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For Peer Review Only Journal: BMJ Open BMJ Open BMJ Open: first published as 10.1136/bmjopen-2012-002540 on 3 May 2013. Downloaded from Nodding Syndrome in Ugandan Children - Clinical features, Brain imaging and Complications; an observational case series For peer review only Journal: BMJ Open Manuscript ID: bmjopen-2012-002540 Article Type: Research Date Submitted by the Author: 27-Dec-2012 Complete List of Authors: Idro, Richard; Mulago Hospital/Makerere University, Department of Paediatrics and Child Health; Oxford University , Nuffield Department of Medicine Opoka, Robert; Mulago Hospital/Makerere University, Department of Paediatrics and Child Health Aanyu, Hellen; Mulago Hospital/Makerere University, Department of Paediatrics and Child Health Kakooza, Angelina; Mulago Hospital/Makerere University, Department of Paediatrics and Child Health Piloya, Theresa; Mulago Hospital/Makerere University, Department of Paediatrics and Child Health Namusoke, Hanifa; Mulago Hospital/Makerere University, Department of Paediatrics and Child Health http://bmjopen.bmj.com/ Musoke, Sarah; Mulago Hospital/Makerere University, Department of Paediatrics and Child Health Nalugya, Joyce; Mulago Hospital/Makerere University, Department of Psychiatry Mwaka, Amos; Mulago Hospital/Makerere University, Department of Internal Medicine White, Steven; Great Ormond Street hospital for Children, Department of Neurophysiology Chong, Kling; Great Ormond Street hospital for Children, Department of on September 23, 2021 by guest. Protected copyright. Neuroradiology Atai-Omoruto, Anne; Mulago Hospital/Makerere University, Department of Community Medicine and Family Health Mworozi, Edison; Mulago Hospital/Makerere University, Department of Paediatrics and Child Health Nankunda, Jolly; Mulago Hospital/Makerere University, Department of Paediatrics and Child Health Kiguli, Sarah; Mulago Hospital/Makerere University, Department of Paediatrics and Child Health Aceng, Jane; Ministry of Health, Headquarters Tumwine, James; Ministry of Health, Headquarters <b>Primary Subject Paediatrics Heading</b>: Secondary Subject Heading: Neurology Keywords: Paediatric neurology < PAEDIATRICS, Epilepsy < NEUROLOGY, For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 1 of 26 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2012-002540 on 3 May 2013. Downloaded from 1 2 3 4 Developmental neurology & neurodisability < PAEDIATRICS 5 6 7 8 9 10 11 12 13 14 15 For peer review only 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 http://bmjopen.bmj.com/ 34 35 36 37 38 39 40 41 on September 23, 2021 by guest. Protected copyright. 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 2 of 26 1 BMJ Open: first published as 10.1136/bmjopen-2012-002540 on 3 May 2013. Downloaded from 1 2 3 NODDING SYNDROME IN UGANDAN CHILDREN - CLINICAL FEATURES, BRAIN IMAGING 4 5 AND COMPLICATIONS; AN OBSERVATIONAL CASE SERIES 6 7 8 Author’s names 9 10 Richard Idro, Robert Opika Opoka, Hellen Aanyu, Angelina Kakooza-Mwesige, Theresa Piloya, 11 Hanifa Namusoke, Sarah Bonita Musoke, Joyce Nalugya, Paul Bangirana, Amos Deogratius 12 13 Mwaka, Steven White, Kling Chong, Anne D Atai-Omoruto, Edison Mworozi, Jolly Nankunda, 14 15 Sarah Kiguli, JaneFor Ruth Aceng, peer James K Tumwinereview only 16 17 18 1Department of Paediatrics, Mulago hospital/Makerere University College of Health 19 20 Sciences, Kampala, Uganda 21 2Centre for Tropical Medicine, Nuffield Department of Medicine, Oxford University 22 3 23 Department of Psychiatry, Mulago hospital/Makerere University College of Health 24 Sciences, Kampala, Uganda 25 26 4Department of Internal Medicine, Mulago hospital/Makerere University College of Health 27 28 Sciences, Kampala, Uganda 29 5Department of Neurophysiology, Great Ormond Street hospital for Children, London, UK 30 31 6Department of Neuro-Radiology, Great Ormond Street hospital for Children, London, UK 32 7 33 Department of Community Health and Family Medicine, Mulago hospital/Makerere http://bmjopen.bmj.com/ 34 University College of Health Sciences, Kampala, Uganda 35 8 36 Ministry of Health Head Quarters, Kampala, Uganda 37 38 39 Correspondence to Dr Richard Idro, Department of Paediatrics, Mulago hospital/ 40 41 Makerere University College of Health Sciences, P.O Box 7072, Kampala, Uganda on September 23, 2021 by guest. Protected copyright. 42 Email: [email protected] 43 44 45 46 Tel: +256-41-531875 47 48 49 Word count 50 51 Abstract 296 52 Text 3,546 53 54 55 56 57 58 59 60 1 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 3 of 26 BMJ Open 2 BMJ Open: first published as 10.1136/bmjopen-2012-002540 on 3 May 2013. Downloaded from 1 2 3 ABSTRACT 4 5 Objectives: Nodding syndrome is a devastating neurological disorder of uncertain aetiology 6 7 affecting children in Africa. There is no diagnostic test and risk factors and symptoms that would 8 allow early diagnosis are poorly documented. This study aimed to describe the clinical, 9 10 neurophysiologic and brain imaging (MRI) features and complications of nodding syndrome in 11 Ugandan children. 12 13 14 15 Design: Case seriesFor peer review only 16 Participants: 22 children with nodding syndrome brought to Mulago National Referral hospital 17 18 for assessment. 19 20 Outcome measures: Clinical features, physical and functional disabilities, electro- 21 encephalogram (EEG) and brain MRI findings and a staging system with a progressive 22 23 development of symptoms and complications. 24 25 26 Results 27 28 The median age of symptom onset was 6(range 4-10) years and median duration of symptoms 29 was 8.5(range 2-11) years. Sixteen of 22 families reported multiple affected children. Physical 30 31 manifestations and complications included stunting, wasting, lip changes and gross physical 32 33 deformities. The bone age was delayed by 2(range 1-6) years. There was peripheral muscle http://bmjopen.bmj.com/ 34 wasting and progressively, generalised wasting. Four children had nodding as the only seizure 35 36 type; 18 in addition had myoclonic, absence and generalised tonic-clonic seizures developing 1- 37 3years in the course of illness. Psychiatric manifestations included wandering, aggression, 38 39 depression and disordered perception. Cognitive assessment in 3 children demonstrated 40 41 profound impairment. The EEG was abnormal in all, suggesting symptomatic generalized on September 23, 2021 by guest. Protected copyright. 42 epilepsy. There were different degrees of cortical atrophy on brain MRI but no hippocampal 43 44 changes. Five stages with worsening physical, EEG and brain imaging features were identified: 45 46 a prodrome, development of head nodding and cognitive decline, other seizure types, multiple 47 complications, and severe debilitation. 48 49 50 Conclusions 51 52 Nodding syndrome is a neurologic disorder that may be characterised as probably symptomatic 53 54 generalized epilepsy. Clinical manifestations and complications develop in stages which might 55 be useful in defining treatment and rehabilitation. Studies of risk factors, pathogenesis, 56 57 management, and long-term outcome are urgently needed. 58 59 60 2 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 4 of 26 3 BMJ Open: first published as 10.1136/bmjopen-2012-002540 on 3 May 2013. Downloaded from 1 2 3 ARTICLE SUMMARY 4 5 6 7 Article focus 8 • This paper offers detailed descriptions of the clinical features and complications of 9 10 nodding syndrome in Ugandan children and the neurophysiologic and brain imaging 11 12 features. 13 • It also proposes a clinical staging system for the disease. 14 15 For peer review only 16 Key messages 17 18 • Nodding syndrome is an epidemic neurologic disorder affecting children in parts of sub- 19 20 Saharan Africa that may be characterised as probably symptomatic generalized epilepsy 21 and with features of an epileptic encephalopathy. 22 23 • Patients progressively develop both physical and functional deficits including multiple 24 25 seizure types, cognitive and physical decline, malnutrition, and psychiatric features. Five 26 such stages could be identified. 27 28 • The proposed clinical stages are associated with worsening cortical atrophy on brain 29 30 imaging and more severe epileptiform and background EEG changes. These stages 31 may be useful in guiding treatment and rehabilitation. 32 33 http://bmjopen.bmj.com/ 34 35 Strengths and limitations of this study 36 • Although the sample size is small and there is no comparison group, this is the first 37 38 study to carefully document a range of co-morbidities and complications in nodding 39 40 syndrome, describe the natural history and provide a staging system, and combine these 41 with extensive neurophysiology and brain imaging data. on September 23, 2021 by guest. Protected copyright. 42 43 • The study patients however may not be representative of the population as they were 44 not randomly drawn from the community. 45 46 • The study did not investigate aetiology and the proposed staging was derived from 47 48 parental descriptions rather than prospective observations and therefore suffers from 49 recall. 50 51 • The resolution of our brain MRI images is quite low. 52 53 54 55 56 57 58 59 60 3 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 5 of 26 BMJ Open 4 BMJ Open: first published as 10.1136/bmjopen-2012-002540 on 3 May 2013. Downloaded from 1 2 3 BACKGROUND 4 5 Nodding syndrome is an emerging and devastating neurological disorder of uncertain aetiology 6 7 affecting children in sub-Saharan Africa. Current estimates suggest there are about 10,000 8 affected children1. The syndrome was first reported in Tanzania in 1960’s2 and subsequent 9 3 4-6 7 8 10 reports have come from Liberia , South Sudan and Uganda . The syndrome is characterized 11 by head nods, now determined as atonic seizures, often in association with feeding and 12 13 development of other seizure types and cognitive decline6 9.
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