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ObjectiveTo report a prospectively planned analysis of two randomised controlled trials with embedded comparisons of prednisolone versus tetracosactide depot for the treatment of infantile epileptic spasms syndrome (IESS).MethodsIndividual patient data from patients randomly allocated to prednisolone or tetracosactide depot were analysed from two trials (UKISS, ICISS). The comparison was embedded within trials in which some patients also received vigabatrin but only patients receiving monotherapy with randomly allocated hormonal treatments are included in this analysis. The main outcome was cessation of spasms (Days 13–14 after randomisation). Lead time to treatment and underlying aetiology were taken into account. Cessation of spasms on Days 14–42 inclusive, electroclinical response (EEG Day 14), plus developmental and epilepsy outcomes (at 14 months in UKISS and 18 months in ICISS) are also reported. Minimum treatment was prednisolone 40 mg per day for two weeks or tetracosactide depot 0·5 mg IM on alternate days for two weeks, all followed by a reducing dose of prednisolone over two weeks.Results126 infants were included in this study. On tetracosactide depot, 47 of 62 (76%) were free of spasms on Days 13–14 compared to 43 of 64 (67%) on prednisolone (difference 9%, 95% CI -7·2% to +25·2%, chi square 1·15, p = 0·28). For Day 14–42 cessation of spasms, on tetracosactide depot, 41 of 61 (67%) were free of spasms compared to 35 of 62 (56%) on prednisolone (difference 11%, 95% CI -6·4% to +28·4%, chi square 1·51, p = 0·22). There was no significant difference in mean VABS score between infants who received prednisolone compared with those who received tetracosactide depot (74·8 (SD 18·3) versus 78·0 (SD 20·2) t = −0·91 p = 0·36). The proportion with ongoing epilepsy at the time of developmental assessment was 20 of 61 (33%) in the tetracosactide group compared with 26 out of 63 (41%) in the prednisolone group (difference 8%, 95% CI -9·2% to +25·2%, Chi [2] 0·95, p = 0·33).SignificanceWith hormone monotherapy, either prednisolone or tetracosactide depot may be recommended for infantile epileptic spasms syndrome.

Identifying Roots presents a cultural history of Alex Haley’s Roots, examining the strategy and tactics Haley employed in developing a family origin story into an acclaimed national history. More than an investigation into Alex Haley’s legacy, Identifying Roots unearths the politics of beginnings and belongings. While we all come from somewhere, this book examines the terms on which our roots can work as a tradition to embrace rather than a past to leave behind. And it investigates why some of the texts we read also seem to read us back. Identifying Roots invites readers to reimagine the way we tell stories. A provocative study that draws upon Black studies, the history of religions, and anthropology, this book underscores the social drama and dynamics that define our scriptures. Nimbly moving between the stories of Alex Haley, his characters, and the world that received them, Newton reminds us that our roots are stories of consequence.

ObjectiveTo determine the underlying etiologies in a contemporary cohort of infants with infantile spasms and to examine response to treatment.MethodsIdentification of the underlying etiology and response to treatment in 377 infants enrolled in a clinical trial of the treatment of infantile spasms between 2007 and 2014 using a systematic review of history, examination, and investigations. They were classified using the pediatric adaptation of International Classification of Diseases, Tenth Revision (ICD‐10).ResultsA total of 219 of 377 (58%) had a proven etiology, of whom 128 (58%) responded, 58 of 108 (54%) were allocated hormonal treatment, and 70 of 111 (63%) had combination therapy. Fourteen of 17 (82%, 95% confidence interval [CI] 59% to 94%) infants with stroke and infarct responded (compared to 114 of 202 for the rest of the proven etiology group (56%, 95% CI 48% to 62%, chi‐square 4.3, P = .037): the better response remains when treatment allocation and lead time are taken into account (odds ratio 5.1, 95% CI 1.1 to 23.6, P = .037). Twenty of 37 (54%, 95% CI 38% to 70%) infants with Down syndrome had cessation of spasms compared to 108 of 182 (59%, 95% CI 52% to 66%, chi‐square 0.35, P = .55) for the rest of the proven etiology group. The lack of a significant difference remains after taking treatment modality and lead‐time into account (odds ratio 0.8, 95% CI 0.4 to 1.7, P = .62). In Down syndrome infants, treatment modality did not appear to affect response: 11 of 20 (55%) allocated hormonal therapy responded, compared to 9 of 17 (53%) allocated combination therapy.SignificanceThis classification allows easy comparison with other classifications and with our earlier reports. Stroke and infarct have a better outcome than other etiologies, whereas Down syndrome might not respond to the addition of vigabatrin to hormonal treatment.

Background Focal epilepsies are caused by a malfunction of nerve cells localised in one part of one cerebral hemisphere. In studies, estimates of the number of individuals with focal epilepsy who do not become seizure-free despite optimal drug therapy vary according to the age of the participants and which focal epilepsies are included, but have been reported as at least 20% and in some studies up to 70%. If the epileptogenic zone can be located surgical resection offers the chance of a cure with a corresponding increase in quality of life. Objectives The primary objective is to assess the overall outcome of epilepsy surgery according to evidence from randomised controlled trials. The secondary objectives are to assess the overall outcome of epilepsy surgery according to non-randomised evidence and to identify the factors that correlate to remission of seizures postoperatively. Search methods We searched the Cochrane Epilepsy Group Specialised Register (June 2013), the Cochrane Central Register of Controlled Trials (CENTRAL 2013, Issue 6), MEDLINE (Ovid) (2001 to 4 July 2013), ClinicalTrials.gov and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) for relevant trials up to 4 July 2013. Selection criteria Eligible studies were randomised controlled trials (RCTs), cohort studies or case series, with either a prospective and/or retrospective design, including at least 30 participants, a well-defined population (age, sex, seizure type/frequency, duration of epilepsy, aetiology, magnetic resonance imaging (MRI) diagnosis, surgical findings), an MRI performed in at least 90% of cases and an expected duration of follow-up of at least one year, and reporting an outcome relating to postoperative seizure control. Data collection and analysis Three groups of two review authors independently screened all references for eligibility, assessed study quality and risk of bias, and extracted data. Outcomes were proportion of participants achieving a good outcome according to the presence or absence of each prognostic factor of interest. We intended to combine data with risk ratios (RR) and 95% confidence intervals. Main results We identified 177 studies (16,253 participants) investigating the outcome of surgery for epilepsy. Four studies were RCTs (including one that randomised participants to surgery or medical treatment). The risk of bias in the RCTs was unclear or high, limiting our confidence in the evidence that addressed the primary review objective. Most of the remaining 173 non-randomised studies had a retrospective design; they were of variable size, were conducted in a range of countries, recruited a wide demographic range of participants, used a wide range of surgical techniques and used different scales used to measure outcomes. We performed quality assessment using the Effective Public Health Practice Project (EPHPP) tool and determined that most studies provided moderate or weak evidence. For 29 studies reporting multivariate analyses we used the Quality in Prognostic Studies (QUIPS) tool and determined that very few studies were at low risk of bias across the domains. In terms of freedom from seizures, one RCT found surgery to be superior to medical treatment, two RCTs found no statistically significant difference between anterior temporal lobectomy (ATL) with or without corpus callosotomy or between 2.5 cm or 3.5 cm ATL resection, and one RCT found total hippocampectomy to be superior to partial hippocampectomy. We judged the evidence from the four RCTs to be of moderate to very low quality due to the lack of information reported about the randomised trial design and the restricted study populations. Of the 16,253 participants included in this review, 10,518 (65%) achieved a good outcome from surgery; this ranged across studies from 13.5% to 92.5%. Overall, we found the quality of data in relation to the recording of adverse events to be very poor. In total, 118 studies examined between one and eight prognostic factors in univariate analysis. We found the following prognostic factors to be associated with a better post-surgical seizure outcome: an abnormal pre-operative MRI, no use of intracranial monitoring, complete surgical resection, presence of mesial temporal sclerosis, concordance of pre-operative MRI and electroencephalography (EEG), history of febrile seizures, absence of focal cortical dysplasia/malformation of cortical development, presence of tumour, right-sided resection and presence of unilateral interictal spikes. We found no evidence that history of head injury, presence of encephalomalacia, presence of vascular malformation or presence of postoperative discharges were prognostic factors of outcome. We observed variability between studies for many of our analyses, likely due to the small study sizes with unbalanced group sizes, variation in the definition of seizure outcome, definition of the prognostic factor and the influence of the site of surgery, all of which we observed to be related to postoperative seizure outcome. Twenty-nine studies reported multivariable models of prognostic factors and the direction of association of factors with outcome was generally the same as found in the univariate analyses. However, due to the different multivariable analysis approaches and selective reporting of results, meaningful comparison of multivariate analysis with univariate meta-analysis is difficult. Authors' conclusions The study design issues and limited information presented in the included studies mean that our results provide limited evidence to aid patient selection for surgery and prediction of likely surgical outcome. Future research should be of high quality, have a prospective design, be appropriately powered and focus on specific issues related to diagnostic tools, the site-specific surgical approach and other issues such as the extent of resection. Prognostic factors related to the outcome of surgery should be investigated via multivariable statistical regression modelling, where variables are selected for modelling according to clinical relevance and all numerical results of the prognostic models are fully reported. Protocols should include pre- and postoperative measures of speech and language function, cognition and social functioning along with a mental state assessment. Journal editors should not accept papers where adverse events from a medical intervention are not recorded. Improvements in the development of cancer care over the past three to four decades have been achieved by answering well-defined questions through the conduct of focused RCTs in a step-wise fashion. The same approach to surgery for epilepsy is required.

We investigated the prevalence of neurodevelopmental impairment and health conditions in 85 children aged 9 to 19 years with isolated ventriculomegaly (assessed by fetal ultrasound) using a cross-sectional, parental questionnaire-based survey. If we assume all nonresponders had no impairment (thus addressing a “best case scenario”), our results still indicate an important excess of adverse outcome: 6% (5/85) would have epilepsy; 12% (10/85) in special school; 29% (25/85) with education or language support, and 7% (6/85 children) with severe behavior disturbance. We conclude neurobehavioral difficulties, special educational needs, and epilepsy are common in older children with isolated, including mild, fetal ventriculomegaly.

Born in Dar Es Salam, Tanzania, where his parents had moved from Goa in India, Michael Joseph Noronha was the sixth of eight children. The family moved to Pune, India, when he was 5, and at the age of 15 he moved to Dublin with his older brother and sister. He studied medicine and passed with flying colours. After house jobs in Dublin, Bradford, and Edinburgh, Michael retuned to Bradford as a registrar in general medicine. A research post at Leeds …

BACKGROUND: Infantile spasms constitute a severe form of epileptic encephalopathy. In the International Collaborative Infantile Spasms Study (ICISS), we showed that combining vigabatrin with hormonal therapy was more effective than hormonal therapy alone at stopping spasms between days 14 and 42 of treatment. In this planned follow-up, we aimed to assess whether combination therapy was associated with improved developmental and epilepsy outcomes at 18 months of age.METHODS: In ICISS, a multicentre, open-label, randomised controlled trial, infants were enrolled from 102 hospitals (three in Australia, 11 in Germany, two in New Zealand, three in Switzerland, and 83 in the UK). Eligible infants had a clinical diagnosis of infantile spasms and a hypsarrhythmic (or similar) electroencephalogram (EEG) no more than 7 days before enrolment. Participants were randomly assigned (1:1) by a secure website to receive hormonal therapy with vigabatrin or hormonal therapy alone. If parents consented, there was an additional randomisation (1:1) of type of hormonal therapy used (prednisolone or tetracosactide depot). Block randomisation was stratified for hormonal treatment and risk of developmental impairment. Parents and clinicians were not masked to therapy, but investigators assessing epilepsy and developmental outcomes at 18 months were masked to treatment allocation. Minimum doses were oral prednisolone 10 mg four times a day or intramuscular tetracosactide depot 0·5 mg (40 IU) on alternate days with or without oral vigabatrin 100 mg/kg per day. The primary outcome at 18 months was development as assessed by the Vineland Adaptive Behaviour Scales (VABS) composite score. Secondary outcomes were the presence or absence of epileptic seizures or infantile spasms in the previous 28 days, as recorded by parents and carers, and the use of any anti-epileptic treatment (including ketogenic diet) in the previous 28 days. Analysis was by intention to treat. The trial is registered with the ISRCTN registry, number 54363174, and EudraCT, number 2006-000788-27.FINDINGS: Between March 7, 2007, and May 22, 2014, 766 infants were screened and, of those, 377 were randomly assigned to hormonal therapy with vigabatrin (n=186) or hormonal therapy alone (n=191). 362 infants were assessed for developmental and epilepsy outcomes at 18 months, 181 in each treatment group. Mean VABS scores did not differ significantly between the combination therapy group and the hormonal therapy alone group (73·9 [SE 1·3] vs 72·7 [1·4], difference -1·2 [95% CI -4·9 to 2·6], p=0·55). Presence of epilepsy at the assessment at age 18 months was similar in both treatment groups (54 [30·0%] of 180 infants who received combination therapy vs 52 [29·2%] of 178 who received hormonal therapy alone; difference 0·8% [95% CI -8·8 to 10·4], p=0·90). Presence of spasms was also similar in both treatment groups (27 [15·0%] of 180 infants on combination therapy vs 28 [15·7%] of 178 on hormonal therapy alone; difference 0·7% [95% CI -6·9 to 8·3], p=0·85). At the 18-month assessment, 158 (44·1%) of 358 infants were on some form of anti-epileptic treatment. Initial control of spasms between days 14 and 42 of treatment was associated with higher mean VABS scores at 18 months (79·1 [SE 1·2] vs 63·2 [1·1], difference 15·9 [95% CI 12·4 to 19·5], pINTERPRETATION: Combination therapy did not result in improved developmental or epilepsy outcomes at 18 months. However, early clinical response to treatment was associated with improved developmental and epilepsy outcomes at 18 months. Longer lead-time to treatment was associated with poorer outcomes. Rapid diagnosis and effective treatment of infantile spasms could therefore improve outcomes.FUNDING: The Castang Foundation, Bath Unit for Research in Paediatrics, National Institute of Health Research, the Royal United Hospitals Bath NHS Foundation Trust, BRONNER-BENDER Stiftung/Gernsbach, University Children's Hospital Zurich.

Background Febrile seizures occurring in a child older than one month during an episode of fever affect 2-4% of children in Great Britain and the United States and recur in 30%. Rapid-acting antiepileptics and antipyretics given during subsequent fever episodes have been used to avoid the adverse effects of continuous antiepileptic drugs. This is an updated version of a Cochrane Review previously published in 2017. Objectives To evaluate primarily the effectiveness and safety of antiepileptic and antipyretic drugs used prophylactically to treat children with febrile seizures; and also to evaluate any other drug intervention where there is a sound biological rationale for its use. Search methods For the latest update we searched the following databases on 3 February 2020: Cochrane Register of Studies (CRS Web), MEDLINE (Ovid, 1946 to 31 January 2020). CRS Web includes randomised or quasi-randomised controlled trials from PubMed, Embase, ClinicalTrials.gov, the World Health Organization International Clinical Trials Registry Platform (ICTRP), the Cochrane Central Register of Controlled Trials (CENTRAL), and the specialised registers of Cochrane Review Groups including the Cochrane Epilepsy Group. We imposed no language restrictions and contacted researchers to identify continuing or unpublished studies. Selection criteria Trials using randomised or quasi-randomised participant allocation that compared the use of antiepileptics, antipyretics or recognised Central Nervous System active agents with each other, placebo, or no treatment. Data collection and analysis For the original review, two review authors independently applied predefined criteria to select trials for inclusion and extracted the predefined relevant data, recording methods for randomisation, blinding, and exclusions. For the 2016 update, a third review author checked all original inclusions, data analyses, and updated the search. For the 2020 update, one review author updated the search and performed the data analysis following a peer-review process with the original review authors. We assessed seizure recurrence at 6, 12, 18, 24, 36, 48 months, and where data were available at age 5 to 6 years along with recorded adverse effects. We evaluated the presence of publication bias using funnel plots. Main results We included 42 articles describing 32 randomised trials, with 4431 randomised participants used in the analysis of this review. We analysed 15 interventions of continuous or intermittent prophylaxis and their control treatments. Methodological quality was moderate to poor in most studies. We found no significant benefit for intermittent phenobarbital, phenytoin, valproate, pyridoxine, ibuprofen, or zinc sulfate versus placebo or no treatment; nor for diclofenac versus placebo followed by ibuprofen, paracetamol, or placebo; nor for continuous phenobarbital versus diazepam, intermittent rectal diazepam versus intermittent valproate, or oral diazepam versus clobazam. There was a significant reduction of recurrent febrile seizures with intermittent diazepam versus placebo or no treatment at six months (risk ratio (RR) 0.64, 95% confidence interval (CI) 0.48 to 0.85; 6 studies, 1151 participants; moderate-certainty evidence), 12 months (RR 0.69, 95% CI 0.56 to 0.84; 8 studies, 1416 participants; moderate-certainty evidence), 18 months (RR 0.37, 95% CI 0.23 to 0.60; 1 study, 289 participants; low-certainty evidence), 24 months (RR 0.73, 95% CI 0.56 to 0.95; 4 studies, 739 participants; high-certainty evidence), 36 months (RR 0.58, 95% CI 0.40 to 0.85; 1 study, 139 participants; low-certainty evidence), 48 months (RR 0.36, 95% CI 0.15 to 0.89; 1 study, 110 participants; moderate-certainty evidence), with no benefit at 60 to 72 months (RR 0.08, 95% CI 0.00 to 1.31; 1 study, 60 participants; very low-certainty evidence). Phenobarbital versus placebo or no treatment reduced seizures at six months (RR 0.59, 95% CI 0.42 to 0.83; 6 studies, 833 participants; moderate-certainty evidence), 12 months (RR 0.54, 95% CI 0.42 to 0.70; 7 studies, 807 participants; low-certainty evidence), and 24 months (RR 0.69, 95% CI 0.53 to 0.89; 3 studies, 533 participants; moderate-certainty evidence), but not at 18 months (RR 0.77, 95% CI 0.56 to 1.05; 2 studies, 264 participants) or 60 to 72 months follow-up (RR 1.50, 95% CI 0.61 to 3.69; 1 study, 60 participants; very low-certainty evidence). Intermittent clobazam compared to placebo at six months resulted in a RR of 0.36 (95% CI 0.20 to 0.64; 1 study, 60 participants; low-certainty evidence), an effect found against an extremely high (83.3%) recurrence rate in the controls, a result that needs replication. When compared to intermittent diazepam, intermittent oral melatonin did not significantly reduce seizures at six months (RR 0.45, 95% CI 0.18 to 1.15; 1 study, 60 participants; very-low certainty evidence). When compared to placebo, intermittent oral levetiracetam significantly reduced recurrent seizures at 12 months (RR 0.27, 95% CI 0.15 to 0.52; 1 study, 115 participants; very low-certainty evidence). The recording of adverse effects was variable. Two studies reported lower comprehension scores in phenobarbital-treated children. Adverse effects were recorded in up to 30% of children in the phenobarbital-treated groups and 36% in benzodiazepine-treated groups. We found evidence of publication bias in the meta-analyses of comparisons for phenobarbital versus placebo (seven studies) at 12 months but not at six months (six studies); and valproate versus placebo (four studies) at 12 months. There were too few studies to identify publication bias for the other comparisons. The methodological quality of most of the included studies was low or very low. Methods of randomisation and allocation concealment often did not meet current standards, and 'treatment versus no treatment' was more commonly seen than 'treatment versus placebo', leading to obvious risks of bias. AUTHORS' CONCLUSIONS: We found reduced recurrence rates for intermittent diazepam and continuous phenobarbital, with adverse effects in up to 30% of children. The apparent benefit for clobazam treatment in one trial needs to be replicated. Levetiracetam also shows benefit with a good safety profile; however, further study is required. Given the benign nature of recurrent febrile seizures, and the high prevalence of adverse effects of these drugs, parents and families should be supported with adequate contact details of medical services and information on recurrence, first aid management, and, most importantly, the benign nature of the phenomenon.

BackgroundInfantile spasms constitutes a severe infantile epilepsy syndrome that is difficult to treat and has a high morbidity. Hormonal therapies or vigabatrin are the most commonly used treatments. We aimed to assess whether combining the treatments would be more effective than hormonal therapy alone.MethodsIn this multicentre, open-label randomised trial, 102 hospitals (Australia [three], Germany [11], New Zealand [two], Switzerland [three], and the UK [83]) enrolled infants who had a clinical diagnosis of infantile spasms and a hypsarrhythmic (or similar) EEG no more than 7 days before enrolment. Participants were randomly assigned (1:1) by a secure website to receive hormonal therapy with vigabatrin or hormonal therapy alone. If parents consented, there was an additional randomisation (1:1) of type of hormonal therapy used (prednisolone or tetracosactide depot). Block randomisation was stratified for hormonal treatment and risk of developmental impairment. Parents and clinicians were not masked to therapy, but investigators assessing electro-clinical outcome were masked to treatment allocation. Minimum doses were prednisolone 10 mg four times a day or intramuscular tetracosactide depot 0·5 mg (40 IU) on alternate days with or without vigabatrin 100 mg/kg per day. The primary outcome was cessation of spasms, which was defined as no witnessed spasms on and between day 14 and day 42 from trial entry, as recorded by parents and carers in a seizure diary. Analysis was by intention to treat. The trial is registered with The International Standard Randomised Controlled Trial Number (ISRCTN), number 54363174, and the European Union Drug Regulating Authorities Clinical Trials (EUDRACT), number 2006-000788-27.FindingsBetween March 7, 2007, and May 22, 2014, 766 infants were screened and, of those, 377 were randomly assigned to hormonal therapy with vigabatrin (186) or hormonal therapy alone (191). All 377 infants were assessed for the primary outcome. Between days 14 and 42 inclusive no spasms were witnessed in 133 (72%) of 186 patients on hormonal therapy with vigabatrin compared with 108 (57%) of 191 patients on hormonal therapy alone (difference 15·0%, 95% CI 5·1–24·9, p=0·002). Serious adverse reactions necessitating hospitalisation occurred in 33 infants (16 on hormonal therapy alone and 17 on hormonal therapy with vigabatrin). The most common serious adverse reaction was infection occurring in five infants on hormonal therapy alone and four on hormonal therapy with vigabatrin. There were no deaths attributable to treatment.InterpretationHormonal therapy with vigabatrin is significantly more effective at stopping infantile spasms than hormonal therapy alone. The 4 week period of spasm cessation required to achieve a primary clinical response to treatment suggests that the effect seen might be sustained, but this needs to be confirmed at the 18 month follow-up.FundingThe Castang Foundation, Bath Unit for Research in Paediatrics, National Institute of Health Research, the Royal United Hospitals Bath NHS Foundation Trust, the BRONNER-BENDUNG Stifung/Gernsbach, and University Children's Hospital Zurich.

Aim: we aimed to investigate the relationship between movement disorders, changes on brain magnetic resonance imaging (MRI), and vigabatrin therapy in children with infantile spasms. Method: retrospective review and brain MRI analysis of children enrolled in the International Collaborative Infantile Spasms Study (ICISS) who developed a movement disorder on vigabatrin therapy. Comparisons were made with controls within ICISS who had no movement disorder. Results: ten of 124 infants had a movement disorder and in eight it had developed on vigabatrin therapy. Two had a movement disorder that resolved on dose-reduction of vigabatrin, one had improvement on withdrawing vigabatrin, two had resolution without any dose change, and in three it persisted despite vigabatrin withdrawal. The typical brain MRI changes associated with vigabatrin therapy were noted in two infants. Ten control infants were identified. Typical MRI changes noted with vigabatrin were noted in three controls. Interpretation: it is possible that in two out of eight cases, vigabatrin was associated with the development of a movement disorder. In six out of eight cases a causal relationship was less plausible. The majority of infants treated with vigabatrin did not develop a movement disorder. MRI changes associated with vigabatrin do not appear to be specifically related to the movement disorder

This seminar discusses the history and development of techniques for surgical intervention for people with refractory focal epilepsy. Published surgical success rates and prognostic factors associated with post-operative seizure freedom from individual studies have been variable and contradictory. We present here the key findings of a Cochrane systematic review of all evidence published since the introduction of magnetic resonance imaging (MRI) to pre-operative surgical assessment in 1984. Our findings show the usefulness of uncontrolled case series is now past. Future studies with a prospective controlled design should focus on specific research questions to help improve results and provide better-informed advice.

Purpose The ILAE recommends baseline recordings of 30min to detect abnormalities supporting a clinical diagnosis of epilepsy in children. A shorter recording time may be better tolerated by children and be more resource-efficient. Our aim was to determine how many abnormalities supporting a diagnosis of epilepsy would be missed by reducing the recording time of paediatric standard electroencephalograms (EEGs) from 20 to 15min. Methods We evaluated standard EEGs of 300 patients aged 2 months to 17 years referred consecutively with confirmed or suspected epilepsy. EEGs were recorded for 20min on digital media. A digital copy of each EEG was truncated to give consecutive sequences of 10min (sequence "A") and 5min duration (sequences "B" and "C" respectively). A panel of EEG raters blinded to the children's' details other than age identified these sequences as "normal" or "abnormal" if they contained spike waves, discrete sharp waves or notched slow waves in the respective EEG period. Results EEGs of 297 children were analysed (three were omitted for technical reasons). 109 out of 297 EEGs (37%) had specific abnormalities supportive of a diagnosis of an epilepsy. 17 of these EEGs showed the abnormality in EEG sequences "B" or "C" and 7 (95% CI: 1.9–12.2) out of these demonstrated the abnormality in sequence "C" only. 105 out of 297 EEGs had non-specific findings. Conclusion We conclude that reducing the recording time of standard EEGs to 15min may miss abnormalities in 2.36% [95% CI: 0.63–4.09%] overall and 6.42% [95% CI: 2.2–11.8%] of those with an abnormality supportive of an epilepsy to explain the reported symptoms. This result should inform any future discussions on seeking resource-efficiencies.

Summary Purpose: Infantile spasms is a severe infantile seizure disorder. Several factors affect developmental outcome, especially the underlying etiology of the spasms. Treatment also affects outcome. Both age at onset of spasms and lead time to treatment (the time from onset of spasms to start of treatment) may be important. We investigated these factors. Methods: Developmental assessment using Vineland Adaptive Behaviour Scales (VABS) at 4 years of age in infants enrolled in the United Kingdom Infantile Spasms Study. Date of or age at onset of spasms was obtained prospectively. Lead time to treatment was then categorized into five categories. The effects of lead time to treatment, age of onset of spasms, etiology, and treatment on developmental outcome were investigated using multiple linear regression. Key Findings: Age of onset ranged (77 infants) from 2 months in 21 and not known in 6. Each month of reduction in age at onset of spasms was associated with a 3.1 [95% confidence interval (CI) 0.64–5.5, p = 0.03] decrease, and each increase in category of lead time duration associated with a 3.9 (95% CI 7.3–0.4, p = 0.014) decrease in VABS, respectively. There was a significant interaction between treatment allocation and etiology with the benefit in VABS in those allocated steroid therapy being in children with no identified etiology (coefficient 29.9, p = 0.004). Significance: Both prompt diagnosis and prompt treatment of infantile spasms may help prevent subsequent developmental delay. Younger infants may be more at risk from the epileptic encephalopathy than older infants.

Purpose: To examine the underlying etiology of infantile spasms from the United Kingdom Infantile Spasms Study (UKISS), using the pediatric adaptation of ICD 10. Methods:?Infants were enrolled in a randomized controlled trial or a parallel epidemiologic study. Etiological information included history, examination, and investigations. The infants were classified as proven etiology, if a neurologic disease was identified; as no identified etiology, if no neurologic disease was identified; and as not fully investigated, if a major piece of information was missing. Proven etiology was subclassified using the pediatric adaptation of ICD 10. The results were then examined to identify further methods of classification. Results: Of 207 infants, 127 (61%) had proven etiology, 68 (33%) had no identified etiology, and 12 (6%) were not fully investigated. Etiologies were prenatal in 63, perinatal in 38, postnatal in 8, and 18 other. The most common etiologies were: hypoxic–ischemic encephalopathy (HIE) 21 (10%), chromosomal 16 (8%), malformations 16 (8%), stroke 16 (8%), tuberous sclerosis complex (TSC) 15 (7%), and periventricular leukomalacia or hemorrhage 11 (5%). The remaining 32 etiologies were all individually uncommon. Response to treatment is given for individual etiologies. Discussion:?Our method of classification allows the reporting of results by individual diseases, disease groups, or categories and is structured and clear. It avoids the use of poorly defined terms such as symptomatic and cryptogenic. It can adapt to new neurologic diseases, such as gene defects, and can be used for comparison of different groups of infants, thereby aiding meta-analysis.

Background Infantile spasms is the name given to a difficult to treat, severe infantile epilepsy with high morbidity. The United Kingdom Infantile Spasms Study (UKISS) showed that absence of spasms on days 13 and 14 after randomisation was more common in infants allocated hormonal treatments than vigabatrin. At 12–14 months, those with no identified aetiology allocated hormonal treatment had better development. However, epilepsy outcome was not affected by treatment allocated. It is not known if the difference in development persists as the infants grow. Methods Infants in UKISS were followed up blind to treatment allocation by telephone at a mean age of 4 years using the Vineland Adaptive Behaviour Scales (VABS) and an epilepsy questionnaire. Findings 9 of 107 enrolled infants had died. 77 were traced and consented to take part. The median (quartile) VABS scores were 60 (42, 97) for the 39 allocated hormonal treatment and 50 (36, 67) for the 38 allocated vigabatrin (Mann–Whitney U=575; p=0.091; median difference (95% CI): 8 (−1 to 19)). For those with no identified aetiology, VABS scores were 96 (52, 102) for the 21 allocated hormonal treatment and 63 (37, 92) for the 16 allocated vigabatrin (U=98.5; p=0.033; median difference (95% CI): 14 (1 to 42)).The proportions in each treatment group with epilepsy were similar. Interpretation For all 77 infants, development and epilepsy outcomes were not significantly different between the two treatment groups. The better development seen at 14 months in those with no identified aetiology allocated hormonal treatment was seen again at 4 years in this study.

This study examined children with an acute encephalopathy illness for evidence of viral infection, disordered blood-brain barrier function, intrathecal immunoglobulin synthesis, and interferon (IFN) production, and related their temporal occurrence to outcome. A prospective study of 22 children (13 males, 9 females; age range 1mo to 13y, median 2y 4mo), recorded clinical details, with serum and cerebrospinal fluid (CSF) analysis near presentation and then on convalescent specimens taken up to day 39 of the neurological illness. Outcome was assessed with standard scales between 18 months and 3 years after presentation. A history consistent with viral infection was given in 17 children but laboratory evidence of viral infection was found in only 7 (7/17). In 18 out of 21 children, an elevated CSF:serum albumin ratio indicative of impairment of the blood-CSF and blood-brain barriers was detected at some stage of the illness. In 14 of the 15 children with a raised immunoglobulin G index, and in 12 of the 14 children where the CSF was positive for oligoclonal bands, this was preceded by, or was observed at the same time as, an abnormal albumin ratio. Sixteen children (16/18) had elevated IFN-alpha levels in serum, or CSF, or in both. We conclude that these findings indicate an initial disruption of the blood-brain barrier followed by intrathecal antibody production by activated lymphocytes, clonally restricted to a few antigens. This is the first in vivo study to show this as an important pathogenetic mechanism of encephalitis in children. Poor outcome was associated with young age, a deteriorating electroencephalogram pattern from grade 1 to grade 2, and the degree of blood-brain barrier impairment, particularly when prolonged, but not with Glasgow Coma Scale score. The persistence of IFN-alpha was associated with a good prognosis.

The potential efficacy of temporal and extratemporal resection in patients with partial epilepsy uncontrolled by anti-epileptic drugs is undisputed. However, there are still uncertainties about which patients will benefit most. A systematic review of the available literature has been undertaken by four pairs of reviewers to assess the overall outcome of epilepsy surgery and to identify factors better correlated to seizure outcome. A Medline search for studies on epilepsy surgery published since 1984 was performed. Studies were included if they had a well-defined population and design, a sample size of at least 30 patients, an MRI performed in least 90% of cases, an expected duration of follow-up of at least one year, and a post-operative outcome measured as seizure remission. A good outcome was considered as seizure control or seizure-free status for at least one year or Engel class I. Based on the review of 47 articles meeting all the eligibility criteria, febrile seizures (odds ratio, OR, 0.48 ; 95% confidence interval, CI, 0.27-0.83), mesial temporal sclerosis (OR 0.47 ; 95% CI 0.35-0.64), tumors (OR 0.58 ; 95% CI 0.42-0.80), abnormal MRI (OR 0.44 ; 95% CI 0.29-0.65), EEG/MRI concordance (OR 0.52 ; 95% CI 0.32-0.83), and extensive surgical resection (OR 0.24 ; 95% CI 0.16-0.36) were the strongest prognostic indicators of seizure remission (positive predictors) ; by contrast, postoperative discharges (OR 2.41 ; 95% CI 1.37-4.27) and intracranial monitoring (OR 2.72 ; 95% CI 1.60-4.60) predicted an unfavorable prognosis (negative predictors). Firm conclusions cannot be drawn for extent of resection, EEG/MRI concordance and post-operative discharges for the heterogeneity of study results. Neuromigrational defects, CNS infections, vascular lesions, interictal spikes, and side of resection did not affect the chance of seizure remission after surgery. Despite a number of limitations, the results of the review provide some insight into the selection of the best surgical candidates in clinical practice but raise concerns on the quality of published reports, and may serve as the basis for the identification of better standards to assess surgical outcome in observational studies.

Adult-centred studies continue to show poor information provision and understanding in people with epilepsy. This study explores whether paediatric neurologists work within a consultation framework designed to meet information needs. A questionnaire on how to give the diagnosis was sent to 32 UK Paediatric Neurologists. Consultation content was largely determined intuitively rather than on a shared knowledge of the process involved. Little consensus was identified in relation to analogy and the usefulness or awareness of available unevaluated literature; but most acknowledged the value of a specialist epilepsy nurse. Most responses were based on a typical medical agenda but less than 20% addressed emotional responses and adaptation. Three approaches were identified-'pro-active' (running the risk of overload but recognising the right of parents to information), 'reactive' (more individually tailored, but assumes doctors can judge parental reactions) and 'drip-feed' (protective and pre-selecting topics to meet the situation). Our aim to establish a guideline proved impossible. Further study should develop more detailed models of the disclosure process, and identify epilepsy explanations that can be consumer-tested.

We report on a large family with myoclonus-dystonia resulting from an epsilon-sarcoglycan mutation, with prominent early and late lower-limb involvement. The proband's condition has evolved to include marked lower-limb dystonia and dystonic gait impairment in the fourth decade. Other family members had evidence of prominent lower-limb involvement at presentation or a more typical phenotype of axial and upper-limb myoclonus and dystonia. Prominent lower-limb involvement developing late in the disease course is an atypical feature and exemplifies the wide phenotypic heterogeneity observed in people with myoclonus-dystonia.

Background Febrile seizures occurring in a child older than one month during an episode of fever affect 2% to 4% of children in Great Britain and the United States and recur in 30%. Rapid-acting antiepileptics and antipyretics given during subsequent fever episodes have been used to avoid the adverse effects of continuous antiepileptic drugs. Objectives To evaluate the effectiveness and safety of antiepileptic and antipyretic drugs used prophylactically to treat children with febrile seizures. Search methods We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2011. Issue 3); MEDLINE (1966 to May 2011); EMBASE (1966 to May 2011); Database of Abstracts of Reviews of Effectiveness (DARE) (May 2011). No language restrictions were imposed. We also contacted researchers in the field to identify continuing or unpublished studies. Selection criteria Trials using randomised or quasi-randomised patient allocation that compared the use of antiepileptic or antipyretic agents with each other, placebo or no treatment. Data collection and analysis Two review authors (RN and MO) independently applied pre-defined criteria to select trials for inclusion and extracted the pre-defined relevant data, recording methods for randomisation, blinding and exclusions. Outcomes assessed were seizure recurrence at 6, 12, 18, 24, 36 months and at age 5 to 6 years in the intervention and non-intervention groups, and adverse medication effects. The presence of publication bias was assessed using funnel plots. Main results Thirty-six articles describing 26 randomised trials with 2740 randomised participants were included. Thirteen interventions of continuous or intermittent prophylaxis and their control treatments were analysed. Methodological quality was moderate to poor in most studies. We could not do a meta-analysis for eight of the 13 comparisons due to insufficient numbers of trials. No significant benefit for valproate, pyridoxine, intermittent phenobarbitone or ibuprofen versus placebo or no treatment was found; nor for diclofenac versus placebo followed by ibuprofen, acetominophen or placebo; nor for intermittent rectal diazepam versus intermittent valproate, nor phenobarbitone versus intermittent rectal diazepam. There was a significant reduction of recurrent febrile seizures with intermittent oral diazepam versus placebo with a relative risk (RR) of 0.67 (95% confidence interval (CI) 0.48 to 0.94) at 24 months), RR of 0.61 (95% CI 0.15 to 0.89) at 48 months, with no benefit at 6, 12 or 72 months. Phenobarbitone versus placebo or no treatment reduced seizures at 6, 12 and 24 months but not at 18 or 72 month follow up (RR 0.60, 95% CI 0.42 to 0.84 at 6 months; RR 0.59, 95% CI 0.46 to 0.75 at 12 months; and RR 0.65, 95% CI 0.49 to 0.88 at 24 months). Intermittent rectal diazepam versus no treatment or placebo also reduced seizures (RR 0.60, 95% CI 0.41 to 0.86 at 6 months; RR 0.65, 95% CI 0.49 to 0.87 at 12 months; RR 0.2, 95% CI 0.1 to 0.39 at 18 months; RR 0.36, 95% CI 0.18 to 0.71 at 36 months), with no benefit at 24 months. Intermittent clobazam compared to placebo at 6 months resulted in a RR of 0.09 (95% CI 0.02 to 0.30), an effect found against an extremely high (83.3%) recurrence rate in the controls and which is a result that needs replication. The recording of adverse effects was variable. Lower comprehension scores in phenobarbitone treated children were found in two studies. In general, adverse effects were recorded in up to some 30% of children in the phenobarbitone treated group and in up to 36% in benzodiazepine treated groups. Evidence of publication bias was found in the meta analyses of comparisons for phenobarbitone versus placebo (8 studies) at 12 months but not at 6 months (6 studies); and valproate versus placebo (4 studies) at 12 months; with too few studies to identify publication bias for the other comparisons. Authors' conclusions No clinically important benefits for children with febrile seizures were found for intermittent oral diazepam, phenytoin, phenobarbitone, intermittent rectal diazepam, valproate, pyridoxine, intermittent phenobarbitone or intermittent ibuprofen, nor for diclofenac versus placebo followed by ibuprofen, acetominophen or placebo. Adverse effects were reported in up to 30% of children. Apparent benefit for clobazam treatment in one recent trial needs to be replicated to be judged reliable. Given the benign nature of recurrent febrile seizures, and the high prevalence of adverse effects of these drugs, parents and families should be supported with adequate contact details of medical services and information on recurrence, first aid management and, most importantly, the benign nature of the phenomenon. Plain Language Summary Prophylactic drug management for febrile seizures in children Seizures occurring in association with fever are the most common neurologic disorder in children, affecting two to four per cent of all children. On average, one out of three children with febrile seizures have recurrent seizures. In this review the effects of antiepileptic and antipyretic medications to prevent recurrent seizures was examined. No significant or important benefits of these medications were found for children with febrile seizures. Adverse effects of the medications were common. The benefit found for treatment with clobazam in one 2011 study needs to be repeated to show that this finding is reliable. Meanwhile, parents and families should be supported with the adequate contact details of medical services and information on recurrence, first aid management and, most importantly, the benign nature of the phenomenon.

Encouraging consultation questions There is great power in the spoken word and doctors should beware misunderstandings. The first author spent some time in general practice. On a home visit to a man in bed with pneumonia he was bidding farewell to the man’s wife at the front door when she said, “He is still off the greens doctor”. The first author did not understand what she meant. She explained that 20 years previously her husband had had a bout of diarrhoea and vomiting. The senior partner had advised that he should “stay off the greens”—presumably for a short period. For the 20 years that followed not one green leaf had passed this man’s lips. Arguably, the most powerful medical intervention is the spoken word, yet how we communicate with families is little studied. The hospital clinic is the active point of contact between families, their children, and local paediatric services. From the family’s point of view this is an essential interchange, often viewed with apprehension for many weeks as a result of worry over underlying disease or illness, real or perceived. For the doctor on many services the clinic is a stressful time commitment with a varying agenda: identifying (not missing) significant illness, assuring where appropriate, giving adequate supervision for trainees, and avoiding them too making mistakes. A typical scenario would be: “the parents in front of you are in tears, the last child no better, trainee at the door with a question, over-running 40 minutes already, and waiting lists growing” In that interchange between families and doctors moments are precious. Despite best efforts it is easy to get things continuously wrong. The authors found that children with epilepsy attending a clinic continued to misunderstand the nature of their problem.1 Another dimension was opened up in a study of …

Febrile seizures occurring in a child older than one month during an episode of fever affect 2% to 4% of children in Great Britain and the United States and recur in 30%. Rapid-acting antiepileptics and antipyretics given during subsequent fever episodes have been used to avoid the adverse effects of continuous antiepileptic drugs. To evaluate the effectiveness and safety of antiepileptic and antipyretic drugs used prophylactically to treat children with febrile seizures. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2011. Issue 3); MEDLINE (1966 to May 2011); EMBASE (1966 to May 2011); Database of Abstracts of Reviews of Effectiveness (DARE) (May 2011). No language restrictions were imposed. We also contacted researchers in the field to identify continuing or unpublished studies. Trials using randomised or quasi-randomised patient allocation that compared the use of antiepileptic or antipyretic agents with each other, placebo or no treatment. Two review authors (RN and MO) independently applied pre-defined criteria to select trials for inclusion and extracted the pre-defined relevant data, recording methods for randomisation, blinding and exclusions. Outcomes assessed were seizure recurrence at 6, 12, 18, 24, 36 months and at age 5 to 6 years in the intervention and non-intervention groups, and adverse medication effects. The presence of publication bias was assessed using funnel plots. Thirty-six articles describing 26 randomised trials with 2740 randomised participants were included. Thirteen interventions of continuous or intermittent prophylaxis and their control treatments were analysed. Methodological quality was moderate to poor in most studies. We could not do a meta-analysis for eight of the 13 comparisons due to insufficient numbers of trials. No significant benefit for valproate, pyridoxine, intermittent phenobarbitone or ibuprofen versus placebo or no treatment was found; nor for diclofenac versus placebo followed by ibuprofen, acetominophen or placebo; nor for intermittent rectal diazepam versus intermittent valproate, nor phenobarbitone versus intermittent rectal diazepam.There was a significant reduction of recurrent febrile seizures with intermittent oral diazepam versus placebo with a relative risk (RR) of 0.67 (95% confidence interval (CI) 0.48 to 0.94) at 24 months), RR of 0.61 (95% CI 0.15 to 0.89) at 48 months, with no benefit at 6, 12 or 72 months. Phenobarbitone versus placebo or no treatment reduced seizures at 6, 12 and 24 months but not at 18 or 72 month follow up (RR 0.60, 95% CI 0.42 to 0.84 at 6 months; RR 0.59, 95% CI 0.46 to 0.75 at 12 months; and RR 0.65, 95% CI 0.49 to 0.88 at 24 months). Intermittent rectal diazepam versus no treatment or placebo also reduced seizures (RR 0.60, 95% CI 0.41 to 0.86 at 6 months; RR 0.65, 95% CI 0.49 to 0.87 at 12 months; RR 0.2, 95% CI 0.1 to 0.39 at 18 months; RR 0.36, 95% CI 0.18 to 0.71 at 36 months), with no benefit at 24 months. Intermittent clobazam compared to placebo at 6 months resulted in a RR of 0.09 (95% CI 0.02 to 0.30), an effect found against an extremely high (83.3%) recurrence rate in the controls and which is a result that needs replication.The recording of adverse effects was variable. Lower comprehension scores in phenobarbitone treated children were found in two studies. In general, adverse effects were recorded in up to some 30% of children in the phenobarbitone treated group and in up to 36% in benzodiazepine treated groups. Evidence of publication bias was found in the meta analyses of comparisons for phenobarbitone versus placebo (8 studies) at 12 months but not at 6 months (6 studies); and valproate versus placebo (4 studies) at 12 months; with too few studies to identify publication bias for the other comparisons. No clinically important benefits for children with febrile seizures were found for intermittent oral diazepam, phenytoin, phenobarbitone, intermittent rectal diazepam, valproate, pyridoxine, intermittent phenobarbitone or intermittent ibuprofen, nor for diclofenac versus placebo followed by ibuprofen, acetominophen or placebo. Adverse effects were reported in up to 30% of children. Apparent benefit for clobazam treatment in one recent trial needs to be replicated to be judged reliable. Given the benign nature of recurrent febrile seizures, and the high prevalence of adverse effects of these drugs, parents and families should be supported with adequate contact details of medical services and information on recurrence, first aid management and, most importantly, the benign nature of the phenomenon

Investigators from Virginia Commonwealth University, Norwegian Center for Epilepsy and University of Southern Denmark carried out twin studies to analyse the genetic influence of developing epilepsy after febrile seizures.

Objective : To determine whether the prevalence of schizophrenia among the homeless population of Edinburgh resident in hostels has changed between 1966 and 1992. Design: Comparison of two cross sectional surveys. Settings--Hostels for homeless people in Edinburgh. Subjects--In 1966 a random sample of 98 residents of three common lodging houses. In 1992 a random sample of 198 residents of nine hostels. Main outcome measure--Prevalence of schizophrenia. Results: The prevalence of schizophrenia in 1992 was 12/136 (9%) compared with 20/79 (25%) in 1966 (odds ratio 0.29; 95% confidence interval 0.13 to 0.62; P=0.001). Adjustment for confounding by age, current hostel, and duration of unemployment by means of logistic regression produced an adjusted odds ratio of 0.22 (0.08 to 0.58). Conclusions: The prevalence of schizophrenia was lower in 1992 even after other changes in the population resident in hostels occurring between 1966 and 1992 were taken into account. The findings are not consistent with an increase in the prevalence of schizophrenia among homeless people despite a 66% reduction in adult psychiatric beds in the region during 1966-92.

Infantile spasms is a severe infantile seizure disorder. Several factors affect developmental outcome, especially the underlying etiology of the spasms. Treatment also affects outcome. Both age at onset of spasms and lead time to treatment (the time from onset of spasms to start of treatment) may be important. We investigated these factors.Developmental assessment using Vineland Adaptive Behaviour Scales (VABS) at 4 years of age in infants enrolled in the United Kingdom Infantile Spasms Study. Date of or age at onset of spasms was obtained prospectively. Lead time to treatment was then categorized into five categories. The effects of lead time to treatment, age of onset of spasms, etiology, and treatment on developmental outcome were investigated using multiple linear regression.Age of onset ranged (77 infants) from1 to 10 months (mean 5.2, standard deviation 2.1). Lead time to treatment was 7 days or less in 11, 8-14 days in 16, 15 days to 1 month in 8, 1-2 months in 15,2 months in 21 and not known in 6. Each month of reduction in age at onset of spasms was associated with a 3.1 [95% confidence interval (CI) 0.64-5.5, p = 0.03] decrease, and each increase in category of lead time duration associated with a 3.9 (95% CI 7.3-0.4, p = 0.014) decrease in VABS, respectively. There was a significant interaction between treatment allocation and etiology with the benefit in VABS in those allocated steroid therapy being in children with no identified etiology (coefficient 29.9, p=0.004).Both prompt diagnosis and prompt treatment of infantile spasms may help prevent subsequent developmental delay. Younger infants may be more at risk from the epileptic encephalopathy than older infants.

To examine the underlying etiology of infantile spasms from the United Kingdom Infantile Spasms Study (UKISS), using the pediatric adaptation of ICD 10.Infants were enrolled in a randomized controlled trial or a parallel epidemiologic study. Etiological information included history, examination, and investigations. The infants were classified as proven etiology, if a neurologic disease was identified; as no identified etiology, if no neurologic disease was identified; and as not fully investigated, if a major piece of information was missing. Proven etiology was subclassified using the pediatric adaptation of ICD 10. The results were then examined to identify further methods of classification.Of 207 infants, 127 (61%) had proven etiology, 68 (33%) had no identified etiology, and 12 (6%) were not fully investigated. Etiologies were prenatal in 63, perinatal in 38, postnatal in 8, and 18 other. The most common etiologies were: hypoxic-ischemic encephalopathy (HIE) 21 (10%), chromosomal 16 (8%), malformations 16 (8%), stroke 16 (8%), tuberous sclerosis complex (TSC) 15 (7%), and periventricular leukomalacia or hemorrhage 11 (5%). The remaining 32 etiologies were all individually uncommon. Response to treatment is given for individual etiologies.Our method of classification allows the reporting of results by individual diseases, disease groups, or categories and is structured and clear. It avoids the use of poorly defined terms such as symptomatic and cryptogenic. It can adapt to new neurologic diseases, such as gene defects, and can be used for comparison of different groups of infants, thereby aiding meta-analysis.

OBJECTIVES: C1q deficiency is a rare inherited defect in the early part of the complement cascade. In this report, we describe the varied clinical features of patients with this condition as well as the characteristic autoantibody profile. METHODS: A large Pakistani family with a high degree of consanguinity is described in which the father and five sons have C1q deficiency, all with different clinical manifestations. RESULTS: Clinical features of C1q deficiency can vary from almost no disease to fulminant bacterial infection and localized lupus-like skin, renal or CNS disease. Autoantibodies to ribonucleoproteins such as anti-Sm and Ro, but not dsDNA, were present. CONCLUSIONS: Awareness of the spectrum of clinical disease, autoantibody profiles and tests required to confirm the diagnosis of C1q deficiency are important if this life-threatening immunodeficiency disease is to be managed correctly.

Infantile spasms (IS) are a serious epileptic encephalopathy that occur most commonly between 2 and 14 months. The spasms occur in association with hypsarrhythmia or similar on EEG. There is often coincident psychomotor arrest or regression. Between March 2007 and May 2014, infants with IS and a compatible EEG were enrolled in a multicenter treatment trial. Participating countries were the UK, Germany, Switzerland, Australia and New Zealand. Infants were randomised to receive either hormonal therapy and vigabatrin or hormonal therapy alone. A second stage randomization allowed hormonal treatment to be allocated as either prednisolone or tetracosactide depot. Minimum doses were: vigabatrin 100 mg/kg/day, prednisolone 40 mg per day, or IM tetracosactide depot 0.5 mg on alternate days. Hormonal treatment was continued for 2 weeks and then weaned over 2 weeks. Vigabatrin was continued for 3 months and then weaned over a month. The early primary outcome measure was cessation of spasms on and between days 14 and 42. Analysis is by intention to treat. 377 children were enrolled and early clinical outcome data will be available on 376 (1 case withdrew). 186 were allocated hormonal therapy and vigabatrin and 191 were allocated hormonal therapy alone. We will report on the primary clinical outcome and serious adverse clinical events. Developmental outcome at 18 months of age will be reported in a subsequent paper. To date this is by far the largest treatment study of infantile spasms ever undertaken.

There is an unexplained excess of type 1 diabetes and other organ-specific autoimmune diseases in children with Down’s syndrome, but the immunogenetic characteristics of diabetes in Down’s syndrome have not been investigated. We studied the frequency of islet autoantibodies in 106 children with Down’s syndrome and no history of autoimmunity and analyzed HLA class II genotypes in 222 children with Down’s syndrome, 40 children with Down’s syndrome and type 1 diabetes, 120 age- and sex-matched children with type 1 diabetes, and 621 healthy control subjects. Co-occurrence of at least two islet autoantibody markers was observed in 6 of 106 nondiabetic children with Down’s syndrome compared with 13 of 2,860 healthy age-matched children (P < 0.001). There was an excess of diabetes-associated HLA class II genotypes in children with Down’s syndrome and type 1 diabetes compared with age- and sex-matched healthy control subjects (P < 0.001). Down’s syndrome children with type 1 diabetes were, however, less likely to carry the highest risk genotype DR4-DQ8/DR3-DQ2 than children with type 1 diabetes from the general population (P = 0.01) but more likely to carry low-risk genotypes (P < 0.0001). The frequency of subclinical islet autoimmunity is increased in Down’s syndrome, and susceptibility to type 1 diabetes in Down’s syndrome is partially HLA mediated. Other factors, possibly including genes on chromosome 21, may increase the penetrance of type 1 diabetes in Down’s syndrome.

The Epilepsies, an update of A Clinical Guide to Epileptic Syndromes and their Treatment (2002) through the same publisher, continues to force the pace. I still find many of my colleagues talking (and thinking) of grand mal and petit mal: and such clinicians will have difficulty conceptualizing the epilepsies rather than epilepsy. The truth is that this is ‘state of the art’. Everyone must now say to themselves, ‘Is it epilepsy?’; ‘Which seizure type?’ and last of all, and most challenging, ‘Which epilepsy?’. In practice much has to be done in retrospect. The ‘classification pending’ file is large in my practice. Were there really localizing features? What is to be made of the varying asymmetry on the EEG? However, for most, with the passing of a few months, clarification of the history especially, and where appropriate a repeat EEG, the definition of the epilepsy becomes possible. Although one would expect much dogma in a book which defines a classification, there is very little. The emphasis is on a pragmatic approach around a classification that is expected to change. The necessarily pragmatic approach of clinical practice is compared with the structure of scientific classification. Lumpers and splitters are compared to botanists and gardeners, who in turn are compared to scientists and clinicians. Tom Panayiotopoulos writes ‘The botanists, like all scientists, need a taxonomy, other gardeners, like all practising physicians need something to use in daily work’. Hughlings Jackson (1874) is quoted in the context of this debate as indicating that the scientific classification (taxonomy) is ‘for the better organisation of existing knowledge and for discovering the relations of new facts; its principles are methodological guides to further investigation to great utilitarian value, but not directly’. This remains true today. I think all of us in paediatric neurological practice acknowledge that the definition of the phenomenon in small parts allows it better to be studied. Then as new knowledge emerges we may—or may not as the case may be—realize that many of the small parts are part of the same continuum; that a particular variety of phenotypes may represent many genotypes and indeed that a genotype may lead to many phenotypes. The Epilepsies is more than a comprehensive definition of seizure types and EEG appearances. It contains lists of practice points and pitfalls that will be useful even to the experienced. The colour coding is at times imprecise (red for the pitfalls and blue for the practice points), but then there is bound to be overlap between these two areas anyway. The yellowish headings seem not to represent any particular message and that particular colour might usefully be dropped next time round. Meanwhile we have a book not to be kept on the shelf but rather to be thumbed regularly for details of the challenging children we see, to be checked almost day by day to see to what extent their epilepsy might be defined. We should try to link this in our resource-stretched health service, to computerized databases, to audit and research and to the best approach to treatment, prognosis and so on. The advantage of multicentre input could readily be pursued—and that is not to mention a fruitful liaison with the neurogeneticists. Nine of the fourteen chapters in the book define some eighty syndromes (this exercise is not for the faint-hearted). However, probably 80% of the children have an epilepsy under the twenty commonest headings (the rest requiring a more specialist approach). An editorial point concerns children ‘suffering from’ epilepsy—an expression I dislike. They may ‘have’ an epilepsy but we can reassure ourselves that 80% will go into remission. If we all take the content of this book seriously and work together to advance knowledge and improve our approach, any ‘suffering’ will diminish as time goes by. All paediatric neurologists and paediatricians with special responsibility for epilepsy, and neurodevelopmental paediatricians, should have a copy and strive to put the examples into practice.

Summary Background Infantile spasms is a severe infantile seizure disorder that is difficult to treat and has a high morbidity. Absence of spasms on days 13 and 14 after randomisation is more common in infants allocated hormone treatments than in those allocated vigabatrin. We sought to assess whether early control of spasms is associated with improved developmental or epilepsy outcomes. Methods Infants enrolled in the United Kingdom Infantile Spasms Study (UKISS) were randomly assigned hormone treatment (n=55) or vigabatrin (n=52) and were followed up until clinical assessment at 12–14 months of age. We assessed neurodevelopment with the Vineland adaptive behaviour scales (VABS) at 14 months of age on an intention to treat basis. Findings Of 107 infants enrolled, five died and 101 survivors reached both follow-up assessments. Absence of spasms at final clinical assessment (hormone 41/55 [75%] vs vigabatrin 39/51 [76%]) was similar in each treatment group (difference 1·9%, 95% CI −18·3% to 14·4%; χ 2 =0·05; p=0·82). Mean VABS score did not differ significantly (hormone 78·6 [SD 16·8] vs vigabatrin 77·5 [SD 12·7]; difference 1·0, 95% CI −4·9 to 7·0; t 99 =0·35, p=0·73). In infants with no identified underlying aetiology, the mean VABS score was higher in those allocated hormone treatment than in those allocated vigabatrin (88·2 [17·3] vs 78·9 [14·3]; difference 9·3, 95% CI 1·2 to 17·3; t 95 =2·28, p=0·025). Interpretation Hormone treatment controls spasms better than does vigabatrin initially, but not at 12–14 months of age. Better initial control of spasms by hormone treatment in those with no identified underlying aetiology may lead to improved developmental outcome.

This case series describes four children who had meningitis in the neonatal period. After a stable period of years, they developed a myelopathy caused by chronic arachnoiditis. The myelopathy was precipitated by a fall in two cases, and in two cases there was an acute deterioration after surgery. A history of neonatal meningitis should be taken into consideration before planning surgery or anaesthesia. Careful intra-operative positioning, immobilisation of the neck, and maintenance of blood pressure is important but may not prevent this complication.

Summary Background Infantile spasms, which comprise a severe infantile seizure disorder, have a high morbidity and are difficult to treat. Hormonal treatments (adrenocorticotropic hormone and prednisolone) have been the main therapy for decades, although little evidence supports their use. Vigabatrin has been recorded to have a beneficial effect in this disorder. We aimed to compare the effects of vigabatrin with those of prednisolone and tetracosactide in the treatment of infantile spasms. Methods The United Kingdom Infantile Spasms Study assessed these treatments in a multicentre, randomised controlled trial in 150 hospitals in the UK. The primary outcome was cessation of spasms on days 13 and 14. Minimum doses were vigabatrin 100 mg/kg per day, oral prednisolone 40 mg per day, or intramuscular tetracosactide depot 0·5 mg (40 IU) on alternate days. Analysis was by intention to treat. Findings Of 208 infants screened and assessed, 107 were randomly assigned to vigabatrin (n=52) or hormonal treatments (prednisolone n=30, tetracosactide n=25). None was lost to follow-up. Proportions with no spasms on days 13 and 14 were: 40 (73%) of 55 infants assigned hormonal treatments (prednisolone 21/30 [70%], tetracosactide 19/25 [76%]) and 28 (54%) of 52 infants assigned vigabatrin (difference 19%, 95% CI 1%–36%, p=0·043). Two infants allocated tetracosactide and one allocated vigabatrin received prednisolone. Adverse events were reported in 30 (55%) of 55 infants on hormonal treatments and 28 (54%) of 52 infants on vigabatrin. No deaths were recorded. Interpretation Cessation of spasms was more likely in infants given hormonal treatments than those given vigabatrin. Adverse events were common with both treatments.

Two individuals with pyruvate dehydrogenase (PDH) deficiency due to missense mutations in the gene for the E1alpha subunit (PDHA1) presented during childhood with dystonia. The first patient, a male, presented at age 4 years with dystonia affecting the lower limbs, which responded to treatment with combined carbidopa and levodopa. The second patient, a female, was first investigated at age 6 years because of a dystonic gait disorder. In both patients, the main clue to the biochemical diagnosis was a raised concentration of lactate in the cerebrospinal fluid. PDH activity was significantly reduced in cultured fibroblasts in both cases. Dystonia is a previously unrecognized major manifestation of PDH deficiency and is of particular interest as the mutations in the PDHA1 gene in these patients have both been identified previously in individuals with typical presentations of the condition.

Epilepsy is a common treatable disorder with an incidence in the UK of about 0.05% and a prevalence of 0.5%.1 The average secondary school has about 6 children with the condition. A paediatrician who has diagnosed epilepsy will feel pressure to prescribe medication—as indeed will a clinician in adult practice. In view of the efficacy of anti-epileptic drugs,2 this is understandable. The primary aim of therapy is of course to prevent seizures, but do anti-epileptic drugs alter the natural history of the condition, either in the short term or by enhancing the chance of long-term remission? Should the benign epilepsies of childhood be treated differently? How do medication and everyday life issues interact? This paper deals with the factors that should influence the decision to prescribe. The focus is on childhood and adolescence, but much of the published work relates to adults and many of the points are relevant to an adult population too.

Primary malignant melanoma of the meninges is described in a 5-year-old boy who presented with a 3-month history suggestive of subacute meningitis. Clinically the diagnosis of tuberculous meningitis was made and antituberculous treatment was begun. Despite this treatment, the patient's condition continued to deteriorate. Through cytologic examination of the cerebrospinal fluid malignant melanoma cells were identified, emphasizing the importance of this investigation in children with atypical meningitis. The diagnosis of malignant melanoma of the meninges was confirmed on brain biopsy.