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154 Cards in this Set

  • Front
  • Back
Neuronal Structure
-nucleus w/ prominent nucleolus
- nissel substance (RNA rich rough ER)
-lipofuscin from unbroken down material
Glial Cells
- Oligodendrocytes : make myelin sheath in CNS equivalent to Schwann cells in PNS; round regular dark nuclei surrounded by a pale halo histologically; one cell myelinates several axons
*Luxol Fast Blue stains myelin*
- Astrocytes : star cells; stain with GFAP(glial fibrillary acidic protein) along with ependymal cells; induce blood brain barrier and surround blood vessels; support neuronal processes; act as sink for ions and NTs
- Ependymal cells : lining of ventricular system
Microglial Cells
- bone marrow derived histiocytic cells similar to Kupfer cells of liver
- cigar-shaped elongated nuclei
- aggregate into clusters in viral infections
- turn into foamy macrophages, indistinguishable from monocytes
Meninges
- three layers (dura, arachnoid and pia)
- three spaces (epidural, subdural and subarachnoid)
-CSF flows through subarachnoid space along with vessels supplying the brain
-venous sinuses reabsorb CSF
Choroid Plexus
- main function = production of CSF (~500ccs a day)
- found in the ventricles and may protrude through foramen of Luschka in cerebellopontine angle.
- calcifications occur with aging
Stroke Terminology
STROKE - acute, persisting focal neuro deficit due to vascular cause; either purely ischemic vs. hemorrhagic;

TRANSIENT ISCHEMIC ATTACK (TIA) - focal neuro deficit from ischemia lasting less than 24 hours w/ full recovery; usually several minutes representing transient blockade; warn of HIGH RISK for subsequent stroke

REVERSIBLE ISCHEMIC NEUROLOGIC DEFICIT (RIND) - stoke syndome lasting more than 24 hours w/ full recovery; usually represent small infarctions
Key Brain Anatomy Features
1)cerebral control is contralateral (motor - precentral gyrus, sensory - post central)
2)left hemisphere dominant for speech (90% rt. handers, 60% lft. handers)
3)cerebellar and brainstem control is IPSILATERAL
4) descending motor pathways cross in MEDULLA(pyramidal decussation)
5) Cerebral cortex = higher integrative function - language formation/processing and spatial conceptualization
Stroke Localization Implications
1) CEREBRAL lesions have contralateral sydromes with motor and sensory components
2) BRAINSTEM lesions can cause "crossed patterns" *ie. ipsilateral face and CN deficits w/ contralateral arm and leg
3) APHASIAS suggest cortical involvement in left (dominant) hemisphere
4) SPATIAL CONSTRUCTION deficits suggest cortical involvement in right(non-dominant) side
Vascular Anatomy Review
- four vessels supply brain 2 internal carotid (anterior circ.) and 2 vertebral merging into basilar(posterior circ.)
-internal bifurcates into ACA and MCA; basilar into PCA
-small penetrating branches of ant. and post. circ. supply deep structures/cerebellum
-penetrating aa. of basilar and PCA supply BRAINSTEM
-OPTHALMIC A. is first major branch of internal carotid
Typical Stroke Syndromes:
Anterior Cerebral Artery (ACA)
-CONTRALATERAL distal leg weakness and numbness; motor + sensory

-distal > proximal
Typical Stroke Syndromes:
Middle Cerebral Artery (MCA)
-CONTRALATERAL face and arm greater than leg weakness; motor + sensory deficit

-w/ appropriate cortical signs (aphasia or constructional deficit)
Typical Stroke Syndromes:
Typical Lacunar Infarcts
-pure motor hemiparesis
-pure hemisensory loss
-clumsy hand (dysarthria)
-risk factors are HTN and diabetes
- mechanism - direct vessel wall damage and thickening, luminal narrowing
- usually minor and rapidly improve
Typical Stroke Syndrome:
Posterior Cerebral Artery (PCA)
Cerebellar Artery and
Unilateral Brainstem Infarction
-PCA: CONTRALATERAL visual field deficit (hemianopsia)

Cerrebellar A.: IPSILATERAL limb ataxia

Brainstem: IPSILATERAL cranial nerve deficits + CONTRALATERAL motor and sensory deficits; vertigo, diplopia, ataxia and dysarthria are common
*Watershed infactions = boundary zones, usually occurs in hypotensive episode or flow limiting stenosis of carotid a.*
What are the four intracranial hemorrhages?
1)INTRAPARENCHYMAL - deep brain (basal ganglia, cerebellum, wht. matter); rapidly progressing; usually due to HTN also embolus, tumors, vasculitis, AV malformations, coagulopathies, drugs; large = increased ICP, herniation and frequent death
2)SUBARACHNOID - ruptured aneurysm or trauma (typically at junctions of major aa.); sudden onset with severe headache, neck stiffness, lethargy and coma; complications - hemorrhage, arterial spasm, brain swelling, herniation, DVTs; mortality rate is high
3)SUBDURAL - venous bleed; chronic mass effect with headache, hemiparesis, depressed mental state; common in alcoholics/elderly with minor head trauma
4)EPIDURAL - arterial bleed; usually following head trauma; rapid accumulation of localized hematoma with herniation and death
What are the mechanisms of vascular occlusion?
1)ATHEROSCLEROSIS/THROMBOSIS - slow/stuttering stroke over a number of hours; limited to major neck and cerebral aa. and cirle of willis; HTN, diabetes and smoking are highest risk factors; occasional venous thrombosis
2)EMBOLIC - sudden onset stroke with early or late hemorrhage; wedge-shaped cortical infarct
a)cardio - mural thrombus from calcified/mechanical/infected heart valve; can have AV septal defect (paradoxical emboli); repeated emboli are randomly distributed due to turbulent blood flow
b)artery to artery - plaques in vessel walls that embolize to other distal vessels; steriotypical TIAs as blood flow is laminar (monocular blindness due to opthalmic a. occlusion is a good example)
3)VASCULOPATHIC - lacunar (HTN and diabetes), inflammatory conditions (vasculitis, neurosyphylis), arterial wall dissection (minor trauma like whiplash, chiropractic manipulation, athletic injury), and spasm
What are the physiologic consequences?
1)ISCHEMIC CORE: cessation in membrane ionic gradient and electrical function of neurons; excessive Ca influx, cell swelling, activation of enzymes to damage proteins and structures; neurons die in 4 minutes and glial cells take hours
2)ISCHEMIC PERIPHERY ("penumbra") - nl brain tissue regulates blood flow; ischemic tissue loses reg. and diffusion is reliant on pressure; periphery has some collateral circulation and supplies some O2 and glucose; can persist for hours and areas of clinical deficit can be revived
How are stroke patients managed?
HISTORY - onset, TIAs, cardiac problems, FH
EXAM and STUDIES - BP, auscultation, EKG, U/A, CXR
BRAIN IMAGING - CT (fast and reliable to rule out hemorrhage), MRI (best resolution, high sensitivity to early stroke changes, DWI - recent infarcts, MRA - stenosis/occlusion of major aa.), carotid doppler, electrocardiograph, cerebral angiography
BLOOD WORK - CBC, ESR, coag studies
What is the primary prevention of stroke?
1)Risk factor modification: HTN treatment, smoking cessation, diabetes management, excercise, decrease cholesterol, etc.
2)Aspirin - better for women than men
3)Cardiac abnormalities - heart valves manage with warfarin
4)Carotid stenosis - endarterectomy used in high grade stenosis (>80%)
What is the treatment for acute stroke?
1)Supportive - maximize profusion, maintain BP, maintain vascular volume, avoid hyperglycemia, fevers and watch for complications
2)Aspirin - given acutely results in less risk of recurrence/extension
3)Anticoagulation - full dose IV heparin NOT adivisable for most pts. (considered for cardioembolic pts.), also used in stroke in 'evolution', acute dissection, and thrombosis
4)IV tPA - beneficial in first 180 minutes of stroke onset, delayed delivery is harmful,
5)Intra-arterial thrombolytics (pro-urokinase) - effective in stroke of less than 6 hrs duration
6)Neuroprotection - glutamate receptor antagonists (NMDA and nonNMDA), antioxidants, mild hypothermia
What is secondary stroke prevention?
-ASPIRIN is first antiplatelet drug used; combination with DIPYRIDAMOLE is more effective than aspirin alone (headache is common side effect)
-CLOPIDOGREL is slightly better than aspirin alone in patients with coronary, peripheral or cerebral vascular dz.
-TICLOPIDINE stops ADP dependent aggregation and is more efficatious than asprin but not used due to SEs (diarrhea, neutropenia, thrombotic, and TTP)
-STATINS and WARFARIN
What is the evolution of cerebral hemorrhage?
-external capsule hemorrhage dissects anteriorly into the lateral ventricle
-blood enters aqueduct and 4th ventricle irritating autonomic control --> cardiorespiratory arrest
-2/3 show spontaneous secondary hemorrhage into pons
-clinical course is rapid and death in 1-2 days
-pontine hemorrhage invariably fatal due to location to autonomic control
-cerebellar hemorrhage have better prognosis
What are the most significant causes of subarachnoid bleeding?
95% are from saccular or "berry" aneurysms (ballooning of arterial wall with thinning and fragmentation of media and elastica); always occur at branch points (anterior cerebral 37%, internal carotid 36%, MCA 21%, verterobasilar 5%, multiple 20%); congenital defects

4% are atherosclerotic aneurysms - more likely to be thrombosis
What is a germinal matrix hemorrhage?
-disease of premature infant
-germinal matrix is zone of proliferation of neuronal and glial cells around the neural tube that will later be the ventricles
-all neurons migrate to final place by 24 weeks
-hemorrhage into periventricular germinal matrix is most common pathology of premature infants born btwn 24-35 weeks
-most occur in thalamostriate groove near foramen of Monro
What is the pathogenesis of germinal matrix hemorrhage?
-b/f 35 weeks bf to brain is shunted by recurrent aa. of Huebner bypassing the cortex, shunts stopped at 35 wks
- vessels are large and thinned walled (one layer of endothelial cells) destined to become major venous drainage
-pulmonary parenchymal immaturity leads to hemodynamic fluctuations with both decreased flow and hypoxemia
-changes in bf to germinal matrix causes damage to vessels leading to rupture and blood spreads readily through matrix and surrounding tissue
What can happen after germinal matrix hemorrhage?
1 - acute ICP raised preventing bf to brain --> brain death
2 - infant survives prone to obstructive hydrocephalus
3 - hematoma into matrix destroys oligodendrocyte progenitors leading to decreased myelination later
4 - when reaching internal capsule may destroy long tracts
What are the epidemiological factors in MS?
-most common disabling condition of young people
-highest prevalence in northern European descent and rare in native populations (Eskimos, Lapps, Aborigines)
-concordance rate of 26% btwn monozygotic twins --> strong genetic component
What are the genetic factors in MS?
-clinical expression of disease probably initiated by environment
-overrepresented in MHC Class II genes: HLA-DRB 1501 or DR2 halotype
-in ppl w/o DR2 the IL-4 receptor genes are more prominent
-APOE may cause an accelerated course, null CNTF shows an earlier development of disease
What is the pathology of MS?
-inflammation, demyelination and axonal degeneration --> hallmark MS lesion is plaque that is sharply demarcated from the white matter
-activated monocytes and lymphocytes cross the the endothelial cells and enter brain parenchyma (interaction with integrins and cells surface adhesions facilitate migration)
How is MS diagnosed?
-key criterion is to determine recurrence (no specific diagnostic test)
-classic criteria: relapses at different times and different CNS location "dissemination in space and time"; appearance of new lesion on follow up MRI 3-6 mo later CONFIRMS diagnosis
-can also use "McDonald criteria" - evoked potentials and spinal fluid exam for increased IgG synthesis and oligoclonal bands
What would the differential diagnosis of MS be?
-Sjogren syndrome (immune cells attack exocrine glands)
-Neuromyelitis Optica (immune cells attack optic nerve and spinal cord)
-SLE and Sarcoidosis
-Tumor and vitamin deficiencies (vitD)
What imaging studies should be performed in MS?
-MRI vefore and after infustion with gadolinium - T1 and FLAIR
-FLAIR best shows white matter lesions: enhanced lesions indicate active MS
-T1 shows low density lesions called "black holes" that indicate permanent damage
What are the acute treatments of MS?
-prevention of inflammation with immunomodulatory drugs
-acute attacks are often self limited
-use of IV methylprednisolone for significant flares of optic neuritis, brain stem dysfunction or progressive motor weakness (longterm use is not recommended)
What are the long term treatments of MS?
-Interferon-beta and Glatiramer are first line in relapsing/remitting MS
-Interferon Beta: inhibits entry or activated cells into the CNS, decrease of interferon gamma, augmentation of non-specific suppressor function; given by subcutaneous injection; SE(s) flu-like symptoms
-Glatiramer Acetate: mimcs myelin-basic protein (MBP) to induce tolerance to myelin products, induction of Th2 regulatory cells; given daily as subcutaneous injection; SE(s) injection site reactions, lipoatrophy, chest pain
-other suppresive therapies including cyclophosphamide, azathioprine, methotrexate and mycophenolate mofetil
-monoclonal antibodies: tysabri, campath, rituximab,
What can cause CNS demyelination?
-immunologic attack on myelin membrane (MS and post-infections encephalomyelitis)
-viral infection of oligodendrocytes (PML)
-toxic insult/metabolic derangement (CO poisoning, acute hypoxic episodes, methanol poisoning)
-central pontine myelinolysis (CPM)
-Machiafava-Bignami syndrome: rapid deterioration of corpus callosum and adjacent white matter associated with alcoholism
What is the pathology of acute and chronic plaques?
-Acute: cellularity greater than in normal white matter due to infiltration of monocytes/macrophages with some lymphocytes and reactive astrocytes
-Chronic: cellularity is less than in normal white matter; most axons still present; oligodendrocytes, macrophages, lymphocytes are gone; fibrillary astrocytes remain and replace oligos
-Shadow plaques: incomplete demyelination; most axons are myelinated and oligodendrocytes are still present
What is Devic's Neuromyelitis?
-variant of MS with a different pathogenesis
-patients present with optic neuritis and transverse myelitis occuring w/in a few weeks of each other
-lesions are more destructive than typical MS plaques --> axonal loss along with demyelination
What is Acute Disseminated Encephalomyelitis?
-acute perivenous, post-infectious, post-vaccinal encephalomyelitis
-result of an aberrant immune response to an infectious agent in a perivascular distribution, circulating lymphocytes become sensitized to a central component of myelin
-disease is monophasic and self limited
-most virulent form shows marked edema and petechial hemorrhages (actue hemorrhagic leukoencephalitis)
What are the inherited diseases of myelin - leukodystrophies?
-metabolic defect often shared by Schwann cells and oligos
-myelin is normally formed during early post-natal development but myelin turnover is blocked by specific enzyme defects resulting in an accumulation of breakdown products that are toxic to Schwann cells and oligos
-Metachromatic leukodystrophy: defect in aryl sulfatase leading to sulfatide accumulation; "metachromatic with aniline dyes
-Krabbe's (globoid cell) leukodystrophy: defect in galactocerebrosidase leading to accumulation of cerebroside causing syncytia to form in macrophages ingesting degenerated myelin
-Adrenoleukodystrophy: X-linked abnormality resulting in accumulation of long-chain fatty acids in oligos, Schwann cells, and adrenal cortex
What is the primary pathology of cell body disorders?
-Motor neuron disease: ALS (pure motor neuropathy w/o sensory symptomes
-sensory ganglionitis: paraneoplastic syndrome with circulating Ab(s), often associated with occult neoplastic dz; attack DRG cells resulting in pure sensory neuropathy
-genetic degenerative disease: Friedreich's ataxia
What is the primary pathology of diseases of spinal nerve roots?
-Radiculopathy: inflammatory infiltrates or neoplastic infiltrates in SAS and spine; frequently compresses spinal roots
What is the primary pathology in diseases of peripheral nerve axons?
-axonal neuropathy: etiology is mostly unknown; known etiologies are nutritional deficiency diseases(vitB12, thiamine) and toxins (vincristine, arsenic, uremia); all usually result in "axonal dying-back neuropathy" where most distal portions of longest axons degenerate before proximal portions resulting in symmetrical distal sensory and motor findings
-inflammation or ischemia w/in axon may destroy axons distal to the lesion, patchy, "mononeuritis multiplex, vascular diseases (SLE, PAN) and sarcoidosis
-diabetes: progressive mixed sensory and motoraxonal degeneration not related to small vessel disease
-autoimmune attack against epitopes of axolemma exposed at nodes of Ranvier (axonal variant of Guillain-Barre)
-systemic amyloidosis
What is the primary pathology of diseases of myelin sheath?
-aquired demyelinating neuropathy (Guillain-Barre): immune attack on peripheral myelin (peripheral equivalent of MS); most common cause of demyelinating neuropathy; myelin sheath stripped by macrophages, destruction of myelin is patchy resulting in segmental demylination, remyelination results in shorter and thinner myelin internodes --> increased nodes of Fanvier = slowed conduction velocities
-toxic demyelination: lead poisoning
-genetic defects in leukodystrophies (metachromatic, adrenoleukodystrophy)
What is the primary pathology in the diseases of the NMJ?
-pre-synaptic (Lambert-Eaton): ab binding to voltage gated Ca channels of axon terminus block Ca influx preventing release of acetylcholine(associated with occult cancer)
-post synaptic (myasthenia gravis): ab to acetylcholine receptor prevents Ach from binding and initiating ligand gated depolarization; Ab-ag complex causes focal destruction of post synaptic membrane (simplification)
-animal venoms block synaptic transmission by binding Ach receptor, cholinesterase or channels
-genetic defects of Ach receptor subunits or proteins involved in synaptic cell cycling
What is the primary pathology in diseases of the muscle cell?
-denervation: NMJ is interrupted trophic input is lost and cell undergoes atrophy; weakness and atrophy affectdistal more than proximal because distal portions of longest axons are affected earlier
-myopathy: degenerating myocytes leak muscle proteins (creatinine kinase, myoglobin) into blood; weakness more frequently proximal than distal
Peripheral Neuropathy
Focal Axonal Injury (Wallerian degeneration)
-due to inflammatory disease
-may directly involvenerve fascicles but usually involves blood supply to fascicles
-random, patchy distribution w/in individual nerves
-biopsy usually shows asymmetric loss
Peripheral Neuropathy
Diffuse Axonal "dying back" Degeneration
-finding in most symmetric axonal distal neuropathies
-typically distal portions of long axons affected before proximal
-"stocking-glove" distribution"
-usually due to pathology affecting metabolism of nerve cell
-toxins (vincristine, uremia), nutritional deficiency, idiopathic
Peripheral Neuropathy
Primary Demyelination
-toxins affecting Schwann cells, but usually an autoimmune attack (Guillain-Barre) or genetic defect of myelin synthesis (CMT-1)
-segmental demyelination with rapid remyelination preceded by mitotic division of injured Schwann cells
-"onion bulbing" --> thickened nerve fascicles
What is the mechanism of Myasthenia gravis?
POST SYNAPTIC
-circulating anti-ACH receptor antibodies
-Ab binds to receptor, complex becomes endocytosed by a lysosome, leading to decreased post-synaptic receptor density
-Ab on receptor blocks ACH from attaching and having effects
-Ab-ag complex attracts complement, activating macrophages to strip off large segments of the synaptic sarcolemma
What is the mechanism of Congenital cholinesterase deficiency?
SYNAPTIC
-markedly reduced end-plate cholinesterase histochemical staining
-presynaptic axon termini abnormally small
What is the mechanism of Lambert Eaton Myasthenic Syndrome?
PRE-SYNAPTIC
-circulating Ab to voltage-gated Ca channel on PRE-SYNAPTIC membrane
-reduced Ca inflow during depolarization --> reduced vesicles fusing with membrane --> reduced release of ACH
What are the neuropathic changes seen in muscle pathology?
1) grouped atrophy - several overlapping motor units lose innervation (type 1 and 2 fibers)
2) fiber type grouping - loss of normal "checkerboard" ATPase pattern due to denervation followed by reinnervation
3)target fibers - loss of myosin filaments and mitochondria from center due to denervationa and reinnervation
4) "nuclear bags" - remote denervation; loss of all contractile elements shrinking to a collection of nuclei in a sarcolemmel sac
Inflammatory myopathies:
Polymyositis, Dermatomyositis, Collagen Vascular Disease and Vasculitis
-POLYMYOSITIS: scattered myofibril necrosis and/or regeneration w/ diameter variation; variable amt of lymphocytic infiltrate; markedly elevated CPK; primary autoimmune attack against myocyte
-DERMATOMYOSITIS: focal atrophy of fibers at periphery of fascicles and loss of endomysial capillaries; "moth-eaten" myocytes; primary autoimmune attack agains endothelial cells
-COLLAGEN VASCULAR DISEASE: SLE, mixed CT, RA; myofiber necrosis and inflammatory infiltrate (more prominent that seen in polymyositis)
-VASCULITIS: often no necrosis of muscle because of adequate collateral circulation, occasional infarct
Inflammatory Myopathies:
Inclusion Body Myositis, Para-infectious (viral) Myositis, Sarcoid, Parasites
-INCLUSION BODY MYOSITIS: focal degeneration "rimmed vacuoles" or inclusion bodies with autophagic vacuoles filled with membranous debris (containing filaments of hyperphosphorylated tau, beta amyloid, prion protein); slowly progressive; CPK is not usually high
-PARA-INFECTIOUS (VIRAL) MYOSITIS: acute rhabdomyolysis; no lymphocytic infiltrates occuring at end of flu-like illness; monophasic and self limited
-SARCOID: typical granulomas
-PARASITES: trichinella, toxo
What are the Sarcolemmal-ECM defects?
-Dystrophinopathies(X-linked): Duchenne (severe) and Becker (less severe); dystrophin binds to dystroglycansarcoglycan complex stabilizing the sarcolemma during contraction; degeneration due to tearing of sarcolemma
-Sarcoglycanopathies (autosomal recessive): limb girdle muscle dystrophy histopath similar to dystrophinopathy
-Laminin Deficiency: alpha 2-isofor of basal lamina protein (muscle dystrophy + brain development affected with white matter changes)
-Dysferlinopathy (autosomal recessive): mild adult onset of proximal LGMD
-Caveolinopathy (autosomal dominant LGMD): membrane protein involved in transmembrane transport and signal transduction with a mutation
What are the channelopathies?
MYOTONIC DYSTROPHY (autosomal dominant): CTG repeat in DMPK gene, age of onset related to CTG expansion, worse through paternal inheritance; abnormality of membrane depolarization/repolarization (occurs in Chloride channel)
MYOTONIA CONGENITA: can be autosomal recessive loss of function or dominant negative - cholride channel
MALIGNANT HYPERTHERMIA: autosomal dominant, exposure to inhalant anesthetic/depolarizing mm. relaxant resulting in tetany + fever + lactic acidosis + rhyabdomyolysis; mutation of voltage gated Ca channel on SR causing sustained activation of contractile mechanism
What are the congenital myopathies?
MYOFIBRILLAR (cytoskeletal defects): nemaline myopathies (mutation in tropomyosin, troponin, alpha-actin), variable severity, accumulation of nemaline rods; central core disease (mutation in same Ca channel as in malignant hyperthermia) variable weakness
MYONUCLEAR: centronuclear (mild hypotonia/weakness) and myotubular (sever congenital myopathy leading to respiratory failure in infancy
What are the disorders of carbohydrate metabolism?
MUSCLE SPECIFIC MYOPHOSPHORYLASE DEFICIENCY (McArdle's): excercised induced lactic accumulation, acute necrosis following exercise, absence of enzymatic activity in muscle biopsy
ACID MALTASE (Pompe's): severe glycogen accumulation in skeletal and cardiac mm. along with liver, weakness of respiratory muscles
What are the disorders of fatty acid metabolism?
DEFICIENCY OF SERUM CARNITINE: usually associated with liver disease/ secondary deficiency of carnitine synthesis escess lipid in mm. fibers
DEFICIENCY OF CARNITINE TRANSPORTER: prevents serum carnitine from entering myofiber
DEFICIENCY OF CARNITINE PALMITYL TRANSFERASE: needed to transport fatty acids across outer and inner mito membrane, rhabdomyolysis with stress
What are the defects of oxidative phosphorylation?
-due to mutation of mitochondrial DNA
-"ragged red fibers" accumulation of ultrastructurally abnormal mitochondria, syndromes include MELAS, MERRF, KSS (Kearns-Sayre Syndrome) and PEO (Progressive external ophthalmoplegia
How do you diagnose a motor neuron disease?
-"diseases of exclusion" need to eliminate other causes before arriving at diagnosis
-suspect ALS if there is upper + lower motorneuron weakness, also suspect post-polio or spinal muscular atrophy with just lower
-EMG: will see diffuse spontaneous activity, fasciculation and large motor unit potentials firing rapidly
-Biopsy: neurogenic abnormalities (angular fibers/group atrophy)
How do you diagnose a neuropathy?
-sensory signs, absent reflexes, symptoms of tingling/numbness, distal weakness
-EMG distinguishes between axonal or demyelinating and localizes site of nerve entrapment
-Biopsy: cause --> inflammatory, infiltrative (amyloid), demyelinating (G-B
How do you diagnose Neuromuscular Transmission Disease?
-fluctuating weakness; easy fatigueability (MG), increased strength with effort (Lambert Eaton); "tensilon test" give AChE inhibitors, MGs get stronger
-Repetitive nerve stimulation: low frequency (fatigue in presynaptic and postsynaptic disorder) and high frequency (indcremental response in Ca dependent presynaptic disorder)
-Biopsy: nothing without biopsy samples that contain end-plates
How do you diagnose myopathies?
-usually proximal weakness, high CPK and small CMAP
-Biopsy: cause --> inflammatory (acute vs. subacute), dystrophies, mito disease, lipid or glycogen storage disease
-MITO DISEASES: exercise intolerance, tachycardia and profuse sweating, lactic acidosis, neurologic affects, respiratory chain deficiency; PEO - eyelid ptosis, w/ involvement of other organ systems (KSS); MERRF - ragged red fibers, myoclonus/generalized seizures, ataxia, myopathy; MELAS - mitochondrial encephalomyopathywith lactic acidosis, early onset stroke, dementia, seizures, ragged red fibers
Tumors of the Nervous System: general findings
-metastasis to sites like lungs, lymph nodes and liver are not a significant problem
-"benign" and "malignant" along with grades I to IV are used to classify tumors; benign tumors can still be fatal
-there is high risk of spread along CSF pathways, treatment of the entire craniopinal axis must sometimes be used when there is spread
Pilocytic astrocytoma
-primarily a pediatric tumor
-commonly located in cerebellum, chiasm hypothalamus, brainstem
-usually no progression to more aggressive grades, usually well circumscribed with no infiltration
-microscopically - bipolar fibrillary astrocytes
Infiltrating astrocytoma / Glioblastoma Multiforme
-primarily in adults
-commonly located in the hemispheres/deep white matter
-diffuse infiltration fo parenchyma, can't be completely resected; poorly circumscribed mass
-microscopic: proliferation of atypical astrocytic cells into normal brain parenchyma
-difference btwn primary GBMs and secondary GBMs: primary account for 90% and occur in somewhat older populations
Oligodendroglioma
-primarily in adults, commonly located in the hemispheres
-diffusely infiltrating and cannot be resected
-respond better to chemo than astrocytomas
-microscopic: fried egg appearence, cells with regular round to ovoid nuclei
-loss of chrom 1p or 19q: need to distinguish on a molecular level to distinguish from an astrocytoma
Ependymoma
-infratentorial = kids, supratentorial = adults and kids, spinal ependymoma = adults
-commonly in and around the ventricles or in sc
-can be resected based on location; pronosis better in adults than kids
-tendency to spread along CSF space, low grade tumors are typically well circumscribed
-microscopic: immunohistochemical staining is positive for GFAP
Pituitary Adenoma
-primarily in adults
-can present with microadenoma with endo problems or as a macroadenoma w/ or w/o hormone production causing problems due to size
-typically well circumscribed consisting of sheets, nests or ribbons
Ganglioma/Gangliocytoma
-primarily seen in kids / young adults
-commonly seen in the temporal lobe --> associated with chronic epilepsy
-can be cured by complete resection
Meningioma
-primarily seen in adult females
-typically in the dura, vascular and well circumscribed
-excellent prognosis with complete resection, but complete resection may not be possible due to location
-porr prognositic factors include: high proliferation, brain invasion, loss of architecture, areas of tumor necrosis
-can occur as manifestation of NF2
Chordoma
-primarily in adults
-notochord reminants in nucleus pulposus of spine most are in sacrum or clivus
-microscopic: myxoid matrix and epithelioid cells, bubbly cytoplasm
Medulloblastoma
-malignant pediatric tumor
-cerebellar mass, grossly well circumscribed
-may present with blockage of CSF flow of the fourth ventricle
-microscopic: small blue cell tumor that grow in sheets, also see focal rossette formation
-primary prolem is aggressive local growth that can spread through the CSF
-seen w/ increased frequency in familial syndromes (Gorlin's, Li-Fraumeni)
Pineoblastoma
-malignant pediatric tumor
-penial region mass, small blue cell tumor with focal rossette formation,
-familial retinoblastoma patients(due to mutation in the Rb gene) can develop pineoblastomas
Craniopharyngioma
-occur most often in young adults
-suprasella/sella tumors
-derived from Rathke's pouch, grossly lobulated, cystic tumors with oil like "cholesterol crystal" fluid and calcification

COLLOID CYST/ RATHKE'S CLEFT CYST - incidental autopsy finding in pituitary/ pituitary stalk
Metastatic Disease in the Brain
-sigle or multiple lesions
-well circumscribed nodules found anywhere (leptomeninges usually associated with tumor cells in the CSF)
-can be hemmorhagic and affect neurologic function through compression
Lymphoma
-can occur in two different settings 1) sproadic extranodal lymphoma or 2) in immunocompromised patients
-both are typically deep parenchymal lesions
-tumors show temporary response to steroids but overall prognosis is poor
Schwannoma
-primarily in adults
-arrise from cranial nerves (esp. 8th), also arise from spinal nerve roots or peripheral branches
-microscopically: palisading of nuclei "school of fish", spindles nuclei with a wavy/buckled/bend shape and blunt tips
-multiple schwannomas associated with NF2
Neurofibroma
-commonly occur in adults
-central large nerves, plexus or nerve roots or peripheral nerve branches
-mixed cell population of fibroblasts, perineurial cells, mast cells and Schwann cells
-there are different forms: small subcutaneous nodules not infrequently found as sporadic lesions; diffuse soft tissue large masses associated with NF1, can be large and disfiguring; plexiform neurofibromas expand in normal shell of perineurium, bag of worms gross appearance, always associated with NF1
Malignant Peripheral Nerve Sheath Tumors (MPNST)
-primarily in adults, associated with nerve roots or plexus
-half occur in NF1 and half ar sporadic
Familial Tumor Syndromes
NF1 - autosomal dominant; gene on 17q; risk of neurofibromas, MPNSTs, optic gliomas, astrocytomas, learning disability and seizures; can see Lisch nodules, pheochromocytoma, cafe-au-lait spots
NF2 - autosomal dominant; gene on 22q; vestibular schwannomas, meningiomas and ependymomas (spinal)
TUBEROUS SCLEROSIS (TSC): autosomal dominant; mutation on gene 9q or 16p encoding hamartin and tuberin; clinically seizures and learning delay
VON HIPPEL LINDAU DISEASE (VHL): autosomal dominant; mutation on VHL gene on 3p to induce the transcription of hypoxia induced genes; at risk for hemagioblastomas in brain and retina, renal cysts, renal cell carcinoma, islet cell tumors and pheochromocytoma
LI-FRAUMENI SYNDROME: autosomal dominant; p53 mutation on 17p; can get astrocytoma, medulloblastoma,osteosarcoma, breast cancer, leukemia adrenocortical carcinoma
GORLIN'S SYNDROME: autosomal dominant; mutation on PTCH gene on 9q; medulloblastomas and others
What are the signs and symptoms os CNS infections?
-fever, headache, meningismus, photophobia, n/v, neck pain and stiffness, seizures, change of mental status
-meningeal signs (nuchal rigidity, Kernig's sign (painful knee extension), Brudzinski's sign (lifting of legs when head is lifted), focal neurologic signs (hemiparesis, CN palsies), skin lesions
Subdural Empyema
-infection between DURA and ARACHNOID
-crescent-shaped nypodense collection over cerebral convexity, can have interhemispheric region enhancement
-intracranial subdural empyema is a complication of either sinusitis(frontal) or otitis media/mastoiditis. rare complication fo head trauma, neurosurgery, bacteremia or dental infection
-pathogens: oral strep, bacteroides fragilis, S. aureus and H. influenza
-surgical drainage required
-pathogenesis: infection in frontal sinus veins spreads through emissary veins across the skull into subdural space in into the interhemispheric region
Intracranial Epidural Abscess
-pus collection btwn dura mater and skull, associated with osteomyelitis, can cross dura along emissary veins and infect subdural space
-insidious onset with sinus/ear pain, local headache to generalized headache, leading to alteration of neurologic status and seizures
-almost always associated with head trauma or a complication of sinusitis, otitis media, mastoiditis, craniotomy; always associated with osteomyelitis and septic thrombophlebitis
-pathogens similar to subdural
-surgical drainage required
Acute Bacterial vs. Aseptic Meningitis
-bacterial is more severe; CSF: low glucose, high white count, lots of neutrophoils, positive gram stain and culture; may have positive blood culture
-aseptic: usually more benign; CSF: normal glucose, small wht cell increase, lymphocytes are predominant, CSF gram stain/blood cultures are negative
Treatment of Bacterial Meningitis
-vancomycin plus ceftriaxone for S. pneumo, N. meningitidis, S. agalactiae, E.Coli
-high dose ampicillian when Listeria is suspected
Causes of Actue Aseptic Meningitis
-viral: enterovirus, arbovirus, herpes, mums, influenza, parainfluenza, HIV
-leptospirosis
-syphillis
-lyme disease
-drugs (NSAIDS, TMP/SMX
-SLE
When should you suspect encephalitis?
-meningitis symptoms
-change of mental status, forcal neuro exam, personality changes, temporal lobe syndromes (hallucinations, erratic behavior, short term memory loss), frontal lobe syndromes (loss of smell, motor weakness)
Etiology of Viral Encephalitis
-enteroviruses (echo, coxsackie, polio, hep A)
-arthropod-born
-herpes (HSV1 and 2, VZV, EBV, CMV
-measles, mumps, rubella
-HIV, JC Virus (PML), Rabies (variable incubation period, multifocal areas of neuronal degeneration and perivascular cuffing, cytoplasmic inclusion(negri body) found in least devastated areas)
What is Reye's Syndrome?
Acute fatty liver degeneration, encephalopathy with cerebral edema and elevated intracerebral pressure
-no CSF pleocytosis, follows viral infection (usually H. flu or varicella)
-epidemiologically associated with aspirin use
Acute Disseminated Encephalomyelitis
-previously called post-infectious encephalitis
-occurs 2-12 days after respiratory viral infection, measles, varicella, rubella or mumps
-abrupt onset of symptoms with frequent seizures, lethargy and coma
-treatment is with steroids, and IV immunoglobulins
Subacute and Chronic Meningitis
-TB, neurobrucellosis, fungal, syphilis, lyme disease, acanthamoeba
Brain Abscesses
-contiguous spread: sinusitis, otitis media, dental infections, bacteremia, inoculation
-in AIDS patients: toxo, nocardia, TB, listeriosis, crypto, aspergillosis
Epidural Infections
-usually bacterial and almost always secondary to head trauma
-more common in the spinal canal with a true epidural space; compression of the spinal cord can result leading to ischemic necrosis (a surgical emergency)
-mycobacterial infection also a common source of compression
Subdural Infection
-usually bacterial pyrogenic that can be loculated with focal abcesses or a massive empyema
-usual route is through paranasal sinuses
What is the pathogenesis of acute bacterial meningitis?
Inflammatory response with neutrophil migration to the CSF --> meningeal inflammation compresses arterial blood flow through the subarachnoid space causing brain ischemia --> edema fluid escapes parenchymal vascular bed causing swelling of the brain and increased ICP --> CSF glucose levels fall causing increased anaerobic metabolism and CSF protein rises with breakdown in the blood-brain barrier
Chronic Meningitis
-TB: granulomatous inflammation can be seen throughout the meninges, most severe at base of brain around the brainstem and sc; frequently obstructs CSF outflow from 4th ventricle
-SYPHILIS: lymphocytic infiltrate of CSF found in early infection; three froms of tertiary neurosyph 1) meningovascular (meninges) 2) paresis (parenchyma) 3) tabes dorsalis (long tracts of sc, dorsal roots)
-LYME DISEASE: borrelia burgdorferi infection with cranial and spinal root involvement
Fungal CNS Infection
-cryptococcus is most common fungal infection producing chronic menigitis
-common with AIDS and immunosuppression patients
-hematogenously spread from a primary lung focus (primary infection is asymptomatic, prevalent in pigeon poop)
-can be found in CSF with "india-ink" test
Protozoal CNS Infections
-TOXOPLASMOSIS: most common opportunistic infection of brain in AIDS patients (also immunocompromised and neonates)
-present in animal feces and raw meat, reaches brain by blood stream
- a lesion forms that looks grossly like an abscess with central necrotic tissue and little macrophage activity; toxo is toxic to small vessels and creates and expanding area of infarction
-CONGENITAL TOXO: transplancental transmission during the 3rd - 7th month of gestation; causes widespread destruction of central grey and white matter with cystic degeneration and calcification
-others (uncommon): Naeglaria, entameba histolytica, hartmannella-acanthameba (normal gut organism that affects immunocomprimised), trypanosomes
Multicellular Parasite CNS Infection
-CYSTICERCOSIS: larvae of pork tapeworm Taenia solium, common in Central and South America; larval lesions due to ingestion of ova in food contaminated by infected people or autoinfection in people with intestinal tapeworm infection; widespread lesions in meninges, parenchyma and ventricles
-ECHINOCOCCAL cysts: larval stage of dog tapeworm, common in areas where sheep are raised
Herpes Simplex Encephalitis
-most common viral encephalitis in immunocompromised hosts, acute focal presentation
-produces asymmetric hemorrhagic necrosis of inferior surface of temporal and/or frontal lobes leading to spread to underlying white matter
-entry through to be through olfactory epithelium or CN 5
-patients die from massive swelling in contained frontal-temporal region
Arbovirus Encephalitis
-usually incidental human infections spread by mosquito or tick bites, endemic and seasonal, acute disseminated presentation
-autopsy shows swollen brains with widespread cell necrosis and microglial invation
-RICKETTSIA: rocky mountain spotted fever, infection of endothelial cells causes brain edema and death due to swelling
-ENTEROVIRUS: poliomyelitis, predilection for motor neuron infection in anterior horns and brainstem
HIV Encephalitis
-HIV can produce a chronic encephalitis or myelitis
-primarily confined to lymphocytes or monocytic cells
-characteristic lesions are multiple foci of white matter degeneration with clusters of microglial nuclei
-multinucleated giant cells have HIV identified in microglial cells
-loss of cortical neurons and pruning of dendritic arborizations of cortical neurons may be responsible for dementia seen with infection
-
Progressive Multifocal Leukoencephalopathy (PML)
-opportunistic infection in AIDS patients and immunosuppressed organ transplant patients
-confined to white matter where there are multiple centrifugally expanding areas of myelin degeneration
-oligodendrocyte nuclei at expanding margins are swollen and filled with JC virus
-astrocytes may be infected but do not replicate the virus
-
Subacute Sclerosing Panencephalitis (SSPE)
-persistent viral infection which has almost disappeared with the invention of the measles vaccination
-found in kids with typical measles syndrome of pharyngitis who recovered and ultimately died due to progressive deterioration fo the CNS (atrophy and gliosis of cortex and white matter)
-intranuclear inclusions were filled with paramyxovirus nucleocapsid in neurons, oligos and astrocytes
-viral RNA is passed from cell to cell through adhesions by viral neuraminidase
-encephalopathy not due to virus entering the brain rather due to an autoimmune demyelination (post-infectious encephalomyelitis
Prions
-neurogenerative diseases that are both genetically inherited and transmissible
-CJD: sporadic form, rapidly progressive dementing illness lasting a few months; spongy degeneration of background neuropil with neuronal loss and some astrocytic proliferation; infectious agent can be transmitted (others are fatal insomnia, GSS and vCJD)
-infectious protein encoded by a gene present in normal ppl; normal PrP is post-translationaly modified to PrPSc which is resistant to proteases; 10% is familial
-see rapid dementia, ataxia and myoclonus
Demenitia in General
- age is most significant risk factor, 5-10% of population aged 65-75 has dementia, 10-15% from 75-85 and 50% over 85
- "an aquired persistent impaiment of intellectual function that involves memory and one other area of cognitive function (language, visuo-spatial skills, emotion/personality, abstration, judgement, etc.) that is severe enough to interfere with ADLs
- presenile dementia<65 and senile>65
- vs. delirium: due to different etiologies; dementia = chronic progressive course of cognitive impairment; delerium = acute and affects global cognitive function and alertness
What are the causes of Dementias?
-Degenerative (Alzheimer's, Huntington's, Dem. with Lewy Bodies, Frontaltemporal, Prions)
-Endocrine (hypothyroid, hypo- hyperparathyroid, pit dz, adrenal dz)
-Metabolic (ETOH, electrolyte disturbance, renal dz, B12/folate def.)
-Exogenous (toxins, drugs)
-Neoplasms (CNS tumos, paraneoplastic syndromes)
-Trauma
-Infection
-Affective Disorder (depression)
-Structural (vasculitis, normal pressure hydrocephalus)
How do you diagnose dementia?
HPI
-onset of disease (acute or gradual)
-memory problems, use of language, psychiatric manifestations, ADLs
PE
-appearance and affect
-mental status exam: MMSE has low sensitivity but is specific for cognitive impairment
-Lab tests: BLOOD STUDIES - Dementia panel including CBC, B12, glucose, electrolytes, calcium, TSH, RPR, and HIV),LFTs, blood cultures, vasculitis screens; IMAGING STUDIES - evaluate for subdural hemorrhage, generally MRI or CT; EEG (rule out seizures); CSF; Functional imaging (PET and SPECT looking for regional decreases in brain activity); Genetic studies (generally not performed except for rare incidences familial forms of AD, FTD, Huntington's or Prions)
Alzheimer's Disease
-most common cause of dementia in the elderly (10% of people over age 65 and 50% over age 85)
- clinical features: short term memory loss followed by differing degrees of disorientation to "3 As"- agnosia (forgetting to use common items), apraxia (difficulty with learned motor movements), aphagia (difficulty with understanding or expression)
-frontal release signs (snout, grasp, palmomental, rood and suck) can be observed early on
-should not have focal weakness or numbness
-in later stage of dz may show gegenhalten (increased mm. tone), myoclonus, and seizures; if in early stages may think of some other dz process
-patients die from aspiration pneumonia or sepsis from bladder infection
-Three major diagnostic catagories: 1) definite AD- pathologically confirmed with characteristic plaques and tangles 2) probable AD- clinical criteria suggest AD only cause of dementia 3) possible AD- AD present with other conditions contributing to the demented syndrome
-genes associated: Presenilin1 (PS1), Presenilin2 (PS2), APP and ApoE
Dementia with Lewy Bodies
-main features: mild parkinsonism (rigidity, bradykinesia, hypophonia, reduced facial expression, tremor), hallucinations ("friendly type" that they are fully aware are hallucinations) and large fluctuations in level of alterness/conciousness
-parkinsonian features not as responsive to meds as in normal Parkinson's
-brain path shows nuclear inclusions consisting primarily of alpha-synucelin scattered throughout the neurons rather than isolated to dopamine neurons
Frontotemporal Dementia (FTD)
-compromise 10% of dementia patients and 20% of those patients under 60
-early appearance of behavior/personality changes (impulsivity, decrease in tact, public exposure, stealing, etc)
-on exam will see "frontal release" symptoms (grasp, snout, and palmomental (scratching the palm causes the ipsilateral chin to itch
-memory not affected early in the disease due to location along with visuospatial
-some pts. have language function affected early, progression of the disease leads to a common feature of reduced speech output and mutism
-called tauopathies as tau is the central protein
Vascular Dementia
-commonly thought of in two ways: 1)multi-infarct dementia (MID), patient has several subcortical strokes to global loss of cognition 2) Binswanger's disease, repeated small lacunar type strokes leading to white matter encephalopathy: difference between the two are determined by CT or MRI
-usually see a "step-wise" decline rather than a gradual one
-characteristic features: hypertension, abrupt onset of symptoms after recovery, gait difficulty, inappropriate emotionalism
-most probably coexist with AD
Normal Pressure Hydrocephalus
-classice triad 1)gait disturbance 2)urinary incontinence and 3)dementia; may also show spasticity in lower extremities and decreased coordination in upper extremities
-less cortical pathology ("3 A's") than seen in AD
-usually have a history of head trauma/subarachnoid hemorrhage, cause is scarring of arachnoid granulations preventing CSF resorption
-treatment is usually placement of a shunt to divert CSF out of the brain into the peritoneum
AIDS Dementia Complex/HIV Encephalopathy
-observed in 70% of patients with AIDS, common in late disease
-insidious onset with forgetfulness, apathy, social withdrawl, impaired balance, leg weakness,etc.
-on exam will see cerebellar ataxia, upper motor neuron signs of weakness, hyperreflexia, extensor plantar responses
-could see myoclonus, seizures, quadraparesis and psychosis
-MRI shows diffuse atrophy of white matter involvement
What is the therapy for dementia?
-best known treatment of AD is cholinesterase inhibitors (tacrine, donepezil, rivastigmine, and galantamine) that inhibit activity of acetylcholinesterase increasing ACh in the post-synaptic terminal --> better memory formation
-effect on the patient is subtle and tends to stabilize the disease rather than improve symptoms
-also use NMDA partial antagonists (memantine) that protect from glutamate toxicity and stimulate memroy formation --> statistically significant affect when combined with anticholinesterase in late AD
What happens in neurodegenerative diseases of the sc? cerebellum? hippocampal area? and frontal cortex?
-sc: muscle weakness
-cerebellum: ataxia
-hippocampal area: memory deficits
-frontal cortex: apathy, disinhibition, or depression
What are the diseases of the archicortex and neocortex and how do they present?
-AD, Dementia with Lewy Bodies, Pick's disease, FTDP-17, Corticobasal degeneration
-dementia with problems like impaired memory function or personality changes
What are the diseases of the basal ganglia and how do they present?
-Parkinson's, Huntington's, Triatonigral pattern of multiple system atrophy
-movement disorders with abnormalities in muscle tone and speed of movement
What are the diseases of the brain stem and/or cerebellum?
-Progressive supranuclear palsy (PSP), Spinocerebellar ataxias, Dentatorubropallidoluysian atrophy
-movement disorder with cerebellar features/ataxia (not PSP)
What are the diseases of the sc and how do they present?
-motor neuron disease, ALS, spinal muscular atrophy, Friedreich's ataxia
-variable presentation with mixed upper and lower neuron signs, weakness or ataxia
Pathology of AD
-prominent changes in medial temporal lobes grossly
-two main histologic changes are neurofibrillary tangles (hyperphosphorylated tau protein most seen in large pyramidal neurons)and senile plaques (extra-cellular accumulations of beta-amyloid; can distinguish diffuse, neuritic and burnt-out
-also see hirano bodies in hippocampus with degeneration
Parkinson's Disease (Lewy Body disease)
-presents with bradykinesia, rigidity and tremor
-primary feature is neuronal loss in pars compacta of substantia nigra, pigment-laden macrophages ("tomb-stones") can also be found; lewy bodies are a very helpful diagnostic feature (homogeneous red/eosinophillic core surrounded by a clear halo
-accidental ingestion of toxin MPTP has been linked to parkinson-like dz in humans
-has been linked to mutations in alpha-synuclein, parkin, DJ-1 and PTEN-induced kinase 1 which may cause mitichondrial and oxidative stress, also leading to accumulation of substrates
Pick's Disease
-one of the more rarer forms of dementia
-atrophy in fronto-temporal distribution with thin atrophied cortical ribbons, caudate has significant atrophy mimicking Huntington's
-see Pick bodies histologically that are prominent in the pyramidal cells of the hippocampus, look like "ballooned neurons"
-characterized by accumulation of 3-repeat tau isoforms
-80% are sporadic
Corticobasal Degeneration (CBD)
-affects the neocortex and basal ganglia (atrophy with pigment loss of the nigra) clinically manifesting as akinetic rigid syndrome with dementia (movement and dementia)
-cells look like Pick cells "ballooned neurons"
-is a tauopathy with 4-repeat tau
Progressive Supranuclear Palsy (PSP)
-downward gaze is preserved as a reflex movement and patients loose their ability to voluntarily gaze downwards followed later by upward gaze
-can affect multiple nuclei leading to a diverse and variable presentation
-grossly is not associated with alterations
-hyperphosphorylated tau are 4-repeat tau along with CBD, can be hard to distinguish between the two
Huntington's Disease
-dominant neurodegenerative movement disorder primarily affecting the basal ganglia, patients can develop dementia late
-see degeneration of normal function in striatum (caudate and putamen) manifesting as chorea and rigidity
-histologically see neuronal loss (faster in small to medium sized GABAergic neurons) and gliosis
-caused by an increased number of CAG repeats in huntington gene on chromosome 4 <29 not associated wtih disease state >40 typically means clinical disease, increase in number means increase in severity and degrease in age of onset
Multisystem Atrophies (MSA)
-presentation depends on what nuclei are primarily affected
-striatonigral atrophy = parkinsonism; olivopontocerebellar atrophy = ataxia; Shy-Drager = degeneration of sympathetic preganglionic cells
-see glial cytoplasmic inclusions
-abnormal accumulations of MSA have a tubular morphology
Cerebellar ataxias
-triplet repeat diseases causing protein accumulations that can be seen as nuclear inclusions, diseases are not associated with distinct pathologic changes
-group includes spinocerebellar ataxias and others like dentatorubruopallidoluysian atrophy
Friedreich's Ataxia
-autosomal recessive disease linked to a GAA triplet repeat expansion in centromeric frataxin gene on 9q
-patients develop ataxia, sensory neuropathy, cardiomyopathy and diabetes mellitus
-see degeneration of dorsal root ganglion cells, dorsal columns, and cerebellar tracts
Motor Neuron Disease (ALS)
-primarily affects the primary motor neurons in sc (anterior horn cells or lower motor neurons), CN motor neurons and pyramidal neurons in primary cortex
-see a mixture of UMN and LMN degeneration
-most cases are autosomal dominant and some have Cu/Zn superoxide dismutase gene mutations
Spinal Muscular Atrophy (SMA)
-genetically determined degenerative diseases of LMN associated with anterior horns, the roots look shrunken
-SMA1 is most severe in acute infantile form also known as Werdnig's Hoffman disease, infants are "floppy" at birth and die of early due to respiratory failure
What are seizures?
-acute onset of neurologic dysfunction symptoms
-paroxysmal episodes of brain dysfunction manifested by stereotypical alterations on behavior; symptoms (sensory, motor, autonomic w/ or w/o loss of conciousness
-excessive or oversynchronized discharges of cortical neurons or ineffectice recruitment of inhibitory neurons together with excessive neuronal excitation, imbalance of GABA/NMDA
-epilepsy = recurrent unprovoked seizures
What is the pediatric vs. adult etiology of seizures?
PEDS: genetic, congenital malformations, infection, tumor, metabolic disorder, idiopathic
ADULTS: tumor, trauma, vascular, infection, occult cortical dysplasias, idiopathic
What are the partial seizures?
SIMPLE PARTIAL SEIZURES: no impaired conciousness; motor symptoms - involves motor strip, abnormal movements of extremities, jacksonian March-spread over motor strip, Todd's paralysis post-ictal weakness of seizing limb; sotmatosensory - sensory strip involvement, temporal (hearing or smell) occip (visual); autonomic - temporal lobe (tachycardia, pallor, flushing, sweating); phychological - frontal or temporal (patients are aggitated)
COMPLEX PARTIAL: impaired conciousness, onset followed by loss of conciousness, can progress to a generalized seizure, frequently seen in adult onset epilepsy, usually found in temporal lobe
What are the generalized seizures?
-always occur with a loss of conciousness
-can be convulsive or nonconvulsive movements
-types: absence (starring spells), clonic (convulsive), tonic (stiffness), tonic-clonic, myoclonic (rapid jerks), atonic (drop attacks)
What are Psuedoseizures/Psychogenic seizures?
-seizure-like episodes without abnl cerebral discharge
-may be psychiatric
-movements are not tonic-clonic, video EEG can be helpful in dx
How do you diagnose epilepsy?
-can be done on clinical history alone: H&P important in evaluating type and etiology of seizure/syndrome
-Lab and imaging: rule out metabolic disorders and structural lesions
-EEG: aid in the diagnosis and characterization of seizure type/syndrome
Electroencephalography (EEG)
- measure of electrical activity (post-synaptic currents, IPSP and EPSP) produced by brain and recorded by electrodes on the scalp
-determines level of alertness/encephalopathy and stage of sleep
-EPILEPTIFORM DISCHARGES: abnormal wave forms (sharp waves, spikes, spike and wave, polyspike and wave); change must break from the background (change in frequency, sudden onset and termination, should last greater than 10 sec)
What are febrile seizures?
-seen from 6 mo. to 6 y.o.
-brief tonic-clonic seizures not associated with infection or other cause
-EEG abnl only during seizure
-possibly related to too rapid of a rise in a fever
-prognosis is good as most outgrow the seizures by 5, don't always treat with meds
What are Infantile Spasms?
-onset < 6 mo., spasms are less than 5 sec.
-head drop, neck flexion, arm extension or a mix
-EEG - hypsarrhythmia (disorganized chaotic background)
-treat with depakote w/ ACTH possibly; also surgery if focal area is found
What is Lennox Gastaut Syndrome?
-age of onset 6 mo. - 2 yrs, different types of seizures (complex partial, generalized, drop attacks, etc.)
-associated with mental retardation, EEG shows slow spike and wave
-usually follows infantile spasms
What are Absence Seizures?
-onset < 13yrs, conciousness impaired by "starring spell"
-very brief < 10 seconds, sensitive to hyperventilation
-very responsive to Ethosuxide (dramatic improvement) and can be outgrown
What is Myclonic Epilepsy?
-Juvenille Myoclonic Epilepsy is the most common with onset in the teen years
-usually generalized convulsive seizures, sensitive to sleep deprivation and photic stimulation
-responds well to Valproic Acid (Depakote)
What is temporal lobe epilepsy?
-onset in late tenns/early adult, mostly idiopathic
-complex partial seizures are mostly seen; EEG shows focal discharge from temporal lobes
-can see hippocampal atrophy/sclerosis on imaging
-doesn't respond to meds, can respond very well to surgery if an appropriate candidate
Dilantin/Fosphenytoin
-good for focal and generalized seizures
-affects sodium channels
-works through the P450 system
-TOXICITY:ataxia, nystagmus, sleepiness
-SEs: rash, tremor, hepatotoxicity, purple glove, increased fatial har, gum hypertrophy (avoid use in teens)
-watch out fo rapid infusion bradycardia/heart block
Phenobarbital
-good for focal and generalized seizures
-affects Na channels and GABA receptors
-popular with babies, easy to get levels
-watch for respiratory depression/hypotension with rapid IV infusion
Valproic Acid/Depakote
-good for GENERALIZED seizures
-affects Na channels and GABA receptors
-P450 enzyme inhibitor
-can cause elevated LFTs and liver failure; also pancreatitis, thrombocytopenia, rash, tremor, sedation
Carbamazepine/Tegretol
-good for focal onset seizures, could aggravate generalized epilepsies
-Na channels are affected
-STRONG P450 INDUCER = DRUG DRUG INTERACTIONS
-SEs: rash, elevated LFTs, hyponaturemia
-TOXICITY: tremor, sedation, n/v, double vision
Topiramate/Topamax
-good for focal and generalized
-Na channels, GABAa receptors and glutamate receptors affected
-SEs: weight loss, sedation, kidney stones, inability to sweat
-also used in chonic migranes
Lamotrigine/Lamictal
-focal and generalized
-affects Na and glutamate
-"stimulant" effect (insomnia)
-NEVER USE WITH DEPAKOTE
Levetiracetam/Keppra
-focal and generalized seizures
-unclear mechanism of action, renally excreted
-associated with rare mood swings and ataxia
Ethosuximide/Zarontin
-absence seizures only, affects Ca channels
-SEs: GI upset, rash, rare - SLE agranulocytosis, parkinsonian changes
Status Epilepticus
- a NEUROLOGIC EMERGENCY
- a seizure that lasts greater than 30 minutes, greater than 2 seizures in a row without regaining conciousness in between
-new onset seizures, infection, trauma, SAH, stroke Drugs, etc.
-treatment: ABCD, Lorezepam, phenytoin, and do labs (CBC, LFTs, head CT, drug screen and possible LP)
-second and third line treatments: phenobarbital and depakote; ICU admission, intubation, pentobarbitol and midazolam