Clinical

• Decreased consciousness, confusion • Excitability, convulsions • Motor/sensory disturbances • Extrapyramidal movement disorders Toxic • Disturbance of coordination • Behavioral psychological change Sumeet Kumar National Neuroscience Institute, Duke-NUS Medical School Singapore

Toxic Imaging

• Disturbance of normal brain function from • Suspect metabolic/toxic interaction of a chemical compound (toxin) – Bilateral symmetric abnormalities with the brain – Deep grey nuclei, cortex, white matter – FLAIR Endogenous Exogenous – DWI – T1 Metabolic – Potentially reversible

Inborn errors of metabolism/acquired

Imaging features Exogenous Toxins Selective Vulnerability

• Grey matter structures: – Energy depletion o Household o Occupational o Adulterated food • White matter: o Drugs of abuse – Accumulation of lipophilic o Therapeutic drugs toxins • Chemotherapy CO poisoning Pallidal necrosis • Antimicrobials o Radiation Imaging features Selective Vulnerability Toxins

• Grey matter structures: • CO – Energy depletion • Metronidazole • Chemotherapeutic agents • White matter: • Alcohol – Accumulation of lipophilic • Methanol toxins • Heroin, Cocaine Toluene abuse • Organic solvents

Imaging features Neurovascular complications Carbon Monoxide

• Colourless, odourless gas CO • Smoke inhalation Ischemia/ PRES, RCVS Hemorrhage • Intentional/ Accidental – Gas stove – Faulty vehicle • Environmental Incomplete combustion Hypertension Vasospasm – Forest fires Aneurysm Vasculitis – Volcano eruptions Carbon containing Hypotension Venous thrombosis compound

Toxicology and Lab CO has 250x more affinity for Hb CO inhibits mitochondrial than O2 function

Brain lipid peroxidation

Oxygen free radical formation Cellular damage

Reduces O2 carrying capacity of Hb Hypoxia

Dries et al. "Inhalation injury: epidemiology, pathology, treatment strategies." Scand J Trauma Resusc Emerg Med Acute CO poisoning CO poisoning A 67 year old gentleman with a history of depression was found unconscious by his son in an enclosed room with a stove of burning charcoal Signs and symptoms of carbon monoxide poisoning Initial CT brain was normal CO% Symptoms 0-10 No symptoms 10-20 , shortness of breath White matter 20-30 Headache, shortness of breath, nausea, dizziness Demyelination 30-40 Severe headache, vomiting, 40-50 Confused, passing out, tachycardia, tachypnoea Delayed 50-60 Syncope, , coma leukoencephalopathy >70 Rapidly fatal

• Long Term sequelae- Cognitive impairment, Movement disorders, Depression Day 20 Day 35

Adapted from Clinical practice of emergency medicine: Carbon Monoxide Poisoning

CO poisoning + Cortex A 40 year old lady with a history of depression was found by a friend unresponsive in a room with burning charcoal and dense noxious fumes • CO poisoning- globus pallidus Caudate Putamen • Methanol poisoning- putamen • Cyanide- putamen

Bilateral symmetric necrosis of globus pallidus

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

Hypoxic ischemic injury

Focal cortical injury Temporal lobes hippocampi

Infarct Edema

Hegde et al. Differential Diagnosis for Bilateral Abnormalities of the Basal Ganglia and Thalamus Radiographics 2011 Metronidazole toxicity Chemotherapeutic drugs

Doses > 2gm/day Reversible Toxic effects in the CNS: Confusion • Methotrexate Dysarthria Leukoencephalopathy Gait Abn • Cytarabine Neuro vascular Weakness • Vincristine Immune related Dentate nuclei • Asparaginase Dorsal pons/ • Corticosteroids medulla Tectum Periaqueduct Grey AJR 2009, P Sharma et al

Metronidazole toxicity 60/M Brain Treatment-induced abscesses Nov 2015 Leukoencephalopathy

Seizures Acute neurotoxic effect-Methotrexate Transient ischemic attacks Encephalopathy Ataxia Cerebral white matter -acute- restricted diffusion -chronic- gliosis and encephalomalacia

Treated with Risk factors for methotrexate-induced Metronidazole neurotoxic effects: High-dose treatment Intrathecal treatment Dentate signal abN Young age Resolved 2 months after Associated cranial radiation therapy stopping Rx Feb 2016 Patients often recover spontaneously

Dentate nucleus 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.

S Khandilkar, Clin Rad 2016 Side Effects of Oncologic Therapies in the Pediatric Central : Update on Neuroimaging Findings. Radiographics 2011 Methotrexate induced neurotoxicity PRES

Typical features Atypical features: enhancement, hemorrhage, restricted Intrathecal Methotrexate diffusion Less commonly affected regions: brainstem, basal ganglia, or cerebellum

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

Courtesy Zoran Rumboldt

Chronic Methotrexate induced neurotoxicity

Drugs of Abuse

Courtesy Zoran Rumboldt

PRES Alcohol- Ethanol • Most commonly abused drug in the world • 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 Wernicke’s encephalopathy

Alcohol Ataxia

Direct Cirrhosis Nutritional Acute thiamine effects deficiency

Osmotic Marchiafava Seizure related Neurodegenerative myelinolysis Bignami disease Global confusion Ophthalmoplegia

Alcohol brain injury Wernicke’s encephalopathy

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

Periqueductal Mamillary Medial thalami grey matter bodies

Acute Ethanol poisoning Marchiafava Bignami Disease

• Rare Rare complication • Binge drinking • Blood Eth levels above: 80mg% Acute Chronic Severely • Reduces forebrain function impaired • Life threatening brain swelling consciousness Corpus callosum • Non convulsive Dysarthria • Acute demyelination- white matter esp Splenium Muscle rigidity corpus callosum, Optic pathway esp opt nerves/ Death AbN gait Chiasm Marchiafava Bignami Disease Methanol Toxicity

Early Hemorrhage Formic acid Necrosis -Accumulates in

Metabolic Corpus Callosum Methanol Formaldehyde putamen acidosis Late Cavitations -Optic neuritis/ Atrophy Retinal damage

Fatal dose: 60-120 ml G Zuccoli AJR 2010

Methanol Toxicity Methanol Toxicity

• Can be fatal, blindness Bilateral • putaminal Illegal liquor: necrosis Moonshine, Bootleg • Very high proof-95% alcohol Hemorrhage • Ethanol laced with methanol to increase the Variable alcohol content T1 hyperintensity enhancement

AJR 2009, P Sharma et al

Methanol Toxicity Methanol Toxicity

Bilateral putaminal necrosis Alcohol dehydrogenase

Metabolic Methanol Formaldehyde Formic acid acidosis

Basal ganglia nuclei Subcortical wm Brainstem

AJR 2009, P Sharma et al Cerebellum Chasing the dragon Heroin

Semisynthetic drug Inhalation Derived from opium Toxic leukoencephalopathy

Neurovascular complications Intravenous Infection Hypoxic Ischemic Encephalopathy Seizures

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

Chasing the dragon Cocaine

Vapour Inhalation Hallmark drug for producing both ischemic stroke and intracranial hemorrhage Heroin Pyrolysate

Highly lipophillic

Spongiform leukoencephalopathy

Chasing the dragon 40/M Comatose positive for opoids

Symmetric Mechanism: Blocks reuptake of carrier of monoamines Cerebellar white matter Sparing the dentate and cortex • Vasoconstriction • Increased blood pressure • Tachycardia Posterior cerebral white • Increased cardiac output matter Stroke Subarachnoid hemorrhage Posterior limb IC Parenchymal hemorrhage

Case courtesy of Luc van den Hauwe https://americanaddictioncenters.org/cocaine-treatment/ Cocaine induced Vasospasm Cocaine induced PRES

Vasospasm in a 52-year-old man with a history of recent cocaine abuse, focal stenosis Cocaine-induced PRES in a 17-year-old boy. FLAIR changes in the subcortical of the left middle cerebral artery 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 B Tamarazi et al. Your Brain on Drugs: Imaging of Drug-related Changes in the Central Nervous System. Radiograohics 2012

Cocaine-induced ischemia. Organic solvents

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

• Lipophilic • Chronic Encephalopathy

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

Chronic solvent induced Cocaine induced Hemorrhage Encephalopthy

Cerebral white matter

Posterior limb of IC Pons Cerebellar white matter Sparing dentate

Atrophy

16-year-old patient who had inhaled toluene for 6 years Cocaine-induced aneurysm rupture with subarachnoid and parenchymal hemorrhage in a 47- year-old man with underlying aneurysm of the left middle cerebral artery

Kubilay Aydin et al. AJNR Am J Neuroradiol B Tamarazi et al. Your Brain on Drugs: Imaging of Drug-related Changes in the Central Nervous System. Radiograohics 2012 2002;23:1173-1179 ©2002 by American Society of Neuroradiology Take Home Messages

1. Bilateral Symmetric abn- think Metabolic/ Toxic

2. Distribution- Selective vulnerability

3. Toxicology- Lab support

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