DRUG AND TOXIN INDUCED SEIZURES

George Braitberg
Emergency Medicine, Monash University, Department of Medicine. Southern Health,
Dandenong Hospital, David Street, Dandenong Victoria 3175, Australia

Both drugs and toxins can cause seizure. In these cases the usual management my not
alleviate the seizures and treatment specific to the toxin may be required. In this talk we will
review various causes of toxin and drug-induced seizures and their treatment.
1. List the toxins and drugs that may cause seizures
2. Discuss the evaluation and treatment of these patients.

There are primary and secondary mechanisms of seizure. Primary mechanisms refer to the
properties of a substance that directly affect the central nervous system (CNS). Typical
examples include stimulants, isoniazid, theophylline etc. Medication withdrawal causes primary
seizures as in alcohol withdrawal seizures (e.g. excessive stimulation of primed NMDA
receptors or up regulation of receptors)1. Secondary seizures occur as a result of impaired
substrate availability or utilization: hypoxia (e.g. opiates), blockade of oxygen utilization (e.g.
carbon monoxide, cyanide), reduced oxygen carriage capacity (e.g. methemoglobinemia,
anaemia), cerebral oedema, lack of energy (uncoupling of oxidative phosphorylation - salicylate
or dinitrophenol), or disturbances of glucose and electrolyte metabolism2. Seizures can occur
when serum sodium falls below 115 mmol/L (115 mEq/L) or where there is a rapid decrease in
sodium concentration, which may occur following the use of ecstacy3. Hypernatraemia may
also lead to seizures, as can hypomagnesemia and hypocalcaemia4.
In the setting of suspected ingestion, the differentiation of seizure and convulsion may be
important. Seizure refers to an episode of abnormal neurologic function caused by an abnormal
electrical discharge of neurons. The seizure is the ictus and the post-seizure period is the post-
ictus. The term convulsion refers to an episode of excessive or abnormal motor activity.
Convulsions may occur with seizures but also in the absence of central ictal activity5. A number
of toxidromes cause both myoclonic jerking and seizure, such as serotonergic syndrome,
sympathomimetic overdose or tricyclic antidepressant (TCA) poisoning. The myoclonic jerks

1
Curry SC, Mills KC and Graeme KA. Neurotransmittter. In Goldfranks Toxicologic Emergencies. Goldfrank L,
Flomenbaum N; Lewin, Howland M, Hoffman R, Nelson L (eds). Seventh Edition. Chapter 10:137-171
2
Delanty N, Vaughan CJ Frnch JA. Medical causes of seizures. Lancet. 1998;352(9125):383-390
3
Traub SJ, Hoffman RS and Nelson LS. The ecstasy hangover: Hyponatremia due to 3,4-
Methylenedioxymethamphetamine. J Urban Health. 2002;79(4):549-555
4
Whang R Hampton EM Whang DD. Magnesium homoestasis and clinical disorders of magnesium deficiency.
Ann Pharmacother . 1994;28:220-226
5
Wilkes GR in Textbook of Emergency Medicine. Cameron P, Jelinek G, Kelly AM, Murray L and Heyworth J
(eds) Chuchill Livingstone. Edinburgh. 2000:293-299
caused by strychnine are often regarded and treated as seizures. Strychnine acts as a
selective, competitive antagonist of glycine at its postsynaptic receptors in the spinal cord and
brain stem, causing uncontrollable muscle action, without generally causing seizure1.
The incidence of drug induced seizures is unknown. Estimates range from 0.08%6,7 to an
estimated that 6.1% of new onset seizures8. There is very little data available about the
epidemiology of drug induced seizures although it is well acknowledged that many drugs lower
the seizure threshold and cause seizures in poisoning, interaction and withdrawal. Alldredge et
al9 reported an incidence of 0.3% of recreational drug abuse related medical complications. In a
recent article Thundiyil et al10 examined 386 cases of drug induced seizure reported to the
Californian Posion Control System in 2003. Of the 386 cases identified, buproprion was the
leading cause (23%), followed by diphenhydramine (8.3%), tricyclic antidepressants (7.7%),
tramadol 7.5%, amphetamines (6.9%,), isoniazid (5.9%) and venlafaxine (5.9%). In their area
they noted a decline in tricyclic antidepressant overdoses (while there was an overall increase in
the total number of antidepressant overdoses).
In a study on psychoptropic medication, it appears that in general, the epileptogenic risks of the
newer psychotropic agents appear to be quite low as long as dosing strategies are consistent
with recommended guidelines11.
Seizures occurred in 9% of patients who received high-dose phenothiazines12.
Seizures are associated with poor outcome. In one study13, sixteen percent of patients with
aspiration pneumonitis had a seizure, compared with only 2% of patients without (p < 0.001).
Specific drugs
Cocaine and other stimulants
Cocaine was reported to cause seizures in 29 of 989 patients (3%)14. The interval ranged from
a few minutes (usually after IV use) to 12 hoursError! Bookmark not defined.. In humans,

6
Alldredge BK. Seizure risk associated with psychotropic drugs: clinical and pharmacokinetic considerations.
Neurology. 1999;53(5) Supp 2:S68-S75
7
Porter J, Jick H. Durg induced anaphylaxis, convulsions, deafness and extrapyramidal symptoms. Lancet
1977;1:1582-1586
8
Pesola GR and Avardarala J. Buproprion seizure proportion among new onset seizures and drug related seizures
presenting to an emergency department. J Emerg Med. 2002;22(3):235-239.
9
Alldredge BK, Lowestein DH Simon RP. Seizures associated with recreational drug abuse. Neurology
1989;39:1037-1039
10
Thundiyil JG, Kearney TE and Olsen KR. Evolvong epidemiology of Drug induced seizures reported to a Posion
Control Center System. J Med Toxicol. 2007;3(1):15-19
11
Lee KC. Finley PR. Alldredge BK. Risk of seizures associated with psychotropic medications: emphasis on new
drugs and new findings. Exp Opinion Drug Safety. 2003;2(3):233-47
12
Logothetis J. Spontaneous epileptic seizures and electroencephalographic changes in the course of phenothiazine
therapy. Neurology 1967;17:869-877
13
Isbister GK. Downes F, Sibbritt, DBM et al. Aspiration pneumonitis in an overdose population: Frequency,
predictors, and outcomes. Crit Care Med. 2004; 32(1):88-93
14
Zaccara G, Muscas GC Messori A. Clinical Features, Pathogenesis and Mangement of Drug-Induced seizures.
Drug Safety 1990;5(2):109-151
amphetamine induced seizures are also more likely to occur after IV use9. Williams et al15
found that methylenedioxymethamphetamine (MDMA) was associated with seizures when used
with other recreational drugs. Of 48 consecutive MDMA cases, 3 had seizures (6.3%) and 32
patients reported concurrent use of other illicit drugs or alcohol. None of the 16 patients who
used MDMA alone had a seizure.
Antidepressants
Amoxapine was associated with seizure in over 25% of cases reported to poison centres16.
Overall, the rate is estimated rate of cyclic antidepressant induced seizure ranges from 4 to
20%17,18. Apart from amoxapine, TCA-related seizures are almost always accompanied by
widened QRS duration on 12 lead electrocardiogram (ECG). A QRS duration of 0.10 seconds
or longer was moderately predictive of seizures and an interval of 0.16 seconds or longer was
highly predictive of seizures19. Cyclic antidepressant overdoses are more likely to have
multiple or prolonged seizures, which often have abrupt onset and are more likely to die20.
Minimal potential are the monoamine oxidase inhibitors such as tranylcypromine (Parnate),
which may have anticonvulsant properties. Fluoxetine has been reported to cause seizure21.
The selective serotonin reuptake inhibitors and monoamine oxidase inhibitors are more likely to
cause seizures in the setting of serotonin syndrome22.
Lithium
Seizure is one of the serious neurologic effects of lithium toxicity. The effect of lithium on the
EEG is characterized by abnormal generalized slowing and paroxysmal diffuse alpha activity.
These changes usually occur with supratherapeutic serum levels, but occasionally at moderate
or even low concentrations23. In acute overdose, there is a good correlation between

15
Williams H, Dratcu L Taylor R. Roberts M, Oyesfeso A. Saturday night fever: ecstasy related problems in a
London accident and emergency department. J Accid Emerg Med 1998;15:322-326
16
Pimental L and Trommer L. Cyclic Antidepressant overdoses. A review. Emergency Medicine Clinics of North
America. 1994;2:533-547
17
Wedin GP, Odra GM, Klein-Schwartz W et al. Relative Toxicity of cyclic antidepressants. Ann Emerg Med.
1986;15:797
18
Starkey IR, Lawson AA. Poisoning with tricyclic and related antidepressants-a ten year review. Q J Med
1980;193:33-49
19
Boehnert mt Lovejoy FH. Value of the QRS versus the serum drug level in predicting seizures and ventricular
arrhythmias after an acute overdose of tricyclic antidepressants. N Eng J Med. 1985;313-474
20
Olsen KR, Kearney TE, Dyer JE, Benowitz NL, Blanc PD. Seizures associated with poisoining and drug
overdose. Am J Emerg Med. 1993;11:565-568
21
Braitberg G, Curry SC. Fluoxetine induced seizure after overdose. Ann Emerg Med 1995;26:234-237
22
Mills KC. Serotonin syndrome. A clinical update. Critical Care Clinics. 1997;13(4):763-83
23
Struve FA. Lithium specific pathological electroencephalographic changes: a successful replication of earlier
investigative results. Clinical Electroencephalography. 18\987;18:46-53
symptoms and steady state serum levels24. Serum levels are less predictive of seizures in
chronic lithium toxicity25.
Theophylline
Theophylline induced seizures may be prolonged, difficult to control and associated with poor
outcome. Eldridge26 demonstrated the deleterious effect of theophylline as an adenosine
antagonist in a cat seizure model. There are two alternating phases of electrical activity in
humans and animal models of status epilepticus. High frequency spikes associated with high
cerebral oxygen consumption alternate with interictal periods of isolated spike activity. This
spontaneous self termination is mediated by adenosine1. Theophylline antagonises adenosine
A1 and A2 receptors, preventing cessation of seizures and increasing cerebral metabolism and
hypoxia27.
Anticholinergic Agents
Thundiyil et al10 identified diphenhydramine second only to buproprion as leading cause of drug
induced seizures. These seizures tend to be brief in duration.
Isoniazid
Isoniazid (INH) toxicity causes seizures and severe metabolic acidosis. Through multiple
actions, INH and other hydrazines inhibit the gamma aminobutyric acid (GABA) mediated
inhibitory CNS pathways. Seizures may occur without warning, frequently as generalized tonic-
clonic or prolonged, and may be resistant to therapy.28
The immediate goal of treatment is to terminate convulsive activity and then reevaluate the
cause of seizure or convulsion. There are good data to support the initial use of benzodizepines
intravenously (IV) in patients with seizures and status epilepticus. Lorazepam and diazepam are
the most commonly recommended benodiazepines in the United States29,30,31 However

24
Hansen HE, Amdisen A. Lithium intoxication. Quarterly J Med. 1978;47:123-144
25
Okusa MD, Jovita LT. Clinical manifestations and management of Acute lithium intoxication. American Journal
of Medicine. 97(4): 383-9, 1994
26
Eldridge FL, Payadrfar D, Scott SC,Dowell RT. Role of endogenous adenosine in recurrent generalized seizures.
Exp. Neurol 1989;103;179-1850
27
Dragunow M. Adenosine receptor antagonism accounts for the seizure prolonging effects of aminophylline.
Pharmacol Biochem Behav. 1990;36:751-759
28
Nelson LG. Grand mal seizures following overdose with isoniazid. A report of 4 cases. Am Rev Resp Dis.
1965;91:600-604
29
Lowenstein DH, Alldredge BK: Status epilepticus. N Engl J Med 1998 Apr 2; 338(14): 970-6
30
Treiman DM, Meyers PD, Walton NY, et al: A comparison of four treatments for generalized convulsive status
epilepticus. Veterans Affairs Status Epilepticus Cooperative Study Group. N Engl J Med 1998 Sep 17; 339(12):
792-8
31
Bone RC. Treatment of Convulsive status epilepticus. Recommendations of the Epilepsy foundation of
Americas Working Group on Status Epilepticus. JAMA 1993;270(7):854-859
32
Chamberlain JM, Altieri MA, Futterman C, et al: A prospective, randomized study comparing intramuscular
midazolam with intravenous diazepam for the treatment of seizures in children. Pediatr Emerg Care 1997 Apr;
13(2): 92-4
midazolam, given IV, intramuscularly (IM), buccally or intranasally is also safe and efficacious.
In many parts of the world, clonazepam is used as the benzodiazepine of choice32.
Benzodiazepines act on their specific receptors on the GABAA- chloride ion channel.
Benzodiazepines increase the frequency of channel opening, whilst barbiturates increase the
duration of channel opening1.
Specific treatment
Recreational Drugs
Cocaine induced seizures were more likely to be controlled by pretreatment with
phenobarbitone, while methamphetamine induced seizures were better controlled with
diazepam and valproatei.
Isoniazid (INH)

INH and other hydrazines inhibit the formation of pyridoxal phosphate (PLP), a necessary
cofactor in GABA synthesis. Benzodiazepines and barbiturates bind to receptors on the
GABAA complex to increase the affinity of GABA for its receptor and increase the inhibitory
outflow of chloride ions. In the presence of INH poisoning, these anticonvulsants may be
ineffectual as GABA concentrations are low as a result of synthesis inhibition1. The
administration of pyridoxine is effective in terminating INH-induced seizures. If the amount of
pyridoxine ingested is unknown, the initial dose is 5 grams IV push. The dose may be repeated
once in 30 minutes. If the dose of INH is known, the dose of pyridoxine is gram for gram (e.g. 7
grams of INH is treated with 7 grams of pyridoxineii
Alcohol Withdrawal Seizures
Phenytoin does not prevent alcohol withdrawal seizures. Prospective studies indicate the same
rate of seizure in prospective placebo controlled trials.iii,iv A randomised double blind trial
comparing IV phenytoin with normal saline placebo after a witnessed alcohol withdrawal seizure
found the incidence of seizure to be about 20% in both groupsv. In contrast, a prospective
uncontrolled study of 62 patients in acute alcohol withdrawal showed that treatment with
phenobarbital decreased ED length of stayvi.
Theophylline
Pretreatment with a number of anticonvulsants in a rat model of theophylline toxicity
demonstrated the lack of effect of phenytoin when compared to clonazepam, diazepam,
phenobarbital and valproic acid. Theophylline brain or serum concentrations at onset of

32
Hanson GR, Jensen M, Johnson M, White, HS. Distinct features of seizures induced by cocaine and amphetamine
analogues. European J of Pharmacology. 1999.377:167-173
maximal seizures were not statistically different comparing phenytoin (or magnesium) to control.
Diazepam and clonazepam, phenobarbital or valproate significantly raised the concentration
required to produce seizurevii.
Tricyclic antidepressants
The use of phenytoin in a canine experimental model found that there were no differences in
multiple variables, including toxicity and the dose required to cause death. Further, there is
debate about the efficacy in human subjectsviii,ix,x Seizures in tricyclic antidepressants toxicity
should be treated be treated in the standard method.

ii
Wason S, Lacouture PG, Lovely FH: Single high-dose pyridoxine treatment for isoniazid overdose. JAMA 1981;
246:1102-1104.
iii
Alldredge BK, Lowenstein DH and Simon RP. Placebo controlled trial of Intravenous Diphenylhydantoin for
short term Treatment of Alcohol Withdrawal seizures. Am J Med 1989;87:645-648
iv
Chance JF. Emergency Department Treatment of Alcohol Withdrawal seizures with Phenytoin. Ann Emerg Med
1991;20:520-522
v
Rathlev NK DOnofrio GD, Fish SS Harrison, PM Bernstein E, Hossack RW, Pickens L. The lack of Efficacy of
Phenytoin in the prevention of recurrent alcohol related seizures. Ann Emerg Med 1994;23(3):513-518
vi
Young GP, Rores C, Murphy CM, Dailey RH. Intravenous Phenobarbital for Alcohol Withdrawal and
Convulsions. Ann Emerg Med 1987;16;847-850
vii
Hoffman J, Pinto E Gihar D. Effect of Pretreatment With Anticonvulsants on theophylline induced seizures in the
Rat. J Critical Care 1993;8(4):198-202
viii
Hoffman JR and McElroy CR. Drs. Hoffman and McElroy Respond. West J Med. 1981;134(5): 451452
ix
Callaham M. Alkalinization Therapy for Tricyclic Antidepressant Overdose. West J Med. 1981; 134(5): 450451
x
Callaham M, Schumaker H, Pentel P: Phenytoin prophylaxis of cardiotoxicity in experimental amitriptyline
poisoning. Pharmacol Exp There 1988; 245:216-220