Could nodding syndrome in Northern Uganda be a form of autism spectrum disorder? an observational study design.

INTRODUCTION: Nodding syndrome (NS) is associated with high anion gap, biotinidase and acetyl carnitine deficiency, vitamin B6 and D deficiency and internal displacement. The objective of this study was to conduct a metabolic analysis on NS children and review literature on its similarities with ASD. METHODS: We conducted biochemical analysis on blood and urine of NS children at Hope for HumaNs (HfH) centre in 2014 and reviewed literature on its similarities with ASD. Ethical approval was obtained from an IRB. Data analysis was conducted using STATA version 12 and a p-value less than 0.05 was considered significant. RESULTS: We found biotinidase deficiency in NS with a mean 1.98 95% CI(1.61, 2.34; p < 0.001); Acetyl carnitine deficiency 16.92 95% CI(16.10,17.75; p<0.001); Low BMI-for-age 16.92 95% CI(16.10,17.75; p = 0.42); Age 14.08 95% CI(0.78,4.660; p = 0.007); IDP duration 4.82 95% CI(4.48, 5.21; p = 0.92); Age at NS onset 8.02 95% CI(7.03, 9.01; p = 0.001); NS associated with multiple nodding episodes (χ2)=22.15, p=0.005; NS siblings with NS (χ2) = 9.68, p = 0.004; NS were in IDPs (χ2) = 22.15, p = 0.005. CONCLUSION: These findings are indicative that NS is associated with biotinidase and acetyl carnitine deficiency, IDPs, and environmental exposures. There are no new cases of NS reported by Ugandan MOH and WHO since 2012 when the IDP camps were disbanded and communities resettled in their own communities and feed on their own grown foods. Perhaps NS may be akin to Autism Spectrum Disorder (ASD). This finding will help support all efforts towards the treatment and rehabilitation of NS children.

Treatment and rehabilitation outcomes of children affected with nodding syndrome in Northern Uganda: a descriptive case series.

INTRODUCTION: Nodding Syndrome (NS) is a neurological disorder affecting children 5-15 years at onset in East Africa. A major criterion for diagnosis is atonic seizure with dorso-ventral "nodding" of the head. Comorbidities include psychological and behavioral abnormalities, malnutrition, cognitive decline, school dropout and other seizure types. We aimed to describe the presentations and rehabilitation outcomes of NS children at Hope for HumaNs (HfH) centre in Gulu from September 2012 to October 2013. METHODS: Data was obtained from a retrospective review of 32 NS children's medical records at HfH center. Ethical approval was obtained from Gulu University IRB. Data analysis was conducted using WHO AnthroPlus, SPSS and Excel software. RESULTS: Growth statistics showed steady improvement over time using local nutrition and multivitamin supplementation. Severe and moderate stunting was reduced from a combined total of 54.8% to 7.7% and 12.8% respectively. Severe and moderate wasting was reduced from 29.1% to 2.6% and 5.1% respectively. Three groups of NS children were identified and compared in the review; Low seizure occurrence averaging <2 seizures/month (28.1%); Moderate averaging 2-4 seizures/month (34.4%) and High averaging >4 seizures/month (37.5%). CONCLUSION: NS is a neurological disorder of unknown etiology. Treatment with regular high quality local nutrition, multivitamin supplementation, anti-seizures, regular follow up and illness prevention; children's seizures can be reduced or stopped completely. The debilitating malnutrition and stunting of NS children in Uganda could be partially independent of the syndrome but attributable to poor nutrition. NS as observed is not "invariably fatal" but rather a treatable neurological disorder.

A real-time medical cartography of epidemic disease (Nodding syndrome) using village-based lay mHealth reporters.

BACKGROUND: Disease surveillance in rural regions of many countries is poor, such that prolonged delays (months) may intervene between appearance of disease and its recognition by public health authorities. For infectious disorders, delayed recognition and intervention enables uncontrolled disease spread. We tested the feasibility in northern Uganda of developing real-time, village-based health surveillance of an epidemic of Nodding syndrome (NS) using software-programmed smartphones operated by minimally trained lay mHealth reporters. METHODOLOGY AND PRINCIPAL FINDINGS: We used a customized data collection platform (Magpi) that uses mobile phones and real-time cloud-based storage with global positioning system coordinates and time stamping. Pilot studies on sleep behavior of U.S. and Ugandan medical students identified and resolved Magpi-programmed cell phone issues. Thereafter, we deployed Magpi in combination with a lay-operator network of eight mHealth reporters to develop a real-time electronic map of child health, injury and illness relating to NS in rural northern Uganda. Surveillance data were collected for three consecutive months from 10 villages heavily affected by NS. Overall, a total of 240 NS-affected households and an average of 326 children with NS, representing 30 households and approximately 40 NS children per mHealth reporter, were monitored every week by the lay mHealth team. Data submitted for analysis in the USA and Uganda remotely pinpointed the household location and number of NS deaths, injuries, newly reported cases of head nodding (n = 22), and the presence or absence of anti-seizure medication. CONCLUSIONS AND SIGNIFICANCE: This study demonstrates the feasibility of using lay mHealth workers to develop a real-time cartography of epidemic disease in remote rural villages that can facilitate and steer clinical, educational and research interventions in a timely manner.

Could Nodding Syndrome (NS) in Northern Uganda be an environmentally induced alteration of ancestral microbiota?

Hippocrates stated in 460-C.370 BC that, "All diseases begin in the Gut." This statement may be beginning to have meanings in the advent of new diseases such as Nodding Syndrome (NS) and Autism Spectrum Disorder (ASD). Interestingly, a recent publication from China in the journal of microbiology in 2017 suggests that high grain diet had dynamically shifted the composition of mucosa-associated microbiota and induced mucosal Injuries in the colon of Sheep. NS is a devastating childhood neurological disorder characterized by atonic seizure, cognitive impairment, head nodding, wasting and stunted growth. In addition, NS in Northern Uganda is clustered in time (those who were in IDPs), in space (discretely observed on either sides of the two rivers of Aswa and Pager) and in person (onset mainly between the ages of 5-15 years) and therefore exhibits spatial temporality. The first case of NS was noticed in Kitgum district in 1997, one year after the reported displacement of that community into IDP. Prior to that internal displacement, there were no reported cases of NS. The same scenario occurred in the IDPs of Odek, Gulu district where the population was displaced into IDPs in 2001 and approximately a year later in 2002, cases of NS began to appear. In the IDPs, children that eventually developed NS fed nearly exclusively on food ration provided by relief agencies and roughly a year later, cases of NS began to appear. In the other East African countries, there were no reported cases of NS prior to internal displacement and dependence on food ration. The observed common factors in the three East African regions where NS occurs at endemic proportion are perhaps: Internal displacement and feeding on relief food. These researchers suggest that NS may have perhaps resulted from dietary and environmental factors during IDPs which may have been foreign to their GIT and links this observation to the concept of microbiota-gut-brain axis.

Alemtuzumab versus interferon ß-1a in early relapsing-remitting multiple sclerosis: post-hoc and subset analyses of clinical efficacy outcomes.

BACKGROUND: Alemtuzumab is a humanised monoclonal antibody that depletes lymphocytes, causing long-term immunomodulation. In a 3-year, rater-blinded phase 2 study (the CAMMS223 study) in patients with relapsing-remitting multiple sclerosis (RRMS), alemtuzumab reduced relapse rate and the risk of sustained accumulation of disability compared with subcutaneous interferon beta-1a, and the mean expanded disability status scale (EDSS) score of the alemtuzumab cohort improved compared with baseline. Adverse events included infusion-associated reactions, predominantly mild to moderate infections, thyroid disorders, and immune thrombocytopenia. In this study, we further analysed the CAMMS223 data with the aim of determining whether demographic and baseline disease-related characteristics affect the beneficial effects of alemtuzumab. Additionally, we aimed to describe a new outcome measure in multiple sclerosis research: sustained reduction in disability. METHODS: 334 treatment-naive patients with active, early RRMS were randomly assigned in a 1:1:1 ratio to receive interferon beta-1a (44 µg subcutaneously three times per week), or 24 mg per day or 12 mg per day alemtuzumab intravenously for 2 or 3 annual cycles. We analysed freedom from clinical disease activity (CDA; defined as no relapses and no sustained accumulation of disability) and occurrence of sustained reduction in disability (SRD; a ≥1 point decrease on the EDSS sustained for 6 consecutive months for patients with a baseline EDSS ≥2), and analysed efficacy outcomes for subgroups based on age, sex, geographic region, MRI-T1 brain volume, MRI-T2 lesion volume, disease duration, number of previous relapses within 2 years, and EDSS. FINDINGS: 322 patients were analysed. 161 of 215 patients treated with alemtuzumab were free of CDA at 36 months (Kaplan-Meier estimate 71·8%, 95% CI 63·1-78·8%) compared with 52 of 107 patients treated with interferon beta-1a (42·6%, 32·4-52·4%; hazard ratio [HR]=0·31, 0·20-0·46; p<0·0001). For the 199 patients with a baseline EDSS score greater than or equal to 2, SRD was more likely (HR=2·61, 1·54-4·43; p=0·0004) among patients treated with alemtuzumab (66 of 133 patients, Kaplan-Meier estimate 51·6%, 95% CI 43·2-60·7%) than patients treated with interferon beta-1a (15 of 66 patients, 27·2%, 17·2-41·4%). All disability and relapse outcomes showed evidence of beneficial effects of alemtuzumab compared with interferon beta-1a across all analysed patient subsets, and no subgroup of patients consistently responded better than others to alemtuzumab. INTERPRETATION: Alemtuzumab reduced disease activity compared with interferon beta-1a in most of the analysed subgroups. Significantly greater numbers of patients experienced sustained improvement in disability after treatment with alemtuzumab than interferon beta-1a. The efficacy offered by alemtuzumab is a substantial advance in the treatment of multiple sclerosis. FUNDING: Genzyme and Bayer Schering Pharma.

Long-term safety of NGX-4010, a high-concentration capsaicin patch, in patients with peripheral neuropathic pain.

CONTEXT: Postherpetic neuralgia (PHN) and painful human immunodeficiency virus-associated distal sensory polyneuropathy (HIV-DSP) are peripheral neuropathic pain syndromes that are difficult to treat. Current treatment options are often limited by poor tolerability. OBJECTIVES: The objective of the current open-label study was to assess the safety of repeated applications of NGX-4010, a high-concentration capsaicin patch (capsaicin 8%), over one year, in patients with moderate to severe PHN or HIV-DSP. METHODS: Patients had successfully completed a previous NGX-4010 study and had a pain level appropriate for further treatment. Eligible patients had not been treated with NGX-4010 within 12 weeks of study initiation. Patients received pretreatment with a topical local anesthetic (lidocaine 4%) for 60 minutes followed by either a 60-minute (PHN and HIV-DSP patients) or a 90-minute (HIV-DSP patients) treatment with NGX-4010. Patients could receive up to three additional treatments at intervals of > or = 12 weeks. Regardless of the number of treatments received, all patients were followed up for 48 weeks except for those withdrawing early. RESULTS: A total of 106 patients were enrolled and received a total of 293 NGX-4010 treatments. The most frequently reported treatment-emergent adverse events were transient, mild-to-moderate application site erythema, pain, edema, and papules. Small, transient pain-related increases in blood pressure during and immediately after NGX-4010 application were observed. There was no evidence of an increased incidence of adverse events, dermal irritation, intolerability, or impaired neurological function with repeated treatments. CONCLUSION: It is concluded that repeated treatments with NGX-4010 administered over a one-year period are generally safe and well tolerated.

Rituximab in relapsing-remitting multiple sclerosis: a 72-week, open-label, phase I trial.

We evaluated the safety, tolerability, pharmacodynamics, and activity of B-cell depletion with rituximab in patients with relapsing-remitting multiple sclerosis, receiving two courses of rituximab 6 months apart, and followed for a total of 72 weeks. No serious adverse events were noted; events were limited to mild-to-moderate infusion-associated events, which tended to decrease with subsequent infusions. Infections were also mild or moderate, and none led to withdrawal. Fewer new gadolinium-enhancing or T2 lesions were seen starting from week 4 and through week 72. An apparent reduction in relapses was also observed over the 72 weeks compared with the year before therapy.