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CNS PATHOLOGY A.

INTRODUCTION TO CNS PATHOLOGY Neuronal reactions to brain injury Chromatolysis: perikaryon reaction Acute reaction: Cell body swelling, peripheral displascement of nucleus and Nissl substance Red neuron Acute reaction: cell body shrinkage, cytoplasmic eosinophilia (red neuron) and edema, pyknosis of nucleus and Nissl substance Acute brain ischemic lesion Micro: No nucleoli, dense chromatin, preservation of nuclei, eosinophilia, chromatolysis, triangular shape Location: hippocampus CA1 and CA3, 4 sectors, Layer 3&5 of neocortex, Purkinje cells (in cortex and cerebellum) Chronic brain ischemic lesion Micro: sharp edge neurons, nuclear degeneration, cork-screw axons, macrophage infiltration, homogenous change, deeply eosinophilia Consequences: neuronophagyscavenger cells(microglia) are present, neutrophils are found only in suppuration Neuronal atrophy Micro: accumulation of pigment (lipofuscin), nerve degeneration Characterstic of Alzheimers diseases Paarkinsons disease Amyotrophic lateral sclerosis Slow progressive degeneration In prolonged cell deathnumeric neuronal atrophy Hallmark: glial reaction Transynaptic degeneration Micro: cell body hypertrophy, cytoplasm vacuolization, bizarre cells(fenestrated/binuclear neurons)which are signs of neuronal hypertrophya pathologic finding in transsynapic degeneration Site of neuronal atrophy: lateral geniculate bodies, mamillary bodies, neurons of gracile and cuneate nuclei in medulla, lower olivary nucleus Intraneuronal deposits Lipofuscin Present with increasing age Pathological: ceroid-lipofuscinosis due to unknown enzyme deficiency Neuronal mineral Calcium: Psammoma bodies in meningioma Iron: old infarcts, chronic trauma, tertiary syphilis 1

Viral inclusions Cowdry bodies-Herpes virus Owl-eye inclusions: Cytomegalovirus Negri intracytoplasmic bodies: Rabies (rhabdoviridae) Lewy body: Parkinsons disease Neurofibrillary tangles: Alzheimers disease Neuritic plaquesamyloid deposits: Alzheimers disease Neurolipidoses Accumulation of neurolipids Often due to enzyme deficiencies Ganglioside: Tay-Sachs disease Sphingomyelin: Niemmann-Pick disease Glucocerebroside: Gauchers disease Lipid deposits in astrocytes: tuberous sclerosis Glial cells Restoration Regeneration: axonal regeneration Repair: gliosis(glial scarring),neurons are post-mitotic therefore no regeneration= hypertrophy and hyperplasia of fibrillary astrocytes Gliosis may be (a) anisomorphic: cortical scarring; (b) isomorphic: white matter scarring Reactive gliosis will produce excess GFAP (glial fibrillary astrocytic protein) with pink cytoplasm Astrocytes in CNS repair Initially: protoplasmic astrocytes, Late repair: fibrous astrocytes Gemistocytic (reactive) type astrocytes can be found in tumours, with tissue destruction and repair, Rosenthals fbiers and corpora amylacae ( pineal gland) Conversion to fibrillary astrtrocytesgliosis/astrocytosis no fibrosis Alzheimers disease and astrocytes Type I glia: giant, bizarre, eosinophilic, multinucleated astrocytes In white matter Also present in tuberous sclerosis Type II glia: lobular and large nuclei, thick cell membrane astrocytes In late stages of liver disease found in gray matter Type III glia: amorboid glia, haphazard distribution Oligodendrocytes Very vulnerableonly present in white matter They produce myeline and are responsible for mainting myeline sheaths In a demyelnating diseasethere will be loss of oligodendrocytes Microglia The phagocyte of the brain Rod cellsactively phagocytic Foamy cellslipid laden (converted rod cells) 2

After cerebral infarct: microgliamacrophages Tissue reactions to injury Atrophy and edema Senile/pigemented atrophy: lipofuscin Numberic atrophy: >90yoa in otherwise healthy, but seem much earlier in those with advanced arteriosclerosis Edema accumulation of fluid within brain tissue brain volume Consequence of blood brain barrier breakdown ICP ncrease develops because there is no lymphatic drainage in the brain (a) Vasogenic brain edema Etiology: disruption of blood brain barrier increased vascular permeability fluid and plasma protein extravasation extracellular fluid Prominent in white tumour Clinically most common Associated clinical features: tumours, infarction, abscess, trauma Diagnosis: T2 weighted MRI (b) Cytotoxic brain edema (dry edema) Etiology: cellular swelling due to Influx of waterinterference with ATP use by the cell cell cannot maintain homeostasis Causes: intoxication, hypoxia, nutritional deficiencyes, myelin disease, nutritional deficiencies Mostly in white matter Gross: compressed sulci, engorged veins, widened gyri (c) Interstitial edema Transudation of CSF from ventricles across ependymal lining Pathogenesis: CSF outflow obstructionfluid accumulation often around ventricles (periventricular white matter) Micro: vacuolation of cells, white matter Increased intracranial pressure and its manifestations Papilledema, clouding of sensorium, vomiting, blurring of vision, headache Etiology: presence of expanding lesion, or obstruction of CSF flow Definition: CSF pressure > 200 mmH2O With rapid increase in pressure=herniation, slow increase=no herniation Vascular reactions: fibrinoid necrosis, perivascular cuffing, microthrombosis, ring hemorrhage, endothelial proliferation B. HYDROCEPHALUS & BRAIN HERNIATION I. Hydrocephalus Hydrocephalus: pathological increased in cerebral ventricular volume due to 1. Increased CSF production; or 2. Decreased CSF absorption May be congenital or acquired Clinical Triad: dementia, incontinence, gait disturbance

1. Congenital hydrocephalus a. Arnold-Chiari syndrome Fusion of atlas with base of the occipital bpme Leads to tonsillar and cerebeall r herniation b. Others include: sylvian duct stenosis , sylvian duct forking, DandyWalker, Patybasia; MCC is congenital obstruction of acqueduct of Sylvius 2. Acquired hydrocephalus May be communicating/non-obstructivedue to accumulation of fluid Ventricular system remains open May be due to subarachnoid hemorrhage arachnoid granulation reabsorption Non-comunicating/ obstructive Flow of CSF is blocked within the ventricles, due to tumor, acqueduct stenosis Hydrocephalus ex-vacuo Increase of CSF volume and ventricular dilation due to brain atrophy Also found in Alzheimers disease Normal pressure hydrocephalus Ventricular size increases History may include: head trauma, meningitis, subarachnoid hemorrhage II. Herniation Volume is regulated in the brain by a non-expansible housing intracranial/intraspinal space a space occupying lesionmay be diffuse (edema) or localized ( abscess, tumor, hemorrhage) causes injury Herniation: displacement of brain from one intracranial compartment to another due to increased volume of cranial contents May occur slowly (may be subclinical), or be rapidly evolving ( leading to necrosis and infarct) 1. Cingulate gyrus herniation Also known as subfalcial Herniation beneath the falx cerebri May affect the anterior cerebral arter paresis, sensory loss in legs Subfalcine herniation: mass lesion in ipsilateral hemisphere ACA compression Symptomswhich have to do with body regulation, cognition 2. Uncal herniation May be transtentorial (due to a mass above the tentorium cerebelli 4

Herniationof medial temporal lobe CNS II compression oculomotor nerve palsy Symptoms: eye muscle paralysis, pupildilatation May also have occipital infarction If at midbrain & pons damage to reticular formation Gross: Duret haemorrhages= small areas of bleeding in the central and paramedian parts of the upper brainstem-midbrain and pons Eventually results in death 3. Cerebellar tonsil herniation Pathogenesis: vital centre compression circulatory and respiratory collapse Etiology: often accidental due to lumbar puncture Result: compression of medulla respiratory, cardiac arrest May also see Durets haemorrhages 4. Central/transtentorial Pathogenesis: rostrocaudal displacement of hypothalamus and rostral brain steam Clinical picure: papillary size variation, altered respiratory rhythm Diencephalic: lesion in both cerebal hemisphere ventricular compression increase (progressive) in ICP tearing of vessels, secondary hemorrhage 5. Transcalvarial (fungating) a. Hernia sequelae Lateral asymmetric uncal herniation compression of ipsilateral oculomotor nerve papillary dilatation severe brain stem dysfunction

C. ISCHEMIC & HEMORRHAGIC BRAIN INJURY

TRAUMATIC VASCULAR, 5

Red neurons are hallmark of cerebral ischemia Ischemic penumbra: zone of viable tissue that surround the infarct; these cells are at increased risk of irreversible injury Etiology: excitotoxic injry, neuronal depolarization, impaired microcirculation, neuronal apoptosis Diagnosis: MRI-diffusion weighted=cytotoxic edema; MRI-perfusion weighted=measures blood flow Gross: liquefactive necrosis with macrophage infiltration, hole in the brain Global cerebral ischemiatimeline 0-24 h: normal brain 12-24h: neuronal swelling, nuclear pyknosis & karyorrhexis 24-48h: laminar cortical necrosis, softened and edematous brain, discoloration and areas of hemorrhage Stroke/cerebral vascular accident Mostly ischemic (85%), may be hemorrhagic (15%) Pathology: sudden event with CNS function disturbance due to vascular disease Ischemic Hemorrhage 85% of CVA 15% of CVA Older Younger patient Due to atherosclerosis or Due to hypertension, or embolus thrombosis Death after first attack (usually) Survives first and second attack Severe sequelae Milder sequelae Red infarct White infarct Pathophysiology: Predisposing factoratherosclerosis (affecting larger vessels) thromboemboli/aneurysm CVAinfarction Time line Minutescell death 8-12h: ischemia, inflammation 36-48h: swollen and soft necrotic area, loss of definition between white and grey matter, hemorrhage, mass effect=edema Days: coliquative necrosis, macrophage infiltrationphagocytosis, reactive astrocytes, proliferative capillaries at infarct edge Gross: brown infarcthemosiderin is responsible for pigmentation, cortical layer is spared, healing as pseudocysts Brain infarct and global cerebral ischemia Infarction vs cerebral ischemia GCInecrosis around Purkinje cells, pyramindal cells, lamina CI: may be pale or red, arteries affected correspond to focal neurologic deficits, complication: ICP, brainstem lesion 6

Venous infarction: thrombosis at a cerebral sinus Common sites: internal carotid a affects cerebral hemispheres; orticospinal tract internal capsule contralateral hemiparesis Multiple infarct in cerebral cortexmay be a cuase of dementia Necrosis Watershed: at margins of area supplied by major cerebral artery (ie. middle cerebral artery, posterior cerebral artery) Laminar cortical: indication that some neurons are more sensitive to hypoxia than others Hypertension Hypertensive crisis: sudden elevation of blood pressure 220/140 mmHg Pathology: herniation, mass effect (ICP), brain edema, petechial hemorrhage In small vesselslenticulostriate, thalamostriatearise at right angles from major arteries= high BP causes destruction of vessel wallvessel occlusion or rupture hypertensive ischemic stroke In deep arteries supplying basal ganglia: sudden onsent= intracranial (parenchymal) hemorrhage Hypertensive cerebrovascular disease: Hemorrhage in cerebral parenchyma Leads to lacunar infarcts, hypertensive encephalopathy (Binswanger disease) Charcot-Bouchard aneurysm:military or microaneurysm in small penetrating blood vessles of brainstem and midbrain ( lenticulostriate branch of MCA, for example)associated with chronic hypertension Chronic hypertensive encephalopathy: associated with advanced atherosclerosis, eventually progressing to dementia Brain hemorrhage can happen in blood dyscrasias, such as thrombocytopenia Heals by resorption and gliosis, may see hemosiderin Consequence: apoplectic(apoplexybleeding within a closed space) cyst herniation due to increased ICP, brainstem hemorrhage, rupture into ventricular system & acute hydrocephalus Berry aneurysmsmost common type of aneurysm, often occurring in the Circle of Willis Hypertension is the most common cause of berry aneurysm Arteriovenous malformation Can predispose a patient to intracranial hemorrhage Development abnormality of cerebral vessel 7

Lead to saccular aneurysm (remember, berry aneurysms are also saccular) Often in the distribution of the middle cerebral artery, may be anywhere clusters of cavernous vessels without intervening stroma Genetics: automosal dominant inheritance Hamartomas have similar manifestations Consequence: intracerebral and/or subarachnoid hemorrhage Symptoms: headaches(due to repeted episodes of bleeding) or a single catastrophic bleed (or both) Increased risk with: fibromuscular dysplasia, polycystc kidney disease, Ehlers dDanlos syndrome (vascular type), AVM in the brain, coarcation of the aorta Clinical course: seizures, neurologic deficitis (due to ischemia, chronic compression) Saccular aneurysm Common at internal carotid artery bifurcation Consequence: subarachnoid hemorrhage (most common cause), hydrocephalus, brain herniation, cerebral infarction Intracranial hypertension Raise ICP, CSF pressure >15 mmHg Etiology: rapid expansion of a faocal lesion Raise CSF pressure> 200mgH20 Perifocal reaction: localised bleeding, edema, cell infiltration Tissue compression, displacement and destruction Spinal infarct: rare, usually seen in traumatic injury Spinal transection D. CNS INFECTIONS See Micro lectures Mycobacterium tuberculosis Pathology: meningoencephalitis, chronic meningitis, obliterative endarteritis, tuberculomata, tubercles in subarachnoid space along blood vessels In chronic meningitis: grey-green gelatinous, fibrinous exudates in basal brain surfaces Treponema pallidum Syphillis in the brain Cortical atrophy with iron deposits, microglial proliferation Obliterative endarteritis with lymphocytic cuffing Cortical layers: blizzard blow away cortex Granular ependymitis 8

E. BRAIN TUMOURS Generally, brain tumors are clinical malignant, they do not have a capsule, rarely metastasize Mostly occur in the first decade and the 5th/6th decades May circumscribed, or diffusely infiltrating a. Brain tumours within adults These are rare, and often supratentorial Include: glioblastoma multiforme, fibrillary astrocytoma, meningioma, schwannoma of CN VII b. Brain tumours within children Quite common, most common after leukemias Often infratentorial Include: pilocytic astrocytoma, medulloblastoma, brain stem glioma, 4th ventricle ependymoma 1. Clinicopathological features Local effects: focal neurological signsaccording to site of tumor temporal lobe=epilepsy; spinal cord paraplegia Mass effects: features of space-occupying lesions, vasogenic edema, compression of vital structures, brain herniation Pathophysiology: Increased ICP herniation Etiology: tumor (space occupying), perineoplastic cerebral edema, blockage of CSF flow hydrocephalus, excessive production of CSF choroid tumors If tumor affects cerebral cortex= seizures ( also associated with mental changes, memory deficit, concentration and reasoning) 2. Clinical Manifestations Headache, worsening at night and early morning Projectile vomiting, without nausea Papilledema Sinus bradycardia Hypertension 3. Gliomas Neoplasms of glial cells Most common=astrocytoma, rare=ependymoma, benign=oligodendroma Micro: hypercellularity, infiltrative growth Gross: invasion CSF, perineural invasion Outcome: can spread via CSF, usually not metastatic, may become malignant a. Astrocytoma/glioblastoma 80% of all primary brain tumors Astrocytoma /glioblastoma Most common brain tumor adults Infiltrative, poorly demarcated Well-differentiated and slow growing 9

Glioblastoma multiforme develops in 8-10 mo (Glioblastoma is a malignant form of astrocytoma Astrocytomas in children: infratentorialin the cerebellum; cystic, pilocytic and benign Astrocytoma in adults: supratentoial in the cerebrum, solid, Bfibrillary and malignant Astrocytoma adult Gross: superficial, cortical tumors ( most common least common: parieto-temporal, frontal, basal nuclei, occipital) Malignancy: small tumors, without hemorrhage, non-necrotic are favourable for good prognosis (unfavourable is the opposite) Micro: fibrillaryRosenthal fibers, anaplastic(highly malignant) may be gemistocytic, fibrillary Astrocytoma children Gross: cystic Micro: bipolar elongated cells, Rosenthal fibers, long fibrils, eosinophilic granules Glioblastoma Gross: similar to anaplastic astrocytoma Micro: necrosis, hemorrhage, capillary sprouts, lymphocytic infiltration, monstrous cells Special characteristics: glomeruloid body, pseudopalisading effects Oligodendroglioma Gross: deeply situated, tumor with calcifications Micro: honeycomb features, fried-egg appearance Diagnosis: x-ray, CT, MRI Special characteristics: 50% are mixed type (prognosis-depends on astrom strocytic component) Spinal cord tumours Include ependymoma, neurinoma and meningiom Ependymoma: Located closed to ventricular system, unfavourable prognosis Consequences: hydrocephalus and ventricular dilatation Subtypes: solid/papillary, myxopapillary, subependymoma (nodule in ventricular wall, slow growing), anaplastic Micro: pervascular pseudorosettes, nuclei-free zones=ependymal channels Choroid plexus tumor Intraventricular tumor3rd &4th ventricle affectedhydrocephalus Papillary tumor may mimic the choroid plexus, rare-pleus carcinoma exceptional Micro: hypercelullarity, cuboidal and columnar cells on a fine fibrovascular stroma Medulloblastoma 10

Most common CNS tumor of childhood Rarely occurs >40 yoa Malignant, but sensitive to radiation and/or chemotherapy Can mature into a benign ganglioma Gorss: resembles a lymphoma, central Micro: rosettes Consequence: differentiation to glial cells, neuronal cells, nerve-like structures Primary neuroectoderm tumour Pathogenesis: medduloepitheliomatumour of primitive neurectoderm Least differentiated tumour of the neural tube Neuroblastoma Like medulloblastom, but peripheral Locations: retroperitoneal, adrenal medulla Consequences: differentiation to ganglioneuroma Dysgerminoma Location: third ventricle, pineal region Micro: germ cells (rarely hormonally active) Meningioma Tumor of meningeal sheaths Types: syncytial, fibroblastic, transitional, pasmmomatous, microcystic, papillary Clinical bicture: mass effect, bone destruction Diagnosis: MRIsandglass appearance Dermoid/Colloid cysts Micro: lined by squamous epithelium and filled with keratin(dermoid/epidermoid), or cysts lined with columnar epithelium filled with mucoid material (colloid) Dermoid: slowly expanding, common in temporal lobe Colloid: arise in 3rd ventricle hydrocephalus, blockage of foramen of Munro Primary CNS lymphoma Viral association: EBV infection, AIDS (due to immunosuppression) Gross: nodules, central necrosis, good definition Micro: obviously malignant lymphoid cells, diffuse pervascular distribution, hoppoingreticular fibers around each tumor cell Consequences: poor prognosis Diagnosis: CD20B cell marker Metastatic cancer Lung Melanoma Breast Prostatesoinal cord Kidney

Decreasing incidence

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Choriocarcinoma May lead to contiguous involvement (pituitary adenoma and craniopharyngioma) Etiology pathogenesis factors Genetic: tuberous sclerosis, neurofibromatosis, Von Hippel-Lindau syndrome Secondary tumours may be metastatic or hematopoetic (leukemia, lymphoma) F. NEURODEGENERATIVE DISORDERS May affect the brain cortex (Alzheimers disease, Picks disease=fronto-temporal dementia)) or the basal ganglia and brain stem (Parkinsonism, Huntington disease), motor neurons (amyotrophic lateral sclerosis), spinal column and cerebellum (spinocerebellar degeneration) 1. Alzheimers disease Presenile dementia >50 years, more females than males are affected (increased incideance >65 yoa) Risk factors: APP (amyloid precursor protein) gene mutation chromosome 21, Downs syndrome, tau protein hyperphosphorylation, presenilin mutation, expression of 4 allele of apoprotein E gene APP mutation: A peptide= amyloid A degrading enzyme, normal APP degeneration product May acquire sheet structure APP mutation A peptiteamyloid deposits=plaques in extracellular fluid Tau genemutation Tau is a cytoplasmic proteininvolved in intra-axonal tubule assemble Pathogenesis: tau gene mutation tau hyperphosphorylation neurofibrillary tangel formation aggregation of neuritis and tangles senile plaque formation Presenilin, apoprotein E gene mutation Enhancement of amyloid fibrile formation Pathology Brain atrophy, weight reduction Cortical grey, white matter loss Compensatory secondary hydrocephalus G.PERIPHERAL NEUROPATHIES

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Two patterns of peripheral neuropathies: 1.axonal degeneration; 2.segmental demyelination 1. Mechanisms of degeneration Axonal degeneration Primary injurymyelin sheath disintegration Wallerian degeneration: degeneration of axon distal to injury Occurs secondary to trauma or vascular disease Axonal sprouts: limited regeneration, axons covered by new myelin Axonal regeneration: incomplete regeneration with recovery of function Micro: characteristic myeelin ovoids=degenerating fragments of axons and their myelin sheaths Distal axonal degeneration Nerve cell body injruy Micro: myelin ovoid formation (less conspicuous than in Wallerian degeneration) Segmental demyelination Primary injury of myelin sheath, axon preservation Demyelinated segment acquires new myelin sheath recurrent demyelination & remyelination onion bulb formation Peripheral neuropathy: symmetric sensory loss, atrophy of muscle fibers, muscle weakness Clinical picture: deep tendon reflexes, postural hypotension and constipation( autonomic nervous system involvement),neurologic deficitssecondary to vasculitis a. Leukodystrophy b. Inflammatory demyelinating neuropathies Guillain-Barre-Landry Acute inflammatory demyelinating polyradiculoneuropathy Unknown etiologycan follow a viral infection, mycoplasma infection, due to allergic reaction, surgical procedure, malignancy Pathogensis is likely immunogenic Ascending weaknessdeath from failure of respiratory muscles Micro: infiltration of peripheral nerves by macrophages and reactive lymphocytes+ segmental demyelinaton Treatment: plasmapheresis Chronic inflammatory demyelinating polyradiculoneuropathy Relapses and remissions Micro: similar to GBS, with onion bulbs (recurrent demyelinationremyelination) Treatment: steroids, plasmapheresis 13

c. Hereditary motor-sensory neuropathy Charcot-Mare tooth disease Most common hereditary peripheral neuropathy Genetic: autosomal dominant Etiology: duplication of chr. 17 including peripheral myelin protein 22 Gene for myeline protein zero on chr 1 may be involved Clinical feature: progressive with distal muscle weakness, calf muscle atrophy, pes cavus (high arch in the foot) Micro: onion bulbs Diabetic peripheral neuropathy Etiology: ischemia, metabolic cause of neuropathyunclear Clinical picture: distal symmetric sensory/sensory-motor neuropathy Axonal degeneration, segmental demyelination, secondary to hyaline arteriolaosclerosis in endoneural arterioles 2. Toxic neuropathies Due to chemicals: ethanol (slow), acrylamide, hexane (large caliber axons), organophosphate, vincristine Mostly iatrogenic 3. Neoplasms of PNS Arise from Schwann cells (glial cell of PNS), peripheral nerve sheath cells a. Neoplasms of peripheral nerve sheath Neurofibroma Micro: Antoni A itssuedensely packed spindle cells+ Antoni B tissue loose myxoid region Verocay bodiesformation of palisades with cell nuclei Hyalinization of vascular channel Lipid-laden macrophages Native axons intermingled with neoplastic cells Increased mitoses, cellularitysuspect neurofibromatosis type 1 Common site: 8th cranial nerve (angle between cerebellum and pons) Schwannoma Gross: well circumscribed masses attached to peripheral, cranial nerves(acoustic neuroma) and spinal nerve roots Micro: nuclear palisading, whorls formation, neopalstic cells displaced to periphery Acoustic neuroma difficult to distinguish from meningiomas 14

Neurofibromatosis NF-1 Aka von Recklinghausen disease More common in children than adults Must include 2> of the following 6 light brown spots on skin(caffe-au-lait) spots Two or more neurofibromas or one plexiform neurofibrom Freckling in armpit/groin Two or more Lisch nodules-iris hamartomas nevus Optic glioma Abnormal spine, sphenoid, tibia development First degree relative with neurofibromatosis Malignant peripheral nerve sheath tumors Sarcomas arising from peripheral nerve sheath Usually develops in pre-existing neurofibroma Gross: firm, incompletely demarcates lesions with foci of necrosis and hemorrhage Micro: fibroblast-like cells, elongated nuclei, frequent mitotic figures, necrosis **Triton tumors: MPNSTs and rhamdomyosarcomas H.MYOPATHIES 1. Review of muscle fiber types Motor unit: all fibers of a motor unit are of the same type Type I Type II Red White Slow-twitch Fast-twitch High myoglobin Low myoglobin Metabolism: oxidative Metabolism: glycolysis phosphorylation (many (glycolytic enzymes) mitochondrial enzymes) Rapid, powerful, short Long sustained, weight bearing contractions contractions Dark staining(ATPase at pH=9.4) Light staining(ATPase at pH=9.4)

2. Muscular dystrophy Hereditary, progressive, non-inflammatory degenerative disease of muscle Usually x-linked-- Most common: Duchennes and Beckers Can be autosomal dominant: fascioscapulohumeral, distal, ocular, oculopharyngeal Duchennes 15

Etiology: gene encoding dystrophic on Xp21 region dystrophy is important for myocyte integrity in contraction Clinical features: pseudohypertrophy (proliferation of endomysial connective tissue replaecd by fibrofatty tissue) of calf muscles, Gowers maneuver Wheelchair bound by 10-12 years, death in early 20s Clinical picture: frequent falls, delayed development of muscle skills, drooling, eyelid drooping, scoliosis, contracture deformities Micro: variable fiber size, necrosis and degeneration of myofibers+ myophagocytosis, regeneration of myofibersinternalized nuclei, basophilic cytoplasm; heart: subendocardial fibrosis Labs: increased creatine kinase Diagnosis: electomyogramlow voltage and short duration motor unit potentials/polyphasic potentials ( due to motor unit destruction) 3. Myotonic dystrophy Occurs in late childhood Etiology: trinucleotide repeat CTG near the 3 end of gene (usually several thousand) reduced transcription dystrophila myotonia-protein kinase (encoded by MD gene on 19q) phosphorylation of ion channelsexcitability myotonia Normal: < 30 CTG repeats, minimal effect = 50 CTG repeats Genetics: autosomal dominant inheritance Micro: atrophy of type I, hypertrophy of type II fibers, ring fibers, irregular sarcoplasmic masses Clinical picture: progressive muscle weakness, stiffness, difficulty releasing grip, weakness in hands,wristface(ptosis) Associated findings: gonadal atrophy, cataracts, dementia, smooth muscle Involvement Consequence: anticipationseverity, earlier age of onset with each generation 4. Inflammatory myopathies Immunologically mediated a. Dermatomyositis Proximal skeletal muscle weakness, distal muscles are affected later on Can involve the skin Clinical feature: discoloration of upper eyelids Micro: perivascular mononuclear infiltrates, perifascicular atrophy Complication: increased risk of visceral cancer 16

b. Polymyositis No cutaneous involvement, symmetrical proximal muscle involvement Etiology: damage to myofibers by CD8 T cells No vascular injury Complications: no risk of visceral cancer c. Inclusion body myositis Affects distal muscles first asymmetrical weakness Micro: CD8+ T cells within the muscle, vacuoles within some myocytes, AB peptide (similar to Alzheimers peptide)and hyperphosphorylated tau proteins within myocytes Biopsy: use Congo Red stainfor muscle tissue containing amyloid Treatment: immunosuppresives 5. Myasthenia gravis Autoimmune disease of NMJ Etiology: antibodies to acetylcholine receptors (AChRs ) Clinical features: ptosis, diplopia, generalized weakness; thymic hyperplasia or thymoma may be found Diagnostc: signs improve AChase therapy Treatment: thymectomy is curative; can also give steroids, do plasmapheresis and give anticholisterase 6. Lambert Easton myasthenia syndrome Paraneoplastic syndrome associated with small cell lung carcinoma Etiology: autoantibodies against Ca s+ channels defective release of acetylcholine from presynaptic vesicles (similar to what happens with botulism) Diagnosis: Tensilon test is negative, no anti-Ach R antibotdies Clinical features: weakness, proximal limb,trunk muscle wasting in addition to autonomic dysfunction 7. Multiple sclerosis Abnormalities are primarily confined to the CNS Common sites of demyelination: optic nerves, spinal cord white matter, periventricular white matter Plaques may form close to veins and venules Pathogenesis: Genetic susceptibility & viral interaction Antibodies formed Cross reaction with myelin 17

Autoimmune disease (CD4+ & CD8+ cell mediated) Inflammatory damage to myelin sheaths Areas of demyelinization Plaque formation

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