Toxic and Metabolic Disease of Nervous System

Transcription

1 Toxic and Metabolic Disease of Nervous System Reid R. Heffner, MD Distinguished Teaching Professor Emeritus Department of Pathology and Anatomy January 14,

2 I HAVE NO CONFLICTS OF INTEREST OR DISCLOSURES TO DECLARE. I HAVE NO FINANCIAL INTEREST IN, I RECEIVE NO FINANCIAL SUPPORT FROM AND I HAVE NO CONTRACTS WITH OR GRANTS FROM ANY PHARMACEUTICAL COMPANY OR ANY INDUSTRY

3 Contents Heavy metal-induced disorders Lead and mercury Vitamin deficiencies Vitamin B1 and B12 Alcohol/nutritional diseases Wilson s disease 3

4 Did lead poisoning make Beethoven deaf?

5 Lead poisoning Sources: gasoline, flaking paint, putty, batteries, mining Mechanisms: Binds to -SH groups Heme synthesis-ala dehydrase Generates free radicals that destroy cells Acute and chronic disease 5

6 Prox tubule damage Blocks ALA dehydrase Motor neuropathy 6

7 Lead lines in bone and gums Segmental demyelination Wrist drop, foot drop

8 Mercury Toxicity The Mad Hatter Sources-fish, dental fillings, light bulbs ROS, binds to SH Damage to cerebrum, cerebellum & peripheral nerve

9 Mercury poisoning damages granule cells

10 Vitamin B12 (cobalamin) 10

11 Vitamin B12 (cobalamin) Megaloblastic anemia Protein synthesis Myelin synthesis 11

12 Subacute Combined Degeneration Vitamin B12 Deficiency Symptoms? Schilling test for diagnosis

13 Vacuolar myelinopathy Numerous vacuoles within myelin structures 13

14 Causes Vitamin B1 deficiency Beriberi Diet, dialysis, diarrhea Symptoms Heart failure (cardiomyopathy)-wet [edema] Peripheral neuropathy-dry 14

15 Alcohol & nutrition-related conditions Wernicke-Korsakoff syndrome Leigh s syndrome Hepatic encephalopathy Cerebral cortical atrophy Marchiafava-Bignami syndrome Central pontine myelinolysis Cerebellar atrophy Peripheral neuropathy

16 Wernicke paralysis of eye movements, ataxia, mental confusion found punctate hemorrhages in gray matter around 3 rd and 4 th ventricles Korsakoff disturbance of memory in long-term alcoholism gaps in memory are filled by confabulaton

17 Wernicke s encephalopathy Acute hemorrhages in the mammillary bodies

18 Wernicke s encephalopathy Periaqueductal hemorrhages

19 Wernicke s encephalopathy Hemorrhages around fourth ventricle

20 Wernicke s Perivascular hemorrhages, vacuolar change (edema) Leading to loss of tissue, gitter cells, gliosis later

21 Chronic Wernicke s disease Mammillary bodies are shrunken, rusty colored

22 Chronic Wernicke s Hemosiderin in macrophages Sparing of neurons

23 Leigh s syndrome Onset before 2 Anorexia, vomiting, irritability, crying, seizures Genetically diverse Many genes described Mitochondrial disease often Pathology resembles Wernicke s Spares mammillary body

24 Leigh s syndrome

25 Korsakoff syndrome Involves thalamus and basal forebrain Loss of neurons, gliosis, no hemorrhages

26 Hepatic encephalopathy Liver cirrhosis Confusion, delirium Coma, asterixis Astrocytes metabolize NH 3 26

27 Astrocytes metabolize ammonia 27

28 Alzheimer type II astrocytes Astrocyte name has nothing to do with Alzheimer s disease Type of reactive astrocyte seen in hepatic failure Nucleus is enlarged and clear with no visible cytoplasm

29 ASTROCYTE type II INCLUSIONS Seen in liver disease with serum NH 3 Nucleus enlarged, clear, contains glycogen Alzheimer I cell larger, multiple nuclei, visible cytoplasm Alz II cell

30 Brain atrophy in alcoholics and the malnourished Causes Nutritional Liver failure, especially cirrhosis Probably multifactorial Pattern of atrophy in the cerebrum Thalamus Hippocampus Frontal lobes

31 Normal brain Nonspecific atrophy Loss of neurons, gliosis

32 Marchiafava-Bignami disease Demyelination and atrophy of corpus callosum May spread to centrum semiovale Most common in alcoholics (first described in Italian wine drinkers) Also malnutrition, vitamin deficiency Symptoms: seizures, dementia, aphasia

33 Cortical atrophy + Marchiafava- Bignami

34 Marchiafava-Bignami Demyelination of corpus callosum Process may spread to involve near-by white matter

35 Central pontine myelinolysis Chronic alcoholism, liver disease, malnutrition Prolonged hyponatremia Correction of serum sodium too rapidly Paralysis, dysphagia, dysarthria Involves myelin but spares neurons

36 Central Pontine Myelinolysis LFB shows demyelination Sparing of neurons

37 CPM Normal pons, LFB Process may extend to other parts of brainstem, especially medulla

38 Alcoholic cerebellar atrophy Unsteady staggering gait Other cerebellar signs Affects vermis and the anterior lobe

39 NEURONAL LOSS Normal cerebellum Loss of granular layer cells and Purkinje cells

40 Alcoholic neuropathy Mixed type neuropathy Motor and sensory symptoms

41 Wilson s disease Hepatolenticular degeneration Described by Kinnier Wilson (1912) Disease of copper metabolism Recessive inheritance Mutation in ATP7B gene, chromosome 13 Onset children and young adults Extrapyramidal symptoms-tremor, dystonia, chorea, rigidity Big Robbins, Chap 18, pp

42 Wilson s Disease One of Wilson s Original Patients Normal before onset of symptoms Two years later Dystonic posturing

43 Wilson s Disease-metabolism Ingested copper absorbed in the small intestine; bound to albumin in portal circulation: taken up by hepatocytes. With hepatocyte ATP7B mutations: Less Cu transport into bile Less Cu incorporation into ceruloplasmin Less ceruloplasmin into blood Copper accumulates beyond cellular storage capacity Hepatocytes are damaged by excess copper via free radicals Copper (unbound) is released into circulation and deposited in kidneys, brain and cornea.

44 Wilson s disease diagnosis Low serum ceruloplasmin-blood sample Increased copper in liver-liver biopsy Increased copper excretion in urine-24 hour urine sample 44

45 Wilson s disease Systemic effects Hemolytic anemia Aminoaciduria-renal tubulular dysfunction Cirrhosis with liver failure Biopsy shows steatosis, fibrosis

46 Wilson s disease-brain Putamen and globus pallidus (lentiform nucleus) Copper deposits, loss of neurons, gliosis Alzheimer type II (and type I) astrocytes

47 Kayser-Fleischer ring Copper deposit in Descemet s membrane of cornea

48 Learning objectives Define the terms introduced in class Compare and contrast toxic and metabolic diseases presented in class Based on anatomical structures affected in each disease, predict the clinical symptoms List the diagnostic features of each disease Understand the pathology of each disease Summarize pathogenesis of each disease Characterize the outcome of each disorder 48