Toxic Agitation and Seizures

Dr. Caitlin Wolfe Dalhousie Spring Refresher April 2021 Pathophysiology of seizures from toxic exposures

Learning List common xenobiotics Objectives associated with seizures

Approach to the seizing toxicology patient • No financial disclosures

• Emergency Physician at the Halifax Infirmary • Medical Toxicologist at the IWK Regional Poison Control Centre Disclosures and • Member of the Health Canada network, Affiliations the Canadian Surveillance System for Poison Information (CSSPI) • Assistant Professor, Department of Emergency Medicine, Dalhousie University • Agitation and are features of numerous toxidromes • Anticholinergics, Serotonin syndrome, Sympathomimetics, withdrawal from ethanol or sedative-hypnotics

“Toxic • Pitfalls and risks: • Medical decompensation: hyperthermia, agitation” rhabdomyolysis, arrhythmias… • Behaviour dangerous to self and others • Missed medical diagnoses (long overlap of DDx) • Missed psychiatric diagnoses • Missed physical injuries

• Seizures are the most extreme form • Case series of first seizures = 6-47% are from toxic or metabolic causes

• Seizures can be from: • Acute ingestion Seizures from Toxic • Withdrawal Causes • Chronic use • Drug-drug interactions

• Idiosyncratic • Tramadol, Buproprion • Dose dependent • Theophylline • Enhanced excitatory neurotransmission (glutamate and NMDA) and/or inhibition of GABAergic inhibitory tone

• 4 main direct mechanisms Pathophysiology of • Activity at NMDA and GABA receptors Related • Alteration of neuronal resting potential Seizures • Disturbing ion movements • Antagonism of adenosine • Alteration in biogenic amine and acetylcholine function • Most significant and common of the mechanisms

• Eg. Ethanol • Chronic use decreases seizure threshold 1) NMDA and • Increase NMDA proteins over time • Susceptible patients may seize within 6-48 GABA activity hours of cessation • Usually tonic-clonic, brief, but may come in runs • NB: high degree of overlap with other identifiable causes (namely trauma, infection, …) • Usually sodium channel blockers (or openers, rarely), or potassium channel 2) Alteration blockers/openers • Alters the resting potential, to of membrane hyperpolarize or depolarize the neuron potential • Also the MOA of many anti-epileptics • Endogenous termination of seizures from presynaptic release of adenosine • Co-released with primary from axons • Feedback inhibition of the presynaptic neuron 3) Antagonism • Decreases ongoing excitatory transmission of Adenosine • Eg. Theophylline: adenosine antagonist • Overdose can precipitate seizures and status • Adenosine doesn’t cross BBB, so not useful as antagonist • Give high dose sedatives 4) Alteration in • Eg. amphetamine type stimulants, cocaine • Although have NDMA activity too biogenic amine • Enhances or provokes monoamine or ACh neurotransmission • Indirect causes • Anoxic injury • Ischemic stroke • Brain trauma • Metabolic and biochemical derangements Pathophysiology of • Hyponatremia • Hypoglycemia Toxin Related • Acidosis Seizures

• Kindling • Myoclonus • GHB

• Hyperreflexia Seizure mimics • Tetanospasmin, strychnine

• Convulsive syncope • Increased risk of: • Status epilepticus • ECG changes Complications • Cardiac dysrhythmias of seizures • Aspiration pneumonitis/pneumonia • Anoxic brain injury • Rhabdomyolysis • Hyperthermia Xenobiotics associated with seizures Concentration Related Idiosyncratic Withdrawal Related Tonic-Clonic “seizure like” Antihistamines Buproprion Baclofen Strychnine Baclofen Carbamazepine Barbiturates Tetanospasm Monoxide Ergotamines Chloroquine (GHB) Ethanol Cicutoxin Mefenamic acid GHB Cyanide Tramadol Diphenhydramine Domoic acid Hypoglycemics Gyromitrin Lidocaine Organic phosphorus compounds Strychnine Sympathomimetics Thallium Theophylline • Which are the most frequent in practice?

• Poison centre surveillance studies • Antidepressants (34%), stimulants (15%), anticholinergics (10%) • Most common single drug was Buproprion (15%) Xenobiotics • One case series demonstrated that 32% of Buproprion ingestions result in seizures associated with seizures • Recreational drug use presentations to ED • Higher risk ingestions include fentanyl, synthetic cannabinoids • Lower risk including heroin, benzodiazepines, and cannabis • Higher rates of , cardiac arrest, intubation, intensive care admission and death in individuals who seized • Isoniazid • Depletes GABA profoundly • Severe and prolonged seizures • Antidote =

• Buproprion • Seizures reported with < double Tx dose • May cause status Special

• Baclofen considerations • Can cause seizures in BOTH overdose and withdrawal

• Phenytoin generally not recommended • Less efficacious for toxicant induced seizures • Higher risk of complications ABCs IV, O2, bloods, ECG, monitor Early IV benzodiazepines

Toxicologist ’s Consider specific antidotes: - Glucose Assess for possible xenobiotic approach to - Pyridoxine More benzodiazepines! exposure or withdrawal… the seizing - Hypertonic saline - Cyanokit patient

Rule out other organic cause or Barbiturates, propofol, R/o other toxic ingestion (APAP complication intubation… etc.), optimize metabolically, Post Pre next seizure seizure • Multiple direct and indirect causes for seizures seen in toxicology • Extension of toxic agitation • Overlap over many toxidromes Summary • Basics of care are the same • High dose benzodiazepines early, avoid Phenytoin to be safe • Few critical diagnoses that require specific antidotes References

• Wolfe, C. et al. Seizures as a complication of recreational drug use: Analysis of the Euro-DEN Plus data-set. Neurotoxicology, 2019: 183-187. • Sharma, A. and Hoffman, R. Toxin-related seizures. Emerg Med Clin North Am., 2011: 125-139. • R.J. DeLorenzo, W. A. Hauser, A. R. Towne, J. G. Boggs, J. M. Pellock, L. Penberthy, L. Garnett, C. A. Fortner, D. Ko. A prospective, population-based epidemiologic study of status epilepticus in Richmond, Virginia. Neurology Apr 1996, 46 (4) 1029-1035. • Goldfrank’s Toxicologic Emergencies, 11th edition. Nelson LS, Howland MA, Lewin NA, Smith SW, Goldfrank LW, and Hoffman, RS, eds. McGraw-Hill Education, New York, 2019.