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Background: Reactions are commonly associated with the chemotherapy of onchocerciasis. However unmanageable reactions are uncommon when ivermectin (Mectizan®) is used for the treatment of this infection, and this drug has proved to be a great improvement over previously used agents. Serious adverse events (SAE) nevertheless have occurred, and there is considerable concern about the negative effect such events may have on mass drug administration programs. This paper reviews the basic pathogenic mechanisms that can be involved in the destruction of microfilaria by chemotherapeutic agents. A central challenge to filarial chemotherapy is the need to remove parasites from biologically sensitive tissues, a more difficult medical challenge than eliminating nematodes from the gastrointestinal tract. Explanations for the etiology of the serious adverse reactions occurring with ivermectin treatment in specific geographic areas where there is coincident heavy Loa loa infections are hampered by a lack of specific pathological case material. Ways to investigate these possibilities are reviewed. Possible pathogenic mechanisms include embolic vascular pathology accompanied by local inflammation, blood brain barrier mdr1 abnormalities, and genetic predisposition to excessive inflammatory responses. Conclusion: It is important to keep ivermectin, and all its associated adverse clinical events, in perspective with the many other chemotherapeutic agents in general use—many of which produce serious adverse events even more frequently than does ivermectin. Currently available evidence indicates that the pathogenesis of the Loa-associated adverse reactions are probably related to inflammatory responses to microfilariae in specific tissues. However, the possibility of genetic predispositions to pathology should also be considered. [ABSTRACT FROM AUTHOR]

This paper presents a summary of reported cases of Serious Adverse Events (SA's) following treatment with Mectizan® (ivermectin, Merck, Sharpe & Dohme) in onchocerciasis mass treatment programs from January 1, 1989 to December 31, 2001 through a passive surveillance system. A total of 207 SAE cases were reported out of approximately 165 million reported treatments delivered during the period under review, giving rise to a cumulative incidence of 1 reported SAE per 800,000 reported treatments. The mean age was 40 years and 70% of the cases were males. The mean time between ivermectin intake and onset of illness was 1 day. For 57% of the cases (n = 118), that was their first exposure to ivermectin. The majority of cases were reported from Cameroon (n = 176; 85%) with peaks in the incidence of SAE reporting in 1989—1991 and 1994—1995 when the program expanded to ivermectin-naïve populations. Fifty-five percent of the cases from Cameroon (i.e. 97 out of 176 cases) were encephalopathic and were reported from the central-southern region of the country; two-thirds of these cases were 'probable' or 'possible' cases of Loa loa encephalopathy temporally related to ivermectin treatment. Reporting bias may explain some but not all of the differences in SAE reporting between the 34 onchocerciasis-endemic countries that have, or have had, mass treatment programs. Further research is needed to understand the apparent clustering of encephalopathy cases in central-southern Cameroon since L. loa infection alone probably does not explain the increased incidence of this type of SAE from this region. [ABSTRACT FROM AUTHOR]

Of the 207 Serious Adverse Events (SA's) following treatment with Mectizan® (ivermectin, Merck, Sharpe & Dohme) that were reported from 1989 to 2001 through the passive SAE surveillance system required of all onchocerciasis mass treatment programs, 65 were cases of 'Probable' or 'Possible' Loa loa Encephalopathy temporally Related to treatment with Mectizan® (PLERM). A retrospective analysis of these 65 PLERM cases revealed that 97% were from southern Cameroon, 85% were male and 93% were being treated with ivermectin for the first time. The mean time to onset of symptoms was 1.7 days (95% CI: 1.3, 2.2) but the mean time to receiving medical attention after the onset of symptoms was 2.0 days (95% CI: 1.5, 2.6). Hospitalization was reported in 53 cases with a mean duration of 27.5 days (95% CI: 13.3, 41.6, n = 35). Clinical outcome was reported in 34 cases: 64.7% recovered fully, 11.8% had partial neurologic deficit and 23.5% died. For the 32 cases where quantitative L. loa data were reported, the arithmetic means with 95% confidence intervals were for 1) peripheral blood: pre-treatment - 164,250 mf/ml (79,537, 248,963; n = 4); post-treatment within 1 month - 3926 mf/ml (2,128, 5,725; n = 21) and within 5 to 6 months - 7800 mf/ml (3417, 12,183; n = 7); and for 2) cerebrospinal fluid: 32 mf/ml (7, 37; n = 10) within 1 month post-treatment. Pending further research on practical methods to exclude individuals with high intensity L. loa infection from onchocerciasis mass treatment programs, more emphasis should be placed on surveillance and monitoring to ensure early recognition, referral and management of SA's, during the first 2 years when majority of the population is presumably naïve to ivermectin. [ABSTRACT FROM AUTHOR]

Ivermectin (Mectizan®) is the only drug currently recommended for the treatment and control of onchocerciasis. Serious adverse events rarely occur during treatment, except in subjects heavily infected with Loa Loa. This review of drug-related serious adverse events in the treatment of onchocerciasis therefore revisited the pre-Mectizan® reference drugs, DEC and suramin, and other candidate drugs studied extensively for the treatment of human onchocerciasis. The benzimidazole carbamate derivatives and the antibiotic doxycycline were excluded, since no serious adverse events have been reported regarding their use. Using recommended definitions, serious adverse events reported or observed after the use of each drug were summarised, the level of attribution determined, and the results tabulated. Prominence was given to treatment-related deaths. The clinical picture of severe symptomatic postural hypotension is described and used to illustrate the difference between the severity and the seriousness of an adverse event. The epidemiology, management and outcome of serious adverse events are presented. The role of future research is discussed. [ABSTRACT FROM AUTHOR]

In areas co-endemic for loiasis and onchocerciasis, the classic Community-Directed Treatment using ivermectin (Mectizan®) must be adapted as additional program activities, better communication and tighter control of ivermectin stocks are required to minimize risk and manage serious adverse events following ivermectin treatment in patients co-infected with Loa loa. The importance of these serious adverse events on community participation in onchocerciasis control efforts has not been adequately studied. Program implementers do not as of yet fully understand the psychological impact of serious adverse events on communities and therefore have not designed communication strategies that adequately address the real concerns of community members. It is clear, however, that along with an effective case detection and management strategy, a reinforced communication strategy will be required to motivate at least 65% of the total population in onchocerciasis and loiasis co-endemic areas to participate in the treatment program and to take ivermectin over an extended period. This strategy must be based on research undertaken at the community level in order to address the concerns, fears and issues associated with adverse events due to ivermectin — to ensure that communities believe that the benefits of taking ivermectin outweigh the risks. In addition to an overall increase in the time required to sustain onchocerciasis control programs in co-endemic areas, each aspect of the reinforced program and communication strategy — rapid epidemiological assessments, materials development, training, advocacy, community sensitization and mobilization, case management and counselling, supervision, monitoring and evaluation will require additional resources and support from all stakeholders concerned. [ABSTRACT FROM AUTHOR]

In August 2002, 65 cases of Loa-associated neurological Serious Adverse Events were reported after ivermectin treatment. The first signs, occurring within the 12—24 hours following treatment, included fatigue, generalized arthralgia, and sometimes agitation, mutism, and incontinence. Disorders of consciousness, including coma, generally appeared between 24 and 72 hours, and showed a rapid variation with time. The most frequent objective neurological signs were extrapyramidal. The patients presented with haemorrhages of the conjunctiva and of the retina. Biological examinations showed a massive Loa microfilaruria, the passage of Loa microfilariae into the cerebrospinal fluid, haematuria, and an increase in the C-reactive protein, all of which have been correlated with the high intensity of the initial Loa microfilaraemia. Eosinophil counts decreased dramatically within the first 24 hours, and then rose again rapidly. Electroencephalograms suggested the existence of a diffuse pathological process within the first weeks; the abnormalities disappearing after 3—6 months. Death may occur when patients are not properly managed, i.e. in the absence of good nursing. However, some patients who recovered showed sequelae such as aphasia, episodic amnesia, or extrapyramidal signs. The main risk factor for these encephalopathies is the intensity of the initial Loa microfilaraemia. The disorders of consciousness may occur when there are >50,000 Loa microfilariae per ml. The possible roles of co-factors, such as Loa strains, genetic predisposition of individuals, co-infestations with other parasites, or alcohol consumption, seem to be minor but they should be considered. The mechanisms of the post-ivermectin Loa-related encephalopathies should be investigated to improve the management of patients developing the condition. [ABSTRACT FROM AUTHOR]

The occurrence of Serious Adverse Experiences (SA's) following Mectizan® treatment of onchocerciasis in Loa loa endemic areas has been increasingly reported over the past decade. These SA's include a severely disabling, and potentially fatal, encephalopathy, which appears to correlate with a high load of L. loa microfilariae (> 30,000 mf/ml). Previous consultations organized by the Mectizan® Donation Program (MDP) in 1995 and 1999 have developed useful "case" definitions of encephalopathic SA's following Mectizan® treatment and have summarized available evidence on its pathogenesis and optimal clinical management. At both meetings, the need for better understanding of the pathogenesis of the encephalopathy was emphasized, including the need for biological and autopsy specimens from the affected cases. Following a recommendation at the Joint Action Forum of the African Programme for Onchocerciasis Control in December 2001, the MDP, on behalf of the Mectizan® Expert Committee, organized a Scientific Working Group on L. loa associated SA's following Mectizan® treatment in May 2002. The present report includes the background, new evidence, conclusions and recommendations from that Scientific Working Group. The following points represent a summary of the present status: 1. Although there are more and better quality clinical and epidemiological data on L. loa, the pathogenesis of the Mectizan®-related L. loa encephalopathy remains obscure. 2. Very limited progress has been made in research on the pathogenesis of encephalopathy, because of the lack of specimens from cases, and the lack of animal models. 3. There has been no particular breakthrough in terms of the medical management of patients with L. loa encephalopathy; however, a favorable outcome usually results from prompt general nursing and nutritional care which remain the major interventions. The main recommendations for future actions are as follows: 1. validate and update the mapping of L. loa with a combination of remote sensing and RAPLOA techniques. 2. Conduct an expert analysis of the apparent clustering of encephalopathic SA's reported so far. 3. Investigate a possible "pre-treatment" scheme with high-dose albendazole in L. loa endemic communities at high risk of encephalopathic SA's if treated with Mectizan®; this study will be conducted in collaboration with WHO/TDR. 4. Establish a post of Loiasis Technical Advisor for research and operational support in Cameroon, to conduct population surveys and to facilitate better data collection from SAE cases, including postmortem studies as appropriate. 5. Investigate the possibility of developing an animal model of L. loa encephalopathy; this activity would be linked to the above-mentioned research agenda in Cameroon. 6. Investigate the best care model for encephalopathic SA's, including identification of early warning signs and therapeutic interventions. 7. Develop further models for health education messages needed for community compliance with Mectizan® treatment, and family support for SAE cases. 8. Conduct research studies on the safety of combination therapy of Mectizan® and albendazole in areas co-endemic for L. loa and lymphatic filariasis (LF) with coordination from the relevant technical bodies that oversee these issues. The above recommendations will be implemented through a continuing collaboration between the interested parties represented at the Scientific Working Group, involved in onchocerciasis control and/or the Global Programme to Eliminate Lymphatic Filariasis. [ABSTRACT FROM AUTHOR]