Page 849 - Robbins Basic Pathology by Vinay Kumar, Abul K. Abbas, Jon C. Aster

Acquired Metabolic and Toxic Disturbances 835
S U M M A RY
Primary Diseases of Myelin
• Because of the critical role of myelin in nerve conduction,
diseases of myelin can lead to widespread and severe
neurologic deficits.
• Diseases of myelin can be grouped into demyelinating dis-
eases (in which normal myelin is broken down for inap-
propriate reasons—often by inflammatory processes), and
dysmyelinating diseases (metabolic disorders that include
the leukodystrophies in which myelin structure or its
turnover is abnormal).
• Multiple sclerosis, an autoimmune demyelinating disease,
is the most common disorder of myelin, affecting young
adults. It often pursues a relapsing-remitting course, with
eventual progressive accumulation of neurologic deficits.
• Other, less common forms of immune-mediated demyelin-
ation often follow infections and are more acute
illnesses.
ACQUIRED METABOLIC AND
TOXIC DISTURBANCES
Toxic and acquired metabolic diseases are relatively
common causes of neurologic illnesses. Because of its high
metabolic demands, the brain is particularly vulnerable to
nutritional diseases and alterations in metabolic state. Sur-
prisingly, even though metabolic alterations might be
expected to affect the entire brain uniformly, there can be
very distinct clinical presentations because of unique fea-
tures or requirements of different anatomic regions. A few
of the more common types of injury, particularly those
with distinct patterns of damage, are discussed here.
Nutritional Diseases
Thiamine Deficiency. In addition to the systemic effects of
thiamine deficiency (beriberi), there also may be abrupt
onset of confusion, abnormalities in eye movement, and
ataxia—a syndrome termed Wernicke encephalopathy. Treat-
ment with thiamine can reverse these deficits. If the acute
stages go untreated, they are followed by largely irrevers-
ible profound memory disturbances (Korsakoff syndrome).
Because the two syndromes are closely linked, the term
Wernicke-Korsakoff syndrome is often applied.
The syndrome is particularly common in the setting of
chronic alcoholism but also may be encountered in patients
with thiamine deficiency resulting from gastric disorders,
including carcinoma and chronic gastritis, or from persis-
tent vomiting.
MORPHOLOGY
Wernicke encephalopathy is characterized by foci of hemor-
rhage and necrosis, particularly in the mammillary bodies but
also adjacent to the ventricles, especially the third and fourth Toxic Disorders
ventricles. Despite the presence of necrosis, there is relative
preservation of many of the neurons in these structures.
Early lesions show dilated capillaries with prominent endo-
thelial cells and progress to hemorrhage. As the lesions
resolve, a cystic space appears along with hemosiderin-laden
macrophages. Lesions in the medial dorsal nucleus of the
thalamus seem to best correlate with the memory distur-
bance in Korsakoff syndrome.
Vitamin B12 Deficiency. In addition to pernicious anemia,
deficiency of vitamin B12 may lead to neurologic deficits
associated with changes in the spinal cord, collectively
termed subacute combined degeneration of the spinal cord. As
the name implies, both ascending and descending tracts of
the spinal cord are affected. Symptoms develop over
weeks. Early clinical signs often include slight ataxia and
lower extremity numbness and tingling, which can pro­
gress to spastic weakness of the lower extremities; some-
times even complete paraplegia ensues. Prompt vitamin
replacement therapy produces clinical improvement;
however, if paraplegia has developed, recovery is poor.
Metabolic Disorders
Several systemic derangements may produce CNS dys-
function; only those associated with glucose levels and
liver dysfunction are considered here.
Hypoglycemia. Since the brain requires glucose as a sub-
strate for energy production, the cellular effects of dimin-
ished glucose generally resemble those of global hypoxia.
Hippocampal neurons are particularly susceptible to hypo-
glycemic injury, while cerebellar Purkinje cells are rela-
tively spared. As with anoxia, if the level and duration of
hypoglycemia are sufficiently severe, there may be wide-
spread injury to many areas of the brain.
Hyperglycemia. Hyperglycemia is most common in the
setting of inadequately controlled diabetes mellitus and
can be associated with either ketoacidosis or hyperosmolar
coma. Patients develop confusion, stupor, and eventually
coma associated with intracellular dehydration caused by
the hyperosmolar state. The hyperglycemia must be cor-
rected gradually, because rapid correction can produce
severe cerebral edema.
Hepatic Encephalopathy. Decreased hepatic function may
be associated with depressed levels of consciousness and
sometimes coma. In the early stages, patients exhibit a
characteristic “flapping” tremor (asterixis) when extending
the arms with palms facing the observer. Elevated levels of
ammonia, which the liver normally clears through the urea
cycle, in combination with inflammation and hyponatre-
mia, cause the changes in brain function. Because it is only
one contributing factor, ammonia levels in symptomatic
patients vary widely. Within the CNS, ammonia metabo-
lism occurs only in astrocytes through the action of gluta-
mine synthetase, and in the setting of hyperammonemia,
astrocytes in the cortex and basal ganglia develop swollen,
pale nuclei (called Alzheimer type II cells).
The list of toxins with effects on the brain is extremely long.
Among the major categories of neurotoxic substances are