1. TOXIC INJURY OF THE CNS
Bennet I. Omalu, MD 1

2. OUTLINE 1. ALCOHOL ASSOCIATED CNS TOXICITY
2. CNS TOXICITY OF STREET DRUGS
3. CNS INJURY DUE TO TOXIC GASES
4. CNS INJURY DUE TO INDUSTRIAL/ ENVIROMENTAL CHEMICALS
5. CNS TOXICITY DUE TO THERAPEUTIC AND DIAGNOSTIC DRUGS
6. CNS TOXICITY DUE TO METALS 2

3. ACUTE CNS EFFECTS OF ALCOHOL
ALCOHOL ASSOCIATED CNS TOXICITY
ACUTE CNS EFFECTS OF ALCOHOL
Blood Alcohol Level Effect
< 0.04% Mild euphoria
% Disinhibition, increased self confidence, alteration of judgment
% Confusion, loss of critical judgment, memory impairment, sleepiness
% Ataxia, analgesia, disorientation, exaggeration of emotions
% Stupor, marked incordination
>0.4% Anesthesia, deep coma, death 3

4. ACUTE CNS EFFECTS OF ALCOHOL
ALCOHOL ASSOCIATED CNS TOXICITY
ACUTE CNS EFFECTS OF ALCOHOL
Gross and microscopic findings:
Occasional subdural or subarachnoid hemorrhages
+/- Intracerebral hemorrhage and infarcts
Cerebral hyperemia and edema
White matter petechial hemorrhages 4

5. ALCOHOL ASSOCIATED CNS TOXICITY
CHRONIC CNS EFFECTS OF ALCOHOL
CEREBRAL ATROPHY
WERNICKE-KORSAKOFF SYNDROME
CEREBELLAR DEGENERATION
PELLAGRA
CENTRAL PONTINE MYELINOLYSIS
MARCHIAFAVA-BIGNAMI DISEASE
MOREL’S LAMINAR SCLEROSIS
FETAL ALCOHOL SYNDROME 5

6. ALCOHOL ASSOCIATED CNS TOXICITY
CEREBRAL ATROPHY
Loss of cerebral white matter volume, non-specific
WERNICKE’S ENCEPHALOPATHY
Due to thiamine deficiency
Responsive to thiamine treatment
Manifests with confusion, apathy, gaze palsies and ataxia
+/- Korsakoff’s pychosis
Retrograde and anterograde amnesia
Confabulation
Irreversible and unresponsive to thiamine 6

7. Wernicke’s Encephalopathy: atrophic and hemorrhagic mamillary bodies
ALCOHOL ASSOCIATED CNS TOXICITY
Wernicke’s Encephalopathy: atrophic and hemorrhagic mamillary bodies 7

8. ALCOHOL ASSOCIATED CNS TOXICITY
CEREBELLAR DEGENERATION
Manifests with truncal instability, broad based stance and gait ataxia
Atrophy of superior vermix
Loss of Purkinje cells and granule cell neurons
PELLAGRA
Due to nicotinic acid deficiency
Manifests with diarrhea, dermatitis and dementia
Widespread chromatolysis of neurons
MARCHIAFAVA-BIGNAMI DISEASE
Manifests with callosal disconnection syndromes
Focal demyelination of central part of corpus callosum 8

9. Chromatolysis of neurons in pellagra
ALCOHOL ASSOCIATED CNS TOXICITY
Loss of Purkinje and Granule neurons
Atrophy of superior vermix
Chromatolysis of neurons in pellagra 9

10. ALCOHOL ASSOCIATED CNS TOXICITY
Central myelinolysis of the corpus callosum in Marchiafava-Bignami Disease
Luxol fast blue stain 11

11. CNS TOXICITY OF STREET DRUGS
COCAINE AND AMPHETAMINE TOXICITY
Manifests with mydriasis, blurred vision, dystonia, hypereflexia, myoclonus, seizures, coma and death
Associated with intracranial and intracerebral hemorrhages and infarcts
HEROIN TOXICITY
Manifest with nausea, vomiting cardiorespiratory depression, coma and death
Associated with small vessel angitis, cerebral infarcts and leukoencephalopathy
MPTP TOXICITY (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)
Causes irreversible drug induced parkinsonism
Generates hydroxyl and free radicals
Inhibits mitochondrial oxidation 10

12. Biopsy showing delayed demyelination, luxol fast blue
CNS TOXICITY OF STREET DRUGS
Heroin associated leukoencephalopathy: MRI, T2 hyperintensity of centrum semiovale
Biopsy showing delayed demyelination, luxol fast blue 11

13. CNS INJURY DUE TO TOXIC GASES
CARBON MONOXIDE TOXICITY
Binds to hemoglobin with more than 200 x affinity of oxygen
Forms carboxyhemoglobin
Manifests with cerebral edema, white matter petechial hemorrhages
Congestion, hemorrhages and necrosis of globus pallidus
CYANIDE TOXICITY
Usually causes immediate death
If death is delayed, may manifest with cerebral edema, subarachnoid hemorrhages and petechial white matter hemorrhages
May cause necrosis of globus pallidus
NITROUS OXIDE
Manifests with clinical features of vitamin B12 deficiency
Chronic exposure inactivates cobalamin 12

14. CARBON MONOXIDE TOXICITY: bilateral necrosis of globus pallidus13

15. CNS INJURY DUE TO INDUSTRIAL/ ENVIROMENTAL CHEMICALS
METHANOL TOXICITY
ORGANOPHOSPHATE TOXICITY
ANILINE TOXICITY
ETHYLENE GLYCOL TOXICITY
CARBON TETRACHLORIDE TOXICITY
HEXACARBON SOLVENT TOXICITY 14

16. CNS INJURY DUE TO INDUSTRIAL/ ENVIROMENTAL CHEMICALS
METHANOL TOXICITY
Methyl alcohol is commonly consumed as an inebriant
Toxicity is due to hepatic oxidation to formaldehyde and formic acid
May cause permanent loss of vision, delirium, convulsions, coma and death
Causes global hypoxic injury, white matter necrosis and hemorrhages and hemorrhagic infarction of putamen and claustrum
ORGANOPHOSPHATE TOXICITY
Potent inhibitors of acetylcholinesterase
Acute and chronic effects comprise motor axonal neuropathy and chronic myelopathy
Histology: axonal degeneration spino-cerebral and cerebellar tracts 15

17. METHANOL TOXICITY: necrosis and cavitation of putamen16

18. CNS INJURY DUE TO INDUSTRIAL/ ENVIROMENTAL CHEMICALS
ANILINE TOXICITY
Causes the Toxic Oil Syndrome and Eosinophilia-Myalgia syndrome
Acute manifestations: headache, systemic hypereosinophilia, respiratory failure and death
Delayed manifestations: sensory loss, myalgias, encephalopathy, memory/ cognitive deficits
Histology: +/- chromatolysis of neurons
ETHYLENE GLYCOL TOXICITY
Used as antifreeze and commonly ingested as an inebriant
Toxicity mediated by hepatic and renal oxidation to glycoaldehyde, glycolic acid, glyoxylic acid and oxalic acid
Metabolic acidosis is severe
Histology: perivascular birefringent calcium oxalate deposits, meningeal and cerebral congestion and edema 17

19. ETHELENE GLYCOL TOXICITY: perivascular birefringent crystals18

20. CNS INJURY DUE TO INDUSTRIAL/ ENVIROMENTAL CHEMICALS
CARBON TETRACHLORIDE TOXICITY
Used in manufacture of refrigerants, aerosols and shampoo
May cause vertigo, gait ataxia, confusion, lethargy, seizures and coma
Chronic exposure reported to be associated with parkinsonism
Histology: cerebral edema, focal vascular necrosis, venous thrombosis and hemorrhagic infarcts
HEXACARBON SOLVENT TOXICITY
Used in paint, varnish and glue solvents
Chronic exposure produces dysarthria, gait ataxia and blurred vision
Sensorimotor neuropathy may be present
Histology: distal degeneration of long ascending and descending fibers
neurofilamentous axonal swellings. 19

21. CNS TOXICITY DUE TO THERAPEUTIC AND DIAGNOSTIC DRUGS
METHOTREXATE TOXICITY
PHENYTOIN TOXICITY
CLIOQUINOL TOXICITY
LITHIUM TOXICITY
HEXACHLOROPHENE 20

22. CNS TOXICITY DUE TO THERAPEUTIC AND DIAGNOSTIC DRUGS
METHOTREXATE TOXICITY
Folic acid antagonist
CNS toxicity associated with intrathecal administration
Acute symptoms: headache, confusion, seizures and hemiplegia
Delayed symptoms: subacute encephalopathy, myelopathy, optic atrophy
Histology: multifocal coagulative necrosis, demyelination and axonal fragmentation in cerebral and spinal white matter
PHENYTOIN TOXICITY
Used as anticonvulsant and treatment for neuralgia and arrythmias
Acute manifestation: nystagmus, diplopia, dysarthria and ataxia
Chronic exposure: cerebellar degeneration and atrophy, mental deterioration, mild sensory neuropathy
Histology: loss of Purkinje and granule neurons and gliosis 21

23. METHOTREXATE TOXICITY: necrosis and fragmentation of axons22

24. PHENYTOIN TOXICITY: cerebellar degeneration and atrophy23

25. CNS TOXICITY DUE TO THERAPEUTIC AND DIAGNOSTIC DRUGS
CLIOQUINOL TOXICITY
A halogenated hydroxyquinolone used in treatment of intestinal infections
Causes Subacute Myelo-Optic Neuropathy (SMON):
impaired vision, optic atrophy, subacute myelopathy
spasticity and dysesthesiae of lower limbs and trunk
Histology: degeneration of distal axons of optic pathways, posterior spinal and corticospinal tracts, chromatolysis of lumbosacral anterior horn cells, white matter gliosis, degeneration of dorsal root ganglion cells 24

26. CNS TOXICITY DUE TO THERAPEUTIC AND DIAGNOSTIC DRUGS
LITHIUM TOXICITY
Used in treating mania, manic-depressive illness and episodic depression
Acute overdose: coma, encephalopathy with permanent cerebellar degeneration
Histology: neuronal loss and gliosis in cerebellar cortex and dentate nuclei
spongy vacuolation of cerebellar white matter
HEXACHLOROPHENE:
A widely used phenolic antiseptic
Can be absorbed through skin and mucous membranes
May cause visual disturbances, drowsiness, convulsions, coma and death
Histology: intramyelinic edema and spongy degeneration of white matter 25

27. CNS TOXICITY DUE TO METALS
LEAD TOXICITY
MERCURY TOXICITY
MANGANESE TOXICITY
ARSENIC TOXICITY
THALLIUM TOXICITY
TRIETHYLTIN TOXICITY 26

28. CNS TOXICITY DUE TO METALS
LEAD TOXICITY:
Organic and Inorganic lead exposure
Common sources:
Inorganic lead: paint, pottery, cosmetics, car batteries, alcohol distilled in lead pipes
Organic lead: tetraethyl lead used as anti-knock agent in gasoline
Inorganic intoxication: acute encephalopathy, motor mononeuropathy, seizures and pyschiatric disturbances
Organic intoxication: headache, insomnia, confusion, delirium, extrapyramidal movement disorders
Pathology: cerebral edema, hydrocephalus, white matter petechial hemorrhages
Histology: endothelial cell swelling and capillary thrombosis, perivascular proteinaceous exudate, widespread gliosis, spongiosis 27

29. CNS TOXICITY DUE TO METALS
MERCURY TOXICITY:
Organic and Inorganic mercury exposure
Common sources:
Inorganic mercury: a waste product of paper and chloralkali production
Organic mercury: ingestion of contaminated food, transformed into inorganic mercury in CNS
Acute intoxication: tremor, ataxia, vertigo, nystagmus, choreoathetosis, blurred vision, sensory neuropathy
Chronic exposure: mental retardation, cortical blindness, quadriplegia
Pathology: atrophy of calcarine cortex and cerebellum
Histology: loss of small neurons of cerebellum, primary visual, auditory and somatosensory cortex, spongiosis, gliosis, neuronal heterotopia and cortical dysplasia 28

30. MERCURY TOXICITY: intra-neuronal mercury deposits in spinal motor neurons29

31. CNS TOXICITY DUE TO METALS
MANGANESE TOXICITY:
May result from inhaling dust in mines or production of paints and batteries
Manifestation: extrapyramidal movement disorders, psychiatric disturbances and intellectual impairment
Histology: gliosis and loss of neurons in basal ganglia
ARSENIC TOXICITY:
Organic arsenicals are present in some drugs for trypanosomiasis (Melarsoprol)
Acute intoxication may produce acute hemorrhagic leukoencephalopathy
Pathology: cerebral edema with parenchymal hemorrhages
Histology: fibrinoid necrosis of blood vessels with hemorrhage and inflammatory infiltrates 30

32. ARSENIC TOXICITY: acute hemorrhagic encephalopathy involving pons31

33. CNS TOXICITY DUE TO METALS
THALLIUM TOXICITY:
Most commonly occurs from accidental or deliberate ingestion of pesticides or rodenticides
Clinical manifestation resembles arsenical poisoning with
sensorimotor distal axonopathy
chromatolysis of motor neurons
degeneration of posterior column fibers
TRIETHYLTIN TOXICITY
Organic tin that is produced in the manufacture of plastic and glass
Manifestations: raised intracranial pressure, flaccid paraparesis, confusion
confabulation and amnesia
Histology: marked white matter edema due to fluid accumulation in myelin sheath vacuoles 32

34. THALLIUM TOXICITY: neuronal chromatolysis and degeneration of posterior column33

35. TRIETHYLTIN TOXICITY: marked edema of cerebellar white matter
E.M.:intramyelin edema 34