Nodding syndrome (NS) is a neurologic disorder of unknown etiology characterized by vertical head nodding that has affected children aged 5-18 years in East Africa. Previous studies have examined relationships with biological agents (e.g., nematodes, measles, and fungi), but there is limited data on the possible contributions of neurotoxic environmental chemicals frequently used as pesticides/insecticides to the development and progression of this disorder. We examined the levels of persistent organochlorine pesticides (OCPs) in children (5-18 years old) from Kitgum District, Northern Uganda. These children previously lived in internally displaced people\'s (IDP) camps, where they were exposed to various health risks, including contaminated food and water. Exposure to OCPs through contaminated food and water is postulated here as a potential contributor to NS etiology. We analyzed serum (n = 75) and urine (n = 150) samples from children diagnosed with NS, and from seizure-free household controls (HC), and community controls (CC). Samples were extracted using solid-phase extraction (SPE) and extracts were analyzed for OCPs using gas chromatography with a triple quadrupole mass spectrometry (GC-MS/MS). Mean levels of total (∑) ∑OCPs in serum samples from NS, HC and CC subjects were 23.3 ± 2.82, 21.1 ± 3.40 and 20.9 ± 4.24 ng/mL, respectively, while in urine samples were 1.86 ± 1.03, 2.83 ± 1.42, and 2.14 ± 0.94 ng/mL, respectively. Correlation and linear regression analysis indicated that potential markers for ∑hexachlorocyclohexanes (HCHs), ∑chlordane compounds (CHLs), ∑endosulfan and ∑dichlorodiphenyltrichloroethanes (DDTs) were γ-HCH, heptachlor-exo-epoxide, endosulfan-α and p,p\'-DDD in NS cases while in controls were α -HCH, heptachlor, endosulfan-α and p,p\'-DDE, respectively. Since, in some instances, higher OCP levels were found in controls vs. NS cases, we conclude that exposure to organochlorine pesticides is unlikely to be associated with the etiology of NS.

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Can the antibiotic doxycycline unlock new possibilities in the fight against onchocerciasis-associated epilepsy (OAE)? Idro et al. explored this question by investigating for the first time doxycycline\'s impact on nodding syndrome (NS), a severe manifestation of OAE. Results reveal significant findings that may shape future treatment strategies.

OBJECTIVE: To assess long-term mortality and causes of death in children with nodding syndrome, an epileptic disorder of sub-Sahara Africa.
METHODS: Ten children with nodding syndrome were followed over 24 years. The mortality rate was determined as the number of deaths per 1000 person-years of observation. The standard mortality ratio (SMR) was calculated as the number of observed deaths divided by the number of expected deaths in the general population. Patients were started on phenobarbital and treatment response was monitored during the first 20 months of follow-up.
RESULTS: During an observation period of 89.8 person-years, eight patients had died, one patient was found alive, and one patient had been lost to follow-up. This corresponded to a mortality rate of 89.1 deaths per 1000 person-years and a SMR of 21.4 (95 % CI 6.6-36.2). Five deaths were related to status epilepticus, in two cases occurring after inadvertent drug withdrawal. All patients responded on phenobarbital with a reduction of seizure frequency but only four reached a seizure-free period of at least 6 months.
CONCLUSIONS: This long-term follow-up demonstrated high mortality in patients with nodding syndrome. Anti-seizure treatment with phenobarbital was of moderate efficacy. Abrupt interruption of phenobarbital was found leading to seizure aggravation, status epilepticus, and death. Our findings point out the importance of securing continuity of treatment access once anti-seizure therapy is included in health services in resource-poor settings. More rigorous observations and controlled studies are needed to improve the therapeutic options for nodding syndrome.

Nodding syndrome is an epileptic encephalopathy associated with neuroinflammation and tauopathy. This initially pediatric brain disease, which has some clinical overlap with Methyl-CpG-binding protein 2 (MECP2) Duplication Syndrome, has impacted certain impoverished East African communities coincident with local civil conflict and internal displacement, conditions that forced dependence on contaminated food and water. A potential role in Nodding syndrome for certain biotoxins (freshwater cyanotoxins plus/minus mycotoxins) with neuroinflammatory, excitotoxic, tauopathic, and MECP2-dysregulating properties, is considered here for the first time.

BACKGROUND: Nodding syndrome is a poorly understood neurological disorder that predominantly occurs in Africa. We hypothesised that nodding syndrome is a neuroinflammatory disorder, induced by antibodies to Onchocerca volvulus or its Wolbachia symbiont, cross-reacting with host neuronal proteins (HNPs), and that doxycycline can be used as treatment.
METHODS: In this randomised, double-blind, placebo-controlled, phase 2 trial, we recruited participants from districts affected by nodding syndrome in northern Uganda. We included children and adolescents aged 8-18 years with nodding syndrome, as defined by WHO consensus criteria. Participants were randomly assigned (1:1) to receive either 100 mg doxycycline daily or placebo for 6 weeks via a computer-generated schedule stratified by skin microscopy results, and all parties were masked to group assignment. Diagnoses of O volvulus and antibodies to HNPs were made using luciferase immunoprecipitation system assays and immunohistochemistry. The primary outcome was change in the proportion with antibodies to HNPs, assessed at 24 months. All participants were included in safety analyses, and surviving participants (those with samples at 24 months) were included in primary analyses. Secondary outcomes were: change in concentrations of antibodies to HNPs at 24 months compared with baseline; proportion of participants testing positive for antibodies to O volvulus-specific proteins and concentrations of Ov16 or OVOC3261 antibodies at 24 months compared with baseline; change in seizure burden, proportion achieving seizure freedom, and the proportions with interictal epileptiform discharges on the diagnostic EEG; overall quality of life; disease severity at 24 months; and incidence of all-cause adverse events, serious adverse events, and seizure-related mortality by 24 months. This trial is registered with ClinicalTrials.gov, NCT02850913.
RESULTS: Between Sept 1, 2016, and Aug 31, 2018, 329 children and adolescents were screened, of whom 240 were included in the study. 140 (58%) participants were boys and 100 (42%) were girls. 120 (50%) participants were allocated to receive doxycycline and 120 (50%) to receive placebo. At recruitment, the median duration of symptoms was 9 years (IQR 6-10); 232 (97%) participants had O volvulus-specific antibodies and 157 (65%) had autoantibodies to HNPs. The most common plasma autoantibodies were to human protein deglycase DJ-1 (85 [35%] participants) and leiomodin-1 (77 [32%] participants) and, in cerebrospinal fluid (CSF), to human DJ-1 (27 [11%] participants) and leiomodin-1 (14 [6%] participants). On immunohistochemistry, 46 (19%) participants had CSF autoantibodies to HNPs, including leiomodin-1 (26 [11%]), γ-aminobutyric acid B receptors (two [<1%]), CASPR2 (one [<1%]), or unknown targets (28 [12%]). At 24 months, 161 (72%) of 225 participants had antibodies to HNPs compared with 157 (65%) of 240 at baseline. 6 weeks of doxycycline did not affect the concentration of autoantibodies to HNPs, seizure control, disease severity, or quality of life at the 24-month follow-up but substantially decreased Ov16 antibody concentrations; the median plasma signal-to-noise Ov16 ratio was 16·4 (95% CI 6·4-38·4), compared with 27·9 (8·2-65·8; p=0·033) for placebo. 14 (6%) participants died and, other than one traffic death, all deaths were seizure-related. Acute seizure-related hospitalisations (rate ratio [RR] 0·43 [95% CI 0·20-0·94], p=0·028) and deaths (RR 0·46 [0·24-0·89], p=0·028) were significantly lower in the doxycycline group. At 24 months, 96 (84%) of 114 participants who received doxycycline tested positive for antibodies to Ov16, compared with 97 (87%) of 111 on placebo (p=0·50), and 74 (65%) participants on doxycycline tested positive for antibodies to OVOC3261, compared with 57 (51%) on placebo (p=0·039). Doxycycline was safe; there was no difference in the incidence of grade 3-5 adverse events across the two groups.
CONCLUSIONS: Nodding syndrome is strongly associated with O volvulus and the pathogenesis is probably mediated through an O volvulus induced autoantibody response to multiple proteins. Although it did not reverse disease symptoms, doxycycline or another prophylactic antibiotic could be considered as adjunct therapy to antiseizure medication, as it might reduce fatal complications from acute seizures and status epilepticus induced by febrile infections.
BACKGROUND: Medical Research Council (UK).
UNASSIGNED: For the Luo translation of the abstract see Supplementary Materials section.

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OBJECTIVE: The epilepsy prevalence in Maridi County, South Sudan, in 2018 was 43.8 (95% CI: 40.9-47.0) per 1000 persons; 85.2% of the identified persons with epilepsy (PWE) met the criteria of onchocerciasis-associated epilepsy. To address this health problem, an epilepsy clinic was established at Maridi County Hospital in 2020. In August 2023, the impact of the clinic on the lives of PWE and their families was evaluated.
METHODS: At the Maridi epilepsy clinic, data routinely collected by primary healthcare workers as part of patient care was reviewed. We also analyzed findings from two household surveys conducted in 2018 and 2022, which assessed the impact of the clinic on epilepsy care. Moreover, four households, each with four PWE, were visited in a high epilepsy prevalence area. PWE were examined by a neurologist, and in-depth interviews were conducted with family members.
RESULTS: The proportion of PWE on anti-seizure medication increased by 39.7% (95%CI: 35.3-44.2) between 2018 and 2022. The proportion of PWE reporting daily seizures decreased from 27.3% in 2018 to 5.3% in 2022. Of the 754 PWE seen in the clinic in July 2023, only 17 (2.3%) reported side effects. During household visits in July 2023, 13/173 (7.5%) of the visited PWE were found without remaining anti-seizure medication. A high level of epilepsy-related stigma was observed in all visited households.
CONCLUSIONS: The Maridi epilepsy clinic positively impacted the lives of PWE in Maridi. Similar initiatives should be accessible for all PWE living in onchocerciasis-endemic areas. Evidence-based information about OAE is needed to decrease misconceptions and epilepsy-related stigma.