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5. HDS Neuro Psych > Disorders of Myelin and Metabolism > Flashcards

Disorders of Myelin and Metabolism Flashcards

1
Q

Myelin and Metabolic Diseases

Overview

A
  • CNS Demyelinating Disease
    • Multiple Sclerosis
    • Perivenous Encephalomyelitis
    • Central Pontine Myelitis
    • Guillain Barre Syndrome
  • Leukodystrophies
    • Metachromatic Leukodystrophy
    • Krabbe Disease
    • Adrenoleukodystrophy
  • Vitamin Deficiencies
    • Thiamine
    • Korsakoff’s syndrome
    • Vitamin B12
  • Toxins
    • Chemotherapeutic agents
    • Alcohol
  • Metabolic Derangements
    • Hepatic failure
    • Wilson’s Disease
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2
Q

Demyelinating Diseases

A

“White Matter Disease”

  • Pathologic processes which result in loss of myelin sheaths with a relative preservation of axons
  • Examples:
    • Multiple Sclerosis
    • Perivenous Encephalomyelitis (ADEM/ANHE)
    • Central Pontine Myelinolysis
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3
Q

Multiple Sclerosis (MS)

Overview

A

Chronic, immune-mediated, inflammatory disease of the CNS

  • Affects myelin sheaths (causing demyelination) > axons/neurons
  • “Lesions separated in time and space”
    • Multiple relapses and remissions, commonly
    • Lesions in different anatomic locations
      • Each lesion seen as a plaque
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4
Q

Multiple Sclerosis

Epidemiology

A
  • Women make up 60-70% of cases
  • Age of onset 20-40 y/o
  • MS is less common in people living near the equator
  • Pts w/ lower levels of vit D have a higher incidence of relapses
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5
Q

Multiple Sclerosis

Diagnosis

A

Per McDonald criteria, it requires evidence of:

  • Dissemination of disease in space
    • Lesions in distinct anatomical locations within CNS
    • Indicates a multifocal CNS process
    • MRI lesions e/o dissemination in space
  • Dissemination in time
    • Development or appearance of new CNS lesions over time
    • CSF oligoclonal bands of Ig e/o dissemination in time for pts w/ one clinical attack
      • CSF not always required for dx
      • Non-specific, also seen in SLE, sarcoid, syphilis, lymphoma, etc.
  • Nerve conduction studies may show delayed transmission time along demyelinated circuits
  • Other possible explanations must be excluded
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6
Q

Multiple Sclerosis
Disease Progression

A
  • Highly variable from patient to patient
  • Many pts will have a single attack in a single anatomic distribution ⇒ Clinically isolated syndrome (CIS)
    • Not yet considered MS
    • Isolated optic neuritis most common
  • Other will have multiple attacks or continuous progression over years
    • Correlates w/ accrual of multiple CNS lesions
    • Relapses typically last 24-48 hrs & take weeks to recover
    • After each relapse sx can partially resolve, likely d/t partial remyelination
  • Radiologically isolated syndrome (RIS) – incidentally found white matter lesions w/o clinical sx
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7
Q

Multiple Sclerosis

Progression Patterns

A

Four clinical patterns of MS progression:

  1. Relapsing remitting (RRMS)
    • > 80% start w/ relapsing remitting course
  2. Primary progressive (PPMS)
  3. Secondary progressive (SPMS)
    • Mean age of conversion to SPMS is 39-49 y/o
  4. Progressive-relapsing (PRMS)
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8
Q

Multiple Sclerosis

Clinical Presentation

A
  • Sx depend on area affected by the lesion:
    • Optic neuritis (inflammation of the optic nerves) ⇒ blurry vision, dyschromatopsia (abnormal color vision) and pain w/ eye movements
    • Diplopia
    • Weakness (lesion affecting the corona radiata/internal capsule/corticospinal tract)
    • Numbness/tingling
    • Bowel or bladder symptoms (urgency, incontinence, constipation)
    • Gait abnormality (typically paretic or spastic)
    • Fatigue
  • Exam findings also depend on affected area:
    • Decreased acuity, visual field defect, red desaturation (optic neuritis)
    • Abnormal eye movements (most common is internuclear ophthalmoplegia)
    • Decreased strength, abnormal sensation (most common is decreased vibration), sensory level (if there is a spinal cord lesion)
    • Spasticity
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9
Q

Multiple Sclerosis

Gross Findings

A

Plaques of demyelination in white matter

  • Sharply circumscribed areas
  • Concentrated in periventricular zones, may follow periventricular veins
  • Also in optic nerves, brainstem, cerebellum, and spinal cord
  • Plaques may be large or microscopic
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10
Q

MS Plaque
Histology

A
  • See myelin breakdown products, MΦ, and lymphocytes
  • Perivascular lymphocytes in plaques and peri-plaque areas
  • Loss of myelin and loss of oligodendrocytes can be seen w/ special stains
  • Axons within lesions are relatively spared
  • In healed mature plaques, reactive astrocytes
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11
Q

Multiple Sclerosis

Pathogenesis

A
  • Lesions caused by inappropriate cellular immune response vs components of the myelin sheath
    • No definitive cause identified
  • Possible triggers of inflammation: prior trauma, viral infections, psychological stress, dietary and environmental exposures
    • Epstein Barr Virus [leading candidate], Human Herpes Virus-6, Varicella-Zoster Virus
  • ∆ inflammation ⇒ more prone to autoimmunity
    • No clear explanation for susceptibility
    • Genetics may play a role
  • T cells are activated ⇒ cross BBB ⇒ secret cytokines and recruit B cells, T cells and other APCs
  • B cells produce Ab vs oligodendrocytes and myelin ⇒ demyelination and neuronal damage occurs
  • Incomplete remyelination leads to disability
  • Persistent insult w/ partial or no remyelination ⇒ persistent myelin and neuronal damage w/o recovery ⇒ progression of disease
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12
Q

Multiple Sclerosis
Environmental Factors

A
  • MS is less common in people living near the equator
  • Migrant Studies:
    • Environmental factors during childhood seem to be important
    • Risk determined during first 15 years of life
  • Other observations:
    • Highest rate of MS is in Scotland
    • High Vitamin D levels appear to be protective
    • Smoking appears to ↑ risk of MS
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13
Q

Multiple Sclerosis
Immunological Factors

A
  • HLA linkage
    • Higher incidence of MS in HLA haplotypes HLA-A3, B7 and DR2
  • Cellular Immunity
    • CD4 and CD8 T-cells, monocytes/MΦ found in active lesions
    • Balance of T cell subsets in and around plaques may be important humoral immunity
    • Oligoclonal bands of Ig in CSF probably epiphenomenon related to chronic inflammation in CNS
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14
Q

Multiple Sclerosis (MS)

Differential Diagnoses

A
  • Migraine (also associated w/ T2 hyperintensities on MRI brain)
  • Inflammatory disorders:
    • Neuromyelitis optica spectrum disorder (NMOSD)
      • Frequently misdiagnosed as MS at presentation
      • Cell based assay for aquaporin 4 Ab has high sensitivity and specificity
    • Neurosarcoidosis
    • Systemic lupus erythematosus (SLE)
    • Sjogren’s
    • Behçet’s disease
  • Medication related ⇒ TNF inhibitors (Infliximab, Adalimumab, Etanercept) can cause demyelination w/ similar pattern of T2 hyperintensities
  • Infectious:
    • Syphilis
    • HIV
    • Tuberculosis
    • VZV; HTLV-1 (transverse myelitis)
    • Progressive multifocal leukoencephalopathy (JC virus)
  • Neoplastic:
    • Lymphoma
    • Low grade gliomas
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15
Q

Multiple Sclerosis (MS)

Treatment

A
  • Acute setting: steroids do not affect prognosis or disability; but help expedite recovery from relapses
  • Disease modifying therapy: immunomodulatory or immunosuppressant medications that decrease autoimmunity and help prevent new lesions
    • Currently > 10 options approved by the FDA for treatment of RRMS
    • Only one option currently approved for PPMS: Ocrelizumab
    • Current clinical trial evaluating remyelination therapies that could reverse disability
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16
Q

Perivenous Encephalomyelitis

Overview

A
  • Usually in children
  • Acute monophasic episode demyelination
  • Follows 1-2 wks after viral infection or rarely vaccination
  • Headache, meningeal irritation, lethargy, and coma
  • Fatal in 15-20% of pts
  • Survivors have no or minimal sx
  • Two types: ADEM & ANHE
17
Q

Perivenous Encephalomyelitis

Types

A
  • Acute Disseminated Encephalomyelitis (ADEM)
    • Perivenous and perivenular lymphocytes
    • Demyelination w/ relative preservation of axons
  • Acute Hemorrhagic Encephalomyelitis (ANHE)
    • Similar pathology to ADEM w/ hemorrhage added
    • Clinically, often more severe
18
Q

Central Pontine Myelinolysis

A
  • Demyelinating disease
  • Syndrome associated w/ rapid correction of hyponatremia
  • Often iatrogenic d/t rapid increase in serum sodium
  • Also seen in alcoholism and liver transplantation
  • Acute quadriplegia
  • Gross and microscopic evidence of demyelination in basis pontis
  • Affects the corticospinal tracts
  • Monophasic
  • Questionable potential for recovery
19
Q

Guillain-Barre Syndrome

(GBS)

A
  • Demyelination in PNS
  • Seen in children and young adults
  • Subacute presentation of sensory and motor neuropathology
  • Presents w/ loss of DTRs and quadriparesis
  • Can cause respiratory arrest requiring intubation
  • Viral syndrome precedes 40% of cases
  • CSF shows ↑ proteins
  • Axons preserved so regenerated Schwann cells can remyelinate ⇒ complete recovery
20
Q

Leukodystrophies

Overview

A
  • White matter disease caused by inborn error of metabolism
  • Myelin is abnormally formed and degrades
  • Diffuse neuraxis involvement
  • Present in childhood w/ spasticity
  • Degree of anatomic involvement and age at presentation varies
21
Q

Types of Leukodystrophy

A
  • Metachromatic Leukodystrophy
  • Krabbe Disease
  • Adrenoleukodystrophy
22
Q

Metachromatic Leukodystrophy

Overview

A
  • Autosomal Recessive (22q)
    • Deficiency in aryl sulfatase-A (lysosomal)
    • Accumulation of galactosyl sulfatides (lipid)
    • Abnormal lipid breakdown products stain different colors from normal w/ histologic dyes ⇒ “Metachromatic”
  • Widespread hemispheric demyelination
  • PNS demyelination
  • Breakdown products accumulate in viscera and excreted in urine
  • Dx made from serum and urine samples as well as nervous tissue
23
Q

Metachromatic Leukodystrophy

Types

A
  • Childhood forms
    • Present w/ motor symptoms
    • Gradually progress leading to death in 5-10 y/o
  • Adult forms
    • Present w/ cognitive/psychiatric sx, motor symptoms later
    • Slower course than childhood forms
24
Q

Krabbe Globoid Cell Leukodystrophy

A
  • Autosomal Recessive (14q31)
  • Deficiency in galactocerebroside-b galactosidase
    • Results in accumulation of galactocerebroside
    • Metabolized to galactosylsphingosine ⇒ causes oligodendrocyte injury
  • Causes widespread CNS and PNS demyelination
    • Yellow/gray discoloration of white matter
  • Pathologic hallmark
    • Globoid cells ⇒ large, multinucleated MΦ filled w/ abnormal lipid breakdown products
  • Rapidly progressive course
    • Motor symptoms prominent
    • Death before 2 years of age
25
Q

Adrenoleukodystrophy

A
  • Several clinical and genetic forms
    • X linked mutations ⇒ ALD gene
      • Inability to metabolize very long chain fatty acids (VLCFA) within peroxisomes
      • Elevated serum VLCFA
  • Presents w/ widespread CNS demyelination in children and adolescents
  • Association w/ Addison’s syndrome d/t deposition of VLCFA deposition in adrenal cortex
  • Markedly variable in the age of onset and extent of anatomic involvement
26
Q

Wernicke’s Encephalopathy

A
  • Acute severe thiamine (Vit B1) deficiency
  • Delirium, eye movement abnormalities, ataxia
  • Often iatrogenic
    • Borderline thiamine-deficient pts given IV glucose expend their last thiamine reserves
  • Treatment and prevention:
    • Aggressive thiamine loading for all pts who might be borderline thiamine deficient
      • Alcoholics, HIV / AIDS, chemotherapy, immunosuppressed, potential nutritional deficiency
27
Q

Korsakoff’s Psychosis

A
  • Chronic form of Wernicke’s encephalopathy
  • Due to Thiamine (Vit B1) Deficiency
  • Lack of short-term memory
  • Secondary confabulation around lack of memory
  • Largely irreversible
28
Q

Thiamine (Vit B1) Deficiency
Pathology

A

Identical anatomic areas affected in both Wernicke’s and Korsakoff’s

  • Memory dysfunction ⇒ medial dorsal nucleus of thalamus
  • Ataxia and ophthalmoplegia ⇒ walls of third and fourth ventricle
    • Involved in cerebellar input and output
    • Nuclei for ocular movement
  • Mamillary bodies and walls of 3rd ventricle ⇒ difficulty w/ short term memory
  • Neurons destroyed, see petechial hemorrhage (particularly mamillary bodies)
  • In Korsakoff’s see chronic pathology w/ gliosis and vascular hyperplasia
29
Q

Vitamin B12 Deficiency

Pathophysiology

A

Subacute combined degeneration of spinal cord (SACD)

  • Initially, slight ataxia; numbness and tingling in BLE > BUE
  • Progresses to spastic paraparesis and paresthesias of BLE
  • If untreated, can progress to complete paralysis w/ anesthesia of the trunk and legs
  • Treatment w/ B12 can reverse early symptom
  • Pts w/ complete paraplegia show poor recovery
30
Q

Vitamin B12 Deficiency

Pathology

A
  • Degeneration of spinal white matter
    • Concentrated in the posterior and lateral columns of the spinal cord
    • Most marked in mid thoracic regions
  • Myelin sheaths swollen and vacuolated
  • Axonal degeneration in same regions
31
Q

Cancer Treatment

Effects on CNS

A
  • Cancer Chemotherapy
    • Vinca Alkaloids (Vinblastine, Vincristine)
    • Dose-dependent peripheral neuropathy
  • Radiation
    • Progressive vasculopathy w/ secondary necrosis
      • Spinal cord particularly vulnerable
    • Secondary gliomas, meningiomas, sarcomas
  • Chemotherapy + Irradiation
    • Methotrexate/ irradiation combo
    • Leukoencephalopathy w/ periventricular necrotic lesions
32
Q

Ethyl Alcohol

Effects on CNS

A
  • Progressive axonal peripheral neuropathy
  • Degeneration of cerebellar vermis (1%)
  • Truncal ataxia, unsteady gait, and nystagmus
33
Q

Liver Failure
Effect on CNS

A
  • Hepatic Encephalopathy
    • Disturbed consciousness
    • Asterixis (liver flap)
  • Elevated serum ammonia and other substances
  • See “Alzheimer Type II Astrocytes” in brain
    • Large gray matter astrocytes w/ intranuclear glycogen
34
Q

Wilson Disease

Overview

A
  • Autosomal recessive defect in cellular copper metabolism
    • Copper accumulates mostly in brain, eye and liver
    • Serum ceruloplasmin is low
  • Results in:
    • Movement disorders (Basal Ganglia)
      • Choreoathetosis
    • Copper deposition in cornea
      • Kayser-Fleischer ring (Descemet membrane)
        • Brownish ring around iris
    • Liver disease
      • Fatty change, acute → chronic hepatitis, hepatic necrosis
    • Psychosis or dementia
35
Q

Wilson Disease

Pathology

A
  • Gross Pathology
    • Brown discoloration and atrophy of caudate, putamen, globus pallidus
    • Occasional cavitation of putamen
  • Microscopic Pathology
    • Most severe in putamen
    • Neuronal loss
    • Alzheimer II astrocytosis
    • Opalski cells
      • Voluminous cells w/ eccentric nuclei found in basal ganglia
      • Relatively specific for Wilson Disease

5. HDS Neuro Psych (46 decks)

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