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Oct 21, 2010 - Data concerning neurological safety in adults and children treated with mefloquine and ... Malaria is an important cause of infant morbidity and.
Frey et al. Malaria Journal 2010, 9:291 http://www.malariajournal.com/content/9/1/291

RESEARCH

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Artesunate-mefloquine combination therapy in acute Plasmodium falciparum malaria in young children: a field study regarding neurological and neuropsychiatric safety Sarabel G Frey1*, David Chelo2, Mina N Kinkela2, Florence Djoukoue2, Felix Tietche2, Christoph Hatz3, Peter Weber1

Abstract Background: Mefloquine-artesunate combination therapy for uncomplicated falciparum malaria is one of the treatments used in African children. Data concerning neurological safety in adults and children treated with mefloquine and artesunate combination therapy is well documented in Asia. Safety data for neurological and neuropsychiatric side effects of mefloquine and artesunate combination therapy in African children are scarce, although WHO recommends this therapy in Africa. Methods: A phase IV, open label, single arm study was conducted among African children between 10 and 20 kg with acute uncomplicated falciparum malaria. They were treated over three consecutive days with a paediatric fixed-dose combination of artesunate (50 mg/d) and mefloquine (125 mg/d). Parasitological, clinical and neurological examinations and standardized questions about neuropsychiatric symptoms were carried out on days 0, 4, 7, 28 and 63. The primary objective was to assess the neurological and neuropsychiatric safety of artesunatemefloquine combination therapy in young children. Results: From December 2007 to March 2009, 220 children with uncomplicated Plasmodium falciparum malaria were treated with artesunate and mefloquine. 213 children were analysed according to study protocol. 50 neurological and neuropsychiatric adverse events occurred in 28 patients. Eleven drug-related neurological and neuropsychiatric adverse events occurred in eight patients. Sleeping disorders were present in 2.3%, neurological disorders in 1.4%, neuropsychiatric disorders in 1% and eating disorders in 0.5% of the patients. Adverse events were of mild to moderate intensity and resolved spontaneously. Conclusion: African children showed a low percentage of self-limited neurological and neuropsychiatric adverse events, confirming studies on neurological safety in Asian children treated with artesunate and mefloquine. Sleeping disorders were most frequently observed.

Background Malaria is an important cause of infant morbidity and mortality in African children, especially in young children who lack immunity. According to the World Health Organization (WHO), 36% of African children of 3.5 y), dysaesthesia (only >3.5 y), insomnia, nightmares (only >5 y), hyperactivity, anxiety, panic attacks, sadness, mood changes, confusion, aggressive behaviour, tension, visual hallucinations, acoustic hallucinations (only >3.5 y), hearing loss, dysarthria, word-finding disturbance (only >3.5 y), eating behaviour and swallowing disturbance. Questions were addressed to the guardian with specific questions to the child him/herself. To avoid misunderstanding or misinterpretation, all investigators used the same terms to ask those questions. The neurological examination covered twelve items: tremor, dystonia and ataxia, hyperreflexia, hyporeflexia, clonus, dysdiadochokinesis, disturbed vision, nystagmus, double vision, acoustic acuity, forgetfulness, and wordfinding disturbance. For this exam investigators were equipped with an examination set containing a description of the examination process, a reflex hammer, a lamp

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and a Lang Stereo Vision test (item disturbed vision), five coloured building blocks (item forgetfulness), a toy car (item word-finding disturbance), and a Denver Developmental test. Tremor, dystonia and ataxia, hyperreflexia, hyporeflexia, clonus, dysdiadochokinesis, nystagmus, double vision and acoustic acuity were tested doing a standard paediatric neurological examination based on Touwen [7]. Word-finding disturbance was tested by showing the child a toy car, a bird (or telephone), a key, a pen, a chair and asking to name the object. A score of “NOT present” for word-finding disturbance was given if the child could name all objects promptly. Some exams/questions were age restricted to certain age limits or modified according to the age of the child. Item forgetfulness was tested in children younger than 3.5 years by presenting the child 3 coloured building blocks in a given order and letting the child repeat the placement after mixing the building blocks. Forgetfulness in children older than 3.5 years was tested by enumerating number groups. To begin the test, the child had to repeat two groups of two digits, then two groups of three digits, then two groups of four digits, then two groups of five digits. During the baseline visit, it was recorded whether a 2digit, 3-digit, 4-digit or 5-digit group could be repeated, and a score of one point per correct repeat was given. During follow-up visits, the forgetfulness was recorded as “present” if there was a decrease in the digit group that could be repeated. For example, if a child was able at baseline to repeat a 4-digit group but could not repeat a 3-digit group on day 28, this was marked as presence of forgetfulness. This procedure was chosen in accordance with tasks from cognitive tests such as Hamburg Wechsler Intelligence Test for Children [8] or Kaufman-Assessment Battery for Children [9]. Children could refuse to participate. If the exam could not be performed investigators scored this with “not done”. Otherwise questions were scored with “yes (disorder present) “ or “no (disorder not present) “ at baseline. In the follow-up visits questions were scored with “no (disorder not present) “ or “yes (disorder present, still the same)” or “yes (disorder present, improved)” or “yes (disorder present, worsened or new)” in which case an adverse event was reported. The option “not done” was chosen if the child was not cooperating. All children were followed up for fever and parasite clearance irrespective of their participation in neurological and neuropsychiatric examinations. Only the appearance of new symptoms - occurring after baseline - was evaluated as an adverse event. If a child was already hyperactive before taking the study

Frey et al. Malaria Journal 2010, 9:291 http://www.malariajournal.com/content/9/1/291

medication, this was not considered as an adverse event at the next study visit, if it was still present. But if hyperactivity appeared newly afterwards during the study course or worsened during two visits, it was reported as an adverse event. The clinical neurological and neuropsychiatric examination is based on standard paediatric neurological examination (based on Touwen [7]); the questionnaire was adapted to symptoms recorded in adults during mefloquine treatment or prophylaxis. With respect to the absence of a standardized test for paediatric neurological and neuropsychiatric evaluation in this age group in a resource-poor setting, the Division of Child Neurology of the University Children’s Hospital of Basel, Switzerland, developed the examination setting used in this study. Laboratory procedure

Laboratory procedures have been described elsewhere [10]. Concomitant medication

Concomitant medication was recorded; children taking other malaria treatments due to a new malaria episode completed all visits up to day 63, but evaluation for neurological and neuropsychiatric events was only validated until the day beginning the concomitant malaria medication. Statistical methods for evaluating neurological and neuropsychiatric safety

Only children who took at least one dose of study medication and who had the neuropsychiatric and neurological exam at least at baseline and day 7 or had a drugrelated neurological or neuropsychiatric adverse event were included in the statistical evaluation of neuropsychiatric and neurological safety. The proportion of adverse events was calculated as well as the confidence interval.

Results Study participants

From December 2007 to March 2009, 220 children with uncomplicated P. falciparum malaria were included in the study, of which 184 children (83.6%) concluded the study according to protocol. 3,800 children had been screened (including blood smear), 220 met the inclusion criteria; 94% were not included because of negative blood smear or parasite count less than 2,000 (amended to 1,000 μl of blood) or more than 250,000. Data from 213 patients were analysed for neuropsychiatric and neurological safety. Two patients were classified as early treatment failure; five patients had no follow-up visits

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and were not evaluable for neuropsychiatric and neurological safety. The youngest child included was seven months old; the oldest seven years and nine months. The mean age was three years and four months. (27 children were younger than 1.5 years, 104 children were between 1.5 and 3.5 years, 51 children were 3.5 to 5 years old and 31 children were older than 5 years). Gender distribution was equal: 104 boys (48.8%) and 109 girls (51.2%) participated in the study. Neurological and neuropsychiatric outcome (safety)

Fifty neuropsychiatric and neurological adverse events occurred in 28 children (13%). Eleven neuropsychiatric and neurological adverse events in eight children (out of 213; 5.16%) were related to the study medication. (Table 1 and Figure 1). The frequency of the occurrence of at least one neuropsychiatric and neurological adverse event related to the study medication was 3.77%, (95% CI 1.6-7.3%). The age distribution of drug-related neuropsychiatric and neurological adverse events did not reveal any differences (age group