Toxic & Metabolic CNS

Diseases
Jeffrey W. Oliver, M.D.
 Learning Objectives
• Tabulate the clinical features, enzyme
deficiencies, and accumulation products in
the following hereditary leukodystrophies:
metachromatic leukodystrophy, Krabbe
disease, adrenoleukodystrophy, Leigh
disease
 Learning Objectives
• Recognize the neurologic clinical and
morphologic features of thiamine and
vitamin B12 deficiencies.
• Evaluate brain morphology (gross and
microscopic) for evidence of
hypoglycemia, carbon monoxide
intoxication, methanol intoxication, and
hepatic encephalopathy.
 Learning Objectives
• Explain the major CNS manifestations of
chronic alcoholism.
• Describe the clinical and morphologic
features of cerebral radionecrosis.
 Metachromatic Leukodystrophy
• AR deficiency of arylsulfatase A (gene on
chromosome 22) leading to accumulation of
cerebroside sulfate (sulfatides), which somehow
breaks down myelin
• Late infantile and juvenile forms have progressive
motor deficits and death in 5-10 years
• Adult form: cognitive followed by motor deficits
 Metachromatic Leukodystrophy
• Striking demyelination with gliosis in CNS
and peripheral nerves
• Vacuolated macrophages have
metachromatic staining with toluidine blue
• Metachromasia of urine a sensitive test
• BM transplant is promising therapy
 Krabbe Disease
• AR leukodystrophy, deficiency of
galactocerebroside β-galactosidase;
alternate pathway results in accumulation of
galactosylsphingosine, which is toxic to
oligodendrocytes
• Onset at age 3-6 months, with stiffness,
weakness, difficulty feeding, usually fatal
by age 2
 Krabbe Disease
• Diffuse loss of myelin in CNS and PNS,
loss of oligos
• Neurons, axons spared
• Multinucleated “globoid” cells around
vessels
 Adrenoleukodystrophy
• Several clinically and genetically distinct
forms with progressive symptoms from both
myelin loss and adrenal insufficiency
• Mutations of ALD gene, which codes for
ATP-binding cassette transporter, result in
accumulation of very long chain fatty acids
(VLCFA)
 Adrenoleukodystrophy
• X-linked juvenile form is most severe, with
rapidly progressive and fatal neurologic
symptoms and adrenal insufficiency
• Adult forms are more protracted, and
predominantly have peripheral neuropathy
• Loss of myelin, with relative preservation
of subcortical U-fibers, gliosis, lymphocytic
inflammation, adrenal cortical atrophy
 Leigh Disease
• A mitochondrial encephalomyopathy due to
enzyme deficiencies in the pathway
converting pyruvate to ATP; usually AR
• Onset at age 1-2 of lactic acidemia,
psychomotor development arrest, feeding
problems, seizures, extraocular palsies,
weakness, hypotonia; fatal in 1-2 years
 Leigh Disease
• Multifocal symmetric regions of gliosis and
demyelination with vascular proliferation in
periventricular areas of midbrain, pons,
thalamus, hypothalamus; neurons are spared
 Thiamine (Vitamin B1)
Deficiency
• Wernicke encephalopathy: sudden
development of psychosis; if untreated may
result in memory disturbances (Korsakoff
syndrome)
• Usually associated with alcoholism, but
may result from thiamine deficiency of any
cause
 Wernicke-Korsakoff syndrome
• Hemorrhage and necrosis of mammillary
bodies and areas surrounding 3rd & 4th
ventricles
• Dilated capillaries hemorrhage, then
become cystic with influx of hemosiderin-
laden macrophages
 Vitamin B12 Deficiency
• Swelling/vacuolization of myelin in both
the ascending and descending tracts of
spinal cord, usually beginning in thoracic
levels; “subacute combined degeneration”
• Early signs of ataxia and numbness are
reversible, but may rapidly progress to
spastic weakness and paraplegia, which
may be irreversible
 Hypoglycemia
• Effects very similar to global ischemia
• Large cortical pyramidal neurons,
pyramidal neurons of Sommer’s sector of
the hippocampus, and Purkinje cells show
selective vulnerability as they do with
ischemia
 Hepatic Encephalopathy
• No neuronal changes, but Alzheimer type II
astrocytes seen in cortex and basal ganglia
 Carbon Monoxide
• Pathologic changes of global hypoxia
• Selective bilateral necrosis of globus
pallidus
 Methanol
• Degeneration of retinal ganglion cells can
result in blindness
• Selective bilateral necrosis of putamen and
white matter necrosis when exposure is
severe
 Ethanol
• Chronic alcoholism can cause atrophy of
anterior cerebellar vermis, with loss of
granular neurons and sometimes Purkinje
cells, resulting in ataxia and nystagmus
• Wernicke-Korsakoff syndrome commonly
occurs due to thiamine deficiency
• Central pontine myelinolysis also common
due to electrolyte disturbances
 Cerebral Radionecrosis
• Months-years following radiation
• Rapidly evolving symptoms of intracranial mass,
including HA, n/v, papilledema, seizures
• Coagulative necrosis, usually of white matter, with
loss of all cells; adjacent vessels with intramural
fibrinoid material “radiation vasculitis”
• Increased incidence of gliomas, meningiomas,
poorly-differentiated sarcomas years later