Disorders of Myelin and Metabolism Flashcards by Quynh Tran

Myelin and Metabolic Diseases

Overview

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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Demyelinating Diseases

“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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Multiple Sclerosis (MS)

Overview

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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Multiple Sclerosis

Epidemiology

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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Multiple Sclerosis

Diagnosis

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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Multiple Sclerosis
Disease Progression

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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Multiple Sclerosis

Progression Patterns

Four clinical patterns of MS progression:

Relapsing remitting (RRMS)
- > 80% start w/ relapsing remitting course
Primary progressive (PPMS)
Secondary progressive (SPMS)
- Mean age of conversion to SPMS is 39-49 y/o
Progressive-relapsing (PRMS)

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Multiple Sclerosis

Clinical Presentation

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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Multiple Sclerosis

Gross Findings

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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MS Plaque
Histology

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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Multiple Sclerosis

Pathogenesis

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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Multiple Sclerosis
Environmental Factors

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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Multiple Sclerosis
Immunological Factors

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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Multiple Sclerosis (MS)

Differential Diagnoses

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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Multiple Sclerosis (MS)

Treatment

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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Perivenous Encephalomyelitis

Overview

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

Perivenous Encephalomyelitis

Types

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

Central Pontine Myelinolysis

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

Guillain-Barre Syndrome

(GBS)

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

Leukodystrophies

Overview

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

Types of Leukodystrophy

Metachromatic Leukodystrophy
Krabbe Disease
Adrenoleukodystrophy

Metachromatic Leukodystrophy

Overview

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

Metachromatic Leukodystrophy

Types

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

Krabbe Globoid Cell Leukodystrophy

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

Adrenoleukodystrophy

* 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

Wernicke's Encephalopathy

* **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**

Korsakoff's Psychosis

* **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

Thiamine (Vit B₁) Deficiency Pathology

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 3^rd 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**

Vitamin B₁₂ Deficiency Pathophysiology

**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

Vitamin B₁₂ Deficiency Pathology

* **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

Cancer Treatment Effects on CNS

* _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**

Ethyl Alcohol Effects on CNS

* **Progressive axonal peripheral neuropathy** * Degeneration of **cerebellar vermis** (1%) * Truncal ataxia, unsteady gait, and nystagmus

Liver Failure Effect on CNS

* **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

Wilson Disease Overview

* _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**

Wilson Disease Pathology

* _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