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

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

ACUTE CNS EFFECTS OF ALCOHOL ALCOHOL ASSOCIATED CNS TOXICITY ACUTE CNS EFFECTS OF ALCOHOL Blood Alcohol Level Effect < 0.04% Mild euphoria 0.05 - 0.09% Disinhibition, increased self confidence, alteration of judgment 0.10 - 0.14% Confusion, loss of critical judgment, memory impairment, sleepiness 0.15 - 0.29% Ataxia, analgesia, disorientation, exaggeration of emotions 0.30 - 0.39% Stupor, marked incordination >0.4% Anesthesia, deep coma, death 3

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

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

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

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

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

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

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

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

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

CARBON MONOXIDE TOXICITY: bilateral necrosis of globus pallidus 13

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

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

METHANOL TOXICITY: necrosis and cavitation of putamen 16

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

ETHELENE GLYCOL TOXICITY: perivascular birefringent crystals 18

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

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

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

METHOTREXATE TOXICITY: necrosis and fragmentation of axons 22

PHENYTOIN TOXICITY: cerebellar degeneration and atrophy 23

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

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

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

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

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

MERCURY TOXICITY: intra-neuronal mercury deposits in spinal motor neurons 29

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

ARSENIC TOXICITY: acute hemorrhagic encephalopathy involving pons 31

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

THALLIUM TOXICITY: neuronal chromatolysis and degeneration of posterior column 33

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