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Clinical Neurotoxicology: A Focus on Drug-induced Seizures

By Currents Editor posted 08-24-2020 10:23

  

By Anthony Jaworski, PharmD, BCCCP 

A reported 6% of new onset seizures and 9% of status epilepticus cases are attributed to drug neurotoxicity.1,2 Over the years, there has been a decline in cases of seizures from cocaine, theophylline and tricyclic antidepressant (TCA) toxicity. There are increasing reports of seizures from newer antidepressants, such as bupropion in the United States and citalopram in Switzerland. In Iran and Australia, the trend in tramadol poisonings are increasing, and seizure is a common complication.  In developing countries, insecticides are most often implicated in seizures related to toxins.3 A partial listing of toxins that can precipitate seizures are included in the mnemonic PLASTIC (Table 1).  

Table 1: Drugs and Chemicals That Cause Acute Seizures4

P

Phencyclidine, pesticides, phenol, propoxyphene

L

Lead, lithium, lindane, local anesthetics

A

Antidepressants, antipsychotics, anticonvulsants, antihistamines, abstinence syndrome

S

Salicylate, sympathomimetic, strychnine, solvents, shellfish (domoic acid)

T

Theophylline, tricyclic antidepressants, thallium, tobacco (nicotine)

I

Isoniazid, insulin (and other causes of hypoglycemia), insecticides

C

Camphor, cocaine, cyanide/carbon monoxide, chloroquine, cyclonite, cicutoxin

 

While drug-induced neurotoxicity may manifest through various mechanisms (Table 2), this article focuses on neurotoxicity of select medications that cause sodium channel dysregulation. Although reports of seizures from this type of neurotoxicity have declined, high complication and fatality rates warrant rapid identification and appropriate management.  

When drug-induced seizures are suspected, identification of the toxidrome through a complete patient history and diagnostic testing (including serum and urine toxicology screenings, electrocardiography and comprehensive metabolic panels) is necessary. Oftentimes, toxins are not identified at the onset of seizures. A general rule in managing seizures resulting from suspected overdose is to avoid phenytoin, which has been shown to lower seizure threshold in local anesthetic, cocaine, theophylline and lindane toxicity. Instead, benzodiazepines and other anticonvulsants that potentiate GABA (ie, phenobarbital, propofol) are considered most appropriate in managing drug-induced seizures.5

Table 2: Mechanisms of Drug-Induced Seizures5

 

Gamma-aminobutyric acid (GABA)

Sodium Channels

Norepinephrine/ Serotonin

Acetylcholine

Metabolic Disturbances

Description

Loss of GABA-mediated inhibitory pathways

Sodium channel blockade and membrane destabilization

Autonomic overstimulation

Cholinergic overstimulation

Disruption in glucose and electrolyte homeostasis

Examples

Alcohol, benzodiazepine withdrawal

Local anesthetics, carbamazepine, bupropion

Selective serotonin reuptake inhibitors

Organophosphate and carbamate pesticides, nerve agents

Hypoglycemia, hyponatremia

 

Seizures induced by sodium channel blockade are seen with TCAs, bupropion, first-generation antihistamines and local anesthetics (including cocaine). In TCA toxicity, QRS widening on electrocardiography has a specificity and sensitivity of 0.69 for predicting seizure, arrhythmias and death.6 Though TCA serum levels may better predict seizures, they are not widely available. In practice, a QRS >100 ms warrants immediate serum alkalization (i.e. pH 7.45 to 7.55) with sodium bicarbonate to increase the sodium gradient and prevent seizures. Despite differences in chemical structure, bupropion toxicity is treated the same way. In severe local anesthetic toxicity, supportive care and benzodiazepines are recommended for seizure management, though propofol theoretically may be beneficial due to the lipid emulsion preparation.5 Intravenous lipid emulsion plays a role in managing cardiotoxicity from fat-soluble drugs (eg, local anesthetics, bupropion, TCAs, central acting beta-blockers) and evidence suggesting its role in neurotoxicity is extremely limited. Despite this, the sequestering of fat-soluble drugs in the vasculature (“lipid sink theory”) may prove beneficial in reducing the amounts of circulating drug.

In light of recent use during the COVID-19 pandemic, attention has been drawn to toxicity from chloroquine and hydroxychloroquine. Massive ingestions lead to sodium membrane blockade and intractable seizures that, together with ventricular dysrhythmias, result in death.  Unfortunately, the minimal doses that precipitate seizures are not well defined, though ingestions of 5 g chloroquine and 4 g hydroxychloroquine have been reported to cause severe symptoms.  In children, as little as 10 mg/kg (1 to 2 tablets) of chloroquine requires medical evaluation. During the pandemic, cases of poisoning and death have been reported with self-medication of chloroquine tablets and chloroquine phosphate, used for treating aquariums. Successful management with high-dose diazepam (2 mg/kg) has been reported. Some evidence suggests that diazepam, unlike other benzodiazepines, may displace chloroquine from cardiac sodium channels, adding potential cardiac benefits.7,8 As with other sodium channel inhibitors, correcting a widened QRS with serum alkalization is warranted.

Special circumstances exist where specific antidotes should be considered (Table 3). Adequate stocking of specific antidotes is essential, considering that reports of adverse outcomes linked to inadequate access exist.10 Best practice standards set by the Institute for Safe Medication Practices suggest hospitals need to ensure the availability of antidotes.11 Guidelines from the American College of Emergency Physicians outline antidote stocking recommendations.12 Where available, poison centers provide information for managing toxicology cases and offer patient-specific toxicology consults which offer clinical recommendations and assistance with antidotes when appropriate.

Table 3: Treatments and Antidotes for Select Neurotoxins

Toxin

Therapy

Carbon monoxide

Hyperbaric oxygen

Insulin

Dextrose

Isoniazid

Pyridoxine

Lead

BAL(Dimercaprol), Calcium EDTA*

Lithium

Hemodialysis**, maintaining eunatremia

Organophosphate insecticides/nerve agents

Atropine/pralidoxime

Sulfonylureas

Dextrose ***, octreotide

*Not to be confused with Sodium EDTA, which is utilized in severe hypercalcemia.

**If kidney function is impaired and [Li+]>4mEq/L OR in the presence of decreased level of consciousness or seizures (EXTRIP Guidelines)9

***Excessive intravenous dextrose may stimulate endogenous insulin production, contributing to subsequent hypoglycemia

  

References

  1. Pesola GR, Avasarala J. Bupropion seizure proportion among new-onset generalized seizures and drug related seizures presenting to an emergency department. J Emerg Med. 2002;22:235-9.
  2. Lowenstein DH, Alldredge BK. Status epilepticus at an urban hospital in the 1980s. Neurology 1993; 43:483-8.
  3. Chen H, Albertson TE, Olson KR. Treatment of drug-induced seizures. Br J Clin Pharmacol. 2016;81(3):412-19.
  4. Osterhoudt KC, Henretic FM. A 16-year-old with recalcitrant seizures. Pediatric Emergency Care. 2012;23(3):304-6.
  5. Wills B, Erickson T. Chemically induced seizures. Clin Lab Med. 2006;26:185-209
  6. Bailey B, Buckley NA, Amre DKA. Meta-analysis of prognostic indicators to predict seizures, arrhythmias or death after tricyclic antidepressant overdose. J Toxicol Clin Toxicol 2004;42(6):877–88.
  7. Chary MA, Barbuto AF, Izadmehr S, et al. COVID-10: Therapeutics and their toxicities. J Med Toxicol. 2020;16(3):284-294.
  8. Koudogbo B, Asseko MC, Nguemby M, et al. Mode of antidotal action of diazepam in the treatment of chloroquine poisoning. J Toxicol Clin Exp. 1986;6(5):307-12.
  9. Decker B, Goldfarb DS, Dargan PI, et al. Extracorporeal treatment for lithium poisoning: systemic review and recommendations from the EXTRIP workgroup. Clin J Am Soc Nephro. 2015;10(5):875-7.
  10. Minns AB, Ghafouri N, Clark RF. Isoniazid-induced status epilepticus in a pediatric patient after inadequate pyridoxine therapy. Pediatr Emerg Care. 2010;26(5):380-1.
  11. Institute for Safe Medication Practices. Best practice 9: 2020-2021 ISMP targeted medication safety best practices for hospitals. 2020
  12. Dart RC, Goldfrank LR, Erstad BL, et al. Expert consensus guidelines for stocking of antidotes in hospitals that provide emergency care. Ann Emerg Med. 2018;71(3):314-25.

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