Aims. Nodding syndrome is a poorly understood acquired disorder affecting children in sub‐Saharan Africa. The aetiology and pathogenesis are unknown, and no specific treatment is available. Affected children have a distinctive feature (repeated clusters of head nodding) and progressively develop many other features. In an earlier pilot study, we proposed a five‐level clinical staging system. The present study aimed to describe the early features and natural history of nodding syndrome and refine the proposed clinical stages. Methods. This was a retrospective study of the progressive development of symptoms and complications of nodding syndrome. Participants were a cohort of patients who had been identified by community health workers and were referred for treatment. A detailed history was obtained to document the chronological development of symptoms before and after onset of head nodding and a physical examination and disability assessment performed by a team of clinicians and therapists. Results. A total of 210 children were recruited. The mean age at the onset of head nodding was 7.5 (SD: 3.0) years. Five overlapping clinical stages were recognised: prodromal, head nodding, convulsive seizures, multiple impairments, and severe disability stages. Clinical features before the onset of head nodding (prodromal features) included periods of staring blankly or being inattentive, complaints of dizziness, excessive sleepiness, lethargy, and general body weakness, all occurring two weeks to 24 months before nodding developed. After the onset of head nodding, patients progressively developed convulsive seizures, cognitive and psychiatric dysfunction, physical deformities, growth arrest, and eventually, in some patients, severe disability. Conclusions. The description of the natural history of nodding syndrome and especially the prodromal features has the potential of providing a means for the early identification of at‐risk patients and the prompt initiation of interventions before extensive brain injury develops. The wide spectrum of symptoms and complications emphasises the need for multi‐disciplinary investigations and care.
Vector control and effective case management are currently the backbone strategies of malaria control. Kitgum district, an area of perennial holoendemic malaria transmission intensity in Northern Uganda, appears to have experienced a malaria epidemic in 2015. This study aimed to describe the malaria trends in Kitgum General Hospital from 2011 to 2017 in relation to climatic factors and the application of population-based malaria control interventions. Hospital records were examined retrospectively to calculate malaria normal channels, malaria cases per 1000 population, test positivity rates (TPR) and to enumerate pregnancy malaria, hospitalizations and deaths. Climatic factors (humidity, temperature and rainfall) and population-based malaria control interventions that had been applied during this period were described. Kitgum district experienced an epidemic between the years 2015 and 2016; the malaria burden rose above the established normal channels. At its peak the number of malaria cases attending KGH was over 20 times above the normal channels. The total number of cases per 1000 population increased from 7 in 2014 to 113 in 2015 and 114 in 2016 (p value for trend <0.0001). Similarly, TPR increased from 10.5% to 54.6% between 2014 and 2016 (p value for trend <0.0001). This trend was also observed for malaria attributable hospitalizations, and malaria in pregnancy. There were no significant changes in any of the climatic factors assessed (p value = 0.92, 0.99, 0.52 for relative humidity, max temperature, and rainfall, respectively). The malaria upsurge occurred in conjunction with a general decline in the use and application of malaria control interventions. Specifically, indoor residual spraying was interrupted in 2014. In response to the epidemic, IRS was reapplied together with mass distribution of long-lasting insecticide treated nets (LLINs) in 2017. Subsequently, there was a decline in all malaria indicators. The epidemic in Kitgum occurred in association with the interruption of IRS and appears to have abated following its re-introduction alongside LLINs. The study suggests that to enable malaria elimination in areas of high malaria transmission intensity, effective control measures may need to be sustained for the long-term.
Nodding syndrome is a highly debilitating, generalized seizure disorder, affecting children in subregions of sub-Saharan Africa. Despite many efforts towards finding its etiology, the exact cause of the syndrome still remains obscure. Therefore, to date, patients only receive a symptomatic care, including the administration of first-generation anti-epileptic drugs (AEDs) for seizure control. Since information about medication effectiveness within this population is completely lacking, the aim of this study was to perform therapeutic drug monitoring (TDM) to seek whether an answer could be provided to the question why for some patients the symptoms decrease, whilst in others the epileptic seizures remain poorly controlled. Seeing the challenging context in which sampling needed to take place (remote areas, devoid of electricity, running water, etc.), dried blood matrices (i.e. dried blood spots (DBS) and volumetric absorptive microsampling (VAMS) devices) were considered fit-for-purpose.Seeing the similarities between the syndrome and other forms of epilepsy, also samples originating from patients suffering from (onchocerciasis-associated) epilepsy were included.In total, 68 patients with Nodding syndrome from Uganda, 58 Ugandan patients with epilepsy and 137 patients with onchocerciasis-associated epilepsy from the Democratic Republic of the Congo (DRC) were included in this study. VAMS samples and DBS were analyzed using fully validated methods, involving manual extraction or fully automated extraction, respectively, prior to quantification using liquid chromatography coupled to tandem mass spectrometry.Analysis revealed that serum concentrations (calculated from DBS) within the respective reference ranges were attained for only 52.9% of the 68 Nodding syndrome patients treated with valproic acid, for 21.4% of the 56 Ugandan epilepsy patients treated with carbamazepine, and for 65.7% of the 137 onchocerciasis-associated epilepsy patients from the DRC treated with phenobarbital. In all other instances, concentrations were subtherapeutic. Furthermore, when comparing DBS to VAMS concentrations, an inexplicable overestimation was observed in the latter. Finally, no obvious link could be observed between the obtained drug concentrations and the amount of seizures experienced during the last month before sampling, disclosing the fact that the level of improvement of some patients cannot simply linked to reaching therapeutic concentrations.
Background Nodding syndrome is a poorly understood neurological disorder of unknown aetiology, affecting several thousand children in Africa. There has been a consistent epidemiological association with infection by the filarial parasite, Onchocerca volvulus and antibodies to leiomodin and DJ-1, cross-reacting with O.volvulus proteins, have been reported. We hypothesized that nodding syndrome is a neuro-inflammatory disorder, induced by antibodies to O.volvulus or its symbiont, Wolbachia, cross-reacting with human neuron proteins and that doxycycline, which kills Onchocerca through effects on Wolbachia, may be used as treatment. Methods This will be a two-arm, double-blind, placebo-controlled, randomised phase II trial of doxycycline 100 mg daily for six weeks in 230 participants. Participants will be patients’ ages≥8 years with nodding syndrome. They will receive standard of care supportive treatment. All will be hospitalised for 1–2 weeks during which time baseline measurements including clinical assessments, EEG, cognitive and laboratory testing will be performed and antiepileptic drug doses rationalised. Participants will then be randomised to either oral doxycycline (Azudox®, Kampala Pharmaceutical Industries) 100 mg daily or placebo. Treatment will be initiated in hospital and continued at home. Participants will be visited at home at 2, 4 and 6 weeks for adherence monitoring. Study outcomes will be assessed at 6, 12, 18 and 24-month visits. Analysis will be by intention to treat. The primary efficacy outcome measure will be the proportion of patients testing positive and the levels or titires of antibodies to host neuron proteins (HNPs) and/or leiomodin at 24 months. Secondary outcome measures will include effect of the intervention on seizure control, inflammatory markers, cognitive function, disease severity and quality of life. Discussion This trial postulates that targeting O. volvulus through drugs which kill Wolbachia can modify the pathogenic processes in nodding syndrome and improve outcomes. Findings from this study are expected to substantially improve the understanding and treatment of nodding syndrome. Trial registration Registered with clinicaltrials.gov ID: NCT02850913 on 1st August, 2016.
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