Browsing by Author "Akun, Pamela"

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    Asymptomatic malaria parasitaemia and seizure control in children with nodding syndrome; a cross-sectional study
    (BMJ open, 2018) Ogwang, Rodney; Anguzu, Ronald; Akun, Pamela; Ningwa, Albert; Kayongo, Edward; Idro, Richard
    Plasmodium falciparum is epileptogenic and in malaria endemic areas, is a leading cause of acute seizures. In these areas, asymptomatic infections are common but considered benign and so, are not treated. The effects of such infections on seizures in patients with epilepsy is unknown. This study examined the relationship between P. falciparum infection and seizure control in children with a unique epilepsy type, the nodding syndrome.
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    Doxycycline for the treatment of nodding syndrome: a randomised, placebo-controlled, phase 2 trial
    (Elsevier Ltd, 2024-07) Idro, Richard; Ogwang, Rodney; Anguzu, Ronald; Akun, Pamela; Ningwa, Albert; Abbo, Catherine; Giannoccaro, Maria P; Kubofcik, Joseph; Mwaka, Amos D; Nakamya, Phellister; Opar, Bernard; Taylor, Mark; Nutman, Thomas B; Elliott, Alison; Vincent, Angela; Newton, Charles R; Marsh, Kevin
    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.BACKGROUNDNodding 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.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.METHODSIn 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.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.FINDINGSBetween 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.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.INTERPRETATIONNodding 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.Medical Research Council (UK).FUNDINGMedical Research Council (UK).For the Luo translation of the abstract see Supplementary Materials section.TRANSLATIONFor the Luo translation of the abstract see Supplementary Materials section. MEDLINE - Academic
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    Epilepsy in Onchocerca volvulus Sero-Positive Patients From Northern Uganda—Clinical, EEG and Brain Imaging Features
    (Frontiers in Neurology, 2021) Ogwang, Rodney; Ningwa, Albert; Akun, Pamela; Bangirana, Paul; Anguzu, Ronald; Mazumder, Rajarshi; Abbo, Catherine; Mwaka, Amos Deogratius; Idro, Richard
    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 Onchocerca volvulus may be an underlying risk factor for the high burden and based upon epidemiological associations, has been proposed to cause a group of disorders—Onchocerca 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 Onchocerca volvulus (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.
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    Household poverty, schooling, stigma and quality of life in adolescents with epilepsy in rural Uganda
    (Epilepsy & Behavior, 2021) Anguzu, Ronald; Akun, Pamela; Katairo, Thomas; Abbo, Catherine; Ningwa, Albert; Ogwang, Rodney; Mwaka, Amos Deogratius; Idro, Richard
    Epilepsy remains a leading chronic neurological disorder in Low- and Middle-Income Countries. In Uganda, the highest burden is among young rural people. We aimed to; (i) describe socio-economic status (including schooling), and household poverty in adolescents living with epilepsy (ALE) compared to unaffected counterparts in the same communities and (ii) determine the factors associated with the overall quality of life (QoL). This was a cross-sectional survey nested within a larger study of ALE compared to age-matched healthy community children in Uganda. Between Sept 2016 to Sept 2017, 154 ALE and 154 healthy community controls were consecutively recruited. Adolescents recruited were frequency and age-matched based on age categories 10–14 and 15–19 years. Clinical history and standardized assessments were conducted. One control participant had incomplete assessment and was excluded. The primary outcome was overall QoL and key variables assessed were schooling status and household poverty. Descriptive and multivariable linear regression analysis were conducted for independent associations with overall QoL. Mean (SD) age at seizure onset was 8.8 (3.9) years and median (IQR) monthly seizure burden was 2 (1–4). Epilepsy was associated with living in homes with high household poverty; 95/154 (61.7%) ALE lived in the poorest homes compared to 68/153 (44.5%) of the healthy adolescents, p = 0.001. Nearly two-thirds of ALE had dropped out of school and only 48/154 (31.2%) were currently attending school compared to 136/153 (88.9%) of healthy controls, p < 0.001. QoL was lowest among ALE who never attended school (p < 0.001), with primary education (p = 0.006) compared to those with at least secondary education. Stigma scores [mean(SD)] were highest among ALE in the poorest [69.1(34.6)], and wealthy [70.2(32.2)] quintiles compared to their counterparts in poorer [61.8(31.7)], medium [68.0(32.7)] and wealthiest [61.5(33.3)] quintiles, though not statistically significant (p = 0.75). After adjusting for covariates, ALE currently attending school had higher overall QoL compared to their counterparts who never attended school (β = 4.20, 95%CI: 0.90,7.49, p = 0.013). QoL scores were higher among ALE with ≥secondary education than those with no or primary education (β = 10.69, 95%CI: 1.65, 19.72). rural area are from the poorest households, are more likely to drop out of school and have the lowest QoL. Those with poorer seizure control are most affected. ALE should be included among vulnerable population groups and in addition to schooling, strategies for seizure control and addressing the epilepsy treatment gap in affected homes should be specifically targeted in state poverty eradication programs.
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    Risk Factors for Nodding Syndrome and Other Forms of Epilepsy in Northern Uganda: A Case-Control Study
    (Pathogens, 2021) Gumisiriza, Nolbert; Kugler, Marina; Mubiru, Frank; Anguzu, Ronald; Ningwa, Albert; Ogwang, Rodney; Akun, Pamela; Mwaka, Amos Deogratius; Abbo, Catherine; Sekibira, Rogers; Idro, Richard
    Epidemiological studies suggest a link between onchocerciasis and various forms of epilepsy, including nodding syndrome (NS). The aetiopathology of onchocerciasis associated epilepsy remains unknown. This case-control study investigated potential risk factors that may lead to NS and other forms of non-nodding epilepsy (OFE) in northern Uganda. We consecutively recruited 154 persons with NS (aged between 8 and 20 years), and age-frequency matched them with 154 with OFE and 154 healthy community controls. Participants’ socio-demography, medical, family, and migration histories were recorded. We tested participants for O. volvulus serum antibodies. The 154 controls were used for both OFE and NS separately to determine associations. We recruited 462 people with a median age of 15 years (IQR 14, 17); 260 (56.4%) were males. Independent risk factors associated with the development of NS were the presence of O. volvulus antibodies [aOR 8.79, 95% CI (4.15–18.65), p-value < 0.001] and preterm birth [aOR 2.54, 95% CI (1.02–6.33), p-value = 0.046]. Risk factors for developing OFE were the presence of O. volvulus antibodies [aOR 8.83, 95% CI (4.48–17.86), p-value < 0.001] and being born in the period before migration to IDP camps [aOR 4.28, 95% CI (1.20–15.15), p-value = 0.024]. In conclusion, O. volvulus seropositivity was a risk factor to develop NS and OFE; premature birth was a potential co-factor. Living in IDP camps was not a risk factor for developing NS or OFE.