Epilepsy Clinical Trial
Official title:
Clinical Features and Potential Etiology of Epilepsy and Nodding Syndrome in the Mahenge Area, Ulanga District
Background: Childhood epilepsy disorders are particular frequent in the area around Mahenge,
southern Tanzania and recent studies have described a novel type of epilepsy with repetitive
head nodding episodes and often progressive cognitive dysfunction. Despite the disease
affecting thousands in Tanzania, Uganda and South Sudan, etiology and pathogenesis of the
disorder termed Nodding Syndrome (NS) is still obscure as the phenotype remains imprecisely
described. Epidemiological associations with Onchocerca volvulus and Mansonella spp. were
noted at different African sites and remain robust even though no evidence for the presence
of O. volvulus in CSF or any previous contact with the CSF was found.
Hypothesis: With regard to the complex host immune reaction to O. volvulus, the investigators
hypothesize that the immune response against filariae might contribute to NS and epilepsy.
The investigators further assume that specific genetic traits might play a role in the
pathogenesis of NS.
Aims In the present study the investigators aim to examine if and how O. volvulus and/or
Mansonella spp. contribute to the pathology of NS/epilepsy and therefore intend to analyze
the filarial infection and the host immune response in affected children. To identify
inherited traits predisposing for epilepsy, NS or specific immune responses, a genetic workup
that includes whole-exome sequencing (WES) is performed. The clinical and EEG characteristics
are further defined. Cognitive impairment of people with epilepsy and NS is assessed using
the Wechsler Nonverbal Scale of Ability (WNV).
Study design: A cross-sectional observational (groups I-III) and a case-control (groups I-V)
study recruiting in total 250 patients and controls (I: people with NS, n=50; II: people with
epilepsy (PWE) and onchocerciasis, n=50; III: PWE without onchocerciasis, n=50; IV: controls
with onchocerciasis but otherwise healthy, n= 50; healthy controls without evidence for
onchocerciasis, n= 50) is performed to describe the clinical characteristics in children with
NS/epilepsy and to evaluate differences in infection and immune response between groups,
respectively. The WNV should be validated in 500 healthy controls to obtain reference data in
rural Africa.
Summary: In summary, the study aims to elucidate clinical characteristics and the
pathogenesis of NS/epilepsy in children of southern Tanzania and role of parasitic infection
as a cause for NS/epilepsy.
Childhood epilepsy disorders are particular frequent in low income countries and especially
common in the area around Mahenge, Ulanga region, southern Tanzania, with an epilepsy
prevalence of up to 39 per 1000 inhabitants. Therefore, in 1959 Prof. Louise Jilek-Aall
founded the Mahenge Epilepsy Clinic to provide basic care to people suffering from convulsive
disorders and to enable further in-depth investigations regarding epilepsy. In the summer of
2005, a multinational a team of researchers including the founder of the clinic, Prof. Louise
Jilek-Aall, Prof. Erich Schmutzhard, Dr. Andrea Winkler and Prof. William Matuja performed
several in-depth etiological investigations. In intensive field research they were able to
examine a large number of clinic patients and healthy controls, perform
electro-encephalographic and magnetic resonance studies and collect biological materials,
such as blood, cerebrospinal fluid (CSF) and skin samples for further sophisticated
laboratory tests in Europe. Among others, the studies confirmed the presence of a new type of
childhood epilepsy with repetitive head nodding episodes and often progressive cognitive
dysfunction. Even though the disease termed Nodding Syndrome (NS) affects thousands in
Tanzania, Uganda and South-Sudan, clinical, metabolic and EEG phenotypes are still
imprecisely described, and etiology and pathogenesis remain obscure. The high familial
occurrence and clustering within circumscribed villages and tribes suggests that genetic
traits might play a role. Epidemiological associations with Onchocerca volvulus and
Mansonella spp. were noted at different African sites. Despite lacking evidence for the
presence of O. volvulus in the CSF the association to NS remains robust.
This is basis for the present study where the investigators aim to examine if and how O.
volvulus and/or Mansonella spp. contribute to the pathology of NS, elucidate associated
genetic traits, further specify the clinical, metabolic and EEG phenotypes. The investigators
will use a cross-sectional observational design including children with NS and epilepsy in
order to describe the clinical characteristics and a case-control design to evaluate
associated factors.
It is intended to enroll 250 patients and controls between 3 and 18 years of age (I: people
with NS, n=50 (inclusion according to the WHO case definition from the first "International
Conference on Nodding Syndrome", Kampala, Uganda, July 2012); II: people with epilepsy (PWE)
and onchocerciasis, n=50; III: PWE without onchocerciasis, n=50; IV: controls with
onchocerciasis but otherwise healthy, n= 50; healthy controls without evidence for
onchocerciasis, n= 50). Patients with cardiovascular or renal comorbidities, a history of
birth or traumatic brain injuries, lacking or withdrawing consent will be excluded. Groups II
to V will be matched to Group I for age, gender and social status.
The investigators intend to analyze the filarial infection and host immune response in
affected children compared to unaffected controls. PCR assays will be performed to
characterize Onchocerca and Mansonella spp. strains found in patients with NS/PWE and
determine Wolbachia loads and features. A novel unique biomarker,
N-acetyltyramine-O,ß-glucuronide (NATOG) will be determined to quantify infection with O.
volvulus and correlated with other markers that define the host immune response and immune
regulation (e.g. regulatory T cells (Treg), cytokines). As polymorphisms in the
multidrug-resistance gene 1 (MDR-1) that alter p-glycoprotein expression or function may
enhance neurotoxicity of widely used antihelmintic drugs, single nucleotide polymorphism
(SNP)-arrays will be determined to investigate if specific polymorphisms might be associated
with NS. In addition, the investigators aim to define the clinical picture and course of NS
and conduct further EEG investigations and validated neuropsychological tests, follow up
patients of previous studies and perform metabolic analyses to specify the metabolic
characteristics of NS. A genetic workup that includes whole-exome sequencing (WES) to
identify traits predisposing to epilepsy, NS or specific immune responses is scheduled.
In summary, the study aims to elucidate factors that contribute to the high prevalence of NS
and epilepsy in the Mahenge area in Southern Tanzania. Also, the research project will have
immediate benefits for the population under investigation as people newly diagnosed with
epilepsy will be offered treatment at the Mahenge Epilepsy Clinic and staff, patients and
relatives will receive further education regarding epilepsy, thereby contributing to
sustainability of a standardized approach to care for children with NS and PWE. Conclusions
drawn from our study will not only relate to the Mahenge area, but may be applicable to vast
numbers of children with NS (northern Uganda and South Sudan) and PWE in other areas.
Dissemination of the data through scientific meetings and publications may stimulate further
research regarding risk factors for epilepsy in the low income countries.
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