An epidemic of dystonic reactions in central Africa

Abstract

In December, 2014, an outbreak of suspected meningitis was investigated in Ituri District, northeastern Democratic Republic of Congo (DRC). Ituri shares borders with Uganda and South Sudan, is well known for political instability, and houses a large displaced population with limited access to health care. Meningitis was suspected by health workers due to neck spasm, interpreted as neck stiffness. However, further investigations (see appendix for details) suggested that bacterial meningitis was not the cause of this outbreak. In the outbreak response that followed, participants provided verbal informed consent prior to interviews, lumbar puncture, and urine collection and the Government of DRC approved the outbreak investigation plan.

The epidemiological pattern of the outbreak (curve, age distribution, evolution) was atypical for meningitis, there were few clinical symptoms or signs of this disease (eg, fever or neck stiffness), and only four of 83 patients who underwent lumbar puncture had cerebrospinal fluid evidence of Neisseria meningitidis. Review of videos of patients by paediatric neurologists suggested facial-truncal dystonia, possibly secondary to drug administration.

Dystonic reactions were defined as the presence of at least one of the following symptoms: muscle spasm of the face, neck, or arm; oculogyric crises; and protrusion and retraction of the tongue.1 Between December, 2014, and August, 2015, 1029 admissions to Médecins Sans Frontières or Ministry of Health centres met the case definitions of dystonia or suspected meningitis; 930 patients had at least one episode of dystonia. 448 (48·2%) were male, 311 (33·4%) were younger than 5 years, 265 (28·5%) were aged 5–15 years, and 354 (38·1%) were older than 15 years. The median duration of admission was 3·7 days (range 1–10). 11 patients died, five of whom were younger than 5 years (see appendix for further details).

When the diagnosis of toxic dystonia, and not meningitis, was suspected, the strategy of investigation changed to a search for a toxic agent causing extrapyramidal reactions. The management of patients with dystonic reactions was modified, lumbar punctures were only performed for those with clear evidence of meningitis, use of empirical antibiotics was reduced, and biperiden was used to alleviate dystonia.

Toxicological analysis was performed on urine samples from nine patients with dystonia (February and March, 2015) and 39 medicines available in pharmacies or procured at a government health centre (March and June, 2015) at the Pharmacology-Toxicology Service, Hôpital Raymond Poincaré, Garches, France. Liquid chromatography coupled to diode array, tandem mass spectrometry, gas chromatography coupled to mass spectrometry, and Q-Exactive hybrid quadrupole-Orbitrap mass spectrometry were conducted on all urine and drug samples (appendix).

Haloperidol was detected in urine from all nine patients with dystonia (median urinary concentration 4 μg/L [range <1 to 49 μg/L]). Haloperidol was also detected in all of nine yellow tablets imprinted with the letters “AGOG” and labelled as diazepam (figure). The median haloperidol dose per tablet was 13·1 mg (range 9·5–19·9). 15 mg of haloperidol is 20–25 times the usual daily maximal recommended dose for a 5 kg child. No diazepam or other toxic substances were detected. No haloperidol was detected in the other 30 medicine samples, which all contained the appropriate active pharmaceutical ingredients. Six of the nine AGOG-marked tablets were obtained from patients with dystonia who had ingested them, and three tablets were bought in a pharmacy or procured at a government health centre.