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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