14)  dysphagia/ptosis in 50s, common in French Canadians
iv. 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
12
AMYOTROPHIC LATERAL SCLEROSIS
1. General
a. Idiopathic, lethal, asymmetric neurodegenerative dz affecting both UMN/LMN  progressive atrophy and weakness
i. Eye mvmt and sphincter tone spared until late in course
ii. Rare familial form assoc w/ SOD1 mutation (ch21)
b. Most common form of adult motor neuron disease
c. Affects men/women equally, age of onset peaks in 6th decade
d. 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 cells
i. SMA1: infantile, aka Werdnig-Hoffman
Fiber type grouping
ii. SMA2: intermediate form
iii. 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 lesions
b. 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 problems
3. Pathology
a. UMN loss  degeneration of pyrimidal tracts, corticospinal tracts, Betz cells of primary motor cortex
i. 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 fibrillations
ii. 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. Tx
a. Riluzole slightly improves life expectancy (4-6mo) and QOL
b. W/o tracheostomy or ventilation support, life expectancy is <2 years after bulbar involvement
c. With predominantly spinal involvement, 5 year survival is <20%
13
COGNITIVE DYSFXN
1. Definitions
a. Aphasia:
b. Anomia:
c. Agraphia:
d. Alexia:
e. Acalcula:
f.
Agnosia:
g. Anosagnosia:
h. Prosopagnosia:
i.
Achromatopsia:
j.
Apraxia:
k. Aprosodia:
l.
Neglect:
m. Disconnection:
APHASIA TYPES
inability to understand and use language
inability to name (word finding difficulty)
inability to write
inability to read
inability to calculate
failure to recognize perceived stimuli
failure to recognize illness (unaware of deficits)
inability to recognize faces (can recognize parts of faces, ID people by voice)
loss of color vision (inferior parietal/occipital lobe lesion)
impairment of skilled mvmt
loss of control of voice intonation/emphasis (usually R side of brain)
ignoring one side of the environment
inability to transmit info from one area of cortex to another (callostomy  R/L hand disconnected)
SPEECH
COMPREHENSION
REPETITION
Poor
Intact
Poor
Damage to 22
Fluent
Poor
Poor
Damage to 44/45
Poor
Poor
Poor
Conduction
Intact
Intact
Poor
Transcortical Motor
Poor
Intact
Intact
Damage anterior to Brocas
Transcortical
Sensory
Echolalia
Intact
Poor
Intact
Damage posterior to Wernickes
Poor
Poor
Intact
Broca’s
Wernicke’s
Global
2.
3.
4.
5.
OTHER
Gerstmann’s syndrome: dominant parietal lobe lesion  tetrad of sx
a. Finger agnosia: cannot name fingers or indicate a finger named for them
b. L-R disorientation: cannot indicate which hand/foot is L vs R
c. Acalculia: inability to carry out calculations, often due to pt mistaking the #s
d. Agraphia: inability to write
Alexia can be +/- agraphia
a. w/ agraphia is worse, due to lesion in dominant parietal lob
b. w/o agraphia still allows for writing, spelling, comprehension, due to posterior dominant/occipital lobe + splenium of CC
Amnesia
a. Types of memory: registration (attention span), short-term, long-term
b. Anterograde: can’t form new memories, occurs in Korsakoff’s syndrome
c. 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/retrograde
ii. Common after traumatic brain injury
e. Transient global amnesia (think transient ischemia attack)
i. Benign but acute onset of profound transient anterograde amnesia
ii. Full recovery of anterograde memory but leaves a permanent memory gap
Vision
a. Cortical blindness: pupillary response preserved but no vision
b. Anton’s syndrome: cortical blindness w/ anosagnosia
c. Balint’s syndrome: oculomotor apraxia, optic ataxia, visual inattention, visuospatial issues
DEMENTIA
1. Mild cognitive impairment: simple memory complaint (corroborated by someone) w/ intact ADLs + normal cognitive fxn
2. Dementia: memory impairment + one of the following w/o delirium
a. Language, judgment, abstract thinking, praxis, constructional abilities, visual recognition
b. Multiple etiologies – Alzheimers is most common (covered below), also due to…
i. Diffuse Lewy body dz
1. Clinical: dementia + motor sx of PD (bradykinesia, cogwheel rigidity, shuffling gait), visual halluc.
2. Pathology: widespread Lewy bodies (α-synuclein inclusions)  atrophy
ii. Vascular dementia
1. Clinical: dementia + step-wise decline in fxn following each vascular event
2. Pathology: multiple infarcts (large or lacunar)  cavitations
iii. Frontotemporal dementia (think Pick’s dz)
iv. Rapidly progressing dementias (covered in prion lecture)
3. Evaluation
a. Labs: CBC & chem7, glucose, BUN/creatine, B12, LFTs, thyroid (Δs in any can cause cognitive impairment)
b. Mini-mental status exam
c. Depression screening (often hard to distinguish)
14
ALZHEIMERS DISEASE (AZ)
1. Epidemiology
a. Most common type of dementia; affects hippocampus especially
b. 90% sporadic, 10% familial (earlier onset + faster progression)
c. Risk increases w/ age, insulin resistance, hypercholesteremia
2. Clinical features
a. Gradual progression (10yrs) vs stepwise in multiple infarct dementia or undulating in DLBD
i. Early sx: impaired recent memory, depression
ii. Late sx: impaired remote memory, poor speech, agitation
iii. End-stage sx: complete amnesia, mute
b. Definitive dx is via autopsy, but imaging can complement evaluation
i. MRI: marked reduction in brain volume (frontal & parietal) + hydrocephalus ex vacuo
ii. fPET: impaired glucose utilization in posterior cingulate gyrus & parietal cortex (DLBD is anterior)
3. Pathologic features
a. Δs that correlate best w/ cognitive fxn are:
i. Severe loss of neurons  gliosis + low brain wt + hydroceph ex vacuo
1. 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. Genetics
a. Trisomy 21 (3 copies of APP gene)  early onset AZ
b. Mutated APP gene assoc w/ familial AZ
c. APO E4 allele assoc w/ sporadic AZ
d. Presenilin 1/2 increase Aβ-amyloid
5. Pathophysiology
a. Beta/gamma secretases abnormally splice APP into β-amyloids I-40 (vessels)/I-42 (neurons) = non-fxnal and toxic
b. Β-amyloids activate caspases that lead to hyperP of tau (tangles)
i. HyperP is also indirectly caused by insulin resistance via disinhibition of GSK3
6. Tx
a. Acetylchoinesterase inhibitors (donepezil, galantamine, rivastigmine) slow progession more than relieve sx
b. NMDA receptor antagonist (memantine)
c. Vit E may slow progression
d. Do not use estrogen for tx
PRION DISEASE
1. 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 dz
2. Pathology
a. Spongiform degeneration  formation of cytoplasmic vacuoles that are filled PrPSC protein
b. Various types of amyloid plaques of prion protein
c. Gliosis excessive for degree of neuronal loss
3. Types
a. 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 cortex
ii. 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 inheritance
c. Gerstmann-Straussler-Scheinker: slower progression than other forms of prion diseases (3-5y)
d. Human BSE: mad cow dz
CLINICAL HEADACHE
1. 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 ↑ pain
2. Primary types (F˃M except cluster)
a. Migraine: neurovascular dz w/ recurring unilateral HA, pulsating quality, assoc w/ N/V, photo/phonophobia, family hx
i. Without aura
1. Must have 5+ attacks lasting 4-72h that meet above criteria
ii. With aura = visual/sensory sx that develop gradually before HA onset (must have 2+ attacks)
1. Aura sx do NOT last more than 1h
2. Aura sx are reversible
3. HA follows aura w/ free interval ˂1h
iii. With typical aura = homonymous visual disturbance, unilateral paresthesias/numbness/weakness, aphasic speech
b. Tension: diffuse bilateral squeezing sensation, can become chronic w/ chronic NSAID use (aka medication misuse HA)
i. Rarely see photophobia, phonophobia, N/V
c. 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 1-2yr
15
3.
4.
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 prednisone
Common associations
a. “Thunderclap” first & worst HA = SAH, get a CT/LP
b. 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 ESR
d. Cherry-red w/ HA in wintertime = CO poisoning
e. ALL headaches can cause N/V
f.
Photopsia = see flashes of light
HEADACHE PHARMACOLOGY
1. 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 pain
a. 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 absorption
4. Acute vs prophylactic tx
a. Use acute during the HA, the sooner the better
i. Tension: acetaminophen, NSAIDS
ii. Migraine: triptans
iii. Cluster: O2 (ipsi nostril)
b. Use prophylaxis when HA are frequent (>2/wk), severe, or have contra to acute drugs
i. Tension: amitriptyline (TCA)
ii. Migraine: beta-blockers, topiramate (anti-convulsant)
iii. Cluster: prednisone, verapamil, lithium
5. Drug-induced (medication misuse) headache
a. 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 drug
6. 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 TREATMENT
DRUG
MOA
5HT-1/DA R agonist  VC
Ergot Alkaloids
Poor oral bioavailability
Triptans
Sumatriptan
5HT-1B/D R agonist  VC
Good for migraine/cluster
Acetaminophen
Not an NSAID, but close
SIDE EFFECTS
Peripheral VC  numbness/tingling, muscle pain, gangrene
DA activation  N/V (may combo w/ metoclopramide)
Contra: vascular dz, pregnancy, liver/kidney dz, concomitant triptans/cyp3A4s
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
Safest of all tx
NSAIDS/ASA
(-) prostaglandins
 VC
Safe but can cause GI bleeding
Safe, can  caffeineism, assoc w/ withdrawal Has (tx is reintroduction)
Caffeine
Midrin
Metoclopramide
Combo of isometheptene (like epi) +
SE are numbness/dizziness
dichloralphenazone (sedative) + acetaminophen
Contra: MAOI (excessive catechol release), antidepressants
Safe, DOC for nausea in migraine, given in combo to ↑ gut motility
Anti-emetic via DA antag
Opiods
Abuse potential
PROPHYLACTIC TREATMENT
DRUG
MOA
SIDE EFFECTS
Tricyclics
amitriptyline
Unknown
B-blockers
propranalol
Unknown
Topiramate
Not given
Verapamil
Ca channel blocker
DOC for tension HA prophylaxis
Anticholinergic SE (drying, constipation)
Contra: pregnancy, glaucoma, urinary retention, concomitant MAOIs
DOC for migraine HA prophylaxis, double dip w/ heart dz
Antiadrenergic SE (fatigue, bradycardia, hypoTN)
Contra: asthma, DM
Migraine HA prophylaxis
Can cause cognitive dysfxn, wt loss
DOC for cluster + migraine HA prophylaxis (takes 3-8wk), double dip w/ heart dz
Valproic acid
Not given
Cluster and migraine HA prophylaxis, double dip w/ seizures or bipolar disorder
Lithium
Enhances 5HT
transmission
DOC for chronic cluster HA prophylaxis, double dip w/ bipolar disorder
Contra: pregnancy, kidney dz, plus it sucks to take it
16
NEUROPATHIC PAIN
1. Pathophysiology
a. Nociceptive pain is via damage to tissue (protective)
i. Quality is “aching” or “throbbing,” responds to NSAIDS/opiods
ii. Normally:
1. Painful stimuli (substance P, TNF, prostaglandins) via nociceptors to DRG
2. Impulse carried to spinothalamic tract to cortex
3. 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 pain
i. 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 pain
a. 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 pain
a. Includes pain assoc w/ diabetic neuropathy, post-herpetic or trigeminal neuralgia, phantom limb
2. Types
a. Diabetic peripheral neuropathy
i. Burning, tingling bilateral sensation in extremities  loss of sensation  foot ulcers/amputation
ii. 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 elderly
ii. Promising vaccine
iii. DOC: gabapentin, pregabalin, tramadol, lidocaine patch, opiods
c. Trigeminal neuralgia (Tic Doloreux)
i. Compression & demyelination of 5th cranial nerve unilaterally, most common in MS
ii. DOC: carbamezapine (or oxacarbazepine)
d. Drug-induced peripheral neuropathy
i. Blood-nerve barrier is weaker than BBB, thus drugs can cross easier & cause toxicity
1. Cancer chemotherapy (80% of pts) disrupts axonal transport/decrease myelin
2. Antiretrovirals + HIV itself causes neuropathy
3. Isoniazid (can be prevented w/ supplemental B6)
ii. Distal axons affected first, followed by Wallerian degen, obvi not helpful
iii. DOC: gabapentin, lidocaine, opioids, TCAs
3. Strategies to treat neuropathic pain
a. Start low, go slow
b. Everyone is different, choice is specific to patient and should account for DDI, co-morbities, SE, etc
DRUG
Gabapentin
Pregabalin
Carbamazepine
Oxcarbazepine
Lidocaine
Amitriptyline (TCA)
Duloxetine
Opiods
Topiramate
Valproic Acid
Tramadol
Capsaicin
MOA
Ca channel blocker
Ca channel blocker
Na channel blocker
INDICATION
All
All
Trigeminal neuralgia
Na channel blocker
SNRI
SNRI
Unknown (for NP)
Na channel blocker
Unknown (for NP)
SNRI
substance P depletion
Post-herpetic
Diabetic, drug-induced
All
All
3rd line option
3rd line option
Diabetic neuropathy
Only in combination
ADVERSE EFFECTS
Dizziness, drowsiness, wt gain, edema, cog dysfxn
Dizziness, drowsiness, wt gain, cog dysfxn, dry mouth
Inducer, SIADH, rash (SJS), aplastic anemia
Oxy not metab to 10-11 epox intermediate = less SE
Only for post herpes, never put on open lesion
DO NOT use if arrhythmias, seizures, MAOIs
DO NOT use if MAOI
Constipation (stool softener/stimulant), resp depression
Wt loss, kidney stones
Inhibitor, THBpenia, hepatotox, wt gain, alopecia
DO NOT use if seizures
Don’t smear all over your hands and then rub your eyes
17
SEIZURES
1. 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-smacking
i. 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 seizure
c. 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 worse
2. Partial seizures (may progress to a secondarily generalized seizure)
a. Simple: consciousness intact
i. 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 confusion
i. Sx: above + able to respond in a limited way (ex: doesn’t recognize name when called, but turns toward noise)
3. Generalized seizures
a. Simple Absence (petit mal): momentary LOC (spontaneously becomes “absent”), transient spike/wave EEG activity, NO
post-ictal confusion, usually begins before puberty
b. Atypical Absence: EEG spike/wave activity more heterogeneous, may have automatisms and worse sx
c. 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 breathing
ii. Clonic phase follows - rhythmic jerking
d. Myoclonic: consciousness appears preserved + sudden shock-like contraction of head/UL, <1s long, common w/ awakening
e. 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 helmet
4. 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 sedation
5. Etiology
a. Childhood (0-10y): perinatal injury, congenital defects
b. Adolescence (10-18y): idiopathic
c. Early adulthood (18-35y): trauma, idiopathic, drugs/EtOH
d. Late adulthood (35+y): brain tumor, vascular diseases, degenerative diseases (like AD)
6. Tx
a. 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 seizures
ii. Valproic acid, lamotrigine, ethosuximide are 1st line for absence, myoclonic, and atonic seizures
SEIZURE PHARM
1. 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 influx
b. 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 data
a. Serious SE include teratogenesis, blood dyscrasias (check baseline), osteoporosis/malacia
3. Clinical pearls
a. MAJOR inducers: phenytoin, carbamazepine, phenobarb
i. Inducers will decrease [] of those drugs metab by CYP, this happens slowly
ii. CBZ also induces own metabolism = initially therapeutic but then levels drop off due to autoinduction  ↑ dose
b. MAJOR inhibitors: valproic acid
i. 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 slowly
d. 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 []
e. All in table below except topiramate/zonisamide (hepatic/renal) have hepatic metabolism
f.
Best scenario is to d/c AED if pregnant, otherwise monotherapy, and always give folate
DRUG
Phenytoin
MOA
Na channel blocker
ADVERSE EFFECTS
acne, hirsuitism, diplopia/ataxia/nystagmus, gingival hyperplasia, ↓OC efficacy
Carbamazepine
Na channel blocker
SIADH, rash, hirsuitism, ↓OC efficacy
Valproic Acid
Na/Ca block, +GABA
Phenobarbital
+GABA
rash (can  Stevens-Johnson syndrome!), THBcytopenia, hepatotox, wt gain, alopecia
Rash, sedation, cognitive dysfxn, ↓OC efficacy
Benzodiazepine
+GABA
Ethosuximide
Ca channel blocker
Lamotrigine
Na channel blocker
Oxcarbazepine
Na channel blocker
rash (can also  Stevens-Johnson Syndrome, NEVER use w/ VPA!!), aplastic anemia
SIADH, ↓OC efficacy
Topiramate
Na, +GABA, -NMDA
wt loss, kidney stones, cognitive dysfxn, ↓OC efficacy
Zonisamide
Na/Ca blocker
kidney stones
SIADH = syndrome of inappropriate ANH release and OC = oral contraceptive
18
EYE MOVEMENTS/DIZZINESS
1. 3 types of neurologic dizziness
a. Vertigo: illusion of mvmt when stationary (rotation, translation, or tilt)
b. Dysequilibrium: imbalance when standing/walking
c. Presyncope: lightheadedness, graying vision
2. 3 types of psychologic dizziness
a. Confusion: poor concentration, agitation
b. Giddiness: excitement/elation
c. Derealization: depersonalization, detachment, déjà vu
3. Goal is to always keep object centered on fovea, thus there are many reflexes to maintain this
a. Vestibular: holds images steady during brief mvmt (ex) driving on bumpy road
b. Nystagmus: quick phase is normal, as it resets the eye back toward visual cue
c. Vestibulo-ocular: involves CNVIII, CNVI, CNIII, MLF to keep eyes fixed when head rotates
i. Oscillopsia = loss of VOR
4. Bedside tests
a. Calorics (Barany’s): COWS CUWD is normal, lack of nystagmus indicates problem w/ vestibular system
i. 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
Nystagmus
direction
Fixation
Gaze
Calorics
Balance
Other
5.
6.
7.
8.
9.
CENTRAL (brainstem/vestibular n)
Single direction
PERIPHERAL (CNVIII, canals)
Both horizontal and vertical
Does NOT suppress nystagmus
No change
Increases nystagmus
Severe problem, unable to tandem, +Romberg
No hearing loss/tinnitus
Suppresses nystagmus
Nystagmus increases w/ gaze toward quick phase side
Little change
Mild problem, poor tandem, -Romberg
Assoc hearing loss/tinnitus
Intranuclear opthalmoplegia: diploplia/vertigo due to non-conjugate lateral gaze
a. Due to destruction of MLF (tract from abducens nuclei to contralateral oculomotor nuclei)
b.  inability to adduct affected eye + physiologic nystagmus in unaffected eye
c. Ex: loss of R MLF  no R adduction + nystagmus in L eye due to diploplia (shown in picture at right)
Episodic Dizziness <1min = BPPV
a. Loose otoconia affect endolymph flow  dizziness, often in posterior canal
b. Dx: nystagmus w/ Hallpike-Dix maneuver
c. Tx: Epley or Semont maneuver to get junk out
Dizziness <1h = TIAs, migraine, panic attacks
Dizziness >1d = Meniere’s dz
a. Episodic increase in endolymph pressure  fluctuating low frequency sensorineural hearing loss + tinnitus
Acute vertigo (1-3d) tx w/ vestibular suppressant (diazepam/droperidol) + antiemetic (promethazine/prochlorperazine) + bed rest
a. If >3d (subacute) stop vestibular suppressants
19
COMA
1. 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. HMS
b. 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. Respirations
i. Lesions at various levels of brainstem are characterized by different pathological breathing patterns
ii. Cheyne-Stokes: crescendo-decrescendo (episodes of apnea and tachypnea)
b. Pupils
i. Pinpoint fixed = pons
ii. Large fixed = dorsal midbrain (tectum)
iii. Unilateral dilated w/ third n palsy = compressed CNIII, often due to uncal herniation
iv. Mid-position fixed pupils = ventral midbrain
v. 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 reflexes
i. +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 direction
1. 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 alive
i. Sleep-wake cycles present
ii. No purposeful response to stimuli, bowel/bladder incontinence
iii. 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 Herniation
i. Respiration: normal to Cheyne-Stokes
ii. Pupils lack direct reflex, dilated on affected side
iii. Oculocephalics: Doll’s eyes
iv. Calorics: 3rd nerve paralysis prevents contralateral adduction (eye won’t cross midline)
v. Response to pain: reflexive only on ipsilateral side
vi. 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 coma
c. 15=normal
5. Pseudocoma States
a. Psychogenic unresponsiveness – pt avoids hitting themselves when arm dropped toward face and resists attempts to
open/close eyelids
b. Locked-in syndrome – pt is completely paralyzed but is awake
c. Abulia (akinetic mutism) – pt is completely apathetic w/ lack of initiative due to lesion in premotor cortex
20
SLEEP
6. Sleep stages
a. Stage 2: spindles & K-complexes
b. Stage 3 & 4: delta (slow-wave) sleep
7. Waking areas = reticular formation, posterior hypothalamus vs sleep-inducing areas = preoptic nuclei, anterior hypothalamus
8. 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 genotype
i. Measure hypocretin-1 in CSF: normal ~300 pg/ml, narcoleptic w/ cataplexy usually has ˂100 pg/ml
b. Sx
i. Excessive daytime sleepiness: daytime napping may be physically irresistible
ii. Cataplexy: REM related phenomenon, lose muscle tone but not consciousness, triggered by emotions
iii. Sleep paralysis, fragmented sleep, hypnogogic (sleep onset) and hypnopompic (at waking) hallucinations common
c. Dx
i. Epworth Sleepiness Scale (ESS) evaluates pt tendency to fall asleep in various situations over past 1mo
1. 24 is maximum
2. Narcoleptics tend to score 16+
3. 10+ is sleepy
4. 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 OR
2. Complaint of EDS + assoc sx (part iii above) + sleep latency <10min + other causes ruled out
d. Tx
i. EDS: structured nighttime sleep/naps, stimulants
1. DA agonists = amphetamines, methylphenidate
2. Non-DA agonists = modafinil, which activates hypocretin region of hypothalamus
ii. Cataplexy: TCAs (nortriptyline), SSRIs (fluoxetine), SNRI (venlafaxine), gammahydroxybutyrate
iii. Sleep fragmentation: good sleep hygiene
9. REM Behavior Disorder
a. 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 twitches
c. Often have rhythmic jerking of legs (sometimes arms) every 5-90s
d. Must r/o panic, PTSD, somnambulism (sleep walking), night terror, nocturnal epilepsy
e. 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 mvmt
b. More common in women and assoc w/ iron deficiency, family hx, dopamine
c. 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
21
BASAL GANGLIA (diencephalon)
1. BG circuit involves direct & indirect pathway
a. Input to striatum is via a motor plan from the prefrontal motor cortex
i. Bereitschafts potential: “readiness,” precedes muscular activity
b. Output to primary motor cortex for execution of mvmt is via thalamus
i. At rest, thalamus tonically inhibited by GABA from GPi/SNpr
c. BG optimizes the motor program but has no role in the motor decision
d. The ONLY things that release GLU (i.e. are excitatory) are
cortex/STN/thalamus
e. GPe and GPi are tonically active unless actively inhibited
2. Disinhibition (two (-) synapses in a row) is how the BG initiates movement
a. Yellow highlighted pair results in disinhibition of the thalamus
b. 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
Cortex
(+) Glut
Striatum
(-) GABA
(-) GABA
GPi
↓↑(-) GABA
(+) Glut
↓(-) GABA
Thalamus
↑↓(+) Glut
Cortex
Direct
Indirect
GPe
STN
Dopamine receptors
a. Dopamine selectively excites the direct pathway and inhibits the indirect pathway
b. 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 GPi
c. 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 GPe
6. Structure of striatum
a. Striatum = caudate, putamen, globus pallidus (interna/externa) and nucleus accumbens
b. 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 dynorphin
ii. Limbic function
d. Matriosome (axons go to D2 R and project to GPe)
i. Enkephalin
ii. Sensorimotor system
e. Medium Spiny Neurons (90-95% of striatum)
i. Abundant spines due to immense amount of input they receive
ii. 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 striosomal
2. D2 R type have enkephalins and project to GPe; primarily matrisomal
3. D3 R type have uncertain function
7. Convergence= connections from many neurons to fewer neurons
8. Parallelism= parallel circuits that never interact
a. Removing DA generates ↑communication b/w parallel circuits so leads to more convergence
9. Hypokinetic disorders
a. Parkinsons: progressive degeneration of the DA neurons from the SNpc means the striatal nuclei fxn w/o DA input
i. Loss of DA on D1 R  NO release of GABA from striatum  GPi no longer inhibited, so it (-) thalamus = NO mvmt
ii. 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 thalamus
b. Huntingtons
i. Connection b/w striatum/GPe is destroyed  NO indirect pathway  same as above
5.
22
CLINICAL MOVEMENT DISORDERS
1. 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 limb
3. 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-infxn
c. Toxic: most common is from over-medicated PD but can be CO poisoning
4. Dystonia: genetic/idiopathic continuous involuntary contraction of muscle groups  abnormal posture
a. 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 dyskinesia
d. Blepherospam: involuntary closing of eye
e. Writing dystonia: occurs only when writing
f.
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  hypokinesia
b. 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 bodies
d. Etiology: both environmental (toxins) + familial, tho twin studies show little evidence for genetics
i. -synuclein mutation (ch4): autoD, early onset (40s) + fast progression + Lewy bodies
ii. Parkin gene (ch6): autoR, early onset (20s) + slow progression + NO Lewy bodies
iii. Dysfunction of proteosomal degradation function (via ubiquitin) may damage SNc
iv. 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 GP
f.
Parkinson’s Plus syndromes
i. MSA (multiple system atrophies)
1. Shy-Drager syndrome: parkinsonism/ataxia/ANS dysfxn
2. Olivopontocerebellar atrophy (OPCA): parkinsonism/cerebellar dysfxn
3. Striatonigral degeneration
ii. PSP (progressive supranuclear palsy): parkinsonism/impaired eye mvmt/cervical dystonia
iii. CBD (corticobasal degeneration): parkinsonism/apraxia/alien hand syndrome
6. Tremor: regular rhythmic mvmts, classified as fast/slow, pill rolling/flex & ext, postural/resting/intention
a. Essential tremor: fast (8-12 Hz) postural, bilateral, increases w/ age, tx w/ primidone or thalamic DBS
b. Can be induced by drugs, adrenaline, etc
7. Tics: repetitive but irregular (ex) Tourettes = both motor/vocal tics that start when ˂21 yr old
8. Myoconus: sudden, focal but irregular
9. Fasiculations: involve motor units, NOT whole muscle (that would be myoclonus)
10. Ataxia: sensory/cerebellar lesion  dyscoordination, dysmetria, dysdiadochokinesis
11. Asterixis: intermittent lapses in postural tone
23
PARKINSON’S PHARM
1. Goal is to restore balance of dopamine and ACh w/in the CNS, thus main drugs = DA agonists + muscarinic ACh antagonists
2. Tx is symptomatic only, it does not alter the course of the dz
3. 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 BBB
4. 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 dose
i. 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 dz
i. 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 resort
f.
Some evidence that L-dopa might actually worsen progression due to production of ROS that damage nerve terminals
g. May cause visual hallucinations (animals/insects/people); may need to tx w/ clozapine or quetiapine
h. 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-dopa
6. IN GENERAL, start pt on anti-chol/amantidine, then add DA agonist, then add levi/carbidopa, then add COMT/MAOIs
DRUG
L-dopa/Carbidopa
Sinemet
MOA
↑DA at nerve terminal
Ergots
Direct DA R agonists
Bromocriptine
Non-Ergots
Apomorphine
Ropinirole
Pramipexole
Rotigotine
Entacapone
COMT(-)  less DA breakdown
Selegiline
Rasagiline
MAO-B(-)  less DA breakdown
Anti-AChs
Benztropine
Trihexyphenidyl
Amantadine
Restores balance, tx tremor but
not bradykinesia/posture/gait
↑ DA synthesis/release
↓ synaptic DA reuptake
Tx tremor/rigidity/bradykinesia
ADVERSE EFFECTS
SE: motor sx (dyskinesias), psychiatric sx, O-HTN, N/V
Narrowing therapeutic window/duration of action w/ dz progression
CIs: hx of melanoma; w/ MAOIs
2nd best efficacy after levo/carbadopa
Bromo: D1 antag/D2 agonist; CIs: 3A4(-), CAD/MI
Apo: D1/D2 agonist, triggers “on” in minutes, CIs: sulfite allergy
Ropin: D2/D3 agonist, efficacious as monotherapy + for “wearing off”
Pram: like ropinirole but may also help w/ depression
Rotig: transdermal patch
Adjunctive therapy, may cause diarrhea/urine discoloration
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
SE: dry mouth, constipation/GI stasis, urinary retention, ↑ eye pressure
Initial monotherapy if mild or adjunct if severe
CIs: BPH, GI obstruction, narrow angle glaucoma
SE: livedo reticularis, edema, seizure/CNS effects
Initial 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 latency
i. Slowed velocity indicates demylination
c. Amplitude: reflects # motor units recruited
i. Decreased amplitude indicates axonal loss
d. Repetitive stimulation: assesses amplitude over time
i. 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 conduction
i. 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 case
b. Amplitude:
i. Neuropathy = large, indicates prior denervation + re-innervation
1. Re-innervation - surviving motor units pick up denervated fibers & these extra muscle cells  bigger
amplitude
ii. Myopathy = small, indicates less recruitment due to loss of muscle cells
c. Recruitment: first increase frequency, then increase #
i. Neuropathy = normal amplitude but less interference vs myopathy = decreased amplitude but full interference
d. SF jitter: assesses temporal variability of 2 muscle fibers of the same motor unit
i. Not specific for myasthenia gravis but very sensitive
24
HIGH YIELD
Red neurons
Cyclopia/cleft lip
Dark CSF + dark WM/light GM
Prolonged F-wave
Alpha-synuclein
L’Hermitte’s sign, Dawson’s fingers, oligoclonal bands
Cowdry-type inclusions
Kernig/Brudzinski signs
Pseudopalisading cells
Soap-bubbly/cystic appearance
Spongiform degeneration
Onion bulbs
Heliotrope discoloration of upper eyelids
Gower’s sign
Hatchet face
Sommers sector
Anti GM1 ganglioside Ab
Multiple CNS lesions in time/space
Ragged red fibers
Diurnal variation of sx
Vision loss when bending over/papilloedema
Rosenthal fibers
Fried egg cell
Gingival hyperplasia
SOD1 mutation
b-blocker vs b-interferon
Recent Campylobacter infxn
Homer-Wright rosettes
Psammoma bodies, whorls
Baby w/ unusual odor
b1 deficiency
Low frequency hearing loss
Elevated ESR
DOC for trigeminal neuralgia
Inducers
Inhibitors
+ Hallpike Dix
+ Romberg
Coma w/ + pupillary light reflex
Decreased hypocretin
Damage to area 44/45
Damage to area 22
Colcichine
Symmetric vs asymmetric neuropathy
SIADH
Thunderclap HA, worst HA of life
Bunina bodies
Natalizumab
Markedly high opening pressure (~200)
Lesion at corticomedullary jxn
Imaging for SC trauma
Disappearance of reflex grasp
Internal capsule lesion
Acute vs chronic SC transaction
Duret hemorrhage
“Repeat” genetic diseases
Lacunar infarct
Charcot-Bouchard aneurysms
Bilateral limbic system lesion
Necrotic neurons following ischemia, e.g. stroke
Holoprosencephaly i.e. problem w/ ventral induction
FLAIR MRI
Prox slowing in anterior horn
Accumulates and forms Lewy bodies in PD
Multiple Sclerosis
HSV encephalitis
Condordant leg/neck mvmt seen in meningitis
Glioblastoma
HIV assoc Cryptococcus encephalopathy
CJD
Recurrent de/remyelination in CIDP
Dermatomyositis
Muscular dystrophy (how these babies push up to stand)
Myotonic dystrophy
Vulnerable area of hippocampus often affected in diffuse hypoxia
MMN
Multiple sclerosis
Increased mitochondria in myopathies
Myasthenia gravis
Pseudotumor cerebri
Pilocytic astrocytoma
Oligodenrocyte
S/E of phenytoin
ALS (familial form, most are idiopathic)
Migraine prophylaxis vs. MS treatment
AMAN, AMSAN
Medulloblastoma
Meningioma
Inborn error of metabolism
Loss of anterograde memory in Korsakoffs
Meniere’s disease
Temporal arteritis
Carbamezapine
Carbamezapine, phenytoin, phenobarb
Valproic acid
Vertical nsystagmus away from lower ear, torsional toward
Central lesion causing nystagmus
METABOLIC coma
Narcolepsy
Brocas aphasia, comprehension intact but speech poor
Wernickes aphasia, fluent but makes no sense
Gout drug that causes myo/neuro/cardiomyopathy
Hereditary vs acquired
SE of carbamezapine/oxcarbazepine
SAH
ALS (eoisinophilic inclusions)
MS drug that can reactive latent JC virus  fatal PML
Bacterial meningitis
Met (or possible absecess, b/c also hemato spread)
CT for fracture, MRI for complications
6mo, at this point baby actually reaches for objects and grasps
 true motor stroke, i.e. no sensory deficits, purely UMN sx
Hyporeflexia vs hyperreflexia
Bleeding in pons, seen in uncal herniation
Fragile X, Huntingtons, myotonic dystrophy
Chronic HTN
Assoc w/ ganglionic bleeds
Often due to trauma,  amniestic syndrome
25
HIGH YIELD IMAGES
26
27
28
29
ANSWERS (LR)
Polymyositis
Edema  mass effect/midline shift
Duret hemorrhage
MCA infarct
Hydrocephalus ex vacuo
Lewy bodies
Meningioma
Ganglionic hemorrhagic stroke
Medulloblastoma
Homer Wright rosettes (medulloblastoma)
Multiple sclerosis (pale = demyelination)
MS plaque
Glioblastoma
Lacunar infarct
Berry aneurysm
Parkinsons (loss of s. nigra pigment on L)
Metastasis at corticomeduallry junction
Pallisading (glioblastoma)
Psammoma bodies (meningioma)
Glioma
Lissencephaly
Osteomyelitis
Cryptococcus 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 SC
HSV encephalitis in temporal lobe (T2 MRI)
Acute purulent meningitis (CT) note the white sulci due to accumulation of pus
Example of FLAIR – dark CSF (like T1) but dark WM/light GM (like T2) be able to recognize!!