Ebook Escourolle poirier’s manual of basic neuropathology Part 2

9
Acquired Metabolic Disorders
L E I L A C HI M E LLI AND F R A N Ç O I S E G R AY

A WIDE range of systemic acquired metabolic
diseases can also affect the central and/or peripheral nervous system (e.g. hypoxia, hypoglycemia,
disorders of serum electrolytes, vitamin deficiencies, and exogenous intoxications). By and large,
the morphologic manifestations of most of these
diseases in the various organs of the body are nonspecific. In the central nervous system (CNS), on
the other hand, lesions may find expression via
selective involvement of some brain regions with
simultaneous complete preservation of others, a
phenomenon often referred to as selective vulnerability. The pathogenesis of the predisposition to injury
of some anatomical areas and/or of some specific,
largely neuronal, cell types varies considerably from
one disease to another and is undoubtedly multifactorial in all. Differences in the vascular patterns of
irrigation and resulting alterations in regional perfusion may explain, at least partly, the phenomenon of
selective vulnerability in some disorders. Regional
variations in the biochemical characteristics of neuronal populations or, most likely, in the distribution

of receptors for various excitatory amino acids may
also play a role in some others.

1. CEREBRAL HYPOXIA
The brain normally receives about 15% of the
cardiac output, consumes about 20% of the
blood oxygen, and consumes about 10% to 20%
of the blood glucose. Different states of deficient
oxygen supply and utilization or deficient substrate may produce prominent cerebral hypoxic
changes:
• Anoxic or hypoxic hypoxia results from decreased

pulmonary access to oxygen. This may be due
to insufficient oxygen in the inspired air. It also
may result from upper airway obstruction or may
accompany pulmonary disorders that impede the
uptake of oxygen. In rare instances (i.e., hyperthermia) it may be due to increased metabolic
demand.
•

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• Anemic hypoxia results from decreased oxygen
transport, either from reduced hemoglobin levels
or reduced capacity of the hemoglobin molecule
to transport oxygen, as occurs in carbon monoxide poisoning.
• Stagnant hypoxia results from reduction or cessation of blood flow. This can be the result of
impaired cardiac output producing global ischemia, or can be localized as is the case in brain
infarcts. The cerebral lesions that result from
stagnant hypoxia are due to a combination of an
inadequate supply of oxygen and glucose and an
accumulation of lactic acid.
• Histotoxic hypoxia results from exposure to intoxicants, such as cyanide or hydrogen sulfide, which
render the neural parenchyma incapable of utilizing oxygen and substrates.
• Oxyachrestic hypoxia results from severe hypoglycemia, where oxygen is not utilized because of the
severe metabolic substrate deficiency.

1.1. Basic Cellular Reactions
to Injury
The basic cellular reactions to injury (see Chapter 1)
seen in cerebral hypoxia mostly involve neurons

(ischemic nerve cell change); glial cells may also be
affected and this may be manifest, for example, as
glial necrosis, reactive gliosis, or rod-shaped microglia and macrophage proliferation.

1.2. Selective Tissue Lesions
The cellular changes resulting from hypoxia are
maximal in those areas of the brain that are regarded
as showing selective vulnerability.
In the cerebral cortex, the neuronal changes are
more pronounced in the third, fifth, and sixth layers
of the neocortex. In addition, the changes are more
severe in the depths of sulci than along the banks or
the apices of the gyri. Widespread, severe destruction of the deeper layers of the cortex leads to laminar (or pseudo-laminar) necrosis (Fig.  9.1). This
descriptive term applies to a phenomenon whereby
the distribution of the necrosis is confined to one or
more layers of the isocortex and may be especially
evident in the parietal and occipital lobes, where
impaired perfusion may exacerbate the effects of
hypoxia. In the most severe cases, the cortical necrosis is not selective.

206

•

FIGURE 9.1 Laminar cortical necrosis. This is often
most severe in the posterior frontal and parietal lobes.

The hippocampus (Ammon’s horn) often shows
selective involvement by hypoxia. This is most evident in the CA1 sector (an area that corresponds
to what is anatomically defined as Sommer’s sector) (Fig. 9.2A, B). The CA3 area (also referred to

as the endplate) is often less severely affected. The
CA2 area tends to be relatively resistant to hypoxic
changes. The regional variation in the susceptibility of the pyramidal hippocampal neurons is now
best explained by implicating the distribution of
excitotoxic receptors as an important pathogenetic
factor.
Among the basal ganglia, the pallidum (especially the medial portion) (Fig.  9.3), the striatum,
especially the lateral half of the putamen, and the
thalamus are selectively vulnerable to hypoxia. The
mammillary bodies may be especially vulnerable
when hypoxia occurs in infancy.
In the cerebellum, cortical involvement is frequent
and affects chiefly the Purkinje cells with secondary
proliferation of Bergmann glia. The dentate nucleus
is also frequently involved.
In the brainstem, the medullary olives are vulnerable areas. In children, the brainstem is sometimes
severely damaged, especially the medial and lateral
reticular formations and the adjacent cranial nerve
nuclei.
Various types of white matter lesions may be
seen in isolation in response to anoxia or in association with gray matter damage. Some white matter lesions consist predominantly of extravasation
of edema fluid due to increased vascular permeability but with preservation of endothelial cells.
These lesions currently are designated as reversible

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A

B

FIGURE 9.2 Cerebral anoxia, involvement of the hippocampus. (A) Gross appearance. (B) Microscopy. Note
the cell loss from the CA1 sector and to a lesser extent the endplate (Luxol fast blue myelin stain).

leukoencephalopathy and may be seen in hypoxia and
other acquired metabolic disturbances or intoxications. Other white matter lesions, often designated
collectively as hypoxic encephalopathy, consist of
varying proportions of demyelination and white
matter necrosis. The degree of severity of these
lesions ranges from small, perivascular foci of demyelination, to focal plaque-like areas of demyelination
and necrosis, and up to large confluent areas of
demyelination and necrosis. The lesions tend to be
most severe deep in the white matter and are often
associated with relative preservation of the subcortical “U” fibers (Fig. 9.4).

that interval, a variable degree of cerebral swelling may be observed. In cases of sudden death
or where only moderate cerebral hypoxia has
occurred, unquestionable signs of hypoxia may
be discerned solely on histological examination;
these changes consist of ischemic neurons in the
most vulnerable areas, where they are difficult to
detect before 4 to 12 hours of survival beyond the
insult.
Depending on the mechanism of cerebral anoxia,
separate and distinctive patterns of ischemic changes
are recognized.

1.3. Variation of Lesions
According to Etiology

A survival time of approximately 48 hours is
necessary for macroscopically visible lesions of
cerebral hypoxia to become apparent. Before

FIGURE 9.3 Bilateral necrosis of the pallidum,
gross appearance.

FIGURE 9.4 Whole-brain section showing extensive white matter demyelination with preservation of
the U fibers in hypoxic leukoencephalopathy (Loyez
stain).

Chapter 9 Acquired Metabolic Disorders • 207


1. 3. 1. C E RE BRAL I N FA R C TS

Cerebral infarcts are the result of localized ischemic
hypoxia due to vascular occlusion (see Chapter 4).
Infarcts and/or ischemic lesions in the boundary
zone areas are the result of global oligemic hypoxia,
especially in the setting of low cerebral blood flow of
sudden onset, even of short duration. These lesions
are one of the possible consequences of acute heart
failure (cardiogenic shock), drug-induced hypotension, or general anesthesia.
1. 3. 2. C ARDI OVASCU L A R  A R R ES T

Cardiovascular arrest exceeding three to four minutes at normal temperature ordinarily causes diffuse
cortical lesions and Ammon’s horn involvement; the
distribution and extent of damage in the basal ganglia and in the brainstem vary (Fig. 9.5). Comparable
lesions are caused by profound hypoglycemia (vide

infra) and status epilepticus.
1. 3. 3. C ARBON MONO X I D E P O I S O NI N G

Carbon monoxide (CO) is produced by incomplete combustion of carbon-containing substances.
Humans are exposed to CO mainly through automobile exhaust, improperly ventilated stoves or
heaters, and tobacco smoke. The toxic effects of
CO result primarily from the decreased capacity of
blood to transport oxygen.
At autopsy examination, the brain of an individual who dies within a few hours of intoxication
is diffusely swollen and congested. The blood within
vessels has the characteristic cherry-red color of

FIGURE 9.5 Diffuse cortical and basal ganglia
lesions in a case of delayed death following cardiovascular arrest.
208

•

carboxyhemoglobin; that hue is also imparted to
the external and cut surface of the brain (Fig. 9.6).
Scattered petechial hemorrhages also may be present. With prolonged formalin fixation, the red discoloration becomes less prominent.
Some individuals who seem to recover clinically
from acute toxic exposure to CO may, some days to
weeks later, develop a neurological syndrome that
includes neuropsychiatric manifestations including personality changes, parkinsonism, dementia,
incontinence, and frank psychosis. In these cases,
different combinations of the neuropathological
abnormalities described below may be found.
Pallidal necrosis is most often observed in fatal
cases of CO intoxication occurring after some delay

after the insult (6 or more days). Microscopic foci
of ischemic or hemorrhagic necrosis may develop
even sooner. The pallidal lesions are usually bilateral but are often asymmetrical. The necrosis usually
involves the anterior portion and inner segment of
the pallidum but may extend into the outer segment
or dorsally into the internal capsule. Although pallidal necrosis is characteristic of and frequently seen
in delayed deaths from CO, it may also be seen in
other conditions associated with hypoxia or anoxia
(Figs. 9.3, 9.7, and 9.8). The selective involvement
of the globus pallidus in CO poisoning has been

FIGURE 9.6 Macroscopic image of the brain from
patient with acute CO poisoning. The postmortem
blood CO saturation was 60%.The cherry-red color
of the carboxyhemoglobin imparts a red hue to the
entire brain.

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FIGURE 9.7 Coronal section showing bilateral
pallidal necrosis. This can be seen following delayed
death from CO or other hypoxic conditions.

attributed to selective vulnerability of pallidal neurons, the result of hypotension and impaired circulation through the pallidal branches of the anterior
choroidal arteries, or the relatively high iron content
of this portion of the brain, which somehow renders
the structure especially susceptible.
Other gray matter regions involved include the

neocortical and hippocampal neurons, and the cerebellar Purkinje cells and granule cells, where there
may be focal neuronal loss.
Lesions of the white matter are also encountered
in individuals who die some time after CO poisoning. These lesions consist of varying degrees of
demyelination and associated necrosis. There may
be small perivascular foci found in the deep white
matter, large confluent areas that extend from the
frontal to occipital poles in the periventricular white
matter, or sharply demarcated foci of demyelination
with relative sparing of axons in the deep white matter (“Grinker’s myelinopathy”) (Fig. 9.8). All these
lesions tend to spare the arcuate fibers.
1.3.4. CYANIDES

Cyanides are histotoxic or cytotoxic agents, the toxicity of which is due to bonding between the cyanide
ion and the ferric iron of intracellular cytochrome
oxidase. This reaction leads to cessation of cellular
respiration. Acute intoxication can result from either
ingestion or inhalation of cyanides and causes respiratory arrest. Rarely, survivors of cyanide intoxication may develop parkinsonism or dystonia.
When death is acute, the brain may be edematous
and in some cases focal subarachnoid hemorrhages

FIGURE 9.8 CO poisoning. Necrosis of the pallidum and white matter necrosis in a case of Grinker
myelinopathy (Loyez stain).

develop. If death occurs some time later, the brain
may show foci of necrosis in the basal ganglia and
white matter and loss of Purkinje cells.
1.3.5 . HYPOGLYCEMIA

Glucose is the principal source of energy in the

CNS. Neuronal stores of glucose and glycogen are
relatively small and need practically continuous
replenishment. A  decrease of glucose level under
1.5mmol/L (25 to 30mg/100mL) leads to brain
damage within one to two hours.
The most common cause of hypoglycemia is an
excess of exogenous insulin. The effects of hypoglycemia are not due just to the energy deficit.
Releases of aspartate and to a lesser extent release of
glutamate probably contribute to neuronal damage
through excitotoxic mechanisms.
In acute hypoglycemia, the lesions are similar to
those of acute hypoxia but not identical. In general,
the pattern of injury is that of selective degeneration
of neurons rather than frank necrosis of all other cellular components. Affected neurons are shrunken
with hypereosinophilic cytoplasm. Initially, the
nucleus is pyknotic, as seen in anoxia, but later may
become eosinophilic and appears to blend in with
the cytoplasm (nuclear dropout). The topography of
the lesions is roughly similar to that in hypoxia, but
Purkinje cells may be relatively spared.

Chapter 9 Acquired Metabolic Disorders • 209


In long-term survivors of severe hypoglycemia
who then come to postmortem examination, the
cerebral cortex may appear thinned and the hippocampi shrunken and discolored. The white matter is
reduced in bulk and the ventricles are dilated. There
may be marked atrophy of the caudate nucleus and
putamen. On microscopic study, the cerebral cortex

shows laminar neuronal loss and gliosis associated
with capillary proliferation. There is often dense
subpial gliosis. The hippocampal pyramidal cell
layer and subiculum are replaced by a loose meshwork of glial tissue. The white matter is usually rarefied and gliotic. The caudate nucleus and putamen
are diffusely gliotic. The globus pallidus is relatively
spared. Moderate neuronal loss and gliosis may be
evident in the thalamus. As in acute hypoglycemia,
the cerebellar cortex, including the Purkinje cells, is
relatively spared.
1. 3. 6. HYPE R T HE RM I A

Acute hyperthermia or heat stroke is a thermal
insult to the cerebral thermoregulatory system controlling heat production and heat dissipation. The
thermal insult may be endogenous in “exertional
heat stroke” or environmental “classic heat stroke.”
It is also a feature of malignant hyperthermia, an
autosomal dominant disorder of the skeletal muscle
characterized by a hypermetabolic response to commonly used inhalation anesthetics and depolarizing
muscle relaxants. Clinically heat stroke is defined as a
syndrome characterized by elevated core body temperature over 40° Celsius and neurological dysfunction. Neuropathological studies are relatively few.
Abnormalities similar to those of hypoxic–ischemic
damage, probably resulting from a combination of
cardiovascular collapse and an increased metabolic
rate, have been described. Severe diffuse loss of
Purkinje cells with consequent degeneration of the
cerebellar efferent pathways is known to occur, but
often in the absence of injury to Ammon’s horn and
other areas susceptible to hypoxia.

FIGURE 9.9 Cross-section of pons from patient

with CPM. Note the ill-defined brown discoloration
of the demyelinative lesion.

complication of the rapid rise in osmolality that
accompanies excessively rapid correction or
over-correction of chronic hyponatremia. The clinical manifestations vary according to the size of the
lesion—from asymptomatic to coma. In life, the
diagnosis can be made by MRI.
At autopsy, the typical CPM lesion appears as a
discolored, destructive area in the basis pontis that
may be centrally cavitated (Fig.  9.9). The lesions
are often triangular, T-shaped, or diamond-shaped
and vary from a few millimeters across (Fig.  9.10)
to lesions that involve nearly the entire basis pontis.
Even when the lesion is extensive, generally at least
a thin rim of intact tissue with myelin preservation

2. ELECTROLYTIC
DISTURBANCES
2.1. Central Pontine Myelinolysis
Central pontine myelinolysis (CPM) is a monophasic demyelinating disease that predominantly
involves the basis pontis. It usually occurs as a

210 •

FIGURE 9.10
(Loyez stain).

Triangular lesion of limited CPM

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anatomically by close apposition of gray and white
matter structures.

2.2. Disorders of Iron Metabolism

FIGURE 9.11 Large section of pons from a patient
with extensive CPM (Loyez stain for myelin).

is present at the lateral and ventral margins of the
basis pontis (Fig.  9.11). Demyelination is usually
maximal in the middle and rostral portions of the
pons. Lesions may extend to the middle cerebellar
peduncles.
Histologically, the CPM lesion is characterized by demyelination with relative preservation
of axons and neuronal perikarya (Fig. 9.12). Acute
lesions contain numerous lipid-laden macrophages but few or no inflammatory cell infiltrates.
Occasionally foci of necrosis and cavitation are
present in the center of the more severe lesions.
Sometimes, especially in more severe cases, CPM
is accompanied by extrapontine demyelinated
lesions. These may involve the subcortical white
matter, striatum, anterior commissure, internal and
external capsules, lateral geniculate bodies, and
cerebellar folia. As is the case in the pons, these
extrapontine sites of involvement are characterized

In primary or secondary hemochromatosis, the
blood–brain barrier provides effective protection
against the diffusion of protein-bound iron into
the CNS. Therefore, hemosiderin iron deposits are
limited to regions of the CNS devoid of the blood–
brain barrier, including the choroid plexuses, the
area postrema, the pineal gland, adenohypophysis, dorsal root ganglia, and a number of vestigial
remnants such as the paraphysis and the subfornical organ. These regions have a gross rusty appearance and show marked Prussian blue reaction with
ferrocyanide.

2.3. Disorders of Calcium
Metabolism
Massive perivascular deposits including calcium
(Fig.  9.13A) but also iron (Fig.  9.13B) and other
minerals may be observed in the basal ganglia and
sometimes in the dentate nucleus, the white matter, and Ammon’s horn (so-called Fahr syndrome)
in a variety of circumstances, including hypoparathyroidism and conditions accompanied by
hypercalcemia.

3. VITAMIN DEFICIENCY
DISORDERS
3.1. Thiamine Deficiency

FIGURE 9.12 Microscopic section of pons from a
patient with CPM. Note the intact neuron in the midst
of an area of demyelination (Klüver-Barrera stain).

The Wernicke-Korsakoff syndrome is caused by
thiamine (vitamin B1) deficiency from inadequate
intake (beriberi, prolonged intravenous therapy

without vitamin supplementation), significant
nutritional deficit as in fasting or famine, gastric
absorption defect such as in hyperemesis gravidarum,
gastrointestinal neoplasms, and gastric plication for
morbid obesity.
The distribution of the lesions of Wernicke
encephalopathy is characteristic (Figs. 9.14 and
9.15] and accounts for the symptoms, which
include disturbances of wakefulness, hypertonia,
and ocular palsies. They are found in the periventricular areas, including the medial aspect of the thalamus, hypothalamus, and mammillary bodies, the
Chapter 9 Acquired Metabolic Disorders • 211


A

B

FIGURE 9.13 (A) Massive perivascular mineral deposits in a case of Fahr disease (H&E). (B) Iron perivascular deposits in the same patient revealed by Perl’s method for iron.

periaqueductal region at the level of the third cranial
nerve, the reticular formations of the midbrain, caudal portion of the corpora quadrigemina, and the
floor of the fourth ventricle. The mammillary bodies
are the most frequently affected structures and are
involved in virtually all cases.
The changes vary with the stage and severity of
the disease. At gross examination, when patients
die during the acute stages of the disease, petechial
hemorrhages involve predominantly the mammillary bodies (Fig. 9.16) and sometimes may be more
extensive (Fig.  9.15). In contrast, the lesions may
be inconspicuous grossly. Patients with less severe,

chronic, or previously treated disease may have
mildly atrophic mammillary bodies that are gray to
brown in color as a result of hemosiderin deposition
(Fig.  9.17). A  narrow band of tissue immediately

adjacent to the ventricular system and around the
aqueduct usually remains unaffected.
At microscopy, the acute lesions display edema,
petechial hemorrhages, myelin loss, and reactive
astrocytosis. Neurons are generally preserved.
Swelling and hyperplasia of endothelial cells make
the capillaries abnormally prominent (Fig.  9.18).
The perivascular spaces may contain lipid-laden
macrophages. Extravasated erythrocytes and
hemosiderin-laden macrophages are seen in the
cases with grossly discernible petechial hemorrhages. In the chronic stages of the disease and in
treated patients the affected regions may show little
more than mild loss of neurons and gliosis. Central
chromatolysis of neurons may result from associated
niacin deficiency (see below).
Korsakoff psychosis is defined clinically as retrograde amnesia and an impaired ability to acquire
new information and is usually encountered in
alcoholic patients with chronic Wernicke encephalopathy. The pathological basis of that syndrome is
debated. It does not seem to result from the lesions
of the mammillary bodies only. Involvement of the
medial dorsal nuclei (Figs. 9.15A and 9.19) and/or
midline region of the thalamus plays an important
causative role, according to some authors.
Thiamine deficiency also produces peripheral neuropathy, including beriberi neuropathy and at least
some cases of so-called alcoholic polyneuropathy.

3.2. Pellagra

FIGURE 9.14 Topographical distribution of the
lesions in Wernicke encephalopathy.
212 •

Pellagra is clinically manifest typically by dermatitis,
diarrhea, and dementia. The disease has long been
recognized among malnourished individuals who
depended on corn as a major part of their diet. It

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A

B

C

D

FIGURE 9.15 Wernicke encephalopathy: topographical distribution of the lesions (Loyez stain).
(A) Periventricular hemorrhagic thalamic lesions. (B) Lesions in the tegmentum of the midbrain at the level of
the third cranial nerve nuclei. (C) Hemorrhages in the tegmentum of the upper pons. (D) Hemorrhagic lesions
in the medullary floor of the fourth ventricle.

FIGURE 9.16 Acute Wernicke encephalopathy.

Note the petechial hemorrhages in the mammillary
bodies and, to a lesser extent, the walls of the third
ventricle.

FIGURE 9.17 Shrunken, discolored mammillary
bodies in a patient who had been treated for previous
episodes of Wernicke encephalopathy.

Chapter 9 Acquired Metabolic Disorders • 213


dorsal nucleus of the vagus, the gracile and cuneate
nuclei, the nucleus ambiguus, the trigeminal nerve
nuclei, the oculomotor nuclei, the reticular formations, and the anterior horn motor neurons of the
spinal cord. In some cases of niacin deficiency there
may be degeneration of the posterior columns and
corticospinal tracts.

3.3. Vitamin B12 deficiency

FIGURE 9.18 Microscopic appearance of the
mammillary bodies from a patient with Wernicke
encephalopathy. Note the petechial hemorrhages and
the swelling of the endothelial cells

results from lack of P-P (pellagra preventive) factor
(nicotinic acid or niacin). It is now known that deficiency of niacin itself, or of tryptophan, an amino
acid precursor of niacin that is deficient in corn,
leads to pellagra. The disease has become very rare
as the result of enriching common foods, such as

bread, with niacin. This vitamin deficiency is now
encountered most often in patients with chronic
alcoholism. In these patients the disease may be clinically atypical, lacking the characteristic skin lesions.
The neuropathological changes resulting from
niacin deficiency consist of isolated neuronal
changes of central chromatolysis type (Fig.  9.20),
without associated glial or vascular alterations. They
affect, in decreasing order of frequency, the Betz cells
of the cerebral motor cortex, the pontine nuclei, the

FIGURE 9.19 Petechial hemorrhages and myelin
loss in the thalamus from a patient with Korsakoff
syndrome.

214 •

Vitamin B12 is obtained primarily from meat and
dairy products. The vitamin must be bound to
“intrinsic factor,” a glycoprotein produced by the
gastric parietal cells, prior to being absorbed by the
body through the ileum. Most cases of vitamin B12
deficiency actually result from inadequate production of intrinsic factor. In pernicious anemia, this is
due to autoimmune atrophic gastritis, more rarely to
gastric neoplasms or gastrectomy. Vitamin B12 deficiency also can result from impaired ileal absorption, in individuals with malabsorption syndromes,
intestinal tuberculosis, regional enteritis, or lymphomas. Rarely the cause of the deficiency is the result
of competitive utilization of the vitamin within the
intestine by the fish tapeworm (Diphyllobothrium
latum) or bacterial overgrowth in intestinal blind
loops or diverticula. Very similar changes (“vacuolar myelopathy”) have been observed in AIDS
patients, resulting from abnormalities of vitamin

B12 metabolism.
Vitamin B12 deficiency affects the hematopoietic (megaloblastic anemia), gastrointestinal (glossitis, anorexia, diarrhea, and weight loss), and nervous
systems. Neurological complications develop in 40%
of untreated cases and can occur in the absence of
hematological abnormalities. The neuroanatomical/
clinical syndrome of nervous system involvement
has been termed subacute combined degeneration of
the spinal cord.
The spinal cord from patients with longstanding severe vitamin B12 deficiency may be mildly
shrunken, with discolored posterior and lateral columns. Histologically, the earliest lesions consist of
vacuolar distention of myelin sheaths, resulting in
a characteristic spongy appearance of the affected
white matter. With further demyelination, lipid-laden
macrophages become scattered throughout the
lesions. Some of the axons traversing the lesions
undergo Wallerian degeneration. Initially astrocytosis is not marked, but dense gliosis may be seen in
patients who have had the disease for a protracted

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B

FIGURE 9.20 Pellagra encephalopathy. Microscopic picture of cell chromatolysis (H&E). (A) In nuclei pontis. (B) In the gracile nucleus.

period. The distribution of the lesions is remarkably constant. They are bilateral and symmetrical
and involve chiefly the long tracts of the spinal cord.

Initial lesions are found in the central part of the posterior column of the thoracic cord, from where they
extend peripherally and affect the corticospinal and
spinocerebellar tracts in the lateral columns. In severe
cases, the lesions may involve virtually all the white
matter, including the anterior columns, only sparing
the fibers adjacent to the gray matter. The severity
of the lesions usually decreases toward the cervical
and lumbar levels, in which they are restricted to
the dorsal and lateral columns, often sparing a small
peripheral zone (Fig. 9.21]. However, changes of secondary ascending and descending tract degeneration
may be associated at those levels. Rarely, the lesions
extend rostrally into the medulla. Occasionally, similar mixed demyelinative and destructive lesions may
be seen in the optic nerve and cerebral white matter.

4. TOXIC
ENCEPHALOPATHIES
The nervous system is particularly susceptible to
noxious agents. There are several reasons for this.
Neurons are continually active and are highly susceptible to energy deprivation; also, they are post-mitotic
cells and cannot divide as a response to toxic insults.
It is also important to recognize that the susceptibility of cells of the CNS to toxic substances in different anatomical regions is quite variable. These
differences are attributable in part to the anatomical
blood–brain barrier’s differential susceptibility to
some toxic substances. The type of exposure, dose,
age, gender and inherent, probably genetic factors

also determine the extent and severity of the toxic
insult. Accordingly, the neuropathological picture is
highly variable, reflecting the selective vulnerability
of some of the neural structures and the diversity of

the underlying mechanisms (e.g., energy deficiency,
excitotoxicity). Some lesions may also result from
visceral disturbances caused by the intoxication. In
some toxic encephalopathies the peripheral nervous
system may also be affected.
Here we describe the most widely recognized
toxic substances that are known to produce lesions
of the CNS.

4.1. Ethanol
Ethanol has many effects upon the CNS. It is well
known that alcoholism potentiates infections, contributes to traumatic injuries, and may increase the
risk of stroke, especially hemorrhagic stroke.
4.1.1 . ACUTE AL COHOL INTOXICATION

Ingestion of large quantities of alcohol can lead
directly to death from cardiorespiratory paralysis.
Blood alcohol levels over 450 to 500 mg/dL are
generally considered as potentially lethal, although
there is considerable individual variation. Autopsy
examination of the brain in fatal cases of acute alcohol intoxication usually shows only cerebral edema.
4.1.2 . CEREBRAL L ESIONS IN CHRONIC
ALC OHOL ISM

Whereas a direct neurotoxic effect of excessive alcohol consumption on the nervous system remains

Chapter 9 Acquired Metabolic Disorders • 215


A

B

C

FIGURE 9.21 Subacute combined degeneration of the spinal cord. (A) Klüver-Barrera stain showing spongy
appearance of the white matter in the central part of the posterior column of the thoracic cord. (B) Bodian Luxol
stain showing vacuolar distention of myelin sheaths. (C) Loyez myelin stain showing demyelination of the posterior and lateral columns of the spinal cord.

controversial, patients suffering from chronic alcoholism develop a wide range of visceral lesions that
have a serious impact on the nervous system:
• Hepatic encephalopathy may result from decompensated cirrhosis leading to hepatic coma and/or
occurring in the setting of a portocaval shunt (see
below).
• Cerebral lesions due to vitamin deficiency include
Wernicke-Korsakoff encephalopathy secondary to
deficiency of vitamin B1 absorption due to alcoholic gastritis and pseudopellagra encephalopathy,
with which it is frequently associated (see above).
• Alcoholic cerebellar degeneration may occur as
an isolated lesion or in association with other
alcohol-related lesions, such as Wernicke
encephalopathy. Its pathogenesis is unclear.
Morphologically similar but generally milder
cerebellar vermal atrophy can also occur as
an age-related phenomenon independent of
alcoholism.
216 •

The clinical manifestations evolve slowly over
months to years and include truncal instability, a

wide-based stance, and an ataxic gait. The vermal
atrophy can be demonstrated by CT and MRI,
but the degree of atrophy does not correlate well
with the severity of the clinical manifestations. The
lesions involve the rostral vermis (Fig. 9.22) and
to a lesser extent the superior surface of the cerebellar hemispheres (Fig. 9.23). The folia are pale,
sclerotic, and separated by widened inter-folial
sulci. The atrophy affects the crests of the folia
more severely than the depths of the inter-folial
sulci. Microscopically, the lesions consist of loss of
Purkinje cells with proliferation of Bergmann glia
and variable depopulation of the internal granular
cells. They are associated with lesions of the dorsal
laminae of the inferior olives. The cerebellar white
matter remains relatively unaffected.
• Central pontine myelinolysis was first described
in individuals with chronic alcoholism but may
also be seen in other conditions in which severe

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commissure (Fig. 9.24B), centrum semiovale
(Fig. 9.24A), and middle cerebellar peduncles.
Histologically, the lesions show loss of myelin with
abundant lipid-laden macrophages and relative sparing of axons.
• Morel’s laminar sclerosis is known to occur in
chronic alcoholism. It is characterized by a glial
astrocytic band-like proliferation localized to the

third cortical layer, especially in the lateral frontal
cortex. This disease is usually associated with,
and probably secondary to, the callosal lesions of
Marchiafava-Bignami disease.
FIGURE 9.22 Superior vermal atrophy from a
patient with chronic alcoholism.

metabolic or electrolytic disturbances are present
(see Section 2.1).
• Marchiafava-Bignami disease is a rare disorder,
the pathophysiology of which is unknown. It
is observed in the setting of chronic alcoholism of long duration and great severity. Rarely,
Marchiafava-Bignami disease has been described
in association with Wernicke encephalopathy or
CPM. The disease is usually diagnosed at autopsy,
but the lesions may be seen by CT and MRI.
Grossly and macroscopically the lesions are
demyelinated or partially necrotic regions in the
interior of the corpus callosum, with relative preservation of a thin strip of myelinated fibers on its
dorsal and ventral surfaces. The involvement is
maximal in the genu and body of the corpus callosum (Fig. 9.24) and may be accompanied by
similar involvement of the optic chiasm, anterior

4.2. Methanol
Methanol poisoning resulting from oral intake, most
often as a substitute for ethanol, may cause acute cerebral and ocular lesions. Methanol itself is neurotoxic;
its catabolites, including formaldehyde and formic
acid, are even more toxic. Formic acid and formates
block cellular respiration and contribute to the metabolic acidosis that is characteristic of this intoxication.
The ocular pathology of the blindness has been

investigated extensively. The lesions include principally optic disc edema and retrolaminar and optic
nerve necrosis.
Pathological changes in the brain include cerebral
edema, demyelination, and necrosis of the subcortical white matter, the lateral aspect of the putamen,
and the claustrum (Fig. 9.25). The putaminal necrosis is often hemorrhagic and may evolve into a massive hematoma. The necrosis of the claustrum is
generally non-hemorrhagic. The white matter lesions
and the retrolaminar demyelination of the optic
nerves are believed to be due to histotoxic myelinoclastic damage caused by formates. The pathogenesis
of the putaminal lesions remains unclear.

4.3. Ethylene glycol

FIGURE 9.23 Atrophy of the rostral vermis and
superior surface of the cerebellar hemispheres in a
patient with chronic alcoholism.

Ethylene glycol is a dihydroxy alcohol that is widely
used as a solvent and a component of certain antifreezes and coolants. Intoxication with this compound
is encountered most often when it is consumed as a
substitute for ethanol or with suicidal intent. Ethylene
glycol is progressively oxidized to more toxic compounds, including glycoaldehyde, glycolic acid, and
glyoxylic acid. A  small proportion is also oxidized
to oxalic acid. The clinical manifestations include
encephalopathy, severe metabolic acidosis, cardiopulmonary failure, and acute renal failure.
Chapter 9 Acquired Metabolic Disorders • 217


A

B

C

FIGURE 9.24 Marchiafava-Bignami disease. (A) Gross appearance showing necrosis of the interior of the corpus
callosum. Note involvement of the adjacent white matter. Whole-brain sections showing necrosis and demyelination
of the corpus callosum and anterior commissure (B) and splenium of corpus callosum (C) (Loyez myelin stain).

Macroscopic examination of the brain in fatal cases
shows edema, meningeal congestion, and, occasionally, petechial hemorrhages. Microscopically, acute
inflammatory cells may be seen in the meninges and

around intraparenchymal blood vessels. Deposits of
calcium oxalate may be seen in and around blood
vessels in the meninges, neural parenchyma, and
choroid plexus. These crystals are birefringent under
polarized light (Fig. 9.26A, B).

4.4. Phenytoin

FIGURE 9.25 Methanol intoxication. Note the
bilateral necrosis of the putamen and claustrum.
218

•

Patients with seizure disorders who have been
treated with phenytoin for prolonged periods may
develop cerebellar cortical atrophy, which can
be documented by CT and MRI during life or at
autopsy. Histopathological studies have shown

folial atrophy, loss of Purkinje cells throughout the
cerebellum, and mild loss of internal granular layer
cells (Fig. 9.27). Whether the drug itself is the sole
factor that causes toxic damage to Purkinje cells
has been difficult to establish since loss of Purkinje
cells may also be the result of hypoxia during seizures or from preexisting brain damage. Reports
of patients with seizure control under long-term

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A

B

FIGURE 9.26 Microscopic sections showing cerebellar cortex and leptomeninges from a patient with ethylene glycol intoxication. (A) Note the refractile calcium oxalate crystals in the vessel walls (H&E). (B) Note the
birefringence of the same crystals when viewed with polarized light.

phenytoin treatment, and who develop cerebellar
atrophy, support the view that phenytoin itself may
be neurotoxic.

4.5. Intoxication by Heavy
Metals and Certain Metalloids
Many different metals and certain metalloids, in
sufficient concentration and determined chemical form, are toxic to humans. It is usually difficult
to correlate a particular type of lesions with a specific etiology. In some hyperacute fatal forms of
intoxication, the clinical course may be so rapid
that, at the time of autopsy examination, histological changes have not yet become evident. Some of

the morphologic changes that may be seen include
edematous or hemorrhagic lesions. In the majority
of cases, the brain lesions are secondary to the multiple visceral disturbances caused by the intoxication.
4.5.1 . AL UMINUM

The neurotoxicity of this element is controversial.
Various aluminum compounds, applied directly
onto or injected into the cerebral cortex of certain
laboratory animals, produce seizures and neurofibrillary tangles, but these lesions are different from the
Alzheimer neurofibrillary tangles seen in humans.
Aluminum toxicity was described most commonly in patients undergoing chronic hemodialysis
and is due to exposure to aluminum in the dialysate
and the use of oral phosphate binding compounds
that contain aluminum.
Dialysis dementia is a syndrome now largely disappeared through the purification, of the water used
in dialysis, characterized clinically by dyspraxia,
asterixis, myoclonus, and dementia. In fatal cases
the brain aluminum content may become elevated
to levels even greater than reported in Alzheimer
disease but neurofibrillary tangles are not present.
4.5.2 . ARSENIC

FIGURE 9.27 Microscopic section of cerebellar
folium from a patient who had been on long-term
treatment with high-dose phenytoin. Note the loss of
Purkinje cells and the mild loss of internal granular
cell layer neurons.

Arsenic intoxication is encountered most often as

the result of occupational exposure or after ingestion with homicidal or suicidal intent. Acute trivalent arsenic poisoning is characterized by abdominal
pain, nausea, vomiting, and diarrhea followed by
renal failure. Death may occur in severe cases.
Chapter 9 Acquired Metabolic Disorders • 219


Chronic arsenic intoxication is manifest by gastrointestinal and dermatological symptoms. A  mixed
sensory and motor neuropathy is a well-known and
often disabling sequela of both acute and chronic
arsenical intoxication. Encephalopathy also has been
reported with acute and chronic arsenic intoxication. Acute hemorrhagic leukoencephalopathy has
been reported in patients treated with organic pentavalent arsenicals. This may have been the result of
a hypersensitivity reaction to the drug, rather than
arsenic intoxication.
4. 5. 3. L E AD

Lead can enter the body through the gastrointestinal and respiratory tracts and, when in organic
compounds, through the skin. Lead encephalopathy is now encountered predominantly in young
children who chew on items coated with lead paint.
Acute encephalopathy produces irritability, seizures,
altered consciousness, and evidence of increased
intracranial pressure. The intoxication usually
responds to sedation and chelation therapy but can
lead to permanent damage. Many authors attribute
the encephalopathy to vascular injury, which seems
to be more severe in the immature nervous system.
At gross examination, the brains are diffusely
swollen. The histological changes include congestion, petechial hemorrhages, and foci of necrosis.
Intraparenchymal capillaries may show necrosis,
thrombosis, and swelling of endothelial cells. There

is a proteinaceous exudate in the perivascular space
extending into the adjacent brain tissue. Periodic
acid-Schiff–positive globules may be seen within
the exudates and in astrocytes. Diffuse astrocytosis
has been reported even in the absence of capillary
changes.

4. 5. 4. MANGANE S E

Manganese exposure may result from inhaling dust
in manganese mines or vapor released during ferromanganese smelting. The clinical manifestations
include headaches, transient psychiatric disturbances, and a hypokinetic extrapyramidal dysfunction that resembles Parkinson disease but is not
responsive to L-dopa.
Pathological studies in humans are limited but
document degenerative lesions in the pallidum and
subthalamic nucleus and, to a lesser extent, the striatum. The substantia nigra is involved in some cases.

220 •

4 .5 . 5. M ERCURY

Acute poisoning from inorganic mercury compounds is manifest clinically predominantly by
gastrointestinal tract and renal tubular injury.
Pulmonary injury is caused by inhalation of metallic
mercury vapors. Neurotoxicity is also a prominent
manifestation of chronic inorganic mercury poisoning, and patients present with behavioral changes,
intention tremor, and movement disorders; peripheral neuropathy may also develop.
Organic mercury intoxication is usually caused
by ingestion of contaminated food. Some years
ago, reports from Japan described a large number

of patients who developed chronic organic mercury intoxication by eating fish contaminated by
methyl mercury (Minamata disease). Other large
outbreaks have resulted from the consumption of
grain treated with an organic mercury fungicide. The
clinical manifestations in these cases included cortical blindness, impaired proprioception, movement
disorders, mental retardation, and quadriparesis.
The neuropathology of organic and inorganic
mercury poisoning is essentially indistinguishable.
The slight differences that may exist possibly reflect
variations in the rate of entry of mercury into the
nervous system. The lesions observed involve the
neurons predominantly. There is cerebral atrophy
involving mainly the anterior portions of the calcarine fissures with loss of neurons, especially the
outer cortical layers, and gliosis. Cerebellar atrophy
is also frequent, notably with loss of granule cell
neurons, mild loss of Purkinje cells, and proliferation of Bergmann glia.
4 .5 . 6. THALLIUM

Most cases of thallium intoxication result from accidental or deliberate ingestion of thallium pesticides
used for insect and rodent control. The clinical picture resembles that of trivalent arsenical poisoning.
The only consistent abnormalities in the CNS are
chromatolysis of spinal motor neurons and degeneration of the posterior columns, related to the sensorimotor distal axonopathy.
4 .5 . 7.   TIN

Inorganic tin is not neurotoxic, but two organic
tin compounds, triethyl-tin and trimethyl-tin, are.
Triethyl-tin causes striking white matter edema
due to accumulation of fluid in vacuoles within

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the myelin sheaths, which are separated along the
intra-periodic lines (see Chapter 1 and Fig. 1.24C).
Trimethyl-tin does not cause intra-myelinic edema
but is toxic to neurons in the hippocampus, the
entorhinal cortex, and the amygdala.

Wilson hepatolenticular degeneration. It is characterized by the presence of Alzheimer type II glia (see
Chapter 1 and Fig. 1.20). The lesions predominate
in the pallidum but may also involve the cerebral
cortex and the dentate nuclei.

5. CNS CHANGES
SECONDARY TO SYSTEMIC
DISEASES

5.3. Multifocal Necrotizing
Leukoencephalopathy

5.1. Respiratory
Encephalopathies
The neuropathology of respiratory encephalopathy,
secondary to chronic bronchopulmonary disease
and essentially due to hypoxia and hypercapnia, is
characterized by diffuse vasodilatation, microscopic
perivascular hemorrhages, and anoxic neuronal
changes of variable intensity.
At postmortem examination, the brain of patients

with who die soon after acute asphyxia shows congestion of the meninges and cortex due to venous
and capillary dilatation (“lilac brain”) (Fig.  9-28).
Perivascular hemorrhages predominating in the
white matter may be seen.

5.2. Hepatic Encephalopathy
Hepatic encephalopathy occurs in the course
of severe hepatic insufficiency in cases of severe
hepatic cirrhosis or hepatitis, in association with
portocaval anastomosis and in individuals with

FIGURE 9.28 “Lilac brain” in a patient who died
from acute asphyxia. Note petechial hemorrhages and
laminar necrosis.

This condition is characterized by the development of multiple, usually microscopic foci of necrosis in the white matter. It often affects the basis
pontis (focal pontine leukoencephalopathy). The
pathogenesis of the lesions observed is unclear.
Affected individuals are predominantly those who
are found to have increased levels of circulating
pro-inflammatory cytokines (e.g., patients with
AIDS, neoplasms treated with radiotherapy and
often intrathecal chemotherapy, sepsis). In most
cases it is discovered at autopsy.
By and large, the lesions are only visible on microscopic examination and consist of well-demarcated
areas of necrosis disseminated in the white matter,
but particularly involving the transverse pontine
fibers (Fig. 9.29A). There is loss of myelin staining,
proliferation of macrophages, and lesions of axons,
which appear swollen and fragmented and tend to

calcify (Fig. 9.29B).

5.4. Paraneoplastic
Encephalomyelopathies
Paraneoplastic CNS syndromes are neurological
disorders that are associated with systemic malignancies and that are unlikely to be the direct result
of involvement by the neoplasm, say by compression, invasion, or metastasis. Excluded, by definition, are iatrogenic complications of radiotherapy or
chemotherapy and opportunistic infections related
to immunodepression secondary to the neoplastic
process itself, to treatment, or to both. Also set apart
are the metabolic or deficiency disorders and vascular disorders associated with the development of
malignant disease.
Paraneoplastic syndromes can affect the central, peripheral, or autonomic systems. The neurological symptoms may be the initial manifestation
of the neoplastic process and can be multifocal.
Comparable idiopathic autoimmune disorders of
the CNS in which no systemic cancer is found have
also been described.

Chapter 9 Acquired Metabolic Disorders • 221


A

B

FIGURE 9.29 Multifocal necrotizing leukoencephalopathy. (A) Whole-brain section of the pons showing
disseminated necrotic foci in the transverse pontine fibers (Klüver-Barrera). (B) Microscopic section showing a
necrotic lesion with vacuolation and central calcification (H&E).

By and large, many paraneoplastic syndromes have

been shown to develop in the setting of autoimmune
mechanisms directed against an oncoantigen aberrantly
expressed by the systemic tumor, which cross-react with
antigens normally present in the nervous system.

In recent decades, specific autoantibodies (IgGs)
and their target antigens have been identified that
are often but not exclusively associated with specific
neoplasms and neurological syndromes (Tables 9.1
and 9.2).

Table 9.1. Paraneoplastic Antibodies, Antigens, Associated Neoplasm and
Neurological/Neuropathological Aspects
Antibodies targeting neural plasma membrane ion and water channels receptors and
synaptic proteins
AN TIBODY

ANTIGEN

TUMOR

N E U R O PAT H O L O G I C A L
P R E S E N TAT I O N

VGK-complex Ab

LGI1, CASPR2

Small cell lung carcinoma
Thymoma

Limbic encephalitis
Peripheral and autonomic
neuropathy
Myoclonus
Limbic encephalitis
Limbic encephalitis

 
NMDA receptor Ab NR1
AMPA receptor Ab GluR1,2
GABA-B receptor Ab GABA-B
P/Q and N-type

P/Q and N-type

Calcium channel Ab Calcium channel
Muscle AChR Ab

Muscle AChR

Neuronal ganglionic Neuronal
AChR Ab

222 •

Ganglionic AChR

Carcinoma of breast, prostate
Ovarian teratoma

Thymic tumors
Carcinoma of breast, lung
Small cell lung carcinoma
Other neuroendocrine tumor
Small cell lung carcinoma

Limbic encephalitis

Paraneoplastic
encephalomyelopathy
Gynecological or breast carcinoma Neuropathies,
Lambert-Eaton syndrome
Thymoma, thymic or
Myasthenia gravis
lung carcinoma
Adenocarcinoma, thymoma
Peripheral and autonomic
neuropathy
Small cell lung carcinoma
Paraneoplastic
encephalomyelopathy

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Table 9.2. Paraneoplastic Antibodies, Antigens, Associated Neoplasm and Clinical/
Neuropathological Aspects
Neuronal Nuclear, Cytoplasmic, and Nucleolar Antibodies
AN TIBODY

ANTIGEN

TUMOR

N E U R O PAT H O L O G I C A L P R E S E N TAT I O N

ANNA-1

ELAVL (Hu) Small cell lung carcinoma

ANNA-2

NOVA 1, 2
(Ri)

Small cell lung carcinoma,
breast carcinoma

ANNA-3

Unknown

Lung or esophageal
carcinomas
Small cell lung carcinoma

AGNA
Mal, Ma2

SOX-1
PNMA1,
PNMA2

Small cell carcinoma
Testicular (Ma2)

Peripheral neuropathy
Lambert-Eaton syndrome
Cerebellar degeneration

Breast, colon, testicular
(Ma1)
Müllerian adenocarcinoma
Breast carcinoma

PCA-1

CDR2 (Yo)

PCA-2

Unknown

Small cell carcinoma

PCA-Tr
Unknown
CRMP-5 IgG CRMP-5

Hodgkin lymphoma
Small cell carcinoma
Thymoma

Amphiphysin Amphiphysin Small cell carcinoma
IgG
Breast adenocarcinoma
GAD65 Ab

GAD65

Thymoma, renal, breast,
or colon adenocarcinoma

In some of these syndromes, the patient develops antibodies against neural cell surface receptors
or channels, the antibodies have a pathogenic role,
and there can be a clinical improvement after early
immunotherapy. In other conditions, the antigens
are not superficial but intracellular, and the immune
reaction is cellular, through MHC class 1 molecules and cytotoxic T-cell mechanisms. Neuronal

Peripheral and autonomic neuropathy
Paraneoplastic encephalomyelopathy
Cerebellar degeneration
Paraneoplastic encephalomyelopathy
Paraneoplastic encephalomyelopathy
Cerebellar degeneration

Brainstem encephalitis
Cerebellar degeneration

Paraneoplastic encephalomyelopathy
Peripheral neuropathy
Paraneoplastic encephalomyelopathy
Peripheral and autonomic neuropathy
Lambert-Eaton syndrome
Cerebellar degeneration
Cerebellar degeneration
Paraneoplastic encephalomyelopathy
Peripheral and autonomic neuropathy
Stiffness
Paraneoplastic encephalomyelopathy
Peripheral neuropathy
Stiffness
Paraneoplastic myelopathy

degeneration is then mediated by cytotoxic T cells.
These disorders, accompanied by autoantibody
markers of neural peptide-specific cytotoxic effector T cells, are generally poorly responsive to
immunotherapy.
The main neuropathological entities encountered in CNS paraneoplastic syndromes are paraneoplastic cerebellar degeneration, paraneoplastic

Chapter 9 Acquired Metabolic Disorders • 223


A

B

C

FIGURE 9.30 Paraneoplastic cerebellar degeneration. (A & B) Massive loss of Purkinje cells and proliferation of Bergmann glia (H&E). (C) Loss of Purkinje cells; preservation of basket fibers and of granular neurons
(Bielschowsky silver impregnation).

encephalomyelitis, and the opsoclonus-myoclonus
syndrome.
5. 4. 1. PARANE OP L A S TI C C ER EB EL L A R
D E G ENE RAT I ON

The clinical course of the disease is generally subacute and manifests as gait ataxia, incoordination,
dysarthria, and often nystagmus. The cerebellum may
be atrophic but is usually macroscopically normal.
Histologically, there is massive, diffuse loss of the
Purkinje cells with proliferation of the Bergmann glia
(Fig. 9.30A) and sparing of the basket fibers and to
a lesser extent of the granular neurons (Fig. 9.30B).
The degeneration of Purkinje cells axons often produces myelin pallor of the amiculum of the dentate
nucleus (Fig. 9.31). Microglial nodules and perivascular mononuclear cuffs in the leptomeninges and
parenchyma are frequent, but inflammation may be
sparse or absent.

224 •

5 .4 . 2. PARAN EOPLASTIC
ENCEPHALOM YELITIS

Subacute polioencephalomyelitis lesions involve
predominantly the gray matter and include, in variable proportion, neuronal loss, nodules of neuronophagia, proliferation of rod-shaped microglia,
astrocytic gliosis, and infiltration by B and T lymphocytes. The latter are mainly of the CD4 inductor/helper type in the perivascular cuffs and of the
CD8 cytotoxic type in the parenchymal infiltration.
B cells may predominate in disorders accompanied

by neural plasma membrane-reactive autoantibodies. The lesions have a characteristic distribution
and show a predilection for the medial temporal
cortex (limbic encephalitis), the rhombencephalon
(medullary pontine encephalitis), the cerebellum,
the gray matter of the spinal cord (poliomyelitis),
and the spinal root ganglia. In some patients, lesions
in these different anatomical locations may coexist; they may also be associated with inflammatory

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A

B

FIGURE 9.31 Paraneoplastic cerebellar degeneration. Myelin pallor of the amiculum of the dentate nucleus,
which is the site of convergence of Purkinje cell axons (Loyez myelin stain).
A

B

C

FIGURE  9.32. Limbic encephalitis. (A)  Gross appearance:  bilateral necrosis of the hippocampus and cerebral amygdala. (B) Microscopic section showing massive loss of pyramidal cells, astrocytic gliosis, and mononuclear perivascular infiltrates. (C) Microscopic section showing nodules of neuronophagia, astrocytic gliosis,
and mononuclear infiltrates both perivascular and diffuse in the parenchyma. Note severe inflammation of the
leptomeninges.
Chapter 9 Acquired Metabolic Disorders • 225

FIGURE 9.33 Medullary pontine paraneoplastic
encephalitis. Microscopic section showing nodules of
neuronophagia, proliferation of rod-shaped microglia,
astrocytic gliosis, and mononuclear infiltration in the
medullary olive.

lesions in the myenteric plexuses, the peripheral
nerves, and/or the skeletal musculature.
Patients with paraneoplastic limbic encephalitis
display behavioral changes, memory loss, and hallucinations. Limbic structures including the hippocampi, cingulate gyri, insular cortex, amygdala,
and parts of the temporal lobe may be affected
(Fig.  9.32A , B, C). The midbrain (Fig.  9.33) and
thalamus may also show similar changes.
Sensory neuropathy is a frequent component
of an encephalomyeloneuropathy. Clinically it is

A

manifest by numbness, paresthesias, dysesthesias,
and reduced or absent reflexes. The peripheral
nerves show axonal degeneration with varying
degrees of secondary segmental demyelination.
Additional pathological changes include degeneration of posterior roots, degeneration and demyelination of the posterior columns of the spinal cord,
and degeneration of dorsal root ganglia (Fig. 9.34A).
Mild perivascular and intraparenchymal infiltrates
of mononuclear inflammatory cells are often present. In the sensory ganglia, inflammatory cell infiltrates may be especially prominent. The number of
ganglion cells is reduced and nodules of Nageotte
are found where the ganglion cells have been lost
(Fig.  9.34B). Autonomic ganglia may be involved
as well as dorsal root ganglia but show less severe

changes.
5 .4 . 3. PARAN EOPLASTIC
O P SOCLON US- M YOCLON US SYN DROM E

The opsoclonus-myoclonus syndrome is rare but
is best known in association with neuroblastomas
in children. Even more rarely, the syndrome also
occurs in adults, in association with small cell carcinoma of the lung or breast carcinoma. Autopsy
examination of the brain of affected individuals may
show no histopathological abnormalities or may
show Purkinje cell loss and/or mild periaqueductal
infiltrates of inflammatory cells.

B

FIGURE 9.34 Paraneoplastic sensory neuropathy. (A) Note demyelination of the posterior columns (Loyez
myelin stain). (B) Spinal ganglion: note loss of ganglion cells, proliferation of satellite cells, and interstitial lymphocytic infiltration.

226 •

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10
Hereditary Metabolic Diseases
F R ÉD ÉR I C S E DE L, HA N S H . G O EB EL , A N D D O U G L A S C.   A NTH O NY

1. INTRODUCTION
Hereditary metabolic diseases were originally identified based on the absence of specific enzyme activities

within distinct metabolic pathways. Identification of
deficiency of enzymatic activity, often with accumulation of an intermediate metabolite within the pathway, eventually led to identification of the involved
gene. Therefore, the original classification of hereditary metabolic disease was based on enzyme deficiencies. More recently, pedigrees with inherited diseases
have been linked to specific genetic loci and, by identifying the involved gene, the protein sequences and
putative protein functions have been established,
without understanding the metabolic pathways that
may be involved. This “reverse” genetics, including findings from more recent methods such as full
exome or whole genome sequencing, has considerably increased the speed of discovery of inherited
metabolic diseases and expanded the categories of
disease that are recognized. As a result, the classification of inherited metabolic diseases is in flux.

One approach is the identification of two major
categories of disorders based on intracellular or
extracellular abnormalities in metabolites. The
first is a group of disorders in which the metabolic derangements are most prominent inside
the cell and often are linked to the dysfunction
of a single cellular organelle. These disorders may
have increased intracellular levels of an intermediate metabolite and may have intracellular accumulation of the metabolite, resulting in a so-called
“storage” disease. The organelles most commonly
involved in these disorders are lysosomes, peroxisomes, mitochondria, and the cytoplasmic
compartment. In the second group of hereditary
metabolic disorders, no intracellular accumulation
is identified. Instead, these disorders are viewed
as systemic biochemical disorders in which biochemical abnormalities are most prominent in the
circulation or in the urine. These are classified by
the biochemical pathways involved and are often
identified by the presence of circulating small molecules or by genetic testing.
•

227

1.1. Biochemical abnormalities
According to the metabolic pathway involved, inherited metabolic diseases involving the nervous system
can be divided into several categories of biochemical
abnormality, many of which display some similarities in clinical presentation, diagnostic methods, and
treatment strategies.
1. 1. 1. ABNORMAL I TI ES I N EN ER G Y
M E TABOL I SM

Energy metabolism disorders include some that
directly affect the respiratory chain and others that
involve metabolic pathways required for energy
production. These defects include respiratory chain
disorders (that can be primary or secondary, as can
occur in organic acidurias), pyruvate dehydrogenase
deficiency, Krebs cycle deficiencies, glucose transport (GLUT1) deficiency, and β-oxidation defects, as
well as disorders involving co-factors such as electron
transfer flavoprotein deficiency, vitamin E deficiency,
biotinidase deficiency, biotin-responsive thiamine
metabolism dysfunction, creatine deficiency syndromes, and coenzyme Q synthesis defects. This
group includes the disorders of mitochondrial function (mitochondriopathies). Acute manifestations
are often triggered by infections and include Leigh
syndrome, acute optic neuropathy, acute cerebellar ataxia, or pseudo-strokes. Chronic presentations
often involve muscles, cerebellum, basal ganglia
(parkinsonism), cortex (epilepsy, myoclonus), or the
peripheral nervous system (axonal polyneuropathy).
In adults, these diseases rarely involve the brain white
matter, and spastic paraparesis is very uncommon.
1. 1. 2. DI SOR DE R S O F L I P I D

M E TABOL I SM

Lipid metabolism disorders include some lysosomal
diseases, mainly sphingolipidoses (Krabbe disease,
metachromatic leukodystrophies, Niemann-Pick A,
B, and C, Fabry disease, Gaucher disease), peroxisomal disorders (adrenomyeloneuropathy, Refsum
disease, disorders of pristanic acid metabolism, peroxisome biogenesis disorders), Tangier disease, and
cerebrotendinous xanthomatosis.
Given the high content of lipids in the nervous
system, these diseases can produce severe neurological symptoms. Leukodystrophies and demyelinating polyneuropathies are hallmarks of disorders
interfering with myelin formation or maintenance.
228 •

A  past history of prolonged neonatal jaundice is
suggestive of disorders of cholesterol and bile acid
metabolism. Splenomegaly is highly suggestive of
some lipid storage diseases, such as Gaucher disease,
Tangier disease, and Niemann-Pick disease (either
type A, B or C). Other presentations are less specific
for lipid metabolism disorders:  cerebellar ataxias,
dementia, psychiatric disorders, epilepsy, and spastic paraparesis. A  slow progression of symptoms,
which corresponds to progressive lipid storage, is
highly suggestive of these disorders.
1 .1 . 3. IN TOXICATION SYN DROM ES

Some metabolic disorders are associated with variable clinical symptoms that correlate with the serum
levels of a small molecule or metabolite. These
include porphyrias, urea cycle defects, organic acidurias, and amino acidopathies. The onset of acute
symptoms that accompany the metabolic crisis is
characteristic of these disorders and has led to their

designation as “intoxication” syndromes. However,
in mild adult forms, symptoms can be progressive,
giving rise to leukoencephalopathies, epilepsy, psychiatric disorders, or spastic paraparesis.
1 .1 . 4. DISORDERS OF
NEUROTRAN SM ITTER M ETABOLISM

Disorders of neurotransmitter metabolism are
mostly represented by defects in the synthesis of
serotonin and dopamine. Clinical signs are related
to dopamine deficiency (dystonia, parkinsonism,
oculogyric crisis), noradrenergic deficiency (ptosis,
myosis, hypotension), or serotonin deficiency (sleep
disturbance, dysthermia, behavioral disturbance).
Dopa-responsive dystonia or parkinsonism is highly
suggestive. Diurnal fluctuations of symptoms are also
characteristic, with improvement in the morning and
worsening during the day. Diagnosis of these disorders relies on analysis of neurotransmitter metabolism
in the cerebrospinal fluid. Cerebral folate deficiency
can be added to this group because it shares several
clinical features and diagnostic methods, although
this syndrome is still highly heterogeneous.
1 .1 . 5. DISORDERS OF M ETAL
M ETABOLISM

Metal storage disorders include Wilson disease, neuroferritinopathy, aceruloplasminemia, PANK2-associated
neurodegeneration, PLA2G6 mutations, and a recently

E S C O U R O L L E & P O I R I E R ’ S M A N U A L O F B A S I C N E U R O P AT H O L O G Y

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identified disorder of manganese metabolism. The
hallmark of these diseases is an abnormality in metal
metabolism that may result in metal deposits, often
in the basal ganglia, sometimes visible on brain MRI.
The main presentations are movement disorders
because of the primary involvement of the basal ganglia. Treatments, when they exist, are mainly based on
metal chelators.

1.2. Morphological classification
Many of the biochemical pathways involved in
inherited metabolic diseases are associated with a
specific cellular organelle. There are three organelles commonly associated with the metabolic
disorders:  lysosomes, peroxisomes, and mitochondria. As a general rule, disorders involving lysosomal
proteins tend to involve catabolic pathways, and
the lack of a lysosomal enzymatic function is often
associated with the accumulation of a metabolite
for which the catabolic pathway is defective. The
accumulation of the nondegraded metabolite in
lysosomes is often referred to as a “storage” disease
and may lead to distention of nerve cell bodies and
their processes, glia, blood vessel walls, or cells outside the nervous system. In particular, the liver and
spleen are involved in some storage diseases, with
the presence of hepatosplenomegaly.
Other disorders involve a separate cellular organelle, the peroxisome. Like the lysosome, the peroxisome is involved in specific catabolic pathways, and
serum levels of metabolites from these pathways are
often increased in peroxisomal disorders. However,
in contrast to lysosomal disorders, intracellular storage of the metabolite is not usually present.
Mitochondria are the third major organelle associated with specific metabolic disorders. Serum levels of intermediary metabolites are often normal,
although impairment of oxidative phosphorylation

may lead to elevations of lactic acid. In addition, the
inheritance has a Mendelian pattern for the mitochondrial proteins encoded in nuclear DNA but a
maternal pattern of inheritance for genes encoded in
mitochondrial DNA (mtDNA).

1.3. Clinical Findings
Some hereditary metabolic disorders tend to affect
neurons and may do so within certain regions
or nuclei. Disorders that involve gray matter, or
neurons, have been termed “poliodystrophies,”
while those involving white matter are called

“leukodystrophies.” The latter disorders are characterized by loss of myelin (demyelination) or abnormal myelin formation (hypomyelination), which is
often evident on MRI of the brain. Hereditary leukodystrophies, in which the production of myelin
may be impaired due to abnormalities in the structure of myelin or in myelin metabolism, are often
considered “dysmyelinating” disorders rather than
“demyelinating” diseases. Pathologically, however,
the process is characterized by the absence of myelin
with a relative preservation of axons.
As a consequence of the many metabolic pathways involved and the different structures and
regions affected, the clinical presentation of hereditary metabolic disease is highly variable. However,
starting from the regions of the brain involved certain types of metabolic disease are more likely and
specific metabolic testing can be performed.
1. Involvement of white matter is particularly common in leukodystrophies, and differential diagnostic considerations include Krabbe disease,
metachromatic leukodystrophy, cerebrotendinous xanthomatosis, Zellweger disease, adrenoleukodystrophy, polyglucosan body disease,
Canavan disease, and phenylketonuria.
2. Progressive involvement of the basal ganglia, especially when mineral deposits are
detected by MRI, is common in disorders of
metal metabolism, and differential diagnostic considerations include Wilson disease,
Hallervorden-Spatz disease, aceruloplasminemia, phospholipase A2 group VI (PLA2G6)

mutation, neuroferritinopathy, and also disorders of dopamine synthesis.
3. Degeneration of the cerebellar or hemispheric
cortex implies a neuronal storage disease or
neuronal metabolic disorder; differential diagnostic considerations include gangliosidoses,
neuronopathic Gaucher disease, Niemann-Pick
disease, neuronal ceroid lipofuscinoses, or
mucopolysaccharidoses.
4. Predominant involvement of the peripheral
nervous system is common in a subset of disorders: Tangier disease, Refsum disease, or the
porphyrias.
5. Predominant involvement of the vascular
system may be seen in Fabry disease and
homocystinuria.
6. Weakness and muscle atrophy are common in
metabolic myopathies and may be seen in glycogenoses or mitochondrial myopathies.
Chapter 10 Hereditary Metabolic Diseases • 229