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PLoS Neglected Tropical Diseases Jan 2021The possibility that onchocerciasis may cause epilepsy has been suggested for a long time, but thus far, an etiological link has not been universally accepted. The... (Review)
Review
BACKGROUND
The possibility that onchocerciasis may cause epilepsy has been suggested for a long time, but thus far, an etiological link has not been universally accepted. The objective of this review is to critically appraise the relationship between Onchocerca volvulus and epilepsy and subsequently apply the Bradford Hill criteria to further evaluate the likelihood of a causal association.
METHODS
PubMed and gray literature published until September 15, 2020, were searched and findings from original research were synthesized. Adherence to the 9 Bradford Hill criteria in the context of onchocerciasis and epilepsy was determined to assess whether the criteria are met to strengthen the evidence base for a causal link between infection with O. volvulus and epilepsy, including the nodding syndrome.
RESULTS
Onchocerciasis as a risk factor for epilepsy meets the following Bradford Hill criteria for causality: strength of the association, consistency, temporality, and biological gradient. There is weaker evidence supporting causality based on the specificity, plausibility, coherence, and analogy criteria. There is little experimental evidence. Considering the Bradford Hill criteria, available data suggest that under certain conditions (high microfilarial load, timing of infection, and perhaps genetic predisposition), onchocerciasis is likely to cause epilepsy including nodding and Nakalanga syndromes.
CONCLUSION
Applying the Bradford Hill criteria suggests consistent epidemiological evidence that O. volvulus infection is a trigger of epilepsy. However, the pathophysiological mechanisms responsible for seizure induction still need to be elucidated.
Topics: Animals; Causality; Child; Databases, Factual; Epilepsy; Humans; Microfilariae; Nodding Syndrome; Onchocerca volvulus; Onchocerciasis; Risk Factors; Seizures
PubMed: 33411705
DOI: 10.1371/journal.pntd.0008965 -
International Journal of Infectious... Mar 2021Nodding syndrome is one of several forms of onchocerciasis-associated epilepsy (OAE) seen among children in areas formerly hyperendemic for the transmission of... (Review)
Review
Nodding syndrome is one of several forms of onchocerciasis-associated epilepsy (OAE) seen among children in areas formerly hyperendemic for the transmission of Onchocerca volvulus. These forms of epilepsy are highly prevalent and clustered in certain villages located close to blackfly (Diptera: Simuliidae) breeding sites. OAE presents with a wide spectrum of seizures, including generalized tonic-clonic and head nodding seizures, impaired cognitive function, growth stunting and delayed puberty. In 2014, the present authors published a perspective paper in this journal which hypothesized that nodding syndrome may be caused by either a neurotropic virus transmitted by blackflies or an endosymbiont present within the O. volvulus parasite. Seven years later, this critical review presents progress in nodding syndrome research, and assesses whether it is still plausible that a neurotropic virus or endosymbiont could be the cause.
Topics: Animals; Biomedical Research; Humans; Nodding Syndrome; Onchocerca volvulus; Onchocerciasis; Prevalence
PubMed: 33556614
DOI: 10.1016/j.ijid.2021.02.006 -
Current Opinion in Infectious Diseases Oct 2018With increasing international travel and mass global population migration, clinicians in nonendemic countries must be familiar with imported neglected tropical diseases... (Review)
Review
PURPOSE OF REVIEW
With increasing international travel and mass global population migration, clinicians in nonendemic countries must be familiar with imported neglected tropical diseases including onchocerciasis, which is commonly known as 'river blindness'.
RECENT FINDINGS
Imported onchocerciasis manifests differently in travelers compared with migrants from endemic areas and is likely underdiagnosed in both groups. Recent clinical studies confirm that eosinophilia is not a sensitive marker for Onchocerca volvulus, with one-third of patients having a normal eosinophil count. Novel diagnostics measuring antibodies to multiple recombinant O. volvulus antigens maintain a high sensitivity while improving specificity compared with conventional pan-filarial serologic testing. A 6-week course of doxycycline has macrofilaricidal activity through Wolbachia depletion and may be useful in nonendemic areas in addition to standard serial ivermectin.
SUMMARY
Recent studies characterizing distinct clinical presentations in travelers and migrants may enable clinicians to better recognize imported onchocerciasis. Although novel diagnostics have improved specificity, most remain restricted to tropical disease reference laboratories and to date there is no marker of cure. Prolonged doxycycline treatment may reduce the need for serial ivermectin, though more potent short-course macrofilaricidal drugs are being developed.
Topics: Animals; Antibodies, Helminth; Communicable Diseases, Imported; Diagnostic Tests, Routine; Disease Management; Doxycycline; Filaricides; Human Migration; Humans; Onchocerca volvulus; Onchocerciasis; Transients and Migrants; Travel
PubMed: 30113326
DOI: 10.1097/QCO.0000000000000483 -
The Pan African Medical Journal 2017Nodding Syndrome (NS) is a childhood neurological disorder characterized by atonic seizures, cognitive decline, school dropout, muscle weakness, thermal dysfunction,...
Nodding Syndrome (NS) is a childhood neurological disorder characterized by atonic seizures, cognitive decline, school dropout, muscle weakness, thermal dysfunction, wasting and stunted growth. There are recent published information suggesting associations between Nodding Syndrome (NS) with cerebrospinal fluid (CSF) VGKC antibodies and serum leiomidin-1 antibody cross reacting with (). These findings suggest a neuro-inflammatory cause of NS and they are important findings in the search for the cause of Nodding Syndrome. These observations perhaps provide further, the unique explanation for the association between Nodding Syndrome and . Many clinical and epidemiological studies had shown a significant correlation between NS and infestation with a nematode, which causes a disease, , some of which when left untreated can develop visual defect ("River Blindness"). While these studies conducted in Northern Uganda and Southern Sudan indicate a statistically significant association with ( infection (using positive skin snips), we observe that ( is generally endemic in many parts of Sub Saharan Africa and Latin America and that to date, no NS cases have been recorded in those regions. This letter to the Editor is to provide additional information on the current view about the relationship between Nodding Syndrome and as seen in Northern Uganda.
Topics: Animals; Humans; Nodding Syndrome; Onchocerca volvulus; Onchocerciasis; Onchocerciasis, Ocular; Uganda
PubMed: 29138647
DOI: 10.11604/pamj.2017.28.1.13554 -
Frontiers in Neurology 2021Globally, epilepsy is the most common chronic neurological disorder. The incidence in sub-Saharan Africa is 2-3 times higher than that in high income countries....
Globally, epilepsy is the most common chronic neurological disorder. The incidence in sub-Saharan Africa is 2-3 times higher than that in high income countries. Infection by may be an underlying risk factor for the high burden and based upon epidemiological associations, has been proposed to cause a group of disorders- associated epilepsies (OAE) like nodding syndrome (NS). To improve our understanding of the disease spectrum, we described the clinical, electroencephalographic (EEG) and magnetic resonance imaging (MRI) features of children with epilepsy and sero-positive for (possible OAEs other than nodding syndrome). Twenty-nine children and adolescents with non-nodding syndrome OAE in northern Uganda were enrolled. A diagnosis of OAE was made in patients with epilepsy and seizure onset after age 3 years, no reported exposure to perinatal severe febrile illness or traumatic brain injury, no syndromic epilepsy diagnosis and a positive Ov-16 ELISA test. Detailed clinical evaluation including psychiatric, diagnostic EEG, a diagnostic brain MRI (in 10 patients) and laboratory testing were performed. Twenty participants (69%) were male. The mean age was 15.9 (standard deviation [SD] 1.9) years while the mean age at seizure onset was 9.8 (SD 2.9) years. All reported normal early childhood development. The most common clinical presentation was a tonic-clonic seizure. The median number of seizures was 2 (IQR 1-4) in the previous month. No specific musculoskeletal changes, or cranial nerve palsies were reported, neither were any vision, hearing and speech difficulties observed. The interictal EEG was abnormal in the majority with slow wave background activity in 52% (15/29) while 41% (12/29) had focal epileptiform activity. The brain MRI showed mild to moderate cerebellar atrophy and varying degrees of atrophy of the frontal, parietal and occipital lobes. The clinical spectrum of epilepsies associated with Onchocerca may be broader than previously described. In addition, focal onset tonic-clonic seizures, cortical and cerebellar atrophy may be important brain imaging and clinical features.
PubMed: 34149607
DOI: 10.3389/fneur.2021.687281 -
PLoS Neglected Tropical Diseases Aug 2023Previous studies have described the association of onchocerciasis (caused by Onchocerca volvulus) with epilepsy, including nodding syndrome, although a clear etiological...
Previous studies have described the association of onchocerciasis (caused by Onchocerca volvulus) with epilepsy, including nodding syndrome, although a clear etiological link is still missing. Cases are found in different African countries (Tanzania, South Sudan, Uganda, Democratic Republic of the Congo, Central African Republic and Cameroon). In our study we investigated immunological parameters (cytokine, chemokine, immunoglobulin levels) in individuals from the Mahenge area, Tanzania, presenting with either epilepsy or nodding syndrome with or without O. volvulus infection and compared them to O. volvulus negative individuals from the same endemic area lacking neurological disorders. Additionally, cell differentiation was performed using blood smears and systemic levels of neurodegeneration markers, leiomodin-1 and N-acetyltyramine-O, β-glucuronide (NATOG) were determined. Our findings revealed that cytokines, most chemokines and neurodegeneration markers were comparable between both groups presenting with epilepsy or nodding syndrome. However, we observed elevated eosinophil percentages within the O. volvulus positive epilepsy/nodding syndrome patients accompanied with increased eosinophilic cationic protein (ECP) and antigen-specific IgG levels in comparison to those without an O. volvulus infection. Furthermore, highest levels of NATOG were found in O. volvulus positive nodding syndrome patients. These findings highlight that the detection of distinct biomarkers might be useful for a differential diagnosis of epilepsy and nodding syndrome in O. volvulus endemic areas. Trial-registration: NCT03653975.
Topics: Animals; Humans; Onchocerciasis; Onchocerca volvulus; Nodding Syndrome; Intestinal Volvulus; Epilepsy; Uganda; Cytokines
PubMed: 37535695
DOI: 10.1371/journal.pntd.0011503 -
PLoS Neglected Tropical Diseases May 2022Annual mass drug administrations (MDA) of ivermectin will strongly reduce Onchocerca volvulus microfilariae (mf) in the skin and in the onchocerciasis patients' eyes....
Onchocerca volvulus-specific antibody and cellular responses in onchocerciasis patients treated annually with ivermectin for 30 years and exposed to parasite transmission in central Togo.
BACKGROUND
Annual mass drug administrations (MDA) of ivermectin will strongly reduce Onchocerca volvulus microfilariae (mf) in the skin and in the onchocerciasis patients' eyes. Ivermectin treatment will also affect the expression of immunity in patients, such that activated immune defenses may help control and contribute to clearance of mf of O. volvulus. Longitudinal surveys are a prerequisite to determining the impact of ivermectin on the status of anti-parasite immunity, notably in risk zones where parasite transmission and active O. volvulus infections persist.
METHODOLOGY/PRINCIPAL FINDINGS
Onchocerciasis patients were treated annually with ivermectin and their Onchocerca volvulus antigen (OvAg) specific IgG and cellular responses were investigated before and at 30 years post initial ivermectin treatment (30yPT). Repeated annual ivermectin treatments eliminated persisting O. volvulus microfilariae (mf) from the skin of patients and abrogated patent infections. The OvAg-specific IgG1 and IgG4 responses were diminished at 30yPT to the levels observed in endemic controls. Prior to starting ivermectin treatment, OvAg-induced cellular productions of IL-10, IFN-γ, CCL13, CCL17 and CCL18 were low in patients, and at 30yPT, cellular cytokine and chemokine responses increased to the levels observed in endemic controls. In contrast, mitogen(PHA)- induced IL-10, IFN-γ, CCL17 and CCL18 cellular production was diminished. This divergent response profile thus revealed increased parasite antigen-specific but reduced polyclonal cellular responsiveness in patients. The transmission of O. volvulus continued at the patients' location in the Mô river basin in central Togo 2018 and 2019 when 0.58% and 0.45%, respectively, of Simulium damnosum s.l. vector blackflies carried O. volvulus infections.
CONCLUSIONS/SIGNIFICANCE
Repeated annual ivermectin treatment of onchocerciasis patients durably inhibited their patent O. volvulus infections despite ongoing low-level parasite transmission in the study area. Repeated MDA with ivermectin affects the expression of immunity in patients. O. volvulus parasite-specific antibody levels diminished to levels seen in infection-free endemic controls. With low antibody levels, antibody-dependent cellular cytotoxic responses against tissue-dwelling O. volvulus larvae will weaken. O. volvulus antigen inducible cytokine and chemokine production increased in treated mf-negative patients, while their innate responsiveness to mitogen declined. Such lower innate responsiveness in elderly patients could contribute to reduced adaptive immune responses to parasite infections and vaccines. On the other hand, increased specific cellular chemokine responses in mf-negative onchocerciasis patients could reflect effector cell activation against tissue invasive larval stages of O. volvulus. The annual Simulium damnosum s.l. biting rate observed in the Mô river basin was similar to levels prior to initiation of MDA with ivermectin, and the positive rtPCR results reported here confirm ongoing O. volvulus transmission.
Topics: Aged; Animals; Cytokines; Humans; Immunoglobulin G; Interleukin-10; Intestinal Volvulus; Ivermectin; Microfilariae; Mitogens; Onchocerca; Onchocerca volvulus; Onchocerciasis; Parasites; Simuliidae; Togo
PubMed: 35503786
DOI: 10.1371/journal.pntd.0010340 -
Parasitology Research Apr 2018Onchocerca ochengi is a nodule-forming filarial nematode parasite of cattle. It is the closest known relative of the human parasite Onchocerca volvulus, with which it...
Onchocerca ochengi is a nodule-forming filarial nematode parasite of cattle. It is the closest known relative of the human parasite Onchocerca volvulus, with which it shares the black fly vector Simulium damnosum. Onchocerca sp. "Siisa" was described in black flies and in cattle and, based on limited mitochondrial sequence information, appeared to be about equally phylogenetically distant from O. ochengi and O. volvulus. Based on molecular genetic markers and apparent interbreeding, we later proposed that O. sp. "Siisa" belongs to the species O. ochengi. However, we did not demonstrate directly that the hybrids were fertile, and we were still unable to resolve the phylogenetic relationship of O. ochengi, O. sp. "Siisa," and O. volvulus, leaving some concerns with the conclusion mentioned above. Here, we present fully assembled, manually curated mitochondrial genomes of O. ochengi and O. sp. "Siisa," and we compare multiple individuals of these two taxa with respect to their whole mitochondrial and nuclear genomes. Based on the mitochondrial genomes, O. ochengi and O. sp. "Siisa" are phylogenetically much closer to each other than to O. volvulus. The differences between them are well within the range of what is expected for within-species variation. The nuclear genome comparison provided no indication of genetic separation of O. ochengi and O. sp. "Siisa." From this, in combination with the earlier literature, we conclude that O. ochengi and O. sp. "Siisa" should be considered one species.
Topics: Animals; Cattle; Cattle Diseases; Genome, Mitochondrial; Genome, Protozoan; Humans; Insect Vectors; Mitochondria; Onchocerca; Onchocerciasis; Phylogeny; Polymorphism, Single Nucleotide; Simuliidae; Skin
PubMed: 29404746
DOI: 10.1007/s00436-018-5783-0 -
Current Research in Parasitology &... 2022Identifying the molecular mechanisms controlling the host's response to infection with is important to understand how the human host controls such parasitic infection....
Identifying the molecular mechanisms controlling the host's response to infection with is important to understand how the human host controls such parasitic infection. Little is known of the cellular immune response upon infection with . We performed a transcriptomic study using PAXgene-preserved whole blood from 30 nodule-positive individuals and 21 non-endemic controls. It was found that of the 45,042 transcripts that were mapped to the human genome, 544 were found to be upregulated and 447 to be downregulated in nodule-positive individuals (adjusted -value < 0.05). Pathway analysis was performed on this set of differentially expressed genes, which demonstrated an impact on oxidative phosphorylation and protein translation. Upstream regulator analysis showed that the mTOR associated protein RICTOR appears to play an important role in inducing the transcriptional changes in infected individuals. Functional analysis of the genes affected by infection indicated a suppression of antibody response, Th17 immune response and proliferation of activated T lymphocytes. Multiple regression models were used to select 22 genes that could contribute significantly in the generation of a classifier to predict infection with . For these 22 genes, as well as for 8 reference target genes, validated RT-qPCR assays were developed and used to re-analyze the discovery sample set. These data were used to perform elastic net regularized logistic regression and a panel of 7 genes was found to be the best performing classifier. The resulting algorithm returns a value between 0 and 1, reflecting the predicted probability of being infected. A validation panel of 69 nodule-positive individuals and 5 non-endemic controls was used to validate the performance of this classifier. Based on this validation set only, a sensitivity of 94.2% and a specificity of 60.0% was obtained. When combining the discovery test set and validation set, a sensitivity of 96.0% and a specificity of 92.3% was obtained. Large-scale validation approaches will be necessary to define the intended use for this classifier. Besides the use as marker for infection in MDA efficacy surveys and epidemiological transmission studies, this classifier might also hold potential as pharmacodynamic marker in macrofilaricide clinical trials.
PubMed: 36082138
DOI: 10.1016/j.crpvbd.2022.100100 -
Acta Tropica May 2018The Mahenge Mountains onchocerciasis focus in south eastern Tanzania was historically one of the most heavily infected areas in the country. The vectors of Onchocerca...
The Mahenge Mountains onchocerciasis focus in south eastern Tanzania was historically one of the most heavily infected areas in the country. The vectors of Onchocerca volvulus are mainly Simulium damnosum complex blackflies, but a species of the Simulium neavei group may also contribute to transmission in some areas. The only detailed studies of parasite transmission in Mahenge were conducted in the late 1960s. The taxonomy of the S. damnosum complex has since been revised and onchocerciasis control through annual community directed treatment with ivermectin (CDTI) commenced in 1997. This study aimed to provide a cytogenetic and molecular update of the S. damnosum complex cytoforms present in Mahenge, and to evaluate the current status of O. volvulus transmission by blackflies following 19 years of annual CDTI. Rivers were surveyed to identify sites of S. damnosum s.l. breeding among the eastern slopes of the mountains, and human landing collections of adult female blackflies were made close to breeding sites. Identification of S. damnosum complex cytoforms was by cytotaxonomy of late-instar larvae and ITS1 amplicon size polymorphisms of larvae and adults. Adult blackflies were pool screened for O. volvulus infection using a triplex real-time PCR. The cytoforms 'Nkusi', Simulium kilibanum and 'Turiani' were found breeding in perennial rivers. 'Nkusi' and S. kilibanum were collected on human bait at 7/7 catch sites and possessed ITS1 profiles most closely resembling the molecular forms 'Nkusi J' and S. kilibanum 'T'. Whereas 'Turiani' was present in rivers, it was not collected on human bait and appears to be zoophilic. Simulium nyasalandicum was collected in low numbers on human bait at 3/7 catch sites. In total, 12,452 S. damnosum s.l. were pool screened and O. volvulus infection was detected in 97/104 pools of bodies and 51/104 pools of heads. The estimated percentage of S. damnosum s.l. carrying infective L3 stage parasites was 0.57% (95% CI 0.43%-0.74%). Onchocerca volvulus transmission by S. damnosum s.l. is continuing in the Mahenge Mountains after 19 years of annual CDTI. Infection rates appear similar to those reported in the 1960s, but a more detailed study is required to fully understand the epidemiological significance of the ongoing transmission. These results provide further evidence that annual CDTI may be insufficient to eliminate the parasite in formerly hyperendemic foci.
Topics: Adult; Animals; Breeding; Female; Humans; Insect Vectors; Ivermectin; Onchocerca volvulus; Onchocerciasis; Rivers; Simuliidae; Tanzania
PubMed: 29410302
DOI: 10.1016/j.actatropica.2018.01.009