Ivermectin as an adjuvant to anti-epileptic treatment in persons with onchocerciasis-associated epilepsy: A randomized proof-of-concept clinical trial

Michel Mandro, Joseph Nelson Siewe Fodjo, Deby Mukendi, Alfred Dusabimana, Sonia Menon, Steven Haesendonckx, Richard Lokonda, Swabra Nakato, Francoise Nyisi, Germain Abhafule, Deogratias Wonya'Rossi, Jean Marie Jakwong, Patrick Suykerbuyk, Jacques Meganck, An Hotterbeekx, Robert Colebunders, Michel Mandro, Joseph Nelson Siewe Fodjo, Deby Mukendi, Alfred Dusabimana, Sonia Menon, Steven Haesendonckx, Richard Lokonda, Swabra Nakato, Francoise Nyisi, Germain Abhafule, Deogratias Wonya'Rossi, Jean Marie Jakwong, Patrick Suykerbuyk, Jacques Meganck, An Hotterbeekx, Robert Colebunders

Abstract

Introduction: Recent findings from onchocerciasis-endemic foci uphold that increasing ivermectin coverage reduces the epilepsy incidence, and anecdotal evidence suggests seizure frequency reduction in persons with onchocerciasis-associated epilepsy, when treated with ivermectin. We conducted a randomized clinical trial to assess whether ivermectin treatment decreases seizure frequency.

Methods: A proof-of-concept randomized clinical trial was conducted in the Logo health zone in the Ituri province, Democratic Republic of Congo, to compare seizure frequencies in onchocerciasis-infected persons with epilepsy (PWE) randomized to one of two treatment arms: the anti-epileptic drug phenobarbital supplemented with ivermectin, versus phenobarbital alone. The primary endpoint was defined as the probability of being seizure-free at month 4. A secondary endpoint was defined as >50% reduction in seizure frequency at month 4, compared to baseline. Both endpoints were analyzed using multiple logistic regression. In longitudinal analysis, the probability of seizure freedom during the follow-up period was assessed for both treatment arms by fitting a logistic regression model using generalized estimating equations (GEE).

Results: Ninety PWE enrolled between October and November 2017 were eligible for analysis. A multiple logistic regression analysis showed a borderline association between ivermectin treatment and being seizure-free at month 4 (OR: 1.652, 95% CI 0.975-2.799; p = 0.062). There was no significant difference in the probability of experiencing >50% reduction of the seizure frequency at month 4 between the two treatment arms. Also, treatment with ivermectin did not significantly increase the odds of being seizure-free during the individual follow-up visits.

Conclusion: Whether ivermectin has an added value in reducing the frequency of seizures in PWE treated with AED remains to be determined. A larger study in persons with OAE on a stable AED regimen and in persons with recent epilepsy onset should be considered to further investigate the potential beneficial effect of ivermectin treatment in persons with OAE.

Trial registration: Registration: www.clinicaltrials.gov; NCT03052998.

Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Fig 1. Trial participants profile.
Fig 1. Trial participants profile.
Fig 2. Evolution of the probability of…
Fig 2. Evolution of the probability of being seizure-free in both treatment arms over time.

References

    1. Colebunders R, Mandro M, Njamnshi AK, Boussinesq M, Hotterbeekx A, Kamgno J, et al. Report of the first international workshop on onchocerciasis-associated epilepsy. Infect Dis Poverty. 2018;7(1):23 10.1186/s40249-018-0400-0
    1. Colebunders R, Nelson Siewe FJ, Hotterbeekx A. Onchocerciasis-Associated Epilepsy, an Additional Reason for Strengthening Onchocerciasis Elimination Programs. Trends Parasitol. 2018;34(3):208–16. 10.1016/j.pt.2017.11.009 .
    1. Colebunders R, Siewe Fodjo JN, Hopkins A, Hotterbeekx A, Lakwo TL, Kalinga A, et al. From river blindness to river epilepsy: Implications for onchocerciasis elimination programmes. PLoS Negl Trop Dis. 2019;13(7):e0007407 10.1371/journal.pntd.0007407
    1. Pion SD, Kaiser C, Boutros-Toni F, Cournil A, Taylor MM, Meredith SE, et al. Epilepsy in onchocerciasis endemic areas: systematic review and meta-analysis of population-based surveys. PLoS Negl Trop Dis. 2009;3(6):e461 10.1371/journal.pntd.0000461
    1. Chesnais CB, Nana-Djeunga HC, Njamnshi AK, Lenou-Nanga CG, Boulle C, Bissek AZ, et al. The temporal relationship between onchocerciasis and epilepsy: a population-based cohort study. Lancet Infect Dis. 2018;18(11):1278–86. 10.1016/S1473-3099(18)30425-0 .
    1. Johnson TP, Tyagi R, Lee PR, Lee MH, Johnson KR, Kowalak J, et al. Nodding syndrome may be an autoimmune reaction to the parasitic worm Onchocerca volvulus. Sci Transl Med. 2017;9(377). 10.1126/scitranslmed.aaf6953
    1. Hotterbeekx A, Lammens M, Idro R, Akun PR, Lukande R, Akena G, et al. Neuroinflammation and Not Tauopathy Is a Predominant Pathological Signature of Nodding Syndrome. J Neuropathol Exp Neurol. 2019;78(11):1049–58. 10.1093/jnen/nlz090 .
    1. Gumisiriza N, Mubiru F, Mbonye M, Hotterbeekx A, Idro R, Makumbi I, et al. Prevalence and incidence of Nodding Syndrome and other forms of epilepsy in onchocerciasis endemic areas in northern Uganda after the implementation of onchocerciasis control measures. 4th African conference on epilepsy, 22–24 August, Entebbe, Uganda 2019. Available at Accessed 8 December 2019.
    1. Levick B, Laudisoit A, Tepage F, Ensoy-Musoro C, Mandro M, Bonareri Osoro C, et al. High prevalence of epilepsy in onchocerciasis endemic regions in the Democratic Republic of the Congo. PLoS Negl Trop Dis. 2017;11(7):e0005732 10.1371/journal.pntd.0005732
    1. Colebunders R, Mandro M, Mokili JL, Mucinya G, Mambandu G, Pfarr K, et al. Risk factors for epilepsy in Bas-Uele Province, Democratic Republic of the Congo: a case-control study. Int J Infect Dis. 2016;49:1–8. 10.1016/j.ijid.2016.05.018
    1. Kipp W, Burnham G, Kamugisha J. Improvement in seizures after ivermectin. Lancet. 1992;340(8822):789–90. 10.1016/0140-6736(92)92329-e .
    1. Twum-Danso NA. Serious adverse events following treatment with ivermectin for onchocerciasis control: a review of reported cases. Filaria J. 2003;2 Suppl 1:S3 10.1186/1475-2883-2-S1-S3 ; PubMed Central PMCID: PMC2147655.
    1. Basanez MG, Pion SD, Boakes E, Filipe JA, Churcher TS, Boussinesq M. Effect of single-dose ivermectin on Onchocerca volvulus: a systematic review and meta-analysis. Lancet Infect Dis. 2008;8(5):310–22. 10.1016/S1473-3099(08)70099-9 .
    1. Colebunders R, Mandro M, Mukendi D, Dolo H, Suykerbuyk P, Van Oijen M. Ivermectin Treatment in Patients With Onchocerciasis-Associated Epilepsy: Protocol of a Randomized Clinical Trial. JMIR Res Protoc. 2017;6(8):e137 10.2196/resprot.7186
    1. Fisher RS, Acevedo C, Arzimanoglou A, Bogacz A, Cross JH, Elger CE, et al. ILAE official report: a practical clinical definition of epilepsy. Epilepsia. 2014;55(4):475–82. 10.1111/epi.12550 .
    1. Fisher RS, Cross JH, French JA, Higurashi N, Hirsch E, Jansen FE, et al. Operational classification of seizure types by the International League Against Epilepsy: Position Paper of the ILAE Commission for Classification and Terminology. Epilepsia. 2017;58(4):522–30. 10.1111/epi.13670 .
    1. Idro R, Namusoke H, Abbo C, Mutamba BB, Kakooza-Mwesige A, Opoka RO, et al. Patients with nodding syndrome in Uganda improve with symptomatic treatment: a cross-sectional study. BMJ Open. 2014;4(11):e006476 10.1136/bmjopen-2014-006476
    1. Bursac Z, Gauss CH, Williams DK, Hosmer DW. Purposeful selection of variables in logistic regression. Source Code Biol Med. 2008;3:17 10.1186/1751-0473-3-17
    1. liang K-Y ZS. Longitudinal data analysis using generalized linear models Biometrika. 1986;73(1):13–22.
    1. Pan W. Akaike's information criterion in generalized estimating equations. Biometrics. 2001;57(1):120–5. 10.1111/j.0006-341x.2001.00120.x .
    1. Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. Research electronic data capture (REDCap)—a metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform. 2009;42(2):377–81. 10.1016/j.jbi.2008.08.010
    1. Harmonization ICo. Available: . Assessed 18th December 2019
    1. World Health Organization. Community directed treatment with ivermectin: report of a multi-country study. UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases; 1996, p. 37 Available: . Assessed 18th December
    1. Colebunders R, Abd-Elfarag G, Carter JY, Olore PC, Puok K, Menon S, et al. Clinical characteristics of onchocerciasis-associated epilepsy in villages in Maridi County, Republic of South Sudan. Seizure. 2018;62:108–15. 10.1016/j.seizure.2018.10.004 .
    1. Colebunders R, J YC, Olore PC, Puok K, Bhattacharyya S, Menon S, et al. High prevalence of onchocerciasis-associated epilepsy in villages in Maridi County, Republic of South Sudan: A community-based survey. Seizure. 2018;63:93–101. 10.1016/j.seizure.2018.11.004
    1. Siewe JFN, Ngarka L, Tatah G, Mengnjo MK, Nfor LN, Chokote ES, et al. Clinical presentations of onchocerciasis-associated epilepsy (OAE) in Cameroon. Epilepsy Behav. 2018;90:70–8. 10.1016/j.yebeh.2018.11.008 .
    1. Van Diessen E vdMF, Cabral V, Otte WM. Community-based rehabilitation offers cost-effective epilepsy treatment in rural Guinea-Bissau. Epilepsy and Behaviour. 2018;79:23–5.
    1. Ballent M, Lifschitz A, Virkel G, Sallovitz J, Lanusse C. Modulation of the P-glycoprotein-mediated intestinal secretion of ivermectin: in vitro and in vivo assessments. Drug Metab Dispos. 2006;34(3):457–63. 10.1124/dmd.105.007757 .

Source: PubMed

Sponsorit ja yhteistyökumppanit

Sairaudet

Huumeiden interventiot

3
Tilaa