Implementation of international guidelines for the treatment of epileptic spasms, is challenging when access to adrenocorticotrophic hormone (ACTH) and vigabatrin is restricted, especially in Low and Middle Income Countries (LMIC). Oral corticosteroids are alternative interventions but evidence for the optimal agent, dose, duration, efficacy and long-term effects are lacking. A systematic review of the literature was performed to assess the quality of evidence of prednisone and prednisolone (oral corticosteroids) for the management of epileptic spasms. There is level C recommendation based on class III evidence to support the efficacy of oral corticosteroids for the acute clinical control of epileptic spasms and EEG resolution. Efficacy of oral corticosteroids in comparison to the internationally recommended intervention of ACTH has class IV evidence supporting level U recommendation. Similarly, there is no data on the risk of relapse with oral corticosteroids (class IV, level U), compared to ACTH. There is class IV evidence supporting level U recommendation for the safety of oral corticosteroids and class II evidence for level B recommendation for ACTH. In terms of oral corticosteroids and effects on long-term development there is class IV evidence leading to level U recommendation, compared to class III evidence supporting level C recommendation for ACTH. Randomized controlled studies are needed to compare oral corticosteroids with ACTH, the optimal dosage and regimen as well as the long-term neurodevelopmental outcomes. Based on the limited existing studies a treatment guideline for LMIC is proposed which could be used to standardize interventions permitting clarification of these unmet questions.

Hormonal control of developmental cell death is the best-established mechanism of neural sexual differentiation. For example, the spinal nucleus of the bulbocavemosus (SNB) is a sexually-dimorphic cluster of motoneurons in the lumbar spinal cord that innervates perineal muscles. Testosterone acts during a perinatal critical period to reduce cell death, and as a result, male rodents have more and larger SNB motoneurons than do females. Conversely, testosterone increases cell death in the anteroventral penventricular nucleus (AVPV), making it larger in females than in males. The Bcl-2 family of proteins has been implicated in mediating developmentally-regulated cell death. The ratio of pro-life (e.g., Bcl-2) to pro-death (e.g., Bax) family members apparently determines a cell's fate. We found that Bcl-2 overexpression increased neuron number in the SNB of females and in the AVPV of males. By contrast, Bcl-2 overexpression increased cell number equally in both sexes in the retrodorsolateral nucleus (RDLN), a spinal nucleus in which cell number is neither sexually dimorphic nor affected by perinatal hormone treatments. An immunocytochemical analysis indicated that Bcl-2, Bcl-xL and Bax are normally present in SNB motoneurons during the perinatal critical period, although their role in mediating SNB apoptosis is unclear. In adulthood, testosterone no longer determines SNB motoneuron survival, but does regulate soma size and dendritic extent. The continued expression of Bcl-2 family members in some neurons after the cell death period suggests additional roles beyond the regulation of cell death. I found that castration of adult male rats reduced Bcl-2 immunoreactivity in SNB motoneurons, and this reduction could be prevented by testosterone; Bax expression was not affected. Although the adult plasticity of SNB motoneurons is well characterized in rats, it has not been elucidated in mice. Four weeks following castration, soma size and dendritic extent shrink in rat SNB motoneurons. However, we showed that in the B6D2F1 strain of mouse, soma size decreased 6 and 12 weeks following castration, but dendritic extent remained unchanged. In addition, although Bcl-2 appears to be regulated by testosterone in the SNB motoneurons of adult rats, overexpression of Bcl-2 could not compensate for castration-induced soma size changes in the mouse SNB.

Includes abstract. Includes bibliographical references.

Background Muscular dystrophies (MD) and myopathies are a distinct group of clinically and genetically heterogeneous inherited muscle diseases. They cause muscle weakness often with cardiac, pulmonary, and musculoskeletal dysfunction, leading to reduced longevity. MDs and myopathies present across all life stages. Delineation of this condition and specifically the subgroups with additional connective tissue involvement is poorly described in subSaharan African populations. Aim To delineate the phenotypic, and where possible genotypic expression, of muscular dystrophies and myopathies with connective tissue involvement in an African setting. Methods A retrospective cohort study was undertaken of children with muscular dystrophy / myopathy and connective tissue involvement who attend a dedicated neuromuscular service. Patient demographics, diagnosis and clinical profile was collated. Patients were allocated into two groups, congenial /infantile and childhood, based on age of onset. Muscle biopsy characteristics, biochemical findings, and where available, genetic analysis were captured. Based on the combined findings children were categorised into connective tissue variant groups i.e., Collagen 6 related myopathies, Rigid Spine Syndrome (SELENON phenotype), LMNA-related, ACTA1 related myopathies, MDC1A, and a subgroup who could not be categorised. Descriptive statistics and categorical variables were compared to evaluate primary study questions. Ethical approval was obtained by the University of Cape Town Human Research Ethics Committee (HREC:549/2019). Families gave informed consent prior to enrolment. Results A total of 57 children were reviewed, 50 of whom met the inclusion criteria of connective tissue spectrum in the setting of muscle disease (female to male ratio 1.3:1). There was a predominance in children from African ancestries, followed by those of European descent. 31/50 (62%) presented in the congenital-infantile age period, the remainder presented after 2 years of age. Children with congenital/infantile onset were more likely to lose independent ambulation compared to children with childhood onset (5/8, 62% vs 3/8 38%). Scoliosis complicated the course in 29/50 (58%) children, again affecting congenital/infantile onset children more when compared to the childhood onset group (19/29, 65%, vs 10/29,35%); (p=0.003), and spinal rigidity was more prevalent in the congenital/infantile onset compared to the childhood group, (8/11 (73%) vs 3/11 (27%)). The childhood group were statistically more at risk of suffering compromising respiratory muscle dysfunction (32/45, 71%, vs 13/45,29%) ;(p=0.04 ). Genetic diagnosis was available for 9 patients. Based on this and the combined phenotypes n=17 were considered part of the Collagen 6 group, n=7 Rigid Spine Syndrome and n=14 LMNA spectrum, n=3 under the ACTA1 mutation expression, n=2 LAMA2 and the remaining 7 could not be categorized or did not fall under one of the main groupings. Conclusion This study confirmed expression of this subgroup of muscular diseases with connective tissue involvement within the SSA population. The burden of disease from these conditions is across multiple systems and significant, requiring specialized care. Early recognition and referral to neuromuscular centre, would improve the potential outcomes for these children with collaborative multidisciplinary team. Serum creatine kinase (CK) levels and clinical markers such as rigid spine, dropped head, and skin laxity could be used in resource limited settings for probable and possible phenotype.

Background: Epilepsy is largely a clinical diagnosis based on the patient's history. Neurological examination, interictal electroencephalogram and neuroimaging can all be normal in patients with epilepsy. Making the correct diagnosis in patients with suspected epilepsy is often difficult. Studies show that some 30% of patients are incorrectly diagnosed as suffering from epilepsy. Further, the diagnosis and treatment of epilepsy is often delayed. In the majority of patients, the diagnosis of epilepsy depends on the description of the attack by a witness but the inter-observer interpretations of verbal descriptions of events can be diverse and challenging. The use of mobile phone video recordings has gained worldwide prominence in recent years, including resource limited settings. This study explores the utility of mobile phone video recordings of paroxysmal events as adjuncts in the diagnosis of epilepsy, particularly in resource poor settings where there may exist significant diagnostic delays and misdiagnoses with far reaching implications on resource allocation and poor clinical outcomes. The aim of the study is to assess the accuracy of witness and referring clinician descriptions and to determine the impact, ideally enabling earlier diagnosis and management, of the use of home video recordings i.e the accuracy and timeliness of epilepsy diagnosis in paediatrics with the aim of improving practice in our setting. The existing literature is explored to guide optimal outcomes and ethical approaches to the tool which can be adapted for the paediatric setting. Objective: This study aims at outlining the utility of home videos in the diagnosis of paediatric epilepsy, and specifically describing how home videos influence the accuracy and timeliness of epilepsy diagnosis in clinical practice. Study design: This study has several arms, firstly a literature review to establish the current body of knowledge and established common practice for this intervention. The literature review critiques if there is an accepted and normed model for the use of this tool or existing evidence to support its use beyond anecdotal practice. Further, to define the apparent advantages and potential disadvantages of the intervention and to identify and develop subsequent study questions for a future prospective arm of the study. This will include questions relating to optimal recommended models for the intervention and safe ethical practice. To further assist with this consolidation of data a convenience sampling of videos randomly sent through to the neurology department over the previous year were retrospectively reviewed to assess the nature and route of the referral, the information included, the quality of the video, any ethical or safety concerns and any subsequent change in practice. Results: Eight studies met the inclusion criteria. Methodologies varied, only three included videos of children and quality of the videos was formally scored in two. Overall the studies supported that home videos of good quality had a role in assisting in the differentiation of epilepsy from non-epileptic events, this outcome increased in the setting that history was provided and with the level of experience of the clinician. Studies did not focus on the ethics or risks of home videos and for some of the studies only a small proportion of the epilepsy client load were able to provide video material. Outcome: Data relating to the role of home video of events in children is overall lacking. There are no official guidelines recommended to families for the acquisition of good quality videos in the management and assessment of seizures. Further, the ethical implications of transfer of sensitive recorded material has not been adequately addressed for this group.

Includes bibliographical references (leaves 76-82). / The spectrum of central nervous system manifestations of DMD is less well described than its musculoskeletal aspects. Although international studies have reported intellectual function ranging from above-average to severe intellectual disability, they have consistently found the average full-scale IQ of affected boys to be reduced by approximately one standard deviation. Fewer reports are available for DMD boys in the pre-school age group. There is also limited data on the behavioural profile of boys with this condition. No material on these aspects of DMD in South African children has been published to date. This pilot case control study aimed to determine the neurocognitive and behavioural phenotype of a cohort of South African children with a confirmed diagnosis of Duchenne muscular dystrophy as compared to the profile of a matched control cohort of children.

Includes bibliographical references (leaves 63-70). / Tuberous sclerosis complex (TSC) is a genetically inherited condition that manifests with benign non-invasive tumours or hamartomas in multiple organ systems. The condition is of autosomal dominant inheritance with an estimated incidence of 1 in 6000 live births. Population based studies estimate the prevalence of TSC to be 1 per 14, 492 population. TSC has myriad presentations but 80 to 90% of these children have seizure disorders. The prevalence of learning disabilities in children with TSC ranges from 38% to 80%. Pervasive developmental disorders (PDD) and attention deficit hyperactivity disorder have been identified in half of the children with TSC. Cutaneous manifestations occur in more than 90% of TSC patients. Cortical tubers, cardiac rhabdomyomas and renal angiomyolipomas are other lesions associated with TSC in children. Currently TSC has no cure and associated complications manifest with advancing age. Parents are faced with the challenge of life long care for these children. Half of the parents of children with TSC suffer significant psychological stress. Child specific factors, health literacy, and social stability are some factors known to impact on parental understanding of a child's chronic illness. Data specific to parental understanding of TSC are limited. Methodology: A retrospective case note review was performed to obtain the patient demographic and clinical presentation data. A prospective observational study provided the parental background characteristics and information on their understanding of TSC. Results: A total of 31 patient case notes were included in the review. The median patient age at the time of data was 132 months (IQR 96.00). The male: female ratio was 4:1. Seizures were observed in 27 patients (87.1%). Infantile spasms were reported in 3 (9.6%) patients while partial seizures occurred in 11 (35.5%) patients. More than one anticonvulsant was required in 15 (48.4%) of the 27 patients with seizures. Fourteen (53.8%) had global developmental delay. Two children (6.4%) were both hyperactive and aggressive and six (19.3%) were considered hyperactive. Aggressive behaviour was observed in four (12.9%) other children. Parents of 21 patients gave consent to participate in the study. The median parental age was 38 years (IQR 10.5). Seven parents (33.3%) had attained a primary level of education. Secondary education was attained by ten parents (47.6%) and three (14.3%) had received tertiary education. A statistically significant difference, p value =0.001, was observed in the change in the level of knowledge on comparison between the parent group that received a leaflet and the one that did not. A parental level of education of grade 8 was associated with a significantly higher baseline knowledge score (p value = 0.045) and a significantly greater change in the level of knowledge score (p value = 0.003). No association was detected between a parent's duration of clinic attendance and the baseline level of knowledge (p value = 0.63) There was no association between a parents baseline level of knowledge and their assessment of the impact of TSC on their child. (p value = 0.61). Conclusions and recommendations: The clinical profile of the cohort of children seen at the Red Cross Children's Hospital is similar to that of other cohorts described in literature. Parental understanding of TSC can be improved by provision of written information for those with at least a grade eight level of education. The information leaflet used in this study can be used to educate parents of children with TSC.

Includes synopsis. / Incldues bibliographical references (p. 195-220). / Peripheral nerve disease was described by Galen (AD 130-200) over a thousand years ago.(3) Detailed anatomical illustrations were documented by Andreas Vesalius in his major work 'De humani corporis fabrica' in 1543.(4) Over the last two centuries an explosion in knowledge in the area has occurred, with a further exponential increase in the last 20 years mostly related to understandings in the field of molecular genetics.(5) Although some degree of diagnostic closure was possible for a number of the hereditary peripheral neuropathies, this has not been the end point of knowledge but only the beginning.

Rationale: The paucity of access to electroencephalograms (EEGs) in sub-Saharan Africa results in a high patient load attending the few centres with neurophysiology units. Sleep state for EEGs performed on children improves yield and reduces artefact. Melatonin induces “natural sleep” without the risk of airway compromise. This study evaluated the effectiveness of oral melatonin in attainment of useful electroencephalograms in South African children. Methods: Consecutive children booked for routine EEG who were either unable to cooperate or were referred for sleep EEG received oral melatonin (3mg < 15kg; 6mg > 15kg) (September 2013-March 2014). Comparison was made to a retrospective control group who received the previous sleep protocol agent, chloral hydrate. Outcome measures were the proportion of children who achieved sleep, useful EEG study data, sleep latency and duration, presence and level of artifacts and presence of recorded EEG study abnormalities. Results: 173 children were recruited, 88 (51%) male, median age 4 years 9 months (interquartile range of 2 years 2 months – 7 years 6 months). 87% of the children achieved stage 2 sleep and were deemed to have successfully entered sleep state. The median sleep latency was 44.5 minutes and the duration of sleep was 25 minutes (range 18.5 – 29 minutes). Children showed no signs of post-sedation irritability or persistent drowsiness. They were awoken and were immediately able to go home. In the melatonin group there were no adverse events, and no child needed their study deferred due to inter-current illnesses. All children administered melatonin cooperated and permitted a successful EEG recording with useful records even if sleep was not achieved. Sedation with melatonin was less successful (74% compared to 88%) in children with developmental and behavioural problems (χ 2 = 6.18, P= 0.046), they also had higher rate of artifacts (χ 2 = 5.83, P=0.05). 33.5% of the study group children (n=58) had abnormal EEG studies. These outcomes were comparable to a historical cohort of age equivalent children who were sedated with chloral hydrate (45.5%) (χ 2 = 1.22, P= 1.27). 79% that received melatonin compared with 86% of those that were sedated with chloral hydrate had artifacts (χ 2 = 0.63, P= 0.42) Conclusion: Melatonin is effective and safe in inducing sleep for EEG recording in our setting.

Introduction: Epilepsy is the most common neurological condition worldwide. Literature on the antiepileptic medications and biochemical markers of bone metabolism has revealed inconsistent results. Most of these studies were undertaken in Europe and America where the burden and the associated comorbidities are different to the ones in Africa. Methods: A hospital based case control study was undertaken at Red Cross War Memorial Children's Hospital where children were recruited from a dedicated Epilepsy clinic and controls were obtained from a day surgical ward. Blood and urine samples were taken for the assessment of markers of bone metabolism. Results: Seventy-five cases and 75 controls were recruited. The median age for the children with epilepsy was 9 years with a range of 1 to 17 and controls 3 years with a range of 1 to 12. Vitamin D deficiency was present in 11(16.2%) of children with epilepsy compared to 6(8.8%) in the control group. Vitamin D insufficiency was present in 30(44.1%) in children with epilepsy compared to 27(39.7%) in the control group. Children with epilepsy on enzyme inducing AEDs had lower mean Vitamin D levels (24.67±11.4 vs 30.72±7.4, p=0.08), lower mean Vitamin D2 (0.25±0.07 vs 0.4±0.17,p=0.0018),lower mean Vitamin D3 (1.61±1.06 vs 2.58±0.86,p=0.004), lower mean serum phosphate levels (1.39±0.2 vs 1.76±0.7,p=0.000) and a higher mean parathyroid hormone levels (4.47±2.33 vs 2.7±0.97, p=0.03) compared to the control group. Children with Epilepsy on enzyme inhibitors had higher mean Vitamin D2 (0.44±0.37 vs 0.25±0.07,p=0.000004) and mean Vitamin D3 (2.26±0.86 vs 1.61±1.06,p=0.028) compared to children on enzyme inducers. Dietary intake and ancestry did not influence Vitamin D levels between the cases and controls. Conclusion and Recommendations: Vitamin D deficiency is common in children with epilepsy on AEDs. Children on enzyme inducing AEDs should be investigated for vitamin D deficiency and managed accordingly.