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2012-01-19 23:14:38
myelin neuro diseases

Diseases of myelin and neurons
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  1. Class I: Acquired allergic (inflammatory) and infectious diseases (demyelinating diseases)
    • Multiple Sclerosis (MS)
    • Acute disseminated encephalomyelitis
    • Acute hemorrhagic leukoencephalopathy (Weston Disease)
    • Progressive multifocal leukoencephalopathy (PML)
    • Idiopathic polyneuritis (Landry-Guillan-Barre) syndrome
    • Diphtheric neuropathy
  2. Multiple Sclerosis
    • The most common of all CNS myelinating disorders (incidence 1:1000, with females affected more than males)
    • Average lifespan expectancy is 25 years or more
    • Generally a chronic disease with exacerbations and remissions over many years
    • Nerve conduction severly slows
    • Disease is characterized by perivenular lymphocyte infiltration and demyelinating areas (plaques)
    • The plaques have a total absence of both oligodendrocytes and myelin (myelin loss is sharpy demarcated when stained for myelin)
    • Plaques can be inactive (gray, retracted, firm, shaprly demarcated irregularly rounded areas), active (yellow-white, poorly demarcated, and soft with hypercellular perivascular and parenchymal infiltrates, particularly at the plaque's edge), or shadow (having a reduced, but not absent, density of myelin, suggesting remyelination) (see figure below)
    • Plaques may show mixed features and tend to appear in the lateral angles of lateral ventricles, posterior horns, and optic nerves
    • Direct phagocytosis is the mechanism for myelin destruction
    • Patients present with optic neuritis, MLF syndrome (internuclear ophthalmoplgeia), hemiparesis, hemisensory symptoms, or bladder/bowel incontinence
    • Lab findings: Increased protein (IgG) in CSF with oligoclonal bands; MRI shows periventricular plaques
    • Treatment: Beta-interferon, immunosuppresion, natalizumab, and symptomatic treatment
  3. Idiopathic polyneuritis
    • Also called Landry-Guillan-Barre syndrome
    • An acute monophasic inflammatory demyelinating disease of the PNS; there is variable axonal (Wallerian) degeneration
    • It is preceded by viral infection (Campylobacter jejuni, herpes, hepatitis, rabies, measles, or mono), or inoculations
    • Affects the peripheral nerves and motor fibers of ventral roots, with the sensory effect less severe than the motor
    • Causes symmetric ascending flaccid muscle weakness/paralysis beginning in the lower extremety (facial paralysis occurs in 50% of cases); limb paresthesias, loss of deep tendon reflexes, and respiratory weakness also occur
    • Autonomic function may be severely affected
    • Almost all patients survive and recover after a few weeks/months
    • Lab findings: Increased CSF protein with normal cell count (albuminocytologic dissociation) and increased protein (causing papilledema)
    • Treatment: Respiratory support, plasmapheresis, IV immune globulins, physical therapy
  4. Diphtheric neuropathy
    • Caused by Corinebacterium diphtheriae
    • Considered a toxic demyelinating disorder because the bacteria's endotoxin is what causes myelin breakdown
    • The endotoxin has a high affinity for PNS internodes (where it produces membrane pores) and Schwann cells (where it inhibits protein synthesis)
  5. Class II: Genetically inherited disorders affecting myelin (Leukodystrophies)
    • Leukodystrophies deal with problems in myelin formation and maintenance
    • The loss of myelin the CNS is massive, with huge, diffuse areas that are usually symmetric
    • Peripheral myelin in sometimes affected, and lesions may sometimes be found even outside of the nervous system
    • Onset is early in life, but later onset forms also exist
    • Some have sudanophilic degradation products, while others fail to stain with sudan or oil red O stains
    • Includes:
    • 1. Lysosomal disorders: metachromatic leukodystrophy and Krabbe's disease (globoid-cell leukodysrophy)
    • 2. Peroxisomal disorders: adrenoleukodystrophy, Refsum's disease (phytanic acid storage disease)
    • 3. Disorders involving the myelin proteins: Pelizaeus-Mertzbacher disease and Charcot-Marie-Tooth
    • 4. Disorders involving amino acid metabolism (Canavan's disease and PKU)
  6. Metachromatic leukodystrophy (MLD)
    • An autosomal recessive lysosomal disorder caused by deficiency in cerebroside sulfate sulfatase (arylsulfatase A or sulfatide sulfatase)
    • Without this enzyme, acidic sulfatide substrates build up in the lysosomes in glial cells (oligodendrocytes and Schwanna cells), and in the myelin membrane
    • Sulfatides also accumulate in other tissues to form metachromatic lamellar inclusions
    • There is diffuse and symmetrical loss of myelin that apres only the most superifical fibers (called U-fibers)
    • The white matter is chalky and firm, and shows a loss of oligodendroglia and gliosis
    • Macrophages exhibit metachromasia and turn brown when stained with cresyl violet or toluidine blue
    • Symptoms: Characterized by severe demyelination, blindness, loss of speech, and peripheral neuropathy and seizures
    • Diagnostic precursor is an enzyme assay
  7. Globoid cell leukodystrophy
    • Also called Krabbe's disease
    • An autosomal recessive disease caused by a deficiency in galactocerebroside-beta galactosidase
    • Unique in that the natrual substrate (galactocerebroside) does not accumulate; instead galactosyl sphingosine accumulates and has toxic effects on oligodendrocytes and Schwann cells
    • Major CNS pathology is severe loss of myelin in cerebellar and cerebellar white matter and astrogliosis
    • Disease is characterized by multinucleated globoid cells (macrophages), which aggregate in clusters in the white matter (these are neither sudanophilic nor metachromatic)
    • *Unlike MLD, globoid cells are filled with elongated tubules
    • The PNS shows segmental demyelination and neuronal degeneration
    • Onset is between 3 and 6 months
    • Symptoms: Severe motor and mental retardation, blindness, and deafness
  8. Adrenomyeloneuropathy (AMN)
    • A milder, clinical varient of Adrenoleukodrystrophy (ALD)
    • Characterized by progressive demyelination, adrenal insufficiency, and high levels of ACTH
  9. Adrendoleukodystrophy (ADL)
    • The most common leukodystrophy, it is X-linked with childhood onset (school-aged)
    • Patients die within 2-3 years after onset
    • Most notable for the principal involvement of two organs: brain and adrenals
    • ADL is characterized by severe demyelination, CNS inflammation, and adrenal insufficiency
    • Mechanism: Peroxisomal oxidation of very long chain fatty acids (VLCFA) is decreased, causing an increase in VLCFA in cholesterol esters, sphingomyelin, and gangliosides; VLCFA lipis are also increased in the blood, adrenal cotex, and testis
    • Histology: Degradation products are sudonophilic, with abundant perivascular inflammatory infiltrates of mononuclear cells and lymphocytes; many macrophages have a striated cytoplasm
    • Symptoms: Severe mental retardation
    • Postnatal diagnosis is made by determining VLCFA in plasma, RBCs, and cultured skin fibroblasts, as well as a linkage analysis with a DNA probe (prenatal is same but done in cultured amniocytes)
    • Treatment: Diets low in VLCFA and monounsaturated fatty acid supplementation (does not prevent neurologic manifestation); gene therapy can arrest the disease
  10. Refsum's Disease
    • Also called phytanic acid storage disease
    • Is an autosomal recessive disorder characterized by the accumulation of phytanic acids because of an enzyme defect in phytanic acid alpha-hydroxylase
    • Phytanic acid is exclusively exogenous in origin, coming from dairy products and ruminant fats
    • Symptoms: Retinitis pigmentosa, peripheral polyneuropathy, and cerebellar ataxia
    • Postnatal diagnosis involves determining plasma levels of phytanic acid
    • Treatment: diets low in phytanic acid and periodic plasmapheresis to reduce phytanate plasma levels
  11. Pelizaeus-Mertzbacher disease
    • Also called sudanophilic leukodystrophy (SLD)
    • An X-linked recessive trait caused by mutations in the PLP gene, resulting in improper formation of the myeline sheat at the intraperiod line (it's not compacted properly)
    • Characterized by an almost complete lack of myelin, with oligodendrocytes reduced in number
  12. Charcot-Marie-Tooth-1A (CMT-1A)
    • Inherited in an autosomal manner
    • Caused by duplication of hte PMP-22 gene
    • Characterized by severe segmental demyelinatoin of peripheral nerves, partial remyelinatoin, and onion bulb formation
  13. Charcot-Marie-Tooth-1B (CMT-1B)
    • Caused by mutations in the P0 protein
    • Characterized by severe segmental demyelination, partial remyelination and onion bulb formation
  14. Charcot-Marie-Tooth-X (CMT-X)
    • An X-linked form of CMT
    • Caused by mutations in connexin-32 (a gap junction protein)
    • This is localized in the paranodal membranes of PNS myelin sheaths
  15. Charcot-Marie-Tooh Disease
    • Also known as hereditary motor and sensory neuropathy (HMSN), it is the most common inherited neuropathy
    • CMT is a group of progressive hereditary nerve disorders that are related to the defective produciton of proteins that involved in the structure and function of peripheral nerves or the myelin sheath
  16. Canavan's disease
    • Also called spongy degeneration of myelin
    • Is an autosomal recessive trait caused by mutation in the N-acetyl aspartic acid deacyclase enzyme, leading to accumulation of N-acetyl aspartic acid (NAA)
    • Characterized by edema of the white matter and extensive myelin loss
    • The myelin sheath also splits athe intraperiod line
    • Mechanism affecting myelin maintainance i still unknown
    • Canavan's resembles the toxic effects seen with hexachlorophene
  17. Phenylketonuria (PKU)
    • An autosomal recessive disorder characterized by defect in phenylalanine hydroxylase such that phenylalanine cannot be converted to tyrosine
    • High phenylalanine metabolites inhibit cholesterol biosynthesis and fatty acid desaturation (why unsaturated fatty acids in myelin lipids are low)
    • Low levels of Tyr and Trp in the brain reduces protein synthesis
    • Symptoms: patients have a musty odor, may be hypopigmented (tyrosine is a precursor for melanin)
  18. Hexachlorophene neuropathy
    • A toxic agent that affects myelin (Class III) by splitting of the intraperiod line and causing vacuolation of myelin
    • No inflammation occurs, and myelin forming cells are not affected
    • A similar pathology is seen with organotins (like triethyltin)
  19. Class IV: Nutritional Deficiencies
    Includes vitamin deficiencies (thiamine, B6, b12), malnutrition, and hypothyroidis
  20. Thiamine Deficiency
    • A vitamin deficiency that produces CNS demyelination, vacuolation of white matter, and sparing of neurons
    • Also produces segmental demyelinaton (affecting the PNS)
  21. B6 (pyridoxine) Deficiency
    • Affects mostly Schwann cells and PNS axons
    • B6 is a necessary cofactor for glutamic acid decarboxylase (GAD), the enzyme that converts glutamate to GABA (an important inhibitory neurotransmitter)
    • A lack of GABA (and lack of inhibitory synapses) can cause seizures
  22. B12 deficiency
    • Causes severe CNS and PNS demyelinatoin with myelin vacuolation but it restricted to the thoracic spinal cord (termed subacute combined degeneration of the cord)
    • Axons are initially preserved, but will develop Wallerian degeneration if the disease is left untreated
    • Etiology: Insufficient intake (strict vegans), malabsorption (Crohn's disease), pernicious anemia, Diphyllobothrium latum (fish tapeworm)
    • Mechanism: decrease of methylation of MBP and accumulation of odd-number/branched fatty acids because of increased concentrations of methylmalonyl-CoA and propionyl-CoA
    • Symptoms: Peripheral neuropathy with sensorimotor dysfunction, degeneration of posterior columns (vibration/proprioception) and lateral corticospinal (spasticity) tracts, and dementia
    • Blood findings: hypersegmented neutrophils, decreased B12, increased homocystein and methylmalonic acid
  23. Malnutrition and hypothyroidism
    • Interfere with the rapid proliferation of oligodendrocytes that must occur before myelination
    • Marked decrease in glial cell number is responsible for the reduced amount of myelin
  24. Progressive multifocal leukoencephalopathy (PML)
    • A viral demyelinating disorder that is a subacute or chronic encephalitis; rapidly progressive and usually fatal
    • It results from reactiation of a latent papova virus (JC virus) in immunodeficient people (patients with leukemia, lymphoma, AIDs, on immunosuppressants)
    • Gross exam shows multiple small and large irregular foci of gray discoloration in the cerebral and cerebellar white batter and brain stem (these often extend into the gray matter)-foci may be granular shrunken or cavitated (Fig 1)
    • Oligodendroglial cells have enlarged nuclei near the edge of the lesion (Fig2) made of packed viral particles
    • Inflammatory cells are sparse, but patient may detoriorate if the immune system is reconstituted
    • Fig 1
    • Fig 2
  25. Acute Disseminated Encephalomyelitis (ADEM)
    • Also called perivenous encephalomyelitis
    • Is an acute demyelinating multifocal dissorder that is preceded by a infection (viral-measles, chicken pox, mumps flu, mono; or bacterial-mycoplasma or scarlet fever) or vaccination
    • Axons not destroyed
    • Distease has sudden onset of headache, fever, decreased level of consciousness, then focal neurological deficits, and coma
    • Gross exam can be unremarkable or show multiple small, round foci
    • White matter surrounding veins is infiltrated with mononuclear cells (see fig)
  26. Acute Hemorrhagic Leukoencephalitis (AHL)
    • A hyperacute form of acute disseminated encephalomyelitis (ADEM), which is commonly preceded by a prodrome
    • Onset is abrupt with fever, headache, vomiting, impaired consciousness, followed by seizures
    • Fatal within days
    • Brain is swollen and soft
    • Cerebral and cerebellar white matter and brain stem show multiple small or large hemorrages that may or may not be evenly distributed
    • These lesions are caued by small veins whose walls have become necrotic because of fibrin infiltration
    • Hemorrhagic lesions:
    • Necrotic veins surrounded by ring hemorrhages:
  27. Central Pontine Myelinolysis (CPM)
    • Rapidly developing demyelinatoin that affects the central portions of the pons
    • Clinical manifestatins include difficulties speaking and swallowing, muscle limb weakness, hypotension, and coma
    • Believed to be caused by rapid correction of hyponatremia or other electrolyte imbalance
    • Morphology shows loss of myelin, dense infiltrates of macrophages, but perserved axons and neurons
  28. Sydenham's Chorea
    • An antibody mediated disease that targets the brain neurons
    • Occurs mainly in children 5-14 years old, with 3:1 girl:boy ratio (7:1 after puberty)
    • Particularly common in the Rocky Mountain region
    • Tends to occur 1-6 month after streptococcal pharyngitis
    • Associated with Rheumatic fever is 60% of cases
    • Thought that molecular mimicry causes the disease, as there is no evidence for bacterial infection of the CNS, for the streptococcal toxin affecting basal ganglia, or emboli from Rheumatic fever to brian causing infarction
    • Neurologic features: chorea that disappears with sleep, dysarthria, gait disturbance, loss of fine motor control, and hemibalismus (aka big swings of arms/legs)
    • Behavioral features: Irritability, mood lability with emotional instability and crying spells, obsessions and compulsions
    • Acute Treatment: Valporate for 3 months to lessen chorea and benazthine penicillin
    • Chorea usually resolves in about 3 months, wih return to normal behavior in 6
    • Children are then given monthly penicillin injections until 21 (after that their risk of getting this is gone)
  29. Myasthenia Gravis
    • An antibody mediated disease that has a bimodal distribution (10-40 years mainly in women, and 50-70 years mainly in men)
    • Caused by antibody blockade of nicotinic acetylcholine receptors (nAChR), with antibody and complement damage to the neuromuscular junctions
    • Antibody crosslinking leads to accelerated degradation of AChR
    • Symptoms: Weakness of bulbar muscles (causing ptosis, diplopia, dysarthria, dysphagia, and chewing difficulty) and skeletal muscles (mainly proximal muscles) that increases in the afternoon or after exercise; relexes and sensory function are normal
    • Associated conditions: thymoma/thymic hyperplasia, other autoimmune disorders (SLE, Graves disease, Rheumatoid arthritis), and thyroid disease (hypothyroidism/hyperthyroidism)
    • First line therapies: acetylcholine esterase inhibitors (pyridostigmine) and corticosteroids
    • Second line therapies: thymectomy, immunosuppressants, and mycophenolate (Cellcept)
    • Emergency and temporary therapy: Plasmapheresis and IvIG
  30. Paraneoplastic Neurological Syndrome
    • A neurological symdrome caused by, or associated with, a malignancy other than metastasis
    • Types include:
    • 1. Immune caused by immune reactivity to tumor/host antigens or a neoplasm that makes antibodies to host proteins (like in myelomas)
    • 2. Metabolic from electrolyte abnormalities (esp. Na) and endocrine issues (excess or lack of hormone)
    • 3. Vascular: clotting abnormalities induced by a tumor
    • Seems to be a case of molecular mimicry because serum and CSF antibodies react with both tumor and specific neuronal populations, and tumor size is smaller in patietns with paraneoplastic antibodies than in controls
  31. Examples of Diseases with Paraneoplastic antibodies
    • Eaton-Lambert is associated with small cell lung neoplasm and the target are Ca2+ receptors
    • Isaac Syndrome is associated with thymomas and the target are K receptors
    • Myasthenia Gravis is associated with thymomas and the target are AChR
    • Encephalomyelitis is associated with lung cancer and targets the brain
    • Cerebellar degeneration is associated with breast cancer and targets the cerebellum
    • Neuropathy is associated with lung and GI cancers and targets peripheral nerves
    • Opsoclonus-myoclonus is associated with neuroblastomas and affects the brainstem
  32. Acute Inflammatory Demyelinating Polyradiculoneuropathy (AIDP)
    • Most common form of Guillan-Barre-Syndrome in the US and Europe
    • Most likely caused by a monophasic cellular immune reaction against peripheral nerve myelin
    • 50% of cases follow a non-secific infection
    • Mecanism of recovery (takes 3-24 months): Schwann cells recover or divide, producing new myelin and wrapping naked axonal segments; this new myelin is thinner, meaning it has a slower motor conduction velocity, but is enough such that muscle functions can return to normal
  33. Devic's Disease
  34. Amyotropic Lateral Sclerosis (ALS)
    AKA Lou Gehrig's Disease
  35. Parkinson's Syndrome
    • A neurodegenerative disease involving loss of dopaminergic neurons in the substantia nigria
    • Cardinal symptoms: Resting tremor, posture instability, difficulty
    • rising and bradykinesia, rigidity with cogwheeling, and micrographia
    • Hypokinesia (bradykinesia) is caused by dopaminergic denervation,
    • resulting in overactivity of the indirect basal ganglia pathway and
    • reduced thalamic outflow to the cortex
  36. Huntington's Disease
    • An AD triplet repeat disease (CAG repeats); this disease is purely hereditary
    • Involves striatal atrophy
    • Hyperkinesia caused by selective loss of GABA projection neurons within the striatum
    • Mutant Huntington protein is found in intranuclear inclusion bodies throughout the brain, but most robustly in the GABA projection neurons
    • Death of striatal projection neurons causes reduced inhibitory outflow from the basal ganglia to the thalamus, causing choreic movement