DEFICIENCY OF METABOLITE -HYPOXIA AND HYPOGLYCEMIA -HYPOVITAMINOSIS SELECTIVE VULNERABILITY (HYPOXIA AND HYPOGLYCEMIA) -SPECIFIC CELL TYPE NEURONS>OLIGODENDROCYTES>ASTROCYTES -SPECIFIC BRAIN REGION PYRAMIDAL NEURONS OF SOMMER S SECTOR (HIPPOCAMPUS CA1) PURKINJE CELLS OF CEREBELLUM NEURONS OF GLOBUS PALLIDUS NEURONS OF CORTICAL LAYERS 3 AND 5 HYPOVITAMINOSIS THIAMINE (VITAMIN B1) COBALAMIN (VITAMIN B12) Degeneration of CA1 post ischemia Chronic alcoholics Gastrointestinal disease Long-term TPN WERNICKE S DISEASE (Thiamine deficiency) Acute Wernicke s Encephalopathy CLINICAL FEATURES CONFUSION OCULAR DISTURBANCES (Gaze Palsies) ATAXIA RETROGRADE and ANTEROGRADE AMNESIA, CONFABULATION = KORSAKOFF S PSYCHOSIS, WITH CHRONIC DISEASE, IRREVERSIBLE NEUROANATOMIC LOCALIZATION MAMMILLARY BODIES MEDIAL DORSAL THALAMIC NUCLEUS NUCLEI AROUND IIIrd and IVth VENTRICLES 1
Chronic Wernicke s Encephalopathy 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, then loss of fine touch, vibration, position sense Progression to spastic paraparesis, ataxia, anesthesia of lower limbs and trunk Associated with Korsakoff s Defective methylation of myelin basic protein and other CNS proteins INBORN ERRORS OF METABOLISM Subacute combined degeneration in spinal cord white matter tracts. 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 thrive Arrest and regression of psychomotor development Hypotonia, ataxia, dystonias, tremors Nystagmus, bizarre eye movements Deafness Seizures Lactic 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 2
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 3
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 associated with hepatic disease Cerebellar vermal degeneration Chronic alcoholism 4
Basal ganglionic degeneration in Wilson s disease Autosomal recessive, defect in copper transporting-atpase, export of copper from cells Usually present end of second decade, or severe mutations in early childhood Dysarthria, dysphagia, dystonia and painful muscle spasms, coarse tremor, dementia; Kayser-Fleisher rings in eye Low serum ceruloplasmin, copper in urine Treat with copper chelating agents Severely affects caudate and putamen, atrophy to cavitation; less severe in globus pallidus and thalamus Neuronal loss, gliosis, macrophages, Alzheimer type II astrocytes Kernicterus Now seen in small, preterm infants with asphyxia, acidosis, hypoglycemia or septicemia. Are very sensitive to even low levels (10 mg/dl) of unconjugated bilirubin. 5