TIS

Chapter 10

Degenerative and Metabolic Disorders

DEGENERATIVE DISEASES OF GRAY MATTER

1. Characteristics:

a. Clinical: steady progression of signs and symptoms

b. Pathology: loss of neurons in stereotyped patterns, generally within functionally related neuronal systems, and atrophy of tracts that originate from the lost neurons.

c. Etiology: often genetically determined; several were originally considered to be simply accelerated aging.

d. Gene defects, gene products, and genotype risk factors have been identified for many disorders

2. Macroscopic abnormalities

a. Atrophy of involved gray matter structures with decreased brain weight.

b. Color changes:

1. light brown discoloration of shrunken gray matter

2. loss of normal pigment (e.g., pale substantia nigra in Parkinson's disease)

c. Secondary atrophy of cerebral white matter and fiber tracts leading from the atrophic gray matter region

d. Enlargement of ventricles due to shrinkage of white matter (e.g., in Alzheimer's disease); called "hydrocephalus ex vacuo".

3. Microscopic Abnormalities

a. Neuronal Changes

1. simple decrease in expected numbers

2. surviving neurons are shrunken, dark, twisted, occasionally chromatolytic

3. peculiar structures within neurons (examples)

a. neurofibrillary tangles (Alzheimer's disease, post-encephalitic states)

b. Lewy bodies (in pigmented neurons in Parkinson's disease and in cortical neurons in Lewy body dementia)

b. Axonal changes

1. Wallerian degeneration = disintegration of axon and myelin sheath distal to a lesion; produces white matter and tract atrophy in CNS

2. senile or neuritic plaques (in Alzheimer's disease) are clusters of abnormal terminal axons around a core of beta-amyloid

c. Astrocyte Changes

1. proliferation (gliosis) and hypertrophy in areas of neuronal loss and white matter degeneration

2. increased compact glial fibers (astrocyte cytoplasmic processes) in degenerating tracts

4. Lesion Localization (sites of neuronal loss and clinical correlates)

a. Cerebral cortex (chiefly frontal, temporal, hippocampus): with senile plaques and neurofibrillary tangles; Alzheimer's disease; Symptoms: dementia, myoclonus, language disturbances; early onset forms tend to be familial.

b. Cerebral cortex and basal ganglia (neostriatum): Huntington's disease; symptoms: chorea, grimacing, gesticulating, lurching gait, eventually dementia; autosomal dominant.

c. Basal ganglia (substantia nigra) with variable cerebral cortical neuronal loss and Lewy bodies; Parkinson's disease; symptoms: resting tremor, akinesia, rigidity, depression with dementia in a few patients; rarely familial. Dementia and hallucinations precede motor signs in Lewy body dementia.

d. Motor neuron loss in cerebral cortex, spinal cord and lower brainstem: amyotrophic lateral sclerosis (ALS). Secondary degeneration of corticospinal tracts and ventral roots. Lower motor neuron symptoms: muscle atrophy, fasciculations, hyporeflexia, dysphagia. Upper motor neuron symptoms: spasticity, variable hyperreflexia, pseudobulbar emotionality. Up to 12% of cases familial; autosomal dominant.

e. Motor neuron loss in spinal cord and lower brainstem: infantile or type 1 spinal muscular atrophy or Werdnig-Hoffmann's disease; early onset (at times prenatal), progressive extremity muscle weakness, atrophy, fasciculations; dysphagia; tongue fasciculations; no upper motor neuron symptoms; usually autosomal dominant.

f. Cerebellum and brainstem; olivopontocerebellar atrophy; primary neuronal loss in basis pontis with secondary loss in cerebellum and olivary nuclei; may combine with degeneration of other basal ganglion or brainstem systems. Symptoms: progressive dysarthria, ataxia, intention tremor; onset in middle age; majority of cases are autosomal dominant.

g. Cerebellum and spinal cord; spinocerebellar atrophy (Friedreich's ataxia); distinctive pattern of spinal cord tract degenerations (posterior columns, spinocerebellar tracts and corticospinal tracts) with primary neuronal loss chiefly in nucleus dorsalis of thoracic spinal cord; dorsal root ganglia; portions of cerebellar folia and nuclei; and portions of motor cortex. Cardiomyopathy is common. Symptoms: ataxia, sensory loss and hyporeflexia chiefly in lower extremities; later nystagmus and dysarthria; onset in childhood and adolescence; autosomal recessive.

h. Differential diagnosis of spinal tract degenerations:

1. Corticospinal tracts: ALS or descendingdegeneration below spinal cord transection or compression. ALS shows ventral root atrophy while descending degeneration does not.

2. Posterior columns and posterior roots; tabes dorsalis.

3. Posterior columns, posterior roots, corticospinaland spinocerebellar tracts: Friedreich's ataxia.

4. Posterior columns, spinothalamic tracts: ascendingdegeneration above level of spinal cord transsection or compression.

5. Irregular lesions that cut across multiple tracts:multiple sclerosis

B. DISEASES OF WHITE MATTER (MYELIN)

1. Definition: A primary abnormality of myelin with relative sparing of axons and variable secondary gliosis. Major types of primary myelin disease include:

a. Demyelination: myelin sheath loses normal staining properties, then fragments and is phagocytosed. Example: multiple sclerosis.

b. Leukodystrophy: a familial abnormality in myelin synthesis or turnover, often leaving non-sudanophilic myelin end-products. Example: metachromatic leukodystrophy (autosomal recessive) and adrenoleukodystrophy (x-linked recessive).

2. Macroscopic Changes: White matter atrophy and myelin loss:

a. Loss of white matter bulk and gray discoloration of remaining tissue. Indicates complete loss of myelin lipids followed by formation of a glial scar.

b. Cysts do not form in most cases of demyelination and leukodystrophy because myelin loss is gradual and axons remain to stabilize the area as gliosis develops.

3. Cysts form following rapid white matter necrosis.

4. Microscopic Changes: Two general types of white matter abnormality

a. Loss of both myelin and axons (Examples: necrosis, Wallerian degeneration).

b. Selective loss or deficiency of myelin with preservation of axons (Examples: multiple sclerosis, leukodystrophy).

c. End products of myelin breakdown.

1. Myelin remnants (neutral lipids) stain with sudan dyes (i.e., sudanophilic). Examples: white matter necrosis, multiple sclerosis, adrenoleukodystrophy and related disorders.

2. Myelin remnants are not sudanophilic. Examples: brown metachromatic sulfatides in metachromatic leukodystrophy, PAS-positive galactocerebrosides in Krabbe's disease.

d. Necrosis, followed by cyst formation in which all tissue elements are destroyed, is not specific to white matter but may occur chiefly in this area.

e. Gliosis is present in both types of lesions: on the periphery of cystic necrosis and diffusely spread throughout areas of demyelination and leukodystrophy.

5. Lesion Localization and Clinical Correlates

a. Focal demyelination in multiple sclerosis produces symptoms that often improve partially:

1. optic nerve lesions produce transient blindness with residual scotomata (blind spots)

2. spinal cord lesions produce transient paraplegia, often leaving sphincter disturbance and spasticity

3. cerebellar and brainstem lesions produce nystagmus, slurred speech, ataxia of gait and extremities

4. multiple, often confluent, cerebral white matter lesions produce dementia and an inappropriate euphoria; many such individual lesions are asymptomatic

b. Diffuse myelin loss in the adult produces dementia, spasticity, akinetic mutism, variable visual loss.

c. Diffuse myelin abnormalities in infants produce retardation of motor development, spastic paralysis.

C. NUTRITIONAL, TOXIC AND METABOLIC DISORDERS

1. Spectrum of disorders: immature and mature nervous systems are susceptible to an enormous number of these disorders. Lesion patterns of many toxic or nutritional deficiency states resemble lesions of certain genetically transmitted, degenerative or metabolic diseases.

2. Prototype toxic/deficiency state: Chronic alcoholism (combined effects of ethanol ingestion and thiamine deficiency)

a. Wernicke-Korsakoff syndrome (thiamine deficiency)

1. Acute Wernicke's encephalopathy: hemorrhagic necrosis of mammillary bodies and adjacent hypothalamus, medial thalamus and brain stem tegmentum; confusion, stupor, oculomotor palsies.

2. Chronic Wernicke-Korsakoff amnestic syndrome: gliosis, neuropil vacuoles, demyelination with relative neuronal preservation in same areas; dementia, profound amnesia with confabulation.

b. Cerebellar degeneration (combined alcohol toxicity and thiamine deficiency)

1. Atrophy and Purkinje cell loss in anterior-superior vermis

2. Clinical: truncal ataxia

c. Hepatocerebral degeneration

1. Numerous, large protoplasmic (Alzheimer Type II) astrocytes; rare cases with cortical and basal ganglia necrosis

2. Clinical: confusion, liver flap (asterixis); rarely severe movement disorder and coma.

d. Direct chronic ethanol neurotoxicity in the adult

1. Loss of cerebral white matter (especially in pre frontal areas) and ventricular enlargement (reversible on CT and MRI)

2. Loss of cerebral cortical neurons, dendrites, and synapses (especially in superior frontal association areas).

3. Clinical: chronic severe cognitive impairment

e. Fetal alcohol syndrome

1. Brain: microcephaly, cerebellar dysplasia, and agenesis of corpus callosum

2. Clinical: growth retardation, microcephaly, and mental retardation

f. Peripheral polyneuropathy: axonal; distal weakness and numbness

g. Myopathy: vacuolization, necrosis; weakness, muscle pain, myoglobinuria

3. Prototype inherited enzyme deficiency state: Tay-Sachs disease (Gm2 gangliosidosis; hexosaminidase a-subunit deficiency).

a. autosomal recessive deficiency of hexosamidase A impairs breakdown and turnover of gangliosides that are important in neuronal structure and function.

b. gangliosides accumulate in neuronal cytoplasmthroughout nervous system (central, peripheral, autonomic) and in retinal neurons.

c. seizures, mental and motor retardation often are apparent at birth with gradual loss of all voluntary function and death by mid-childhood. Retinal gangliosides (white) in retinal neurons around the normal macula produce cherry red spots.

d. macroscopic brain changes: accumulated gangliosides eventually produce a large gliotic brain with loss of internal landmarks.

e. microscopic brain changes: neurons ballooned with ganglioside that has a characteristic ultrastructure (membranous cytoplasmic bodies).

4. Many leukodystrophies (metachromatic, adrenoleukodystrophy) are also inherited enzymatic defects of lipid metabolism.

D. NORMAL OR ASYMPTOMATIC AGING CHANGES OF NERVOUS SYSTEM

With advancing age the following changes occur:

a. Mild loss of weight (100-200 g) with wide sulci and ventricles

b. Mild neuronal loss, most easily seen in cerebellum

c. Neurofibrillary tangles appear in hippocampus, senile plaques are rare

d. Lipofuscin accumulates in neurons and astrocytes

e. Gliosis and corpora amylacea develop beneath pia and ependyma

f. Leptomeningeal fibrosis

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