Chloroquine-induced Acute Dystonic Reactions after a Standard Therapeutic Dose for Uncomplicated Malaria

Acute dystonic reactions (ADR) are extrapyramidal effects that usually occur after the initiation of a wide variety of drugs or triggering factors besides neuroleptics. We report the case of a 54-year-old man who was admitted with an approximately 10-hour history of muscle twitching around the eyes, face and neck after he took the first dose of oral chloroquine phosphate (1 g [600 mg base]) prescribed for uncomplicated malaria. He was given intravenous diazepam (10 mg statum) followed by 10 mg of oral diazepam 3 times a day. The symptoms improved within 30 minutes of treatment, and he was discharged 14 hours later after a complete recovery.

Chloroquine-induced Acute Dystonic Reactions after a Standard Therapeutic Dose for Uncomplicated Malaria *Olusegun A. Busari, 1 Joseph Fadare, 1 Segun Agboola, 2 Olusegun Gabriel, 2 Olayide Elegbede, 2 Yusuf Oladosu 2 online case report A cute dystonic reactions (ADR) are extrapyramidal side effects (EPSE) that usually occur after the initiation or a rapid increase in the dose of neuroleptic drugs. 1 However, the reactions may occur with a wide variety of drugs or triggering factors besides neuroleptics. 2,3ADRs are characterised by the intermittent spasmodic or sustained involuntary contractions of muscles in the face, neck, trunk, pelvis and extremities. 4hey are often not life-threatening, but can cause great discomfort, producing significant anxiety and distress for patients, and may seriously disturb the relationship between the doctor and the patient. 5hloroquine (CQ), a 4-aminoquinoline drug used for both the prevention and treatment of malaria, was discovered in 1934 and introduced into clinical practice in 1947. 5It has been largely replaced by the newer artemisinin-based combination therapy (ACT) as the first line of treatment for uncomplicated malaria due to Plasmodium falciparum.0][11] Thus, CQ still remains a frequently used drug in the treatment of uncomplicated malaria in sub-Saharan Africa.][14] Extrapyramidal syndrome (EPS) following CQ therapy has been reported in the past. 15,16However, in our setting, CQ-induced ADR is very rare.This case report describes an occurrence of ADR in a middle-aged man after commencing a standard dose of oral CQ phosphate for parasitologicallyconfirmed uncomplicated malaria.

Case Report
A 54-year old man was brought to the emergency room (ER) of the Federal Medical Centre, Ido-Ekiti, Nigeria, with a complaint of involuntary muscle twitching around the eyes, face and neck which had started approximately 10 hours prior to presentation.He was experiencing difficulty in speaking and an abnormal posturing of the neck.There was no fever, dizziness, altered consciousness, photophobia or weakness of the limbs.He had been diagnosed with parasitologically-confirmed uncomplicated malaria about 18 hours previously and had immediately been given oral CQ phosphate BP (1 g CQ phosphate [600 mg base]) to be followed by 500 mg (300 mg base) at 6, 24 and 48 hours.The presenting complaint had started within 8 hours of the first dose of CQ.He was not on any other drugs, food or herbal preparations.There was no past history of similar complaints or of any transient ischaemic attack, and he had neither a family history of dystonia nor a history of alcohol ingestion, cigarette smoking or use of illicit drugs such as cocaine.
A general examination revealed an anxious middle-aged man with facial muscle twitching and facial grimace.Other aspects of the general examination were unremarkable.A central nervous system examination showed a fully-conscious man who was well-oriented in time, place and person.There were neither signs of meningeal irritation nor asterixis.There was no cognitive impairment and no cranial nerve palsy.Deep tendon reflexes and tones were also normal.All other systems were grossly normal.All baseline investigations, which included complete blood counts, serum electrolytes, urea and basic urea nitrogen, liver enzymes and function tests, random and fasting blood glucose, and a serum lipid profile, were within normal limits.His resting electrocardiogram was also normal.A peripheral blood smear study for malaria parasites by light microscopy of thick and thin stained blood showed trophozoite and schizont forms of P. falciparum.
A clinical diagnosis of ADR secondary to CQ was made.The drug was discontinued and the patient was treated with intravenous diazepam (10 mg statum followed by 10 mg oral diazepam three times a day).An intravenous access line was also secured and a maintenance dose of an intravenous infusion of isotonic saline was administered.The symptoms improved rapidly within 30 minutes of commencing treatment and the patient was discharged after about 14 hours of admission with complete recovery.He remained well at follow-up one week later.

Discussion
The therapeutic index for CQ is small. 17However, at a standard dose for malaria treatment, the common adverse effects include gastrointestinal problems, headaches, nightmares, blurring of vision and itching.An ADR due to the use of CQ is very rare and there is a paucity of data on it in the literature. 18Achumba et al. reported a case of ADR after a single dose of CQ in a postoperative patient and in the presence of metronidazole. 19he reported case suggested that the ADR might have been an idiosyncratic reaction and probably potentiated by the metronidazole.In our case, the ADR also occurred after a single dose of CQ but in the absence of any other medications.Although ADRs occasionally are dose-related, they are more often idiosyncratic and unpredictable. 19r most drugs that often cause ADR, particularly the neuroleptics, the pathophysiology is a drug-induced alteration of dopaminergiccholinergic balance in the nigrostriatum.They produce ADR by a nigrostriatal dopamine D2 receptor blockade, which results in an excess of striatal cholinergic output. 20The pathophysiological mechanism underlying CQ-associated ADR is not well-known.However, it has been linked to a reduction in forebrain catecholamine levels and an inhibition of neuronal calcium uptake. 19This hypothesis could be supported in part by the effectiveness of benzodiazepines in the reversal of CQ-associated ADR.A normal balance between dopamine and acetylcholine in the basal ganglia involves modulation from gamma aminobutyric acid (GABA)-containing striatonigral neurons.GABA-ergic neurons are inhibitory and antagonise excitatory dopaminergic neurons.[21][22]

Conclusion
Although CQ-induced ADR is a very rare adverse effect, it can be confused with other medical conditions in the ER such as a seizure disorder or a transient ischaemic attack.A detailed historytaking remains pivotal, particularly the medication history, which should be obtained from others if the patient is not able to speak.ADRs occur very rarely in CQ use; thus, its prophylaxis is unnecessary and also not feasible.However, the treatment is usually straightforward and nearly always effective.