Clinical Pharmacology

"Adverse Drug Event of the month"

A patient of malaria with convulsions: Probable chloroquine induced seizure

Case report:
A 27-year-old male normotensive, nondiabetic, smoker was admitted with complaints of low to moderate grade fever, headache and chills for 7 days. At the time of admission, he was well oriented, conscious with no history of epilepsy or alcohol abuse. The thick peripheral blood film was positive for Plasmodium vivax. He was treated with chloroquine (25mg/kg/day) over 3 days, along with symptomatic treatment. On day 4 he suddenly developed difficulty in finding the words and began to stammer which lasted for an hour followed by two episodes on generalized tonic - clonic convulsions which lasted for approximately 5 minutes. A bolus of 5 mg of diazepam injection was administered slowly during the second episode. An EEG done on the same day did not show any abnormality.A diagnosis of chlroquine induced seizure was made. A causality analysis using the Naranjo's algorithm was done and the adverse event was scored at 7 out of a possible total of 13 (score for a probable adverse event being 5-8). He was afebrile and negative for malarial parasite from day 4 and remained free of symptoms. He was discharged on day 5 on phenytoin prophylaxis (200mg /day). A repeat history during discharge revealed that patient had single episode of seizure 10 years back, but was not put on any antiepileptic drug prophylaxis, which was not informed to the physician on admission. This patient was followed up till 1 month. EEG recorded on day 20 was normal and patient was weaned off phenytoin.

Discussion:
Chloroquine is the drug of first choice for Plasmodium vivax malaria. A number of case reports in medical literature have suggested an association between seizures and parenteral chloroquine, both at therapeutic concentrations and over dose 1. Seizures may occur within a few hours of overdose or between one day and several weeks after the start of therapy 1. Seizures complicate the clinical course of more than 30% of patients admitted to hospital for cerebral malaria and are associated with an increased risk of death and neurological sequelae 1. There are many explanations for seizures in malaria. The concentration of chloroquine within brain is approximately 4 times that of plasma due to high tissue binding and experimental evidence suggests that chloroquine may precipitate seizures by attenuation of gamma-ammino butyric acid pathways (GABA ergic mechanism) and enhancement of dopaminergic neurotransmission 2, 3, 4. Also fever itself almost a universal feature of malaria is known to precipitate seizures. Hypoglycemia, hyponatremia and cerebral hypoxia secondary to severe anemia and inadequate cerebral perfusion and past quinine treatment may also precipitate seizures 5, 6, 7. Episodes of convulsions have also been reported for other anti-malarials like quinine and mefloquine, antimicrobials like fluroquinolones and antiulcer agents like cimetidine 8, 9.

Although a possible causal (possible) relationship between the chloroquine and the occurrence of seizures is suggested, there are no reports of association between the concentration of chloroquine or its active metabolite, desethyl chloroquine 1. Hence it is not known whether this association is dose related or idiosyncratic phenomenon. Moreover the role of mental changes, psychoses, anxiety, lethality and personality changes have not been well studied. Even prophylactic chloroquine has also been observed to cause tonic - clonic convulsions and is therefore usually avoided in patients with epilepsy.

Conclusion:
Though there is no need to restrict the prescription of chloroquine in patients with history of epilepsy, the practicing physician should be aware of possible occurrence of neuropsychiatric adverse events like convulsions during the treatment of malaria with chloroquine, especially in predisposed subjects and should critically elicit the information on history of epilepsy. Chloroquine induced seizures respond well to benzodiazepine drugs like diazepam, clonazepam and barbiturates like Phenobarbitone.

References
1. Jane Crawley, Gilbert Kokwaro, David Ouma, William Watkins and Kevin Marsh Trop Med & Int Health 2000; 12: 860.

2. Amabeoku G Involvement of GABAergic mechanisms in chloroquine-induced seizures in mice. Gen Pharmacol 1992; 23: 225- 9.

3. Amabeoku GJ & Chikuni O Chloroquine-induced seizures in mice: the role of monoaminergic mechanisms. EurNeuropsychopharmacol 1993; 3:37-44

4. Amabeoku GJ & Chikuni O GABAergic and dopaminergic systems may be involved in seizures induced by pyrimethamine in mice. Gen Pharmacol 1994; 25:1269-77.

5. Crawley J, Smith S, Kirkham F, Muthinji P, Waruiru C, Marsh K Seizures and status epilepticus in childhood cerebral malaria. Quar JrMed 1996; 89: 591-7.

6. White NJ, Miller KD, Marsh K et al. Hypoglycaemia in African children with severe malaria. Lancet 1987; 1:708-11

7. English MC, Waruiru C, Lightowler C, Murphy SA, Kirigha G, Marsh K Hyponatraemia and dehydration in severe malaria. Arch Dis Child 1996; 74: 201-5.

8. Heeringa M, Kuster JA, Meyboom RH, Bouvy M Convulsions during prophylactic use of mefloquine Parminerva Med 1999; 30:2477-80.

9. Amabeoku GJ & Chikuni O Cimetidine -induced seizures in mice. Antagonism by some GABAergic agents. Biochem Pharmacol 1993; 14:2171-5.

Departments of Clinical Pharmacology & Medicine
Seth GS Medical College and KEM Hospital,
Parel,
Mumbai 400 012