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					Pathology Lab III - Metabolic Diseases of the Nervous System
PATHOLOGY LAB III-METABOLIC DISEASES OF THE NERVOUS SYSTEM
Dr Alden W Dudley Jr

1. Goal and Objectives
2. References
3. Case study: Melvin, a 4 month old boy with developmental delay
4. Differential diagnosis of developmental delay
5. Metachromatic leukodystrophy
6. Krabbe disease (globoid cell leukodystrophy)
7. Adrenoleukodystrophy
8. Pelizaeus-Merzbacher disease
9. Other leukoencephalopathies
10. Neuronal storage disorders
11. Tay-Sachs disease (GM2 gangliosidosis) and related disorders
12. Niemann-Pick disease
13. Gaucher’s disease (glucocerebrosidase)
14. Mitochondrial encephalomyopathies
15. Vitamin deficiencies
16. Hypoglycemia
17. Hepatic encephalopathy
18. Ethanol toxicity and its friends
19. Carbon monoxide toxicity
20. Radiation and drugs (iatrogenic)

1. Goal:
Describe heritable, metabolic, and toxic disorders of the CNS.
Objectives:
(1) Discuss the genetics, clinical features, and morphology of heritable disorders of neurons and glia.
(2) Know the mechanism, impact, and outcome of storage and deficiency states.
(3) Explain the direct and indirect influence of toxins on the CNS.

2. References
(1) Abbas AK and Anthony DC, Frosch MP, DeGirolami U. Central nervous system. In Robbins & Cotran
Pathologic Basis of Disease, 7th. Ed, Elsevier Saunders, Phil. 2005:158-165, 1401-1419.
(2) Dudley AW Jr, Chang LW, Dudley MA, Bowman RE, Katz J. Review of effects of chronic exposure to
low levels of halothane. In Neurotoxicology, Roizin L, Shiraki H, Grcevic N (eds). Vol 1 1977:137-145.
(3) Ellison D, Love S, Chimelli L, Harding BN, Lowe J, Vinters HV. Neuropathology. A Reference Text of
CNS Pathology. Mosby, St Louis, 2004:119-130,415-494.
(4) Harris J, Chimelli L, Krill J, Ray D. Nutritional deficiencies, metabolic disorders and toxins affecting
the nervous system. In Greenfield’s Neuropathology, 8th ed, Love S, Louis DN, Ellison DW (eds)
2008:675-732
(5) Krishnamoorthy KS, Eichler FS, Goyal NA, Small JE, Snuderl M. Case 3-2010: A 5-month-old boy
with developmental delay and irritability. N Engl J Med 2010;362:346-356.
(6) Townsend J, Klatt EC. Neuropathology Illustrated. Dept Pathology, Univ Utah, Salt Lake UT. 2001.
Illustrations are from the author and several of the above.

3. Case study: Melvin, a 4 month old boy with developmental delay

         Melvin is a 4.5 month old boy referred to the Pediatric Neurology Clinic because of
developmental delay and an abnormal neurologic examination. He was born at term to a 36 yo
multigravid mother who abused alcohol and drugs. She discontinued methadone on learning she
was pregnant. Prenatal workup was positive for Hep C and Herpes simplex so she was given
valacyclovir during her last month of pregnancy. Birth weight was 3.7 kg and length 51 cm (both 50-
75th percentile), but head circumference was only 34.5 cm (25th percentile). A newborn serum
metabolic screen, urine toxicology screen, and routine tests were all normal. On discharge he was
feeding normally.

          At the first routine visit to the pediatrician, the mother reported Melvin would rapidly ingest
a small amount of formula, then stop feeding without spitting or vomiting. At 2 mo his weight was
down to the 25th percentile so cereal was added to his formula. At 3.5 mo he was admitted to
another hospital for abrasions on his forehead alleged to be due to accidental trauma. Vital signs
were normal, but his weight was only 5.2 kg (3-10th percentile). There were abrasions over the left
frontal scalp with minimal soft tissue swelling and no ecchymoses. A radiographic skeletal survey for
fractures was normal and CT of the head showed no subdural hematoma or cerebral contusion.
However, there was attenuation along the corticospinal tracts.

         When seen at age 4 mo by his pediatrician, the length was only 55 cm (51 at birth, now <3rd
percentile) and the weight 5.0 kg, also less than 3rd percentile. Melvin was irritable with decreased
interaction, no smiling, and increased muscle tone. A perirectal abscess was treated with amoxicillin
and clavulanic acid and he was referred to the Neurology Clinic. His mother reported that Melvin
slept well, was intermittently cranky, startled easily, and occasionally arched his back. He smiled,
tracked movement of others, and looked around but did not laugh, reach for objects, or roll over.
One year earlier, a sibling died during the perinatal period. The mother was of Scandinavian and
Irish ancestry and the father was Caribbean.

          On exam, Melvin was irritable with frequent crying, but he did not startle. Head
circumference was 40.5 cm (5-10th percentile) while weight was 4.9kg and length 59 cm. There was
increased muscle tone with frequent arching, writhing, and stiffening. Visual attention was normal
and the eyes tracked in all directions. His hands were fisted with adduction and infolding of the
thumbs (cortical thumbs); the grasp reflex was strong. The neck was hyperextended with head lag on
traction. The limbs were extended with increased tone. The leg adductors and hamstrings were
tight with scissoring of the legs. When prone, his body hyperextended when he cried. Moro and
bilateral tonic neck reflexes were present while plantar reflexes were extensor and DTRs were brisk
but not hyperactive.

         The following week Melvin started day care. One week later, he had diarrhea followed the
next day by dry diapers, pallor, and weakness. An admission workup found a fluctuant area in the left
medial gluteus that aspirated purulent material. He was treated with cephalexin but had a poor oral
intake. MRI of the brain on the fifth day showed abnormal tissue in the cerebellar hemispheres,
basal ganglia, deep cerebral white matter, corpus callosum, internal capsule, pons, medulla, and
spinothalamic tracts (Fig 3.1). There was mild volume loss in the thalami and abnormal signals from
the hypothalami while the optic nerves and chiasm were enlarged. There was no mass effect,
hemorrhage, or infarction. Electroencephalography (EEG) was normal, but nerve conduction studies
(NCV) showed slow conduction consistent with a generalized demyelinating sensorimotor
polyneuropathy (Table 2).




        On the ninth day, a lumbar puncture returned light pink and slightly turbid CSF with 3090
RBCs and 1 WBC/mm3 with a differential of 13% polys, 74% lymphs, and 13% monos. The protein was
145 mg/dL (nl 5-55), glucose 62mg/dL (nl 50-75), and lactate 1.9 mmol/L (nl 0.5-2.2). There were no
organisms on Gram stain or culture. Melvin was discharged on the tenth day.
4. Differential diagnosis of developmental delay

         Melvin presented four major problems: feeding (failure to thrive), irritability, hypertonia,
and developmental delay. Feeding requires coordination of the cortex, brain stem, cranial nerves,
breathing, and tongue. This can be crippled by congenital or acquired lesions of the brain or muscle
weakness. The irritability can be due to meningitis, cerebral palsy, drug withdrawal, shaken baby
syndrome, epileptic encephalopathy, infantile spasms, and rare inherited disorders such as Krabbe’s
disease (autosomal recessive lysosomal storage), Menke’s disease (X-linked copper metabolism giving
kinky hair), and pyridoxine deficiency (autosomal recessive with seizures).

Hypertonia may be due to spasticity, rigidity, dystonia, or a combination of those. It can be caused by
lesions in the motor pathway, basal ganglia, thalamus, brain stem, central white matter, spinal cord,
or by muscle or joint disorders. Melvin’s fisting and hyperactive reflexes suggest corticospinal
dysfunction and spasticity. The arching, stiffening, irritability, and feeding problems can all be
attributed to this spasticity.
          Developmental delay can be isolated motor delay or global; Melvin is global. Spasticity and
global development delay fall into two categories: static vs progressive. Those with static usually had
a single insult that interfered with development temporally, but allowed subsequent growth. Those
with progressive encephalopathy lose milestones previously attained. While it is difficult to
distinguish between the two early in the course, Melvin has already shown regression in feeding and
on his MRI.

         The most common cause of static encephalopathy is cerebral palsy, be it prenatal, perinatal,
or postnatal. About 50% are due to isolated strokes, global hypoxia, or periventricular leukomalacia;
10% to cerebral malformations; 10% to TORCH (Toxoplasmosis, Other, Rubella, CMV, Herpes
simplex). MRI is abnormal in 80% of CP children and is the test of choice with that diagnosis. Melvin’s
MRI was inconsistent with a static encephalopathy.

         Symptoms strongly favoring a progressive encephalopathy are: failure to thrive,
developmental regression, loss of hearing or vision, hypotonia, irritability, intractable seizures,
movement disorders, and family history of mental retardation or cerebral palsy. Metabolic and
degenerative disorders that mimic cerebral palsy initially include Lesch-Nyhan syndrome (self-
mutilation by eating fingers), glutaric aciduria, ataxia-telangectasia, gangliosidoses, dopa-responsive
dystonia, and Friedreich’s ataxia. However, other clinical clues assist in those diagnoses such as
oculomotor abnormalities, nystagmus, extrapyramidal movements, ataxia, retinal changes, and
cerebellar signs that were not found in Melvin.

         Neurologic regression is highly suggestive of lysosomal disorders. Separation of those
syndromes can be done when there is dysmorphism, visceromegaly, cherry red spots, seizures, or
cognitive versus motor regression. Gray matter disorders cause early dementia and seizures
whereas white matter problems cause spasticity and motor loss. Because Melvin had spasticity
precede cognitive decline, it suggests a leukodystrophy. Also, he did not have visceromegaly, cherry
red spots or visual loss of gray matter diseases. Within leukodystrophies, he does not have the
Macrocephaly of Alexander’s or Canavan’s diseases or the nystagmus, titubation, and hypotonia of
Pelizaeus-Merzbacher disease.

5. Metachromatic leukodystrophy

         Melvin’s diagnosis is quickly whittled down to metachromatic leukodystrophy (MLD) or
Krabbe’s disease. MLD is due to an autosomal recessive mutation in the arylsulfatase A (ASA) gene.
Myelin formed in utero for the U-fibers connecting neighboring gyri seems to be formed correctly.
However, myelin forming post-partum does not have maternal enzymes in the serum and does not
function. Turnover of formed myelin occurs so there is slow, progressive loss of U-fibers, but some
remain myelinated at death. The MLD child typically functions better than Melvin the first year and
begins to show gait difficulty between ages 1 and 2. Initial hypotonia later becomes spasticity and
dementia is accompanied by optic atrophy.

        MLD has three clinical subtypes, late infantile, juvenile, and adult, that depend on the
number and type of defects on the ASA gene at chromosome 22q13. More than 63 mutations have
been identified to date with many being asymptomatic. Homozygosity for the null mutation causes
the late infantile form, one for null and one for a mutation with residual activity the juvenile form,
while two mutations with residual activity cause the adult form.

          Late infantile MLD has a first year with mild hypotonia followed by frequent falls and
spasticity the second year. Loss of motor function and language, spastic quadriplegia, and cortical
blindness follow rapidly to a vegetative state and death by five years. The juvenile form starts slowly
between 4 and 12 years with behavioral changes and slurred speech preceding extrapyramidal and
motor dysfunction. The adult version comes after puberty in males (even in the elderly) and may or
may not start with peripheral neuropathy. Changes in personality and mental status progress to
motor loss and spasticity, ataxia, dementia, loss of sight, speech, and hearing, and death over years or
decades.

           Both CT and MRI show symmetrical low density in white matter with sparing of subcortical
U-fibers (Fig 5.1). The ventricles enlarge ex vacuo as the disease progresses (Fig 5.1). For reasons
unclear, some individuals lose their myelin in alternating stripes to create a tigroid pattern. At
autopsy, the brain is small with widened sulci. Cross sections show nicely preserved white U-fibers
over thin and gray centrum ovale (Fig 5.2). The ventricles are enlarged with rounded angles. If the
white matter is painted with toluidine blue, it will turn that dye red. If painted with acidic cresyl
violet, it will turn that dye brown. That is how it earned the name metachromatic leukodystrophy or
MLD.
          Light microscopy reveals the metachromatic material to be in the cytoplasm of white
matter oligos and macrophages (Fig 5.3), Schwann cells, oligos, astrocytes, neurons, Kuppfer cells
(Fig 5.4), renal tubular epithelium, lymph nodes, spleen, bile ducts, gall bladder, adrenal medulla,
and islets of Langerhans. Demyelination in the peripheral nerves is segmental and affects large
axons more than small axons (Fig 5.4). The inclusions are 1:1:1 with respect to
cholesterol:galactolipids:phosphatides with most galactolipids being sulphatides. EM studies have
shown the crystals to sometimes be herringbone (Fig 5.5), honeycomb, or tuffstone (parallel pillars
like basalt), apparently determined by components within the 1:1:1 ratio. Glial cells are the most
pleomorphic with regard to their crystals, perhaps because oligos start with the highest proportion of
membrane material.
6. Krabbe disease (globoid cell leukodystrophy)

          This is another autosomal recessive lysosomal disorder, now due to a defect in the
galactosylceramidase gene (also called a galactocerebrosidase). Onset of spasticity and irritability
starts between 1 and 7 months of age, as in Melvin. The CSF protein is elevated early because of
tissue destruction. The infant shows progressive psychomotor regression, demyelinating
polyneuropathy, and, later, optic atrophy with death before age 1 or 2 years. MRI returns an
abnormal signal from most everywhere in the CNS to suggest a toxic or metabolic origin. There is
relative sparing of superficial cortex, but cerebral white matter, cerebellar white and gray,
brainstem, and corticospinal and spinothalamic tracts are decimated (Fig 6.1). On magnetic
resonance spectroscopy, there is marked depression of the N-acetyl aspartate peak.




         The lack of galactosylceramidase in Krabbe disease hinders degradation of both
galactosylceramide and psychosine. The accumulation of psychosine is highly cytotoxic to cause
demyelination and loss of neurons. Visual loss is less common in the early form, but ordinary in later
onset. Prenatal umbilical cord blood transfusion can alter the natural history. Fever is common and
may be due to the leukodystrophy. At 7 months of age, Melvin developed seizures. At eight months,
he had episodes of hypopnea and bradycardia that led to death at age 9 months.

          At autopsy, Melvin’s brain was small yet had a weight of 555 gm. It had the consistency of a
softball rather than gelatin. There was atrophy of the cerebral and cerebellar hemispheres and the
brain stem. The optic nerves and chiasm appeared massively thickened. Coronal sections of the brain
confirmed preserved U-fibers over atrophic pink-gray material that was firm and focally calcified.
Other organs were normal (Fig 6.2).




          Microscopic exam suggested total loss of myelin in most areas. There was marked loss of
neurons and oligodendroglia from cerebellum, basal ganglia, and brain stem with a strong gliosis
that imparted the firm texture. Numerous multinucleated, globoid macrophages infiltrated the optic
nerves and white matter in the perivascular spaces(Fig 6.2). The globoid cells were filled with PAS-
positive material that on EM was composed of needle-shaped or gently curved tubular inclusions
(Fig6.3). This material is formed from galactosylceramide and not found in neurons (Fig 6.4).
          Melvin’s clinical history favored a leukodystrophy with Krabbe’s as the top choice. The
clinical MRI was highly compatible and enzyme kinetic studies were conclusive. The findings at
autopsy confirmed the diagnosis by location, sparing of U-fibers, cell types involved, globoid cell
reaction, and microtubules of galactosylceramide on EM. Genetic counseling for the family is
indicated.

7. Adrenoleukodystrophy (ALD)

          Like MLD, ALD has infantile, juvenile, and adult forms with early onset having a more rapid
course. The ALD gene is on chromosome Xq28 where it encodes a peroxisomal membrane protein
that is an ATP-binding cassette transporter D1 (ABCD1). A deficiency blocks catabolism of very long
chain fatty acids within peroxisomes so their level increases in serum. The greatest effects are on the
adrenal, brain, and testes and can be rapidly fatal or protracted. White matter dysmyelination
spares U-fibers and begins posteriorly. An advancing front of destruction is evident on contrast-
enhanced MRI (Fig 7.1). As the lesion crosses the internal capsule, Wallerian degeneration eliminates
the corticospinal tract to include the pyramids of the medulla (Fig 7.2).
The advancing front of dysmyelination shows a perivascular subacute inflammatory reaction of T cell
lymphocytes, reactive astrocytes, and lipophages (Fig 7.3). Peroxisomes accumulate most in adrenal
cortical cells and testicular Leydig cells, but are also numerous in white matter lipophages (Fig 7.4).
EM shows the contents to be lipids with typical lipid clefts. The juvenile form presents between ages
6 and 9 with adrenocortical insufficiency, visual, gait, auditory, and behavioral symptoms. Death is
usually within three years.
8. Pelizaeus-Merzbacher disease

         This is another X-linked fatal leukodystrophy of infancy that starts as hypotonia, pendular
eye movements, choreoathetosis, and pyramidal signs. Rapid progression to spasticity, dementia,
and ataxia leads to death within a few years. The gene at Xq21-22 encodes proteolipid protein (PLP)
of CNS protein, but not in Schwann cells. Myelin is almost completely lost in the CNS but untouched
in the PNS. Thus, the brain shrivels and has gray “white matter” due to astrogliosis while cranial
(except optic) and peripheral nerves are normal (Fig 8.1). EM can trace single axons exiting nerve
roots with no myelin until they reach the peripheral portion where they look to be normal (Fig 8.2).
The oligos disappear without going through a storage phase of subcellular particles.
9. Other leukoencephalopathies

          Suffice it to say there is a myriad of other leukoencephalopathies with eponymous names
like Canavan’s (Fig 9.1), Aicardi-Goutieres, Cockayne, etc. Each has its own enzyme deficiency creating
a slightly different array of symptoms because of modified patterns of affliction. Some accrete so
much material the infant or child has macrocephaly. Fortunately, they are rare enough that only
pediatric neurologists need know their names for there are no cures. As with other enzyme defects,
they are found within groups that tend to inbreed for religious, social, or geographic reasons. Thus,
we find them in eastern European Ashkenazi Jews, Lumbee Indians in Lumberton, NC, and the
Hatfields and McCoys of western Virginia.
10. Neuronal storage disorders

           Like the leukodystrophies, these are usually autosomal recessive disorders of a catabolic
enzyme that is either missing or defective or has an associated protein (activator, protector, or
transporter) that is defective. The substrate accumulates within lysosomes until cell function is lost or
the neuron itself succumbs. The classes of compounds include gangliosides, sphingolipids,
glycosphingolipids, mucolipids, and mucopolysaccharides. Several of these classes are most active in
the CNS to cause the most severe symptoms in the brain. Most are found in other organs and may
have other symptoms. Since lysosomes are rich in macrophages, organs with many macrophages
(liver, spleen) can be expected to get large as well. The subcellular site of dysfunction can be in the
endoplasmic reticulum, Golgi apparatus, or lysosome, but aggregation is in the lysosome. Again,
these are more common in Ashkenazi Jews.

         Formerly, diagnosis was dependent on findings by light microscopy stain reactions and
electron microscopy inclusion configuration. Now we do skin biopsy for fibroblasts that enable
enzyme kinetic analysis. The few facilities that are interested and capable go on to sequence the
enzyme and gene to determine the locus of the defect. Prenatal genetic analysis is possible and
should be done during pregnancies in families at risk.

11. Tay-Sachs disease (GM2 gangliosidosis) and related disorders

          These infants are retarded with seizures and separated themselves from others by having a
cherry red macula caused by the lysosomal aggregates (Fig 11.1). Described in 1881, it was one of the
first lysosomal disorders described as such in 1969. Hexosaminidase A deficiency allows
accumulation of GM2 ganglioside (a lipid) in lysosomes with enough ballooning of cytoplasm to
cause megalencephaly. The babies are normal at birth, weak at 6 months, blind at 1 year, flaccid at
18 months, vegetative at 24 months, and dead between 2 and 5 years. In reality, GM 2 gangliosides
are accumulating in all cells in the body, but the CNS picture is clinically dominant.
         There are two related disorders with similar clinical symptoms because they also affect
hexosaminidase A (Hex A). Tay-Sachs is due to a mutation on chromosome 15 that affects the α
subunit of Hex A. Sandhoff disease is due to a defect on chromosome 5 that impacts the β subunit of
Hex A. Activator deficiency occurs with a different mutation on chromosome 5 that ends up blocking
cleavage of Hex A. The results are the same as all cells fill with lysosomes containing dense
membranous whorls of Hex A.

         Fifty years ago there was the first reported case of GM1 gangliosidosis in a 9 month old boy
with flaccidity, enlarged liver, depressed nasal bones, slight corneal haze, lumbar kyphosis, and a
cherry red macula. This turns out to be due to a defect on chromosome 3 involving the β-
galactosidase gene (GLB1) with several mutations possible for missense/nonsense,
duplication/insertion, and insertion patterns. Both gray and white matter degenerate for
microcephaly. Hepatosplenomegaly, bony abnormalities, and facial dysmorphism are features of
the infantile form while the adult has slowly progressive pyramidal and extrapyramidal degeneration,
mild intellectual degradation, and no bony or visceral change. Interestingly, inclusions in the CNS on
EM are dense membranous bodies while in viscera they are tubules and filaments.

12. Niemann-Pick disease, types A, B, C, and D

         This is due to accumulation of sphingomyelin and cholesterol in lysosomes to the extent
that the spleen is 10 X normal size, the liver sufficiently enlarged to cause a protuberant abdomen,
and lymph nodes to be visible as well as palpable. The brain has neurons that balloon, then die to
leave shrunken gyri (Fig 12.1) and the retina develops a cherry red spot at the macula about half the
time. EM uncovers dark, membranous whorls like myelin (Fig 12.2). Types A and B affect
chromosome 11p15.1-4 completely (onset in infancy) or partially (adult onset) as sphingomyelin
cannot be broken down to ceramide.




Types C and D are more common than A and B and bear a clinical resemblance. However, they are
due to a problem at chromosome 18q11-12 that affects the transport of LDL and leads to
accumulation of cholesterol. While it may cause hydrops fetalis and a stillbirth, it more often
presents in childhood with ataxia, supranuclear palsy, psychomotor regression, hepatosplenomegaly,
and dysarthria.




13. Gaucher’s disease (glucocerebrosidase)

          This is the most common lysosomal storage disorder affecting (but not of) neurons. This
also is autosomal recessive and compromises the enzyme responsible for cleaving glucose from
ceramide. As usual, there are severe forms causing death by age 2 and milder versions affecting
predominantly viscera. Fortunately, 99% of cases are type I which causes hepatosplenomegaly,
enlarged lymph nodes and dense marrow, anemia, and bone fractures or deformities because of
aggregates of macrophages displacing cortex. Only monocytes accumulate the glucocerebrosidase
and do so mostly outside the CNS (Figs 13.1-.2). Onset is in adulthood when splenomegaly and
pancytopenia become evident.

          It is when the enzyme is totally inactive that type II causes macrophages to accumulate in
the Virchow-Robin space in the brain and prove toxic to neurons (Fig 13.3). Onset is frequently
before age 3 months with oculomotor apraxia and bilateral strabismus, apathy, irritability, loss of
head control, difficulty in sucking and swallowing, frequent crying, dementia, and convulsions until
death provides relief around age 1 or 2. There is hepatosplenomegaly, with enlarged lymph nodes,
marrow and cortex displacement for fractures, and bone pain. Type III is intermediate between types
I and II.
14. Mitochondrial encephalomyopathies

         It is reported that our friends, the mitochondria, are more susceptible to DNA mutations
than our own nuclei. Since the mitochondria trade glucose for energy supporting ATP, it stands to
reason that a mitochondrial mutation is going to affect our muscle and brain more than other organs.
One form of this is Leigh’s syndrome of subacute necrotizing encephalopathy. Lactic academia
arrests psychomotor development in childhood to cause feeding problems, seizures, extraocular
palsies, weakness, and hypotonia with death in 1 to 2 years. It is due to an autosomal recessive
mutation of mitochondrial cytochrome C oxidase or of a protein required for its assembly. The result
is symmetrical thinning of periventricular gray nuclei and the tegmentum of the pons. Loss of neurons
is particularly impressive in the caudate, putamen, and globus pallidus (Fig 14.1). Microscopy shows
loss of myelin as well as neurons to leave a spongy neuropil and consolidation of the few surviving
cells (Fig 14.2).




         Myoclonic epilepsy with ragged red fibers (MERRF) is maternally inherited through a
mutation in mitochondrial tRNA to affect protein synthesis. The patient has myoclonus, seizures,
weakness, and ataxia due to both brain and muscle dysfunction. The brain grossly shows brown
discoloration of the dentate nucleus and inferior olives attributed to iron deposits (Fig 14.3).
Microscopy of the brain shows neuron loss and gliosis in the dentate, olives, substantia nigra, red
nucleus, and basal ganglia. The skeletal muscle (easily biopsied) has ragged red fibers due to large
mitochondria with paracrystalline inclusions.




          Mitochondrial encephalopathy, lactic acidosis, and strokes (MELAS) is another tRNA defect
causing mineralization of small arteries for strokes in addition to weakness and some cognitive
decline. The strokes are often at the top of cerebral or cerebellar gyri as though trauma played a role
(Fig 14.4). Muscle biopsy again shows mitochondrial aggregates causing a ragged red fiber
appearance (fig 14.5).
         Kearns-Sayre ophthalmoplegia plus syndrome is due to a large mtDNA deletion /
rearrangement. The initial symptom is usually mild weakness as an adult progressing to cerebellar
ataxia, external ophthalmoplegia, pigmentary retinopathy, and cardiac conduction defects (heart
block, often compensated by installing a pacemaker). A muscle biopsy again shows large
mitochondria, this time with parking lot inclusions, causing ragged red fibers (Fig 14.6). When the
patient dies years or decades later, the white matter is darker than normal. Microscopy reveals
spongiform changes with decreased myelin (Fig 14.7).
15. Vitamin deficiencies

         Thiamine (B1) deficiency is causing beriberi in a lot of Africans and Haitians right now. In the
setting of alcohol abuse or persistent vomiting, it is likely to abruptly induce psychotic symptoms and
ophthalmoplegia as described by Wernicke. If the patient is given food or multivitamins without a
prior load of thiamine, there will be petechial bleeding into the mammillary bodies and
periventricular gray matter (Fig 15.1) to cause immediate loss of short term memory compensated by
confabulation. You ask what time it is and they talk amicably about the weather. This was described
as Korsakoff’s psychosis so the two disorders are combined as Wernicke-Korsakoff syndrome.
Treatment with thiamine on entry to the ER can abort this complication; failure to do so asks for
trouble. W-K is sometimes an iatrogenic disorder.
         It is also believed that thiamine deficiency can lead to atrophy of the anterior vermis of the
cerebellum (Fig 15.2). Microscopy shows total loss of Purkinje cells and most of the granular neurons.
This causes the unsteady gait of the chronic alcoholic when he is sober. As in all things in medicine,
some patients develop Wernicke-Korsakoff before atrophy of the anterior vermis and vice versa for
reasons that are not understood at all. When one cuts an atrophic brain that shows preferential
atrophy of the anterior vermis, there should be immediate checking of the mammillary bodies and
periventricular gray for atrophy at those locations as well. The aqueduct has hydrocephalus ex vacuo
and the third ventricle becomes diamond-shaped instead of a vertical slit.




          Vitamin B12 (cyanocobalamin) deficiency leads initially to pernicious anemia. Left untreated,
there is a dying back of long axons and their oligodendroglia over a period of weeks or a few months.
The patient develops ataxia, numbness, and tingling in the lower extremities that progresses to
spasticity and paraplegia. Prompt treatment can alleviate the symptoms but delayed therapy will not.
The patient loses myelinated fibers in the corticospinal tract from low cervical on down to the cauda
equina and in spinothalamic tracts from the midthoracic level to the thalamus. A cross section at the
high thoracic level shows demyelination of both sets of pathways so this has been called subacute
combined degeneration of the cord (Fig 15.3).
16. Hypoglycemia

         When diabetics get infections, their insulin control often becomes “brittle” with wild swings
in glucose level. Also, diabetics inject insulin and may get distracted and forget eating. When the
serum glucose level approaches 1,000, the blood is like syrup and they risk congestive heart failure.
When the glucose falls to 40, they have an insufficient quantity for neurons that are already ischemic
from atherosclerosis. Levels below 40 mg/dL cause laminar necrosis of dense layers of neurons (Fig
16.1). The relative vulnerability of neuronal structures is depicted in Fig 16.2. Also, when a diabetic
has ischemia with a high glucose, s/he produces more lactic acid and has more irreversible injury.
There will be confusion, stupor, and coma from ketoacidosis and dehydration. Treatment is
barbiturates for the acidosis and gradual infusion of sugar-free saline for the dehydration. Rapid
infusion would cause cerebral edema and congestive heart failure.
17. Hepatic encephalopathy

         This has been alluded to in other labs and will not be discussed at length here. Seen most
often in alcoholics, it can occur in hepatitis or metastatic disease to the liver with hepatic failure.
Climbing ammonia levels cause swelling of astrocyte nuclei (Fig 17.1) to become Alzheimer type 2
astrocytes.
18. Ethanol toxicity and its friends

         There are many toxins that affect the CNS and PNS separately or together. By far the most
common offender is ethanol with 10% of most populations (20% of Russians) classified as alcoholics
because they drink to an extent that interferes with their work, social, or family life or ability to
function independently. Most alcoholics are in hiding or being cared for by family members so their
true number is not apparent. You reviewed the impact of ethanol on the body in your labs on
Environmental and Nutritional Pathology. You recall the direct toxicity effect of ethanol and its
derivatives (acetic acid as in vinegar and acetaldehyde) on the oropharynx, stomach, pancreas, liver,
heart, muscle, urinary bladder, reproductive system, fetus, and brain. You remember that 50% of
alcohol consumed is non-tax paid moonshine of highly varying quality and that moonshine is a major
segment of the economy of this part of the country. You realize that some moonshiners dilute their
product with methanol or ethylene glycol and desperate drinkers substitute alternative alcohols
(including isopropyl) themselves.

       Their other problems relate to not eating appropriately. They get so many calories through
alcohol, they must develop a “beer belly” if they are getting proper levels of other nutrients from
caretakers (Winston Churchill). If they live alone, they likely are vitamin deficient. Thus, their many
problems in the CNS and PNS can be multifactorial and were isolated with some difficulty for study in
lab animals. Can you imagine working with fifty drunk rhesus monkeys? It has been done.

         A major variable in how an individual will respond to ethanol is the host. Smokers have
elevated levels of cytochrome p450 and other enzyme systems to catabolize ethanol faster than non-
smokers. Conversely, drinkers catabolize tobacco ingredients faster than non-drinkers. Both groups
catabolize medicines and street drugs faster as well. While there are many smokers that do not drink,
very few drinkers do not smoke. That they met their spouse in a bar helps neither member of the
marriage. When one member becomes a full fledged alcoholic, the other “understands”, tolerates,
and abets.

         Ethanol and its metabolites have a direct effect on the CNS and PNS. Most imbibers get
sleepy before becoming comatose. A small percentage will become quite combative because
inhibitory neurons succumbed before activator neurons. (The same is true in rabies infections. Most
animal and human victims present with “dumb” rabies, rather than the Hollywood version. Virginians
that became rabid used to be tied to trees so as not to infect anyone else.) Because the nervous
systems have been narcotized, the drunkard falls asleep in abnormal positions. The arm over the
head develops a brachial palsy (Saturday Morning Syndrome after Friday pay day). The chin against
the chest causes prolonged hypoxia for loss of Purkinje cells and granular neurons throughout the
cerebellum and ataxia (Figs 18.1-.2). Cerebral edema increases as the ethanol and ammonia (from
liver failure) levels rise and can be the immediate cause of death, as in the fraternity initiate
challenged to down an entire bottle at once.
          Unfortunately, the fetus is so susceptible to ethanol that a single drink per day by the
mother will cause the fetal alcohol syndrome. The impact appears to be most severe in the final
trimester when synapses and glial-neuronal relationships are being finalized, so it is never too late to
intervene. The clinical Fetal Alcohol Syndrome (FAS) consists of: microcephaly (45%, Fig 18.3); facial
abnormalities of short palpebral fissures, epicanthal folds, thin upper lip, and small jaw; cardiac
septal defects (18%); delayed development; mental deficiency from borderline to severe (100%);
camptodactyly (permanent flexion of fingers or toes, 55%); hockey stick palmar crease (51%);
refractive errors (40%), strabismus (38%), and microophthalmia (10%); dental crowding in a small
jaw (43%); nail hypoplasia (38%); and genitourinary anomalies (22%). MRI studies show particular
hypoplasia of the cerebellum, corpus callosum, and hippocampal commissures plus a 25%
reduction in blood flow to the temporal lobes compared to controls. Laboratory animals (and
humans) show extensive neuronal and glial heterotopias (Fig 18.4) around the ventricles and in the
subarachnoid space over the cortex. Animal experiments also show preferential loss of retinal
ganglia, spinal cord neurons, and cortical glia. Cortical neurons that ordinarily form straight lines for
easier connectivity become disoriented in position to make connections difficult and possibly
epileptogenic (Fig 18.5).
        (If you ever go to Moscow, visit the Brain Research Institute and ask to see Lenin’s brain. It has
been serial sectioned and stained. Photomicrographs adorn the walls of his brain and one control.
The gross photos show the control to have failed to fill the suprasylvian space normally empty at
birth, but filled by neuronal migration within a few months. The control apparently had an anoxic
birth costing him his neuroblasts in the germinal matrix. Micrographs of cortex show Lenin’s neurons
in perfect alignment horizontally and vertically while the control neurons seem to be erratically
distributed. This is the fetal alcohol syndrome. The control brain had the fetal brain syndrome
compounded by neonatal anoxia. His IQ must have been quite low so he was deliberately selected to
be a defective control for the glory of their great leader, Lenin. Inform them of their mistakes while
you are there – as did I.)

         The resiliency of cortical neurons in chronic alcoholics is astounding. They can be rendered
comatose with blood levels approaching their lethal limit, be dialyzed to remove some alcohol, stay in
coma for a few weeks, be dazed for a month, and return to an acceptable level of unsupervised self
care. However, frontal cortical neurons will have decreased by over 25%, white matter will have
thinned, and there will have been loss of executive function that requires planning and integration of
complex thoughts. There may also be loss of sufficient Purkinje and granular cells for ataxia.

         The most common contaminant of moonshine is methanol. It is metabolized to formic acid
and formaldehyde which are exceedingly small and penetrate all tissues. They cause a dose
dependent death of retinal ganglion cells with loss of visual acuity. They also induce a severe
acidosis with the blood pH going below 7.0 before causing symptoms. If they enter the ER because of
a rumor of bad moonshine and have acidosis, they must be treated immediately with bicarbonate to
prevent relatively sudden death when all compensatory systems have become overwhelmed. Should
they survive the acute crisis, there remains a threat of idiosyncratic fibrinoid necrosis of the arteries
in the heart, pancreas, and putamen (Figs 18.6-7). This can be anticipated by finding amylase levels
in the thousands, an ischemic heart on EKG, and confusion converting to coma as the putamen fails.
         Other contaminants include the heavy metals (Fig 18.8). Chronic lead poisoning causes wrist
drop when the victim holds both arms out straight. The diagnosis is confirmed by getting x-rays to
show lead lines at the epiphysis of long bones (Fig 18.9). Methyl mercury contamination in the adult
causes cortical blindness (retinal cells unaffected), ataxia, and loss of motor coordination (Fig 18.10)
while a fetus will be deaf, dumb, blind, and vegetative.
19. Carbon monoxide toxicity

          Cold months precipitate cases of carbon monoxide poisoning because of faulty heaters or
use of space heaters in a trailer or houseboat. While the first victims were cavemen retreating from
the cold, there was a marked increase in Europe during WWII. These were suicides by grieving
relatives putting their head into an unlit gas oven or homicides by troops killing large numbers of
prisoners. At this time we have about 500 Americans per year lose their life accidentally and less than
100 as suicide by car exhaust fumes in a closed garage.

          Symptoms of carbon monoxide poisoning progress from headache to nausea and vomiting
(cerebral edema, already at 80% of lethal level), syncope, seizures, coma, dysrhythmia, cardiac
ischemia, and death. Atmospheric levels of only 0.04% lead to nausea after 1-2 hr, collapse at 2 hr,
and death at 3-4 hr. Yet, non-smokers can have up to 0.5% carboxyhemoglobin from ambient air
pollution. This is because the affinity of CO for hemoglobin is 200 times greater than O2. Oxygen is
aggressively displaced from hemoglobin by the CO. Thus, seemingly low levels of ambient CO are
associated with high levels of carboxyhemoglobin. An ambient level of 0.1% CO causes immediate
difficulty in movement and death in 2 hours. A level of 0.2% kills in 45 minutes and 0.3% in 30
minutes. At 0.5% there is rapid collapse and death within a few minutes. This is the degree of risk our
firemen face in their careers. On the other hand, catalytic converters in modern cars have reduced CO
from 12% of exhaust fumes to 0.2% for more difficult suicides and more likely survival with partial
brain damage and psychic akinesia (see below).

         If the victim dies immediately, carbon monoxide can be suspected by a cherry red
appearance of the skin and brain from carboxyhemoglobin. Because the globus pallidus and pars
reticulata of the substantia nigra have the highest content of iron in the brain, they are the most
damaged in survivors of severe exposure (Figs 19.1-.2). Those structures can be lost in toto bilaterally
to cause severe rigidity and hypotonia. It should be no surprise that firemen and traffic policemen
(working in tunnels or at busy intersections) have a significantly increased risk for Parkinson’s disease.
          It is important to know CO also affects skeletal muscle and the heart for fatal arrhythmia or
compounding hypotension. The hypotension during CO poisoning increases the chance for hypoxic
damage in other parts of the brain, such as the Purkinje cells, hippocampus, and cortical lamina. Also,
clearing the patient of carbon monoxide requires a long time. Hyperbaric oxygenation has not
provided the relief expected because it is difficult to raise oxygen levels 200 times to rival the CO. The
patient must not return to exercise or a physically active job (butcher) for over one month!
Violation of that guideline will likely lead to a fatal heart attack.

         Victims of low dose exposure can develop an organic psychosyndrome of amotivation to
include inactivity and lethargy, sometimes called psychic akinesia. These victims usually show
thinning of cerebral white matter from basal ganglia to posterior parietal, premotor, and prefrontal
cortex; the limbic basal ganglia loop, to the medial and lateral temporal lobes, hippocampus, anterior
cingulate and orbitofrontal cortex. These areas are controllers of emotion and motivation.

20. Radiation and Drugs (iatrogenic)

         Radiation of the brain for rapidly growing primary or metastatic tumors may be unavoidable.
The radiation therapists know therapy will kill tumor cells, attract leukocytes with their cytokines,
induce edema, and may be fatal. They will divide the total dose over several applications and hope
prior episodes of edema are carried away before there is brainstem herniation (Fig 20.1A). Deliberate
endothelial cell damage to deprive tumors of blood will also deprive adjacent brain tissue (Fig 20.1B).
The white matter will thin and some neurons may be lost. This may be tolerated during short survival
by the elderly, but a child can lose significant function for the remainder of his/her life. Further,
meningiomas and sarcomas begin to rise at the site of therapy 15-20 years later.




          Therapeutic drugs for cancer are not much better. Intrathecal applications of methotrexate
can lead to cerebellar peduncle degeneration and calcification (Fig 20.2). Vincristine stops tumor cell
replication by blocking chromosome separation at the end of mitosis. However, it also interferes with
organelle trafficking down long axons to cause peripheral neuropathy that requires months for
recovery.
Cyclosporine to prevent rejection of transplants causes leukoencephalopathy with macrophages
carrying away vital tissue (Fig 20.3).
          Anesthetics are designed to poison the CNS or PNS so pain will not be perceived. Ether made
everyone in the OR nauseous and the patient vomited on awakening with a risk for aspiration
pneumonia. Halothane was much better tolerated, but still detectable in the lungs of
anesthesiologists returning to work on Monday after a few days off duty. Their children had learning
disabilities so pregnant rats were exposed to very low levels of halothane. The pups had a learning
disability of 30% in both food maze and shock avoidance experiments! Electron microscopy showed
degradative changes in proximal convoluted tubule epithelial cells, hepatocytes, and cortical neurons
in both the mothers and the pups. Neurons showed weakening and disruption of the nuclear
membrane, collapse of RER, distended Golgi apparatus, increase in number and size of lysosomes,
and C-shaped mitochondria sometimes leading to myelin figure formation.

          We have moved on to less toxic anesthetics, but they still poison the CNS. There is also the
problem of epidural blocks for pelvic or leg surgery. Each time the needle goes too deep to get into
the subdural space, the anesthetist has no way of knowing that occurred until the patient awakens
and is still paralyzed. Had the patient been tilted for a better surgical angle on the pelvis, the
anesthetic would get to the brainstem and stop all function of cranial nerves and vital centers. It
takes several hours for the paralysis of the legs to recover.
         Space and time do not permit covering the effects of street drugs (Fig 20.4), psychotic and
other medicines (Fig 20.5), or many other toxins (Fig 20.6). Hopefully, the above illustrations will help
explain the mechanisms and challenges we face. Rationales for therapy can be devised in the ER (IV
muscle relaxants for spasms and contractures). Prepare for the worst and hope for the best.




1.
Reuben is a 25-year-old college graduate with a three year history of behavioral changes and intellectual decline sufficient
to get him fired from teaching grade school. Your neurologic exam uncovers weakness, spasticity, hyperreflexia including
bilateral Babinskis, a stiff, short-stepped gait, and peripheral polyneuropathy. You conclude Reuben has lost function in the
cerebrum, cerebellum, cord and nerves. A peripheral nerve biopsy would be expected to show:
                                            Thickened basement membranes

                                            Onion rings from remyelination

                                            Segmental demyelination

                                            Dying back neuropathy

                                            Amputation neuromas from self-mutilation

2.
Reuben is a 25-year-old college graduate with a three year history of behavioral changes and intellectual decline sufficient
to get him fired from teaching grade school. Your neurologic exam uncovers weakness, spasticity, hyperreflexia including
bilateral Babinskis, a stiff, short-stepped gait, and peripheral polyneuropathy. You conclude Reuben has lost function in the
cerebrum, cerebellum, cord and nerves. When Reuben dies in a few years, you will streak toluidine blue across his white
matter and watch it turn red. Acidic cresyl violet would turn brown. This phenomenon is known as:
                                                        Polychromasia

                                                        Etching

                                                        Metachromasia

                                                        Color modification

                                                        Dye instability

3.
Reuben is a 25-year-old college graduate with a three year history of behavioral changes and intellectual decline sufficient
to get him fired from teaching grade school. Your neurologic exam uncovers weakness, spasticity, hyperreflexia including
bilateral Babinskis, a stiff, short-stepped gait, and peripheral polyneuropathy. You conclude Reuben has lost function in the
cerebrum, cerebellum, cord and nerves. His disorder fits in the category of:
                                                   Progressive encephalopathy

                                                   Spongiform encephalopathy

                                                   Static encephalopathy

                                                   Alcohol abuse

                                                   Chronic lead poisoning

4.
Reuben is a 25-year-old college graduate with a three year history of behavioral changes and intellectual decline sufficient
to get him fired from teaching grade school. Your neurologic exam uncovers weakness, spasticity, hyperreflexia including
bilateral Babinskis, a stiff, short-stepped gait, and peripheral polyneuropathy. You conclude Reuben has lost function in the
cerebrum, cerebellum, cord and nerves. His brother died at age 31 after five years of a similar history. Reuben’s diagnosis
is most likely:
                                        Tay-Sachs disease

                                        Metachromatic leukodystrophy

                                        Adrenoleukodystrophy

                                        Subacute combined degeneration of the spinal cord
                                        Krabbe’s disease

5.
Reuben is a 25-year-old college graduate with a three year history of behavioral changes and intellectual decline sufficient
to get him fired from teaching grade school. Your neurologic exam uncovers weakness, spasticity, hyperreflexia including
bilateral Babinskis, a stiff, short-stepped gait, and peripheral polyneuropathy. You conclude Reuben has lost function in the
cerebrum, cerebellum, cord and nerves. Reuben’s autosomal recessive mutation affected the gene for:
                                          Proteolipid protein

                                          Hexosaminidase A

                                          ABCD1 (ATP-binding cassette transporter D1)

                                          Arylsulfatase A

                                          Galactocerebrosidase

				
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