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

<div><p>Objective</p><p>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.</p> <p>Data sources</p><p>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.</p> <p>Methods</p><p>We searched for studies examining infection status with <i>Onchocerca volvulus</i> in persons with epilepsy (PWE) and without epilepsy (PWOE) providing data suitable for the calculation of pooled odds ratios (OR_p) and/or standardized mean differences (SMD) using random-effects models.</p> <p>Results</p><p>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 OR_p 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 OR_p 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; OR_p 1.74; 95%CI: 0.94–3.20; p<0.076), including two studies of the restricted analysis (106 PWE, 106 PWOE; OR_p 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.</p> <p>Interpretation</p><p>Our results strengthen the hypothesis that, in onchocerciasis foci, epilepsy and infection with <i>O. volvulus</i> 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 <i>O. volvulus</i> is involved in the etiology of epilepsy.</p> </div

Case-control studies on the onchocerciasis-epilepsy relationship: study areas characteristics and odds ratios (OR).

a<p>The first four studies are those achieving control for intensity and time of exposure and gender. In these studies people with epilepsy were matched for gender, age and place of residence to one or two people without epilepsy; in the study by Kaiser et al. (2011), 5 of 38 pairs were not matched for sex.</p>b<p>Pmf = prevalence of skin microfilariae (mf) in subjects aged ≥5 years; PNod = prevalence of nodules in males aged ≥20 years; Hypo = hypoendemic (Pmf<35% or PNod<20%); Meso = mesoendemic (35%≤Pmf<60% or 20%≤PNod <40%); Hyper = hyperendemic (Pmf≥60% or PNod≥40%).</p>c<p>CDTI = Community-Directed Treatment with Ivermectin; VC = Vector control.</p>d<p>OR mf = Odds ratio for epilepsy in patients with skin mf; OR Nod = Odds ratio for epilepsy in patients with nodules; 95%CI = 95% Confidence interval; NA = not assessable.</p>e<p>Passive ivermectin treatment had been organized in these areas before the implementation of the CDTIs organized by the African Program for Onchocerciasis Control (APOC).</p>f<p>OR calculated on the number of persons examined (6 of the 36 controls were “missing” for nodule palpation). If all the missing controls had nodules, the OR would be 1.00 (0.31–3.19) and if none of them had nodules, the OR would be 1.96 (0.62–6.22).</p

Results of studies utilizing supplementary methods for assessment of <i>O. volvulus</i> infection (serology, polymerase chain reaction, circulating antigen).

a<p>n = number of persons examined.</p>b<p>Oncho + = No. of persons with positive onchocerciasis infection status; Oncho − = No. of persons with negative onchocerciasis infection status.</p>c<p>Numbers of persons examined differed slightly between reports from this study. Data for skin snip results alone are presented as given in reference <a href="http://www.plosntds.org/article/info:doi/10.1371/journal.pntd.0002147#pntd.0002147-Knig2" target="_blank">[37]</a>, and for skin snip and skin PCR results combined as given in reference <a href="http://www.plosntds.org/article/info:doi/10.1371/journal.pntd.0002147#pntd.0002147-Knig1" target="_blank">[36]</a>.</p

Case-control studies on the onchocerciasis-epilepsy relationship: results of studies controlling for confounders.

a<p>SMD = Standardized Mean Difference; SD = Standard deviation.</p>b<p>No. mf+/No. mf− = Number of persons with/without microfilaria in skin biopsy; No. Nod +/No. Nod − = Number of persons with/without palpable nodule.</p>c<p>Results of eye examinations not considered.</p>d<p>Mantel-Haenszel weighted summary Odds ratio.</p>e<p>n.r. = not reported in original study <a href="http://www.plosntds.org/article/info:doi/10.1371/journal.pntd.0002147#pntd.0002147-DruetCabanac2" target="_blank">[30]</a>.</p>f<p>Test of Cohen's Standardized Mean Difference <a href="http://www.plosntds.org/article/info:doi/10.1371/journal.pntd.0002147#pntd.0002147-Hardy1" target="_blank">[23]</a>.</p

Additional file 2: of Progress towards onchocerciasis elimination in the participating countries of the African Programme for Onchocerciasis Control: epidemiological evaluation results

ONCHOSIM simulations: brief model description, input assumptions and simulations that were done (DOCX 64 kb

Additional file 1: of Progress towards onchocerciasis elimination in the participating countries of the African Programme for Onchocerciasis Control: epidemiological evaluation results

Multilingual abstracts in the six official working languages of the United Nations. (PDF 732 kb

Life Cycle of <i>O. volvulus</i>

<p>Mean dimensions of parasite stages are: Adult females, 35–70 cm × 400 µm; adult males, 2–4 cm × 150–200 µm; microfilariae, 250–360 × 5–9 µm; L1 larvae, 200 µm × 12 µm (front) and 20 µm (rear); L3, 440–700 × 20 µm. L1 larvae molt into L2, pre-infective larvae, and L2 into L3, infective larvae [<a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.0030371#pmed-0030371-b005" target="_blank">5</a>]. (Illustration: Giovanni Maki, derived from a CDC image at <a href="http://www.dpd.cdc.gov/dpdx/HTML/Filariasis.htm" target="_blank">http://www.dpd.cdc.gov/dpdx/HTML/Filariasis.htm</a>)</p

The Incidence of Blindness and Excess Mortality Rate, by Sex, Plotted against <i>O. volvulus</i> Microfilarial Load

<p>Arithmetic mean of microfilarial counts from two skin snips, taken from the right and left ileac crests, using a 2-millimeter Holth corneoscleral punch. (A) Blindness; (B) excess mortality rate. Error bars denote 95 percent confidence intervals [<a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.0030371#pmed-0030371-b010" target="_blank">10</a>,<a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.0030371#pmed-0030371-b022" target="_blank">22</a>].</p

Analysis of the Relationship of β-<i>tubulin</i> Genotype with Patient and Parasitological Independent Variables Before Treatment.

<p>Odds ratios (OR) and 95% confidence intervals (95% CI) for logistic regression of heterozygote status (vs. homozygote) of worms collected before ivermectin treatment on four independent variables. No. females/nod. = total number of females in the nodule; No. nod. 1994 = total number of palpable nodules in 1994; CMFL = Community Microfilarial Load (reference category: 10–40 microfilariae per skin snip (mf/ss)).</p

β-<i>tubulin</i> Genotype of Female Worms.

<p>β-tubulin genotype of female worms, that could be genotyped, before and after different doses of ivermectin. IVM = ivermectin treatment. † Pooled by treatment frequency.</p