The Pathogenesis of Nodding Syndrome.

Nodding syndrome is a rare, enigmatic form of pediatric epilepsy that has occurred in an epidemic fashion beginning in the early 2000s in geographically distinct regions of Africa. Despite extensive investigation, the etiology of nodding syndrome remains unclear, although much progress has been made in understanding the pathogenesis of the disease, as well as in treatment and prevention. Nodding syndrome is recognized as a defined disease entity, but it is likely one manifestation along a continuum of Onchocerca volvulus-associated neurological complications. This review examines the epidemiology of nodding syndrome and its association with environmental factors. It provides a critical analysis of the data that support or contradict the leading hypotheses of the etiologies underlying the pathogenesis of the syndrome. It also highlights the important progress made in treating and preventing this devastating neurological disease and prioritizes important areas for future research.

Neurological manifestations in Onchocerca volvulus infection: A review.

Human onchocerciasis, caused by infection by the filarial nematode Onchocerca volvulus, is a major neglected public health problem that affects millions of people in the endemic regions of sub-Saharan Africa and Latin America. Onchocerciasis is known to be associated with skin and eye disease and more recently, neurological features have been recognized as a major manifestation. Especially the latter poses a severe burden on affected individuals and their families. Although definite studies are awaited, preliminary evidence suggests that neurological disease may include the nodding syndrome, Nakalanga syndrome and epilepsy but to date, the exact pathophysiological mechanisms remain unclear. Currently, the only way to prevent Onchocera volvulus associated disease is through interventions that target the elimination of onchocerciasis through community distribution of ivermectin and larviciding the breeding sites of the Similium or blackfly vector in rivers. In this review, we discuss the epidemiology, potential pathological mechanisms as well as prevention and treatment strategies of onchocerciasis, focusing on the neurological disease.

Baseline characterization of epilepsy in an onchocerciasis endemic area of the Democratic Republic of Congo.

Increased epilepsy prevalence is reported in onchocerciasis (OC) endemic areas and is associated with the occurrence of distinct syndromes such as nodding disease and Nakalanga syndrome. To date, a causal relationship between OC and epilepsy is still a matter of controversy. We conducted a case-control study of participants with epilepsy and age- and gender-matched presumably healthy controls to elucidate the relationships between OC and epilepsy and explore the role of inflammation and growth factors in an OC endemic area in the Democratic Republic of Congo (DRC). Eighty-two participants with epilepsy (mean age ± SD: 23.2 ± 8.7 years) and 27 controls (mean age ± SD: 22.3 ± 12.0 years) underwent snip skin biopsies to determine Onchocerca volvulus infection status. Serum concentrations of cytokines, chemokines, and growth factors were measured using a Luminex Multiplex Assay kit. Children <19 years of age underwent neurocognitive assessments using the Kaufman Assessment Battery for Children, 2nd edition (KABC-II). Overall, epilepsy was associated with OC (OR = 4.51, z = 3.11, p = 0.0019), and children with OC were more likely to be severely stunted (OR = 11.67, z = 2.62, p = 0.0087). The relationship between epilepsy and OC was no longer significant (z = 1.27, p = 0.20) when stunting was included as a correcting covariate. Epilepsy was associated with poor KABC-II test scores, high serum levels of IL-17, and low levels of IL-1RA, IL-8, and EGF. KABC-II testing scores correlated with serum levels of IL-10, MCP-1 and HGF. Familial history of epilepsy occurred frequently. Future studies should consider cytokines and/or growth factors when assessing susceptibility to epilepsy in OC endemic areas. Additional investigations, preferentially in low-prevalence OC areas, may provide further insights into the concept, risk, and burden of river epilepsy.

Sustainable control of onchocerciasis: ocular pathology in onchocerciasis patients treated annually with ivermectin for 23 years: a cohort study.

UNLABELLED: The evolution and persistence of ocular pathology was assessed in a cohort of Onchocerca volvulus infected patients treated annually with ivermectin for 23 years. Patients were resident in rural Central and Kara Region of Togo and ocular examinations included testing of visual acuity, slit lamp examination of the anterior eye segment and the eye fundus by ophthalmoscopy. Before ivermectin treatment, vivid O.volvulus microfilariae (MF) were observed in the right and left anterior eye chamber in 52% and 42% of patients (n = 82), and dead MF were seen in the right and left cornea in 24% and 15% of cases, respectively. At 23 years post initial treatment (PIT), none of the patients (n = 82) presented with MF in the anterior chamber and cornea. A complete resolution of punctate keratitis (PK) lesions without observable corneal scars was present at 23 years PIT (p<0.0001), and sclerosing keratitits (SK) lessened by half, but mainly in patients with lesions at early stage of evolution. Early-stage iridocyclitis diminished from 42%(rE) and 40%(lE) to 13% (rE+lE)(p<0.0001), but advanced iridocyclitis augmented (p<0.001) at 23 years PIT compared to before ivermectin. Advanced-stage papillitis and chorioretinitis did not regress, while early-stage papillitis present in 28%(rE) and 27%(lE) of patients at before ivermectin regressed to 17%(rE) and 18%(lE), and early-stage chorioretinitis present in 51%(rE+lE) of cases at before ivermectin was observed in 12%(rE) and 13%(lE) at 23 years PIT (p<0.0001). Thus, regular annual ivermectin treatment eliminated and prevented the migration of O. volvulus microfilariae into the anterior eye chamber and cornea; keratitis punctata lesions resolved completely and early-stage sclerosing keratitits and iridocyclitis regressed, whilst advanced lesions of the anterior and posterior eye segment remained progressive. In conclusion, annual ivermectin treatments may prevent the emergence of ocular pathology in those populations still exposed to O.volvulus infection. TRIAL REGISTRATION: www.pactr.org PACTR201303000464219).

Lymphatic filariasis and onchocerciasis.

Lymphatic filariasis and onchocerciasis are parasitic helminth diseases that constitute a serious public health issue in tropical regions. The filarial nematodes that cause these diseases are transmitted by blood-feeding insects and produce chronic and long-term infection through suppression of host immunity. Disease pathogenesis is linked to host inflammation invoked by the death of the parasite, causing hydrocoele, lymphoedema, and elephantiasis in lymphatic filariasis, and skin disease and blindness in onchocerciasis. Most filarial species that infect people co-exist in mutualistic symbiosis with Wolbachia bacteria, which are essential for growth, development, and survival of their nematode hosts. These endosymbionts contribute to inflammatory disease pathogenesis and are a target for doxycycline therapy, which delivers macrofilaricidal activity, improves pathological outcomes, and is effective as monotherapy. Drugs to treat filariasis include diethylcarbamazine, ivermectin, and albendazole, which are used mostly in combination to reduce microfilariae in blood (lymphatic filariasis) and skin (onchocerciasis). Global programmes for control and elimination have been developed to provide sustained delivery of drugs to affected communities to interrupt transmission of disease and ultimately eliminate this burden on public health.

Ivermectin: 25 years and still going strong.

Ivermectin is a drug that many people will never have heard of. Yet thousands of villagers of all ages in communities scattered throughout the remotest parts of Africa and Latin America know its name, and some experts regard it as one of the greatest health interventions of the past 50 years. Ivermectin was brought to the commercial market place for multi-purpose use in animal health in 1981. Six years later it was registered for human use. This remarkable compound has improved the lives and productivity of billions of humans, livestock and pets around the globe, and promises to help consign to the history books two devastating and disfiguring diseases that have plagued people throughout the tropics for generations--while new uses for it are continually being found.

Onchocerciasis situation in the Tukuyu focus of southwest Tanzania after ten years of ivermectin mass treatment.

A purposive cross-sectional epidemiological study was conducted in the Tukuyu Onchocerciasis focus in south-western Tanzania in 2004, ten years after launching the ivermectin mass treatment programme, and 23 years after establishing focal parasite prevalence. The objective was to assess contemporary Onchocerciasis clinical and parasitological situation and assess community knowledge about the disease and its control. From historical data, five villages with high parasite prevalence were selected, two each on the Lufilyo and Kiwira Rivers and one on lower Lumbira River. Skin biopsies were taken from the iliac crest on the left and right buttocks, for examination of Onchocerca volvulus microfilariae. Onchocercal skin lesions were checked using natural light, while nodules were palpated from head to ankles and scored. A structured questionnaire was administered to participants. A total of 438 persons (age=16-99 years) were examined. No skin microfilariae (mf) were detected. Onchocercal skin symptoms were found in 170 (38.8%), of which 30 (6.9%) had nodules, 48 (11.0%) chronic onchodermatitis and 92 (21%) itching. One-third (34.5%) had correct knowledge that black flies ("tusunya") are vectors of onchocerciasis. Half of the respondents (n=217) confirmed taking ivermectin for onchocerciasis treatment, and 428 (97.7%) were willing to continue for any duration. It is concluded that the undetectable skin microfilariae in the study sample was partly attributable to the consequences of ongoing ivermectin mass treatment. It is recommended that the control efforts, as well as monitoring and evaluation be sustained to determine its long term impact, and that a more sensitive technique be used to check O. volvulus skin mf prevalence.

Wolbachia in the inflammatory pathogenesis of human filariasis.

Filarial nematodes cause some of the most debilitating diseases in tropical medicine. Recent studies, however, have implicated the parasites' endosymbiotic Wolbachia bacteria, rather than the nematode, as the cause of inflammatory-mediated filarial disease. Soluble extracts of a variety of filarial species stimulate innate inflammatory responses, which are absent or reduced when using extracts derived from species either devoid of bacteria, or those cleared of bacteria by antibiotics. Characterization of the molecular nature of the bacterial derived inflammatory stimulus points toward an endotoxin-like activity that is dependent on the pattern recognition receptors CD14 and TLR4 and can be inhibited by lipid A antagonists. TLR4 dependent inflammation has been shown to occur in the systemic inflammatory adverse reaction to Brugia malayi following anti-filarial chemotherapy and in the development of neutrophil-mediated ocular inflammation in a mouse model of river blindness. The development of acute and severe inflammatory responses in people infected with Brugia malayi and Onchocerca volvulus is associated with the release of Wolbachia into the blood following death or damage of the worms after anti-filarial chemotherapy. Together these studies suggest that Wolbachia are the principal cause of acute inflammatory filarial disease. Accumulated exposure to acute episodes of inflammation may also underlie the development of chronic filarial pathology. The use of antibiotic therapy to target Wolbachia of filarial parasites may therefore provide a means to prevent the development of filarial pathology.

Antibody responses in onchocerciasis as a function of age and infection intensity.

Onchocerciasis is caused by the filarial nematode Onchocerca volvulus and is a major public health problem in West and Central Africa. With only partial and long-term treatment currently available, there is a need to develop a suitable vaccine. We analysed the antibody response to infective L3 larvae because this stage is thought to be associated with host protective immunity. In addition, we have related our findings to the age, gender and current infection intensity of our participants: variables that may significantly influence antibody production. Interestingly, whilst 90% of our study group were seropositive for adult specific immunoglobulin (Ig)E, only 23% produced L3 specific IgE. This is in contrast to IgG4 where seropositivity was comparable at 96% and 92%, respectively. Furthermore, IgG levels were significantly affected by age and the intensity of infection but unaffected by host gender. This finding is independent for the IgG subclass (IgG1, IgG2, IgG3 and IgG4) and its specificity (L3 versus adult antigen). In summary, we show that L3 larvae induce little specific IgE and the antibody response shows a different isotype balance than that against adult antigens. Both host and parasite variables can influence antibody production in this disease.

Onchocerciasis in a nonendemic population: clinical and immunologic assessment before treatment and at the time of presumed cure.

Although suppressive therapy for onchocerciasis with intermittent ivermectin prevents the development of pathology in endemic populations, the clinical and immunologic effects of therapy in the absence of continued exposure are unknown. To address this question, 14 patients treated with ivermectin for onchocerciasis acquired >10 years ago during temporary residence in Africa were reevaluated. None had evidence of continued infection or pathology at follow-up. Although eosinophilia, serum IgE, and antifilarial antibody levels decreased after ivermectin therapy, none of these parameters was useful in predicting the resolution of symptoms in infected patients. Peripheral blood mononuclear cells isolated from patients at follow-up were more responsive to parasite antigen in vitro, which is as assessed by proliferation and production of interferon-gamma and interleukin (IL)-5. In contrast, antigen-induced levels of IL-10 were significantly decreased at follow-up, consistent with diminished down-regulatory factors rather than a switch from type 2 to type 1 immune responses.

Analysis of renal function in onchocerciasis patients before and after therapy.

The occurrence of renal abnormalities was investigated in patients with onchocerciasis in comparison to individuals without onchocerciasis in Guinea. Serum creatinine levels, excretion of urinary marker proteins, and kidney size by ultrasound were determined. A high prevalence of glomerular as well as tubular dysfunctions was observed; however, no association with onchocerciasis could be detected. We also hypothesized that patients with hyperreactive onchocerciasis might be prone to develop immune-mediated glomerular disorders; however, this could not be verified. Following treatment with ivermectin, a slight but significant increase in the excretion of urinary albumin and alpha1-microglobulin was seen five days after treatment in all treated patients, whereas levels of proteinuria were significantly higher five days after treatment only in patients with high microfilarial densities. Our results indicate that ivermectin can cause glomerular and tubular disturbances in patients with onchocerciasis; however, these are minor and do not seem to be clinically relevant.

Onchocerciasis among school children in Kafa, South West Ethiopia.

A cross-sectional survey was undertaken to determine the magnitude, manifestations, and practices related to Onchocerciasis on 1337 students of six junior secondary schools of Kafa Zone in January 1993. Information on symptoms of the disease and the frequency of common practices that would bring the subjects to the breeding sites was collected by interview, while physical measurements and clinical examination was used to collect data on visual acuity, nutritional status and objective manifestations of the disease. Skin snip from both gluteal areas was examined to determine the microfilarial rate and density of infection, while nutritional status using Body Mass Index for Age (BMI-for Age), and visual impairment following the standard procedures was categorized. The majority, 1179 (88.2%) of the subjects, were aged 15 years and less of which males constituted 54.5% (728). The overall microfilarial carrier rate was 15.6% (95% CI = 13.7-17.6%) while the density of infection was 1.4 mf/mg skin snip. The prevalence and density of infection varied significantly among the twelve aggregates of villages identified based on the similarity of the ecological feature and contiguity of home address of the students. Males had significantly higher rate and density of infection but the difference by age was not significant. The prevalence of infection was significantly higher among the students who had reported frequent bathing, swimming, fishing and collecting firewood at/or near the rivers identified as the probable breeding sites of the vector, while there was no statistically significant association between infection and washing clothes, fetching water or crossing over the rivers. Groin lymph nodes enlargement, photophobia and itching were the leading symptoms complained by the infected subjects. However, only itching and the objective features related to the cutaneous Onchocerciasis were significantly associated to the infection. Visual acuity didn't differ among positive and negative subjects. Nutritional status was significantly associated with Onchocercal infection. Based on these findings recommendations are given on the areas of intervention and further study.

Distribution of mast cells and their correlation with inflammatory cells around Onchocerca gutturosa, O. tarsicola, O. ochengi, and O. flexuosa.

In recent years, bovine Onchocerca species have been used as models for human onchocerciasis in drug screens. They have been suggested for immunology studies and evaluation of vaccine candidates. Therefore, mast cells and their association with other inflammatory cells were studied in five onchocercal species of cattle and deer using immunohistology. Intact mast cells occurred in large numbers in the capsule and septae of nodules, in fibrous tissue adjacent to nonnodular worms, and perivascularly. Inactive and, more frequency, activated and degranulating mast cells were observed within infiltrates in the nodule center or around nonnodular filariae. They were not detected in direct contact with the cuticle of adult worms or of microfilariae or among the macrophages, giant cells, and neutrophils forming the innermost layer around the worms. Eosinophils, but not mast cells, were obviously associated with microfilariae-producing females. The distribution, frequency, and activity of mast cells were similar for all five species and O. volvulus.

Met-11 of HLA class II DP alpha 1 first domain associated with onchocerciasis.

Human infection with the pathogenic tissue nematode Onchocerca volvulus may result in a spectrum of clinical manifestations or in a putatively immune condition. A methionine at amino acid position 11 of the HLA class II DP alpha 1 chain correlates with the occurring disease after infection (relative risk 3.3). The alternative alanine at position 11 is, conversely, associated with protection from disease ("relative protection' 3.5). DPA1*0301 is associated with the localized form of disease after O. volvulus infection.

Effect of ivermectin prophylaxis on antibody responses to Onchocerca volvulus recombinant antigens in experimentally infected chimpanzees.

Antibody responses to recombinant Onchocerca volvulus antigens were studied in experimentally infected chimpanzees. Sera from 3 groups of 6 animals were tested by ELISA with recombinant antigens OC 3.6 and OC 9.3. Groups I and II were treated with 200 micrograms/kg of ivermectin on the day of infection or on day 28, respectively. Group III were untreated controls. Antibodies to OC 3.6 developed during the prepatent period in all 3 groups. In contrast, antibodies to OC 9.3 were usually first detected around the time of onset of patency. Several animals had early antibody responses to OC 9.3, but these animals subsequently failed to develop microfilarial patency. Only 1 of 6 animals in group I produced a strong antibody response to OC 9.3 while all 12 animals in groups II and III developed antibodies to this antigen. Although there was some inconsistency in antibody responses observed in each treatment group, the results suggest that OC 9.3 may be more useful than OC 3.6 for monitoring the efficacy of prophylactic drugs or vaccines for onchocerciasis while OC 3.6 may be useful for detecting exposure to the parasite and early infection, regardless of the later outcome of the infection.