patoloji-ders-notlari

Title

Serdar Balcı

Diseases of the Myelin, Metabolic and Toxic Disorders

Serdar BALCI, MD

PRIMARY DISEASES OF MYELIN

Myelin

Axons are tightly ensheathed by myelin

Electrical insulator that allows rapid propagation of neural impulses

Consists of multiple layers of highly specialized, closely apposed plasma membranes

Assembled by oligodendrocytes

Myelinated axons are present in all areas of the brain

Dominant component in the white matter

Diseases of myelin are primarily white matter disorders

Most diseases of CNS myelin do not involve the peripheral nerves to any significant extent, and vice versa

Myelin in peripheral nerves

Differences of myelin in the CNS and PNS
Peripheral myelin is made by Schwann cells, not oligodendrocytes
Each Schwann cell in a peripheral nerve provides myelin for only one internode
- in the CNS, many internodes are created by processes coming from a single oligodendrocyte
Specialized proteins and lipids are also different
Most diseases of CNS myelin do not involve the peripheral nerves to any significant extent, and vice versa

Diseases involving myelin

Demyelinating diseases of the CNS
- Acquired conditions
- Preferential damage to previously normal myelin
- Most common diseases in this group result from immune-mediated injury
  - multiple sclerosis (MS) and related disorders
- Viral infection of oligodendrocytes
  - multifocal leukoencephalopathy
- injury caused by drugs and other toxic agents
Dysmyelinating diseases (Leukodystrophy)
- Myelin is not formed properly
- Has abnormal turnover kinetics
- Mutations that disrupt the function of proteins that are required for the formation of normal myelin sheaths

DEMYELINATING DISEASES

Multiple Sclerosis

Autoimmune demyelinating disorder
Distinct episodes of neurologic deficits, separated in time, attributable to white matter lesions that are separated in space
Most common demyelinating disorder
- 1/1000 persons in most of the United States and Europe
May become clinically apparent at any age
- onset in childhood or >50 is rare
F:M=2:1
Relapsing and remitting episodes of neurologic impairment
- frequency of relapses tends to decrease during the course of the illness
A steady neurologic deterioration is characteristic in a subset of patients
Combination of environmental and genetic factors
Loss of tolerance to self myelin antigens
Initiating agent, an infectious agent?
15x higher when in first-degree relative
Concordance rate for monozygotic twins 25%
- much lower rate for dizygotic twins
HLA-DR2 most significantly increases the risk for developing MS
Polymorphisms in the genes cytokines IL-2 and IL-7
- activation and regulation of T cell–mediated immune responses

Prominent chronic inflammatory cells within and around MS plaques

Genetic evidence

→ Immune-mediated myelin destruction have a central role

Central role for CD4+ T cells

Increase in TH17 and TH1 CD4+ cells

CD8+ T cells and B cells

Sometimes axonal degeneration occurs
- Toxic effects of lymphocytes, macrophages, and their secreted molecules
- May cause neuronal death

Multiple Sclerosis

White matter disease

Affected areas showing multiple, well-circumscribed, slightly depressed, glassy-appearing, gray-tan, irregularly shaped lesions

Plaques

Commonly arise near the ventricles

Frequent in the optic nerves and chiasm, brain stem, ascending and descending fiber tracts, cerebellum, and spinal cord

Robbins Basic Pathology

Multiple Sclerosis

Robbins Basic Pathology

Sharply defined borders

Active plaque
- Ongoing myelin breakdown
- Abundant macrophages containing myelin debris
- Lymphocytes and macrophages are present
- Perivascular cuffs
- Small active lesions often are centered on small veins
- Axons are relatively preserved but may be reduced in number
Active plaque
Four classes, only one is seen in affected patient
- Type I
  - macrophage infiltrates with sharp margins
- Type II
  - Similar to type I
  - also complement deposition (antibody-mediated component)
- Type III
  - Less well-defined borders
  - Oligodendrocyte apoptosis
- Type IV
  - Nonapoptotic oligodendrocyte loss
Inactive plaques
- Inflammation mostly disappears
- Little, no myelin
- Astrocytic proliferation and gliosis are prominent

Clinical course of MS

The clinical course is variable

Multiple relapses followed by episodes of remission

Recovery during remissions is not complete

Over time there is usually a gradual, often stepwise, accumulation of neurologic deficits

Imaging studies have demonstrated that there are often more lesions in the brains of patients with MS than might be expected from the clinical examination

Lesions can come and go much more often than was previously suspected

Changes in cognitive function can be present
- Much milder than the other deficits
It is hard to predict when the next relapse will occur
CSF examination
- A mildly elevated protein level
- Increased proportion of immunoglobulin
  - Oligoclonal bands
  - Antibodies are directed against a variety of antigenic targets
- 1/3 moderate pleocytosis

Other Acquired Demyelinating Diseases

Immune-mediated demyelination after systemic infectious illnesses
- even mild viral diseases
Not related to direct spread of the infectious agents to the nervous system
- Immune cells responding to pathogen-associated antigens cross react against myelin antigens → myelin damage

Postinfectious autoimmune reactions to myelin

Associated with acute-onset monophasic illnesses
Acute disseminated encephalomyelitis
- Symptoms typically develop a week or two after an antecedent infection
- Nonlocalizing (headache, lethargy, and coma)
  - In contrast with the focal findings of MS
- Symptoms progress rapidly
- Fatal in 20% of cases
- Others recover completely
Acute necrotizing hemorrhagic encephalomyelitis
- More devastating disorder
- Typically affects young adults and children

Neuromyelitis optica

Inflammatory demyelinating disease

Centered on the optic nerves and spinal cord

Antibody-mediated autoimmune disorder

Antibodies to the water channel aquaporin-4 are both diagnostic and pathogenic

Central pontine myelinolysis

Nonimmune process
Loss of myelin involving the center of the pons
Rapid correction of hyponatremia
Mechanism of oligodendroglial cell injury is uncertain
May be related to edema induced by sudden changes in osmotic pressure
Alcoholism and severe electrolyte or osmolar imbalance
Similar lesions can be found elsewhere in the brain
Involvement of fibers in the pons
- rapidly evolving quadriplegia

Progressive multifocal leukoencephalopathy

Demyelinating disease

Occurs after reactivation of JC virus in immunosuppressed patients

DYSMYELINATING DISEASES (LEUKODYSTROPHY)

Leukodystrophies

Inherited dysmyelinating diseases

Clinical symptoms derive from abnormal myelin synthesis or turnover

Lysosomal enzymes

Peroxisomal enzymes

Mutations in myelin proteins

Most are autosomal recessive inheritance

X-linked diseases also occur

Robbins Basic Pathology

Morphology of leukodystrophy

Changes in white matter
Diffusely change in color (gray and translucent)
Volume is decreased
Early in their course
- Some diseases may show patchy involvement
- Others have a predilection for occipital lobe involvement
End
- Nearly all of the white matter usually is affected
- Loss of white matter
- Brain becomes atrophic
- Ventricles enlarge
- Secondary changes can be found in the gray matter
Myelin loss
Infiltration of macrophages
- stuffed with lipid
Specific inclusions created by the accumulation of particular lipids

Clinical Features of Leukodystrophies

Each leukodystrophy has a characteristic clinical presentation
Most can be diagnosed by genetic or biochemical methods
Despite differences in underlying mechanisms share many features because of the common myelin target
Affected children are normal at birth
- Begin to miss developmental milestones during infancy and childhood
Diffuse involvement of white matter
- Deterioration in motor skills
- Spasticity, hypotonia, or ataxia
The earlier the age at onset, the more severe the deficiency and clinical course

ACQUIRED METABOLIC AND TOXIC DISTURBANCES

Acquired Metabolic and Toxic Disturbances

Relatively common causes of neurologic illnesses
Brain is particularly vulnerable to nutritional diseases and alterations in metabolic state
- High metabolic demands
- Unique features or requirements of different anatomic regions
  - Effects are not global
Nutritional Diseases
- Thiamine Deficiency
- Vitamin B Deficiency
Metabolic Disorders
- Hypoglycemia
- Hyperglycemia
- Hepatic Encephalopathy
Toxic Disorders

Thiamine Deficiency

Wernicke encephalopathy
Abrupt onset of confusion
Abnormalities in eye movement
Ataxia
Treatment with thiamine can reverse deficits
If acute stages go untreated
- Irreversible profound memory disturbances
- Korsakoff syndrome

Wernicke-Korsakoff syndrome

Chronic alcoholism
Gastric disorders
- Carcinoma
- Chronic gastritis
- Persistent vomiting
Foci of hemorrhage and necrosis
- Mammillary bodies
- Adjacent to the ventricles
- Third and fourth ventricles
Despite the presence of necrosis, relative preservation of many of the neurons
Early lesions
- Dilated capillaries with prominent endothelial cells and progress to hemorrhage
As lesions resolve
- Cystic space appears along with hemosiderin-laden macrophages
Lesions in the medial dorsal nucleus of the thalamus best correlate with the memory disturbance in Korsakoff syndrome

Vitamin B Deficiency

Pernicious anemia

Neurologic deficits associated with changes in the spinal cord

Subacute combined degeneration of the spinal cord

Both ascending and descending tracts of the spinal cord are affected

Symptoms develop over weeks

Early clinical signs
- Slight ataxia
- Lower extremity numbness and tingling
Progress to
- Spastic weakness of the lower extremities
- Complete paraplegia ensues
Prompt vitamin replacement therapy produces clinical improvement
If paraplegia has developed, recovery is poor

Hypoglycemia

Brain requires glucose as a substrate for energy production

Cellular effects of diminished glucose generally resemble those of global hypoxia

Hippocampal neurons are particularly susceptible to hypoglycemic injury

Cerebellar Purkinje cells are relatively spared

As with anoxia, if the level and duration of hypoglycemia are sufficiently severe, injury is widespread

Hyperglycemia

Inadequately controlled diabetes mellitus
Ketoacidosis, hyperosmolar coma
Confusion, stupor, coma
Intracellular dehydration, hyperosmolar state
Hyperglycemia must be corrected gradually
- Rapid correction can produce severe cerebral edema

Hepatic Encephalopathy

Decreased hepatic function
Depressed levels of consciousness and sometimes coma
Early stages
- “flapping” tremor (asterixis) when extending the arms with palms facing the observer
Elevated levels of ammonia
- ammonia metabolism occurs only in astrocytes through the action of glutamine synthetase
- hyperammonemia → astrocytes in the cortex and basal ganglia develop swollen, pale nuclei (called Alzheimer type II cells )

Toxic Disorders

Lead

Arsenic

Mercury

Organophosphates

Methanol

Ethanol

Radiation

Lead
- diffuse encephalopathy
Arsenic
Mercury
Industrial chemicals
- organophosphates (in pesticides)
- methanol (causing blindness from retinal damage)
- carbon monoxide (combining hypoxia with selective injury to the globus pallidus)
Ethanol
- Acute intoxication is reversible
- Excessive intake can result in profound metabolic disturbances
  - Brain swelling and death
Chronic alcohol exposure
- Cerebellar dysfunction
  - Truncal ataxia
  - Unsteady gait
  - Nystagmus
  - Atrophy in the anterior vermis
Ionizing radiation
- rapidly evolving signs and symptoms
  - headaches, nausea, vomiting, and papilledema
  - even months to years after irradiation
- Large areas of coagulative necrosis
- Adjacent edema
- Blood vessels with thickened walls containing intramural fibrin-like material

Autopsy Pathology: A Manual and Atlas