Christoph Kaiser

Epilepsy in onchocerciasis endemic areas: systematic review and meta-analysis of population-based surveys.

Objective We sought to evaluate the relationship between onchocerciasis prevalence and that of epilepsy using available data collected at community level. Design We conducted a systematic review and meta-regression of available data. Data Sources Electronic and paper records on subject area ever produced up to February 2008. Review Methods We searched for population-based studies reporting on the prevalence of epilepsy in communities for which onchocerciasis prevalence was available or could be estimated. Two authors independently assessed eligibility and study quality and extracted data. The estimation of point prevalence of onchocerciasis was standardized across studies using appropriate correction factors. Variation in epilepsy prevalence was then analyzed as a function of onchocerciasis endemicity using random-effect logistic models. Results Eight studies from west (Benin and Nigeria), central (Cameroon and Central African Republic) and east Africa (Uganda, Tanzania and Burundi) met the criteria for inclusion and analysis. Ninety-one communities with a total population of 79,270 individuals screened for epilepsy were included in the analysis. The prevalence of epilepsy ranged from 0 to 8.7% whereas that of onchocerciasis ranged from 5.2 to 100%. Variation in epilepsy prevalence was consistent with a logistic function of onchocerciasis prevalence, with epilepsy prevalence being increased, on average, by 0.4% for each 10% increase in onchocerciasis prevalence. Conclusion These results give further evidence that onchocerciasis is associated with epilepsy and that the disease burden of onchocerciasis might have to be re-estimated by taking into account this relationship.

Case-control Studies on the Relationship between Onchocerciasis and Epilepsy: Systematic Review and Meta-analysis

Objective A systematic review and meta-analysis of all available case-control studies on the relationship between onchocerciasis and epilepsy. Because age and level of onchocerciasis endemicity in the area of residence are major determinants for infection, an additional analysis was performed, restricted to studies achieving control of these confounding factors. Data sources Medical databases, the “African Neurology Database, Institute of Neuroepidemiology and Tropical Neurology, Limoges,” reference lists of relevant articles, commercial search engines, up to May 2012. Methods We searched for studies examining infection status with Onchocerca volvulus in persons with epilepsy (PWE) and without epilepsy (PWOE) providing data suitable for the calculation of pooled odds ratios (ORp) and/or standardized mean differences (SMD) using random-effects models. Results Eleven studies providing data of qualitative skin biopsies for diagnosis of onchocerciasis were identified. Combined analysis on the total sample of 876 PWE and 4712 PWOE resulted in an ORp of 2.49 (95% confidence interval (95%CI): 1.61–3.86, p<0.001). When this analysis was restricted to those studies achieving control for age, residence and sex (367 PWE, 624 PWOE), an ORp of 1.29 (95% CI: 0.93–1.79; p = 0.139) was found. Presence of nodules for diagnosis of onchocerciasis was analyzed in four studies (225 PWE, 189 PWOE; ORp 1.74; 95%CI: 0.94–3.20; p<0.076), including two studies of the restricted analysis (106 PWE, 106 PWOE; ORp 2.81; 95%CI: 1.57–5.00; p<0.001). One study examined quantitative microfilariae counts in patients without preceding microfilaricidal treatment and demonstrated significantly higher counts in PWE than in PWOE. Interpretation Our results strengthen the hypothesis that, in onchocerciasis foci, epilepsy and infection with O. volvulus are associated. Analysis of indicators giving information on infection intensity, namely nodule palpation and quantitative microfilaria count in untreated patients, support the hypothesis that intensity of infection with O. volvulus is involved in the etiology of epilepsy.

Head nodding syndrome and river blindness: a parasitologic perspective.

To the Editors: Winkler et al. (2008) give an excellent description of the ‘‘head nodding syndrome,’’ a disorder that has been found linked with epileptic seizures in four distinct geographic locations of sub-Saharan Africa (Jilek-Aall et al., 1979; Van der Waals et al., 1983; Kaiser et al., 2000; Lacey, 2003), all of which known as endemic for Onchocerca volvulus, the causative agent of river blindness. Over the last decade, O. volvulus has increasingly been implicated in the observation of clustering excess prevalence of epilepsy (Pion et al., 2009). With this background, the study of Winkler et al. is of great interest because, for the first time, it provides results of magnetic resonance imaging (MRI) and cerebrospinal fluid (CSF) analysis of patients with epilepsy living in an onchocerciasis endemic area. A search for a pathologic substrate inducing epilepsy by O. volvulus should aim at the demonstration of the parasite in the central nervous system (CNS). Certainly, the macrofilarial stages of the parasite, because of their size (length 5–50 cm; width 0.1–0.45 mm), would be expected to produce clearly visible lesions and the absence of such findings argues against the involvement of the adult stage of O. volvulus in the CNS. However, the pattern of the pathologic MRI findings still leaves room for speculation about microfilariae (length 220–300 lm) producing more subtle changes in the brain. Even if no microfilariae are found in the CSF, one may consider changes due to degrading microfilariae, or to persisting immune reactions to these. Winkler et al. do not provide information on antifilarial medication prior to their patients’ enrollment in the study, although this may have significantly influenced the results of their parasitologic examinations. Throughout most of the African endemic areas, patients with onchocerciasis are treated with the microfilaricidal drug ivermectin (Mectizan), which has been made available at no cost by its manufacturer (Merck & Co., Whitehouse Station, NJ, U.S.A.) since 1987. In Mahenge, the study area of Winkler et al., annual mass treatment has been carried out since 1998, with therapeutic coverage reaching up to 70% (WHO/APOC, 2007), and it appears likely that many of their patients already had received ivermectin. The very low microfilarial counts found in dermal biopsies also strongly indicate previous treatment with ivermectin. In view of the potent effect of ivermectin on O. volvulus microfilariae (Bas Çez et al., 2008) it cannot be excluded that in the patients with head nodding examined by Winkler et al. microfilariae could have been present in the CSF before treatment, as they were previously demonstrated in the CSF of untreated patients (Duke et al., 1976). Ultimately, the article of Winkler et al. leaves unsolved the question as to whether the phenomenon of head nodding constitutes a feature of an epileptic syndrome caused by O. volvulus. Future investigations should aim at studying patients without history of antiparasitic treatment and involve appropriate comparison groups of persons without epilepsy. We hope that this most interesting article will stimulate more researchers with neurologic and parasitologic background to get involved in this neglected subject.

Association Between Onchocerciasis and Epilepsy in the Itwara Hyperendemic Focus, West Uganda: Controlling for Time and Intensity of Exposure

In 38 pairs of epilepsy patients and controls matched for time and intensity of exposure to transmission of onchocerciasis, the presence of microfilariae in the skin of epilepsy patients was found insignificantly elevated compared with controls (odds ratio = 1.68; 95% confidence interval [CI] = 0.60-4.57; P = 0.31). This difference was more pronounced when detection of subcutaneous nodules was used as indication of infection with Onchocerca volvulus (odds ratio = 2.77; 95% CI = 0.92-8.33; P = 0.065). These findings from a patient group of limited size suggest that intensity of infection may play a substantial role in the development of onchocerciasis-associated epilepsy. Our results are in contrast to the results of two other independent studies from the identical endemic area; one case concluded a significant positive correlation between onchocerciasis and epilepsy, and the other case concluded a clearly negative correlation. Studies with a greater sample size are needed to confirm this possible relationship.

Results of echocardiographic examinations in a regional hospital of central Sudan

Sixty-seven patients were examined with a small portable echocardiograph in Wad Medani Teaching Hospital in central Sudan. The cardiac alterations detected in the referred patients, namely valvular disease and pericardial effusion, suggested a high prevalence of inflammatory heart disease in this area. Other findings were dilatative cardiomyopathy, congenital heart disease, mitral valve prolapse and a cardiac mass. Echocardiographic examination of patients with advanced hepatosplenic schistosomiasis revealed no evidence of cardiac alterations or abnormal right heart function. For echocardiography a general purpose ultrasound scanner, as defined by the World Health Organization, was used, additionally equipped with M mode facilities. It was concluded that echocardiography is applicable even in remote tropical areas and that its value, considering costs, therapeutic consequences and clinical benefit in developing countries, can be substantial. It was particularly helpful with pericardial disease.

Renal function in Sudanese school children with Schistosoma mansoni infection

Renal function was investigated in 218 school children withSchistosoma mansoni infection in the Province of Gezira in central Sudan and in 65 Sudanese and 65 German age-matched controls. Serum creatinine was normal in all children. A pathological urinary protein-creatinine ratio was found in 3% ofS. mansoni-infected children and in 5% of Sudanese controls but in none of the European children. Characterization of pathological proteinuria using albumin nephelometry, alpha-1 microglobulin immunodiffusion and SDS-polyacrylamide gel electrophoresis in these children showed glomerular, tubular or mixed glomerulotubular patterns. One, 4 and 6 months following treatment of schistosomiasis with praziquantel, stools were re-examined; 57% of patients were cured, 16% were found to be reinfected and 27% had persistent egg excretion. Six months after therapy, pathological urinary protein-creatinine ratios were encountered in 3% ofS. mansoni patients and in none of the 34 reinvestigated controls. Proteinuria was similar in patients with persistentS. mansoni egg excretion and in children cured of schistosomiasis infection. It is concluded that there was no evidence forS. mansoni associated glomerulonephritis in this group of Sudanese children. The high rate of pathological proteinuria inS. mansoni-infected and non-infected Sudanese children may be due to other causes.

Nodding Syndrome, Western Uganda, 1994

Nodding syndrome (NS) is a poorly understood condition, which was delineated in 2008 as a new epilepsy syndrome. So far, confirmed cases of NS have been observed in three circumscribed African areas: southern Tanzania, southern Sudan, and northern Uganda. Case-control studies have provided evidence of an association between NS and infection with Onchocerca volvulus, but the causation of NS is still not fully clarified. We report a case of a 15-year old boy with head nodding seizures and other characteristic features of NS from an onchocerciasis endemic area in western Uganda, with no contiguity to the hitherto known areas. We suggest that the existence of NS should be systematically investigated in other areas.

In Response: A Call for More Case-Controlled Studies on Onchocerciasis and Epilepsy

Dear Sir: We thank Pion and Boussinesq1 for the initiative to reanalyze the data of their study from an onchocerciasis endemic area in Central Cameroon that, in part, had been published in 2002.2 Their finding of a significant association between epilepsy and the presence of subcutaneous nodules corresponds well with our own results obtained in a similar setting in West Uganda.3 As a difference to many studies searching for a relationship between onchocerciasis and epilepsy, the study by Pion and Boussinesq1 and our study3 used clear pair-matched design controlling for time and intensity of exposure to Onchocerca volvulus. To test the robustness of our results, the association between epilepsy and onchocercal nodules should be investigated in other endemic areas with adequate methods. Investigations of this kind would require simple and non-invasive procedures: appropriate sampling of cases and controls and history-taking for the confirmation of epilepsy and nodule palpation. Some data on the issue may even have been assessed in earlier studies but were not fully analyzed or communicated. For instance, in a well-designed study conducted in the Central African Republic,4 the skin of patients with epilepsy and matched controls were examined for microfilaria of O. volvulus by skin biopsy and onchocercal nodules by palpation. Unfortunately, in this publication, the number of subcutaneous nodules was communicated only for the complete sample but not separately for patients and controls.4 In view of the intriguing consistency between the above-mentioned investigations from Cameroon2 and Uganda,3 it would be of interest to know the exact result of nodule palpations carried out in the Central African Republic by Druet-Cabanac and others.4 In our article about the Itwara focus,3 we wanted to illustrate some of the methodological problems of controlled studies of the link between onchocerciasis and epilepsy, and we wanted to call on other researchers to get involved. More rigorous case-controlled studies are needed on this neglected issue.

Onchocerciasis-Associated Epilepsy with Head Nodding Seizures—Nodding Syndrome: A Case Series of 15 Patients from Western Uganda, 1994

Nodding syndrome (NS) is an encephalopathy characterized by the core symptom of epileptic head nodding seizures, affecting children at the age between 3 and 18 years in distinct areas of tropical Africa. A consistent correlation with onchocerciasis was found, but so far, the causation of NS has not been fully clarified. With a systematic analysis of features of a cohort of epilepsy patients examined in the Itwara onchocerciasis focus of western Uganda in 1994, we provide evidence that NS actually occurred in this area at this time, and we demonstrate a correlation between prevalence of NS and that of onchocerciasis in different villages. Following the elimination of onchocerciasis by community-directed treatment with ivermectin and ground larviciding, our data provide a baseline to examine the question whether NS will disappear once its putative cause has been removed.