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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

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Degeneration of CA1 post ischemia

HYPOVITAMINOSIS

THIAMINE (VITAMIN B1)COBALAMIN (VITAMIN B12)

Chronic alcoholicsGastrointestinal diseaseLong-term TPN

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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

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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

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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

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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

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Neuronal cytoplasmic ballooning due to storage disorder

EXCESS OF TOXIC METABOLITES

ETHANOL ABUSE

HEPATIC ENCEPHALOPATHY

UREMIC ENCEPHALOPATHY

WILSON’S DISEASE

KERNICTERUS

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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

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