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DEFICIENCY OF METABOLITE

-HYPOXIA AND HYPOGLYCEMIA-HYPOVITAMINOSIS

SELECTIVE VULNERABILITY(HYPOXIA AND HYPOGLYCEMIA)

-SPECIFIC CELL TYPENEURONS>OLIGODENDROCYTES>ASTROCYTES

-SPECIFIC BRAIN REGIONPYRAMIDAL NEURONS OF SOMMER’S SECTOR

(HIPPOCAMPUS CA1)PURKINJE CELLS OF CEREBELLUMNEURONS OF GLOBUS PALLIDUSNEURONS OF CORTICAL LAYERS 3 AND 5

Degeneration of CA1 post ischemia

HYPOVITAMINOSIS

THIAMINE (VITAMIN B1)COBALAMIN (VITAMIN B12)

Chronic alcoholicsGastrointestinal diseaseLong-term TPN

WERNICKE’S DISEASE(Thiamine deficiency)

CLINICAL FEATURESCONFUSIONOCULAR DISTURBANCES (Gaze Palsies)ATAXIARETROGRADE and ANTEROGRADE AMNESIA,

CONFABULATION = KORSAKOFF’S PSYCHOSIS, WITH CHRONIC DISEASE, IRREVERSIBLE

NEUROANATOMIC LOCALIZATIONMAMMILLARY BODIESMEDIAL DORSAL THALAMIC NUCLEUSNUCLEI AROUND IIIrd and IVth VENTRICLES

Acute Wernicke’s Encephalopathy

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Chronic Wernicke’s Encephalopathy

Associated with Korsakoff’s

SUBACUTE COMBINED DEGENERATION(Vitamin B12 Deficiency)

• Obtain in meat, dairy products, yeast

• Untreated pernicious anemia, gastrectomy/tumors, malabsorption, tapeworms, HIV infection, vegetarians,

• Early symptoms = paresthesias in lower limbs, thenloss of fine touch, vibration, position sense

• Progression to spastic paraparesis, ataxia, anesthesiaof lower limbs and trunk

• Defective methylation of myelin basic protein and other CNS proteins

Subacute combined degeneration in spinal cord white matter tracts.

INBORN ERRORS OF METABOLISM

MITOCHONDRIAL DISORDERS

SUBACUTE NECROTIZING ENCEPHALOPATHY

(LEIGH’S)

PEROXISOMAL DISORDERS

CEREBRAL HEPATORENAL (ZELLWEGER)

LYSOSOMAL DISORDERS

GANGLIOSIDOSES

MUCOPOLYSACCHARIDOSES

CEROID LIPOFUSCINOSIS

SUBACUTE NECROTIZING ENCEPHALOPATHY (LEIGH’S DISEASE)

CLINICAL:Onset in early childhood (juvenile and adult forms

also)Failure to thriveArrest and regression of psychomotor developmentHypotonia, ataxia, dystonias, tremorsNystagmus, bizarre eye movementsDeafnessSeizuresLactic acidosis (blood and CSF)

DEFECT: Disorders in pyruvate dehydrogenase complex or cytochrome C oxidase - autosomal recessive or X-linked

OVERLAPS with MELAS and MERRF mitochondrial syndromes

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GM2 GANGLIOSIDOSIS

(TAY-SACHS AND OTHER VARIANTS)

AUTOSOMAL RECESSIVE; Hexosaminidase mutations lead to accumulation of GM2 ganglioside

CARRIERS 1:30 of Ashkenazii Jewish descent

1:300 in others

CLINICAL: INFANTILE - Severe retardation

Myoclonic seizures

“Cherry red” spot in retina

LATE INFANTILE

JUVENILE

ADULT

GM2 GANGLIOSIDOSIS - PATHOLOGY

MACROCEPHALY

MICROSCOPIC -

Abnormal central and peripheral neurons

Ballooned cytoplasm (“storage”)

“Meganeurites” - enlarged dendrites and proximal axons

Membranous cytoplasmic bodies

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Membranous cytoplasmic bodies seen in mucopolysaccharidoses and other neuronal “storage” disorders Retinal pigmentary degeneration in NCL

Neuronal cytoplasmic ballooning due to storage disorder

EXCESS OF TOXIC METABOLITES

ETHANOL ABUSE

HEPATIC ENCEPHALOPATHY

UREMIC ENCEPHALOPATHY

WILSON’S DISEASE

KERNICTERUS

Alzheimer Type 2 Astrocytes are associatedwith hepatic disease Cerebellar vermal degeneration

Chronic alcoholism

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Basal ganglionic degeneration in Wilson’s disease• Autosomal recessive, defect in copper

transporting-ATPase, export ofcopper from cells

• Usually present end of second decade,or severe mutations in early childhood

• Dysarthria, dysphagia, dystonia andpainful muscle spasms, coarse tremor,dementia; Kayser-Fleisher rings in eye

• Low serum ceruloplasmin, copper inurine

• Treat with copper chelating agents

• Severely affects caudate and putamen,atrophy to cavitation; less severe inglobus pallidus and thalamus

• Neuronal loss, gliosis, macrophages,Alzheimer type II astrocytes

KernicterusNow seen in small, preterm infants with asphyxia, acidosis, hypoglycemiaor septicemia. Are very sensitiveto even low levels (10 mg/dl) of unconjugatedbilirubin.