Toxic encephalopathy Exogenous Toxins

Toxic EncephalopathiesSumeet Kumar

National Neuroscience Institute, Duke-NUS Medical School

Singapore

Toxic encephalopathy

• Disturbance of normal brain function from interaction of a chemical compound (toxin) with the brain

Exogenous Endogenous

Metabolic

Inborn errors of metabolism/acquired

Exogenous Toxins

o Householdo Occupationalo Adulterated foodo Drugs of abuseo Therapeutic drugs• Chemotherapy• Antimicrobialso Radiation

• Decreased consciousness, confusion• Excitability, convulsions• Motor/sensory disturbances• Extrapyramidal movement disorders• Disturbance of coordination• Behavioral psychological change

Clinical Imaging

• Suspect metabolic/toxic– Bilateral symmetric abnormalities– Deep grey nuclei, cortex, white matter– FLAIR– DWI– T1– Potentially reversible

Selective Vulnerability

• Grey matter structures:– Energy depletion

• White matter:– Accumulation of lipophilic

toxins CO poisoningPallidal necrosis

Imaging features

Selective Vulnerability

Toluene abuse

• Grey matter structures:– Energy depletion

• White matter:– Accumulation of lipophilic

toxins

Imaging features

Neurovascular complications

Ischemia/ Stroke Hemorrhage

VasospasmVasculitis

Hypotension

HypertensionAneurysm

Venous thrombosis

PRES, RCVS

Imaging features

Toxicology and Lab

Toxins

• CO• Metronidazole• Chemotherapeutic agents• Alcohol• Methanol• Heroin, Cocaine• Organic solvents

Carbon Monoxide

• Colourless, odourless gas• Smoke inhalation• Intentional/ Accidental

– Gas stove– Faulty vehicle

• Environmental– Forest fires– Volcano eruptions

CO

Carbon containing compound

combustionIncomplete

Dries et al. "Inhalation injury: epidemiology, pathology, treatment strategies." Scand J Trauma Resusc Emerg Med

CO has 250x more affinity for Hbthan O2

Reduces O2 carrying capacity of HbHypoxia

CO inhibits mitochondrial function

Brain lipid peroxidation

Oxygen free radical formationCellular damage

Acute CO poisoning

• Long Term sequelae- Cognitive impairment, Movement disorders, Depression

Signs and symptoms of carbon monoxide poisoning

CO% Symptoms0-10 No symptoms10-20 Headache, shortness of breath20-30 Headache, shortness of breath, nausea, dizziness

30-40 Severe headache, vomiting, fatigue

40-50 Confused, passing out, tachycardia, tachypnoea

50-60 Syncope, seizure, coma>70 Rapidly fatal

Adapted from Clinical practice of emergency medicine: Carbon Monoxide Poisoning

CO poisoning

Bilateral symmetric necrosis of globus pallidus

CaudatePutamenThalamus

A 40 year old lady with a history of depression was found by a friendunresponsive in a room with burning charcoal and dense noxious fumes

CO poisoningA 40 year old lady with a history of depression was found by a friendunresponsive in a room with burning charcoal and dense noxious fumes

Focal cortical injury

Temporal lobeshippocampi

Infarct Edema

Hypoxic ischemic injury

CO poisoningA 67 year old gentleman with a history of depression was found unconscious byhis son in an enclosed room with a stove of burning charcoalInitial CT brain was normal

Day 20 Day 35

White matter Demyelination

Delayed leukoencephalopathy

Basal ganglia + Cortex

• CO poisoning- globus pallidus

• Methanol poisoning- putamen• Cyanide- putamen

Hegde et al. Differential Diagnosis for Bilateral Abnormalities of the Basal Ganglia and ThalamusRadiographics 2011

Metronidazole toxicityDoses > 2gm/day

ConfusionDysarthriaGait Abn

Weakness

Dentate nucleiDorsal pons/

medullaTectum

Periaqueduct Grey

Reversible

AJR 2009, P Sharma et al

Metronidazole toxicity 60/M Brain abscessesNov 2015

Treated with Metronidazole

Feb 2016

Dentate signal abNResolved 2 months after stopping Rx

Dentate nucleus

S Khandilkar, Clin Rad 2016

Chemotherapeutic drugs

Toxic effects in the CNS:• Methotrexate• Cytarabine• Vincristine• Asparaginase• Corticosteroids

LeukoencephalopathyNeuro vascular Immune related

Treatment-induced Leukoencephalopathy

SeizuresTransient ischemic attacks EncephalopathyAtaxiaMyelopathy

Acute neurotoxic effect-Methotrexate

Cerebral white matterSpinal cord-acute- restricted diffusion -chronic- gliosis and encephalomalacia

Risk factors for methotrexate-induced neurotoxic effects:High-dose treatmentIntrathecal treatmentYoung ageAssociated cranial radiation therapy

Patients often recover spontaneously

Methotrexate induced neurotoxicity

Methotrexate-induced neurotoxic effects in a 12-year-old girl with acute lymphoblastic leukemia. (a) Axial FLAIR MR image shows several white matter lesions. (b) Axial diffusion-weighted image shows restricted diffusion in the lesions, which is consistent with acute methotrexate-related toxic effects.

Side Effects of Oncologic Therapies in the Pediatric Central Nervous System: Update on Neuroimaging Findings. Radiographics 2011

Intrathecal Methotrexate

Methotrexate induced neurotoxicity

Courtesy Zoran Rumboldt Courtesy Zoran Rumboldt

Chronic Methotrexate induced neurotoxicityPRES

• In the settings of chemotherapy, immunosuppressive therapy and sepsis- PRES may occur with normal blood pressure

Side Effects of Oncologic Therapies in the Pediatric Central Nervous System: Update on Neuroimaging Findings. Radiographics 2011

PRESTypical featuresAtypical features: enhancement, hemorrhage, restricted diffusion Less commonly affected regions: brainstem, basal ganglia, or cerebellum

Treatment- discontinuing the offending chemotherapy agent, controlling hypertension, and administering anticonvulsive and/or antiedemic therapy

Drugsof Abuse

Alcohol- Ethanol• Most commonly abused drug in the world

Alcohol

Direct effects Cirrhosis Nutritional

Seizure related NeurodegenerativeOsmotic myelinolysis

MarchiafavaBignami disease

Alcohol brain injury

• Acute alcohol toxicity• Wernicke’s encephalopathy• Marchiafavi Bignami disease

Acute Ethanol poisoning

• Rare• Binge drinking• Blood Eth levels above: 80mg%• Reduces forebrain function• Life threatening brain swelling• Non convulsive status epilepticus• Acute demyelination- white matter esp Splenium

corpus callosum, Optic pathway esp opt nerves/ Chiasm

Wernicke’s encephalopathy

Acute thiamine deficiency

Ataxia

OphthalmoplegiaGlobal confusion

Wernicke’s encephalopathy

Mamillarybodies

Periqueductalgrey matter Medial thalami

Marchiafava Bignami DiseaseRare complication

AcuteSeverely impaired

consciousness

Muscle rigidity

Seizures

Death

Chronic

Dementia

Dysarthria

AbN gait

Corpus callosum

Marchiafava Bignami Disease

G Zuccoli AJR 2010

Early Hemorrhage Necrosis

LateCavitationsAtrophy

Corpus Callosum

Methanol Toxicity

• Can be fatal, blindness

• Illegal liquor: Moonshine, Bootleg

• Very high proof-95% alcohol

• Ethanol laced with methanol to increase the alcohol content

Methanol Toxicity

Methanol Formaldehyde Formic acid Metabolic acidosis

Alcohol dehydrogenase

Methanol Toxicity

Methanol Formaldehyde

Formic acid-Accumulates in

putamen-Optic neuritis/ Retinal damage

Metabolic acidosis

Fatal dose: 60-120 ml

Methanol Toxicity

T1 hyperintensity

Hemorrhage

Variable enhancement

Bilateral putaminalnecrosis

AJR 2009, P Sharma et al

Methanol Toxicity

Basal ganglia nucleiSubcortical wm

BrainstemCerebellum

Bilateral putaminalnecrosis

AJR 2009, P Sharma et al

HeroinSemisynthetic drugDerived from opium

IntravenousHypoxic Ischemic Encephalopathy

InhalationToxic leukoencephalopathy

Neurovascular complicationsInfectionSeizures

Chasing the dragon

Vapour Inhalation

Heroin Pyrolysate

Highly lipophillic

Spongiform leukoencephalopathy

Chasing the dragon

Symmetric

Cerebellar white matterSparing the dentate and cortex

Posterior cerebral white matter

Posterior limb IC

Case courtesy of Luc van den Hauwe

40/M Comatosepositive for opoids

Case courtesy: Timo Krings, Luc van den HauweFrom Geibprasert et al. AJNR 2010

Chasing the dragonCocaine

Hallmark drug for producing both ischemic stroke and intracranial hemorrhage

https://americanaddictioncenters.org/cocaine-treatment/

Mechanism:Blocks reuptake of carrier of monoamines

• Vasoconstriction• Increased blood pressure• Tachycardia• Increased cardiac output

StrokeSubarachnoid hemorrhageParenchymal hemorrhage

Vasospasm in a 52-year-old man with a history of recent cocaine abuse, focal stenosis of the left middle cerebral artery

Cocaine induced Vasospasm

B Tamarazi et al. Your Brain on Drugs: Imaging of Drug-related Changes in the Central Nervous System. Radiograohics 2012

Cocaine-induced ischemia.

B Tamarazi et al. Your Brain on Drugs: Imaging of Drug-related Changes in the Central Nervous System. Radiograohics 2012

Cocaine induced Hemorrhage

Cocaine-induced aneurysm rupture with subarachnoid and parenchymal hemorrhage in a 47-year-old man with underlying aneurysm of the left middle cerebral artery

B Tamarazi et al. Your Brain on Drugs: Imaging of Drug-related Changes in the Central Nervous System. Radiograohics 2012

Cocaine-induced PRES in a 17-year-old boy. FLAIR changes in the subcortical white matter involving the posterior frontal and parietal lobes

B Tamarazi et al. Your Brain on Drugs: Imaging of Drug-related Changes in the Central Nervous System. Radiograohics 2012

Cocaine induced PRES Organic solvents

• Occupational/ Substance abuse– Liquid thinner, spray paint, glue, varnish, gasoline– Toluene, trichloroethane, nitrous oxide

• Lipophilic• Chronic Encephalopathy

16-year-old patient who had inhaled toluene for 6 years

Kubilay Aydin et al. AJNR Am J Neuroradiol2002;23:1173-1179

©2002 by American Society of Neuroradiology

Chronic solvent induced Encephalopthy

Cerebral white matter

Posterior limb of IC

Cerebellar white matterSparing dentate

Atrophy

Pons

Take Home Messages

1. Bilateral Symmetric abn- think Metabolic/ Toxic

2. Distribution- Selective vulnerability

3. Toxicology- Lab support Thank you