What Nervous System Disorder Am I?

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diseases in which the myelin sheath is destroyed or disrupted; axons are relatively spared but suffer secondary damage as the disease progresses

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Demylinating disease

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most common demyelinating disease in U.S. and Europe; autoimmune reaction against white matter in the CNS

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MS

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• Neurological deficits separated in time attributable to white matter lesions separated by space
a. Remitting and relapsing; but eventual progress of disease
• PNS white matter is spared
• Associated with DR2 extended haplotype of histocompatability complex; both genetic and environmental factors involved
• T4+ T1H T cells involved; INF-γ secreted-> activates macrophages-> activated macrophages digest white matter
a. Therapies being developed to inhibit T1H
• Women twice as likely to be diagnosed with MS as men; very rare to be diagnosed before 10 or after 50; 1st degree relative increases chances by 15%
• Plaques= brown, glassy; active or inactive; commonly occur alongside the ventricles

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MS

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MS plaques with myelin present, breakdown occurring; macrophages containing lipid rich PAS (+) debris; changes in astrocytes may occur over time; lymphocytes and monocytes in perivascular space

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active MS plaques

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MS plaques with little or no myelin present; reduction in oligodendrocyte nuclei; proliferation of astrocytes and glial cells

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inactive MS plaques

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• Optic neuritis is common first sign as optic nerve becomes involved; unilateral optic deficit
• Cranial nerve signs; opthalmalgia, nystagma, ataxia; due to destruction/involvement of the medial lateral fasiculations
• Motor and sensory loss of trunk
• Incontinence when spinal cord involved
• CSF shows elevate protein levels in most patients and oligoclonial bands

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MS

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Asian disease mimics MS-> plaques are more destructive then in MS, spinal destruction striking

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(neuromyelitis optica/Delvic disease

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young form of MS that results in a fulminant course during several months

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Marburg form

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more diffuse symptoms than MS-> headache, lethargy, coma

follows viral infection or (rarely) immunization to a virus

grayish discoloration around white matter vessels; loss of myelin w/relative preservation of axons; breakdown of myelin associated with lipid ladin macrophages

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ADEM

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similar to ADEM except lesions are more destructive-> damage to small blood vessels, disseminated necrosis of white and gray matter with hemorrhage, fibrin deposition, scattered lymphocytes, many neutrophils

fulminant course-> many fatalities (20%); usually associated with URI

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ANEM

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loss of myelin with relative axon sparing in a symmetrical pattern due to pontis based lesion
• Lesion usually in supratentorial compartment
• Often due to alcoholism, liver transplant, or severe electrolyte imbalance
• Rapid onset quadrapelega, radiological localization of pontine lesion

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Central pontine myelinolysis

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symmetrical myelin degeneration in the fibers of the corpus callosum

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Marchiafava- bignami disease

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damage to grey matter
• Many result in the aggregation of proteins that result in grey matter damage-> “inclusions”; resistant to degradation via ubiquination; cytotoxic
• Neuronal degeneration is selective and diseases often arise w/o preceeding event

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Degenerative diseases

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degeneration disease most commonly found in elderly patients; rare to be diagnosed under 50 but some early onset forms exist.
• Degeneration consists of neurofibrillary tangles, amyloid angiopathy, and neuritic plaques; abundance of Aβ40 and Aβ42
• Degeneration starts with memory loss, personality changes, etc.; progresses to immobile, unresponsive state
• Begins in the entohimal cortex-> hippocampal-> isocortex-> neocortex (Remember: alphabetical order!)

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AD

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• Neritic plaques have both Aβ40 and Aβ42, but diffuse plaques have predominantly Aβ42;
a. Focal, spherical collections of dilated, tortuous, silver staining neuritic processes; often around amyloid core (clear halo)
b. Sparing of primary motor and sensory cortices
c. Diffuse plaques in superficial cerebral cortex-> early alzheimers

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AD

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• microglial cells and reactive astrocytes are found in the periphery of plaques
• Neurofibrillary tangles=bundles of filaments in cytoplasm of neurons that displace/encircle nucleus; flame shaped in pyramid cells
• Decrease in size of gyri, increase in size of sulci; also compensatory increase in vascularization (cortical atrophy)
• Granulovacuolar degeneration= clear interneuronal cytoplasmic vacuoles containing argyrophilic granule; abundant in olfactory bulb and hippocampus
• Hirano bodies= glassy, eosinophilic bodies; paracrystalline arrays of beaded filaments w/actin as major component; hippocampal cells
• # neurofibrillary tangles corresponds with level of dementia; biochm markers include amyloid burden, acetyl cholinesterase absence, etc

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AD

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Protein Aβ formation associated with

found on cell surface, function unknown

endocytosed and processed into Aβ
a. B secretase cleaves region N- terminal of transmembrane domain; γ secretase cleaves transmembrane region
b. Aβ= β sheets that aggregate into plaques

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APP

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associated with chromosome 21-> increased levels of Aβ
a. Also chromosomes 14 and 1-> early onset; acts via prensinelins 1 & 2-> components of γ secretase= more Aβ made

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Familial AD

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• Individuals with ε4 mutation of ApoE gene on chromosome 19; ApoE can bind Aβ/plaques

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AD

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related to chromosome 17->maps Tau production
• Mutations result in different splicing-> W/exon 10 (4 repeat) or w/o exon 10 (3 repeat)
a. Atrophy of frontal and temporal lobes
b. Loss of neurons and gliosis
c. Nigral loss sometimes
d. Presence of neurofibrillary tangles w/either 4 repeat or 3 repeat tau

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Frontal temporal demential/parkinsonian

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lobar atrophy involving frontal and temporal lobes
• Posterior 2/3 of superior temporal lobe spared; parietal and occipital lobes rarely involved
• Early onset of behavioral and personality changes
• Atrophy assumes “knife-like” appearance-> differentiates from AD
• Neuronal loss usually in outer 3 layers of cortex
• Pick bodies= cytoplasmic, oval to round, neurofibrillary inclusions; weakly basophilic, strongly silver staining; tangles contain 3 repeat tau; P. bodies don’t survive death of pt
• Bilateral atrophy of putamen and caudate nucleus sometimes occurs

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Pick disease

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truncal rigidity, disequilibrium, nuchal dystonia; psuedobulbar palsy w/difficulty in speech; ocular disturbances-> initially vertical gaze palsy, eventually all ocular movement; mild progressive dementia
• Occurs 2:1 men; diagnosed in 5th and 6th decade
• Neuronal loss in globus pallidus, subthalmic nuclei, substantia nigra, colliculi, periaqueductal grey matter, dentate nucleus of cerebellum

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Progressive suprnuclear palsy

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affects primary motor, premotor, and anterior parietal lobes;
• Balloon neurons (achromasias) in astrocytes, oligodendrocytes, basal ganglia, and cortical cells
• Loss of pigmentation in substantia nigra and ceruleas
a. Achromasias and tangles
• Pyrimidal rigidity, asymmetric motor disturbances, sensory cortical dysfunction
• Cognitive decline occurs

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corticobasilar degeneration

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result in rigidity, chorea, and postural changes
• Abundance of involuntary, rapid and complex movement; or reduction of voluntary movement

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diseases that affect basal ganglia and brainstem

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characterized by reduced facial expression, stooped posture, festinating (quick shuffle) gait, rigidity, and “pill rolling” tremors
• Have in common lesion/dysfunction of nigrastriatal dopaminergic system (can be induced by drugs that affect this system)

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parkinsonism

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diagnosed in pt with acute parkinsonism w/o toxicity or other etiology
• Pallor of substantia nigra and ceruleus; micro exam reveals loss of pigmented cholinergic cells in these regions due to gliosis
• Lewy Bodies: cytoplasmic, eosinophilic, circular to elongated inclusions of fine fibers containing α synuclein
a. More dense in core, less dense in periphery (halo appearance)
b. Also contain neurofilament antigens, parkin, and ubiquiton
• Level of dementia relative to dopamine deficiency-> can be relieved by L-Dopa but eventually stops working and produces fluctuation

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parkinson's disease

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• MPTP (contaminant of synthesis of illicit psychoactive merpertines)

• Mutations in α synuclein

• DJ-1 mutation

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Causes of parkinson's disease

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• Mutation in gene encoding parkin

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cause of juvenile parkinsons

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• UCH-L1 (enzyme) mutation

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cause of familial parkinsons

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• Clinical course= fluctuations in symptoms-> frontal signs, hallucinations
• Stereo implants of fetal mesencephalic tissue in the striata has shown decrease in symptoms

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parkinson's disease

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characterized by glial cytoplasmic inclusions(usually in oligodendrocytes); considered synucleinopathy but does not stem from mutations to the α synuclein receptor
• Cerebellar atrophy including cerebellar peduncles, pons, substantia nigra, striatum, medulla
• Glial cytoplasmic inclusions include α synuclein, ubiquiton, and αB crystalline
• Main symptoms= parkinsonism and autonomic dysfunction (usually orthostatic hypotension)
• Degree of parkinsonism relevant to inclusions in substantia nigra and striatum; ataxia to disruption of circuits between pons, cerebellum, and inferior olive; and autonomic dysfunction to disruption of the medulla and intermedialateral column in the spinal cord(catecholinminergic nuclei)

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multiple system atrophy

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characterized by progressive motor dysfunction and dementia; death within 15 years; degeneration to striatal neurons
• Brain small in appearance; striking degeneration of caudate nucleus, less striking degeneration of putamen, secondary degeneration of the globus pallidus; degeneration often in frontal lobe, less often in parietal, sometimes in entire cortex
• Enlarged lateral and third ventricles
• Neural loss occurs with both small and large neurons-> small before large; Medium GABA neurons, enkephaline neurons, dynorphin neurons, and substance P neurons particularly affected
• Fibrillary gliosis more extensive than what’s normally seen in glial loss

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Huntington's disease

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• Disregulation of basal ganglia->modulate motor activity; results in loss of inhibitory output to globis pallidus-> increased inhibitory input to subthalmic nuclei-> subthalmic nuclei unable to regulate motor activities as normal->choreoapthetosis
• Gene on 4p16.3 encodes predicting substance huntingtin; normal gene has 6-35 glutamine repeats; disease= more than 35 repeats; the more repeats= earlier onset of disease
• Increased #’s of polyglutamine repeats= protein aggregation= striatal degeneration
• Motor deficits often precede cognitive; early cognitive deficits= forgetfulness, thought affected disorders-> eventually severe dementia; death usually by suicide or infection
• Usually diagnosed in 40s and 50s

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Huntington's disease

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neuronal degeneration affecting cerebellum, spinal cord, peripheral nerves, and other parts of neraxis
• Neuronal degeneration without histopatholigical definition, associated with mild gliosis

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spinocerebellar degeneration

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symptoms referred to cerebellum, spinal cord, peripheral nerves, and other regions in different subtypes
• Neuronal loss from affected areas with secondary white matter degeneration
• Autosomal dominant and recessive forms

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spinocerebellar ataxias

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spinocerebellar ataxia diagnosed in first decade of life
• Begins as gait ataxia, then hand clumsiness, and dysarthria
• Deep tendon reflexes are depressed or absent; plantar flex reflex present
• Joint position and vibration info usually impaired; pain and temp sometimes lost
• Death by pulmonary infection or cardiac disease
• Autosomal recessive-> 9q13 produces frataxin-> GAA repeat expansion results in decreased frataxin levels
• Neuronal loss in posterior columns, corticalspinal, and spinalcerebellar tracts
• Degeneration of neurons in brainstem, cerebellum, spinal cord, and betz cells
• Enlarged heart w/possible pericardial adhesions
• Pes cavus and kyphoscoliosis

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Fredreich ataxia

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spinocerebellar ataxia; autosomal recessive-> 11q 22-23 (telangiectasis locus encodes gene that regulates response to double strand breaks in DNA)
• Generally presents in first decade of life-> recurrent sinopulmonary infections and unsteady gait; speech becomes dysarthric and visual impairment occurs later
• Ataxic dyskinetic disease that is caused by neuronal degeneration in cerebellum-> telangiectasis development in conjunctiva and skin; immunodeficiency
• Damaged DNA replicates w/o cell stopping for repair or apoptosis-> increased cancer risk
• Neuronal loss predominantly in the cerebellum (perkinje and granule cells); also in spinocerebellar tract and anterior horn
• Amphicytes: 2-5X nuclear enlargement
• Lymph node, thymus, and gonads are hypoplastic
• Progress to death by second decade

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ataxia telangectasia

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affects LMN in anterior horns of spinal cord and nuclei of some cranial nerves, UMN in motor cortex
• LMN denervation= muscle weakness, atrophy, and fasiculations
• Clinical presentation= paresis, spasticity, hyperreflexia, babinski sign

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LMN damage

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muscle atrophy and hyperreflexia due to degeneration of LMN in the anterior horns of the spinal cord and UMN projecting into the corticalspinal tract
• Usually diagnosed 50+
• Associated with SOD1 locus on chromosome 21; A4V mutation is most common cause->rapid clinical course/rare loss of UMN
• Anterior roots appear thin and there is neuronal loss in anterior horn throughout spinal cord-> gliosis and loss of myelinated nerves in anterior roots; muscle cells innervated with degenerative LMN may show neurogenic atrophy
• Remaining anterior roots nerves have bubini bodies-> cytoplasmic inclusions that appear to be remnants of autophagic vacuoles; PAS +
• Usually presents with asymmetric hand weakness-> loss of fine motor functions, dropping of objects; cramping/spasticity of arms and legs; fasiculations occur
• Eventually includes respiratory muscles-> pulmonary infections
• Clinical course 1-2 years

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ALS

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X-linked, adult onset; distal limb amyotrophy w/bulbar signs such as atrophy/fasiculations of tongue and dysphagia
• Androgen insensitivity-> gynocomastia, oligospermia, and testicular atrophy
• Cytoplasmic inclusions of aggregated androgen receptor
• Degeneration of LMN in brainstem and spinal cord

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Kennedy Syndrome

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affects LMN in children; like ALS there is selective demyelination/degeneration of anterior roots/horn

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spinal muscular atrophy