New onset movement disorders have been reported following treatment for B12 deficiency but not in late onset cobalamin disorders. We describe an 8-year-old boy who developed a hyperkinetic movement disorder following initiation of treatment of genetically confirmed late-onset cobalamin C deficiency. Jerk-locked averaging showed a cortical origin of the myoclonic movements. Our patient was also unusual in presenting with an acute encephalopathy followed by a static period, and later deterioration with photosensitive epilepsy. Born following an uneventful delivery to consanguineous parents, our patient presented with a history of an acute encephalopathic illness at age 3 1/2 years, while the family lived overseas. During this illness, he had a significant developmental regression in motor ability, recognition and speech; unresponsiveness, continuous involuntary jerking movements involving his right arm and head, and right sided weakness. This left him with sequelae of generalized tonic–clonic epileptic seizures, asymmetric spastic quadriparesis (affecting right side more than the left), intermittent right arm tremor (often at rest, worsening with excitement, upset or emotion; with no surface EEG epileptiform correlates), speech and learning impairment, and behavior difficulties. This initially followed a non-progressive course. By age 5, he was able to communicate in phrases and short sentences. MRI brain performed at the time of the encephalopathic illness showed generalized volume loss with no white matter or basal ganglia involvement. His interictal EEG at age 5 years showed generalized photoparoxysmal response with no clinical correlate i.e., subclinical photosensitivity. By age 7 years, there was a further deterioration with behavior difficulties with more challenging and physically aggressive behavior, motor regression with loss of ability to crawl, loss of speech ability and swallowing difficulties with dribbling. There was an additional perceived element by family of his reluctance or refusal to speak, feed and engage in his normal motor activities. His seizures increased in frequency. He continued to have episodes of motor arrest, up-rolling of eyes and dribbling. He had other often prolonged episodes of generalized tonic extension, repetitive eye blinking and drooling. There was ongoing EEG evidence of a generalized epilepsy with subclinical photosensitivity. His seizures continued despite escalating levetiracetam treatment, which reached a maximum dose of 45 mg/kg/day. At age 8 years, he was admitted to hospital due to deterioration in oral intake and suspicion of malnutrition. Red cell macrocytosis (MCV 95 fL) with high serum vitamin B12 level (1856 ng/L) and normal serum folate level had prompted further investigation. Following further deterioration in oral intake, a percutaneous gastrostomy was inserted under general anesthesia using nitrous oxide. Neurometabolic Investigation results revealed hyperhomocysteinaemia (171 μmol/L; normal range 0–18), hypomethioninaemia (<5 μmol/L; normal range 11–40) and significant methylmalonic aciduria (MMA/Creatinine ratio 1563.8 μmol/mmol creatinine, normal range 1.0–8.0), the day following anesthetic administration, raising suspicion of an inherited cobalamin synthesis defect. Treatment with intramuscular hydroxycobalamin 1 mg daily and oral betaine 1.3 g twice daily (120 mg/kg/day) was commenced the day following nitrous oxide administration. Within 2 days of starting treatment, he developed a mainly right sided hyperkinetic movement disorder involving face, tongue and hands, along with him being upset, a change in behavior, and loss of speech (Video 1). The appearance was polymorphic, including dystonia, chorea, myoclonus, and tremor. The movement disorder was persistent, albeit less prominent, during sleep. It was noted that the movement disorder was exacerbated in the upper limbs when on action, and in the tongue and face when attempting to initiate speech. Standard EEG, 4 days after onset, revealed slow background activity, rhythmic high amplitude delta slow waves, with no epileptiform features. The EEG findings supported an encephalopathy, with significant muscle artifact. Electrophysiological EEG/EMG polygraphy recordings were performed 15 days from the onset of prominent multifocal myoclonus, as illustrated in Figure 1. At the time of this testing, the movement disorder was most prominent in both upper limbs and the face. A sampling rate of 1 kHz was used for EEG data, and surface EMG electrodes were applied bilaterally to deltoids, biceps brachii, triceps brachii, extensor digitorum communis and flexor carpi ulnaris. The technique of jerk-locked back averaging (JLA), and cross-correlation studies were used to analyze the data. The role of JLA technique is to detect EEG cortical activity that is related to myoclonus in space and time. MRI of the brain within 7 days of onset of this presentation revealed symmetrical increased signal in periventricular white matter (predominantly centrum semiovale) and lentiform nucleus, not restricting on DWI. A combination of benzodiazepines (clobazam) and trihexyphenidyl were used for symptomatic relief of the movement disorder. The hyperkinetic movement disorder improved over weeks, with a gradual improvement in alertness, interaction and speech. It is not clear that there was a direct response to medication. Trihexiphenidyl was weaned by week 3 and discontinued by week 4. He continued clobazam for around 12 months in total. Video 2 shows the patient 4 weeks after the onset of the disorder. The movement disorder persisted, however intermittently, for months following this, involving the right upper limb and face. Consequent genetic analysis with sequencing of MMACHC gene showed homozygosity for the nonsense mutation c.394C > T (p.Arg132Ter) known to be associated with late-onset Cobalamin C disease mutation (Combined methylmalonic acidaemia and homocystinuria), inherited in an autosomal recessive form. This is the first report of a post-treatment hyperkinetic movement disorder, in late onset inherited cobalamin deficiencies. In addition, neither an acute encephalopathy followed by a static course nor epilepsy with photosensitivity have been described in late onset cobalamin deficiencies. In infants with acquired vitamin B12 deficiency1-8 and infantile-onset inherited Cobalamin C deficiency,9 a polymorphic movement disorder can appear within days of commencing treatment with parenteral hydroxycobalamin, which involves arms, head, face, and tongue and which subsides within 3–6 weeks.8 EEG recordings do not demonstrate an epileptic origin. Movement disorders including tremors and dyskinesias, as well as both generalized and focal seizures, have been described clinically in children with the pathogenic c.394C > T (p.Arg132Ter) variant, which was found in our patient.10 The importance of the JLA in illustrating the cortical origin of the myoclonus (illustrated in Fig. 1), has not been reported before. JLA shows a spikey cortical transient preceding the EMG discharge of <75 ms, while polygraphy recordings show co-contraction of agonist antagonist and synchronous activation of proximal and distal muscles, illustrating the cortical origin of myoclonus movements. The exact mechanism is still unknown. It has been hypothesized that the sudden availability of cobalamin after prolonged deficiency leads to intense stimulation of cobalamin metabolic pathways and temporary imbalance of substrates.2 It has been reported both as a new phenomenon after treatment, and an exacerbation of a pre-existing mild movement disorder present.2, 4, 8, 10 Indeed, in our patient, there was evidence of a subtle movement disorder present before treatment, with an intermittent right-sided hand tremor witnessed in previous video EEG recordings. This is in keeping with previous reports of patients with this pathogenic genetic mutation.10 It is possible nitrous oxide administration before diagnosis may have contributed to this picture. Nitrous oxide inhibits activity of the cobalamin-dependent enzyme methionine synthase. The use of nitrous oxide as an anesthetic in children with occult cobalamin deficiency and inborn errors of cobalamin metabolic pathway has the potential to cause significant neurological deterioration.11 From our experience, we recommend clinicians to anticipate occurrence or worsening of a movement disorder on treatment of inherited or acquired cobalamin deficiencies in children of various ages, and exercise caution with use of nitrous oxide in this specific group. The authors confirm that the approval of an institutional review board was not required for this work. Written Informed patient consent was obtained for reporting this case from the patient's father. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines. No specific funding was received for this work. The authors declare that there are no conflicts of interest relevant to this work. The authors declare that there are no additional disclosures to report. (1) Research project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript Preparation: A. Writing of the first draft, B. Review and Critique; A.F.: 1A, 1B, 3A P.S.B.: 1A, 1B, 3B P.G.S.: 1C, 3B S.S.: 1B, 3B M.J.S.: 1C, 3B S.R.M.: 1A, 1B, 3B

Hypoxic–ischaemic insults occurring during or after birth can cause both acute and long‐term neurological impairment. The duration of the insult is a critical factor, but most published reports of duration have important limitations. After the onset of a persistent bradycardia in 125 term born infants, abnormal outcomes occurred in two by 10 minutes, in 12 out of 47 (26%) delivered between 11 and 20 minutes, and in 55 out of 65 (85%) delivered after 20 minutes. Series with unspecified gestation or including infants born preterm give comparable results in over 500 additional cases. Before 20 minutes there was little correlation with severity, while after 20 minutes most were severely impaired. Limited neuroimaging data suggest that damage restricted to the basal ganglia and thalamus may begin to occur after 10 minutes, associated Rolandic damage after 15 minutes, and other cortical involvement after 20 minutes. Associated white matter damage can occur after any duration. There were little data for other patterns of damage.

This commentary is on the original article by Lawerman et al. on pages 75‐82 of this issue.

Objectives To report investigations performed in children with progressive neurodegenerative diseases reported to this UK study. Design Since 1997 paediatric surveillance for variant Creutzfeldt-Jakob disease (vCJD) has been performed by identifying children aged less than 16 years with progressive intellectual and neurological deterioration (PIND) and searching for vCJD among them. Setting The PIND Study obtains case details from paediatricians who notify via the British Paediatric Surveillance Unit. Participants Between May 1997 and October 2017, a total of 2050 cases meeting PIND criteria had been notified and investigated. Results Six children had vCJD. 1819 children had other diagnoses, made in 12 cases by antemortem brain biopsy and in 15 by postmortem investigations. 225 children were undiagnosed: only 3 had antemortem brain biopsies and only 14 of the 108 who died were known to have had autopsies; postmortem neuropathological studies were carried out in just 10% (11/108) and only two had prion protein staining of brain tissue. Of the undiagnosed cases 43% were known to come from Asian British families. Conclusions Most of the notified children had a diagnosis other than vCJD to explain their neurological deterioration. None of the undiagnosed cases had the clinical phenotype of vCJD but brain tissue was rarely studied to exclude vCJD. Clinical surveillance via the PIND Study remains the only practical means of searching for vCJD in UK children.

BACKGROUND:Duchenne muscular dystrophy (DMD) is a rare disease that causes the progressive loss of motor abilities such as walking. Standard treatment includes physiotherapy. No trial has evaluated whether or not adding aquatic therapy (AT) to land-based therapy (LBT) exercises helps to keep muscles strong and children independent. OBJECTIVES:To assess the feasibility of recruiting boys with DMD to a randomised trial evaluating AT (primary objective) and to collect data from them; to assess how, and how well, the intervention and trial procedures work. DESIGN:Parallel-group, single-blind, randomised pilot trial with nested qualitative research. SETTING:Six paediatric neuromuscular units. PARTICIPANTS:Children with DMD aged 7-16 years, established on corticosteroids, with a North Star Ambulatory Assessment (NSAA) score of 8-34 and able to complete a 10-m walk without aids/assistance. Exclusions: > 20% variation between baseline screens 4 weeks apart and contraindications. INTERVENTIONS:Participants were allocated on a 1 : 1 ratio to (1) optimised, manualised LBT (prescribed by specialist neuromuscular physiotherapists) or (2) the same plus manualised AT (30 minutes, twice weekly for 6 months: active assisted and/or passive stretching regime; simulated or real functional activities; submaximal exercise). Semistructured interviews with participants, parents (n = 8) and professionals (n = 8) were analysed using Framework analysis. An independent rater reviewed patient records to determine the extent to which treatment was optimised. A cost-impact analysis was performed. Quantitative and qualitative data were mixed using a triangulation exercise. MAIN OUTCOME MEASURES:Feasibility of recruiting 40 participants in 6 months, participant and therapist views on the acceptability of the intervention and research protocols, clinical outcomes including NSAA, independent assessment of treatment optimisation and intervention costs. RESULTS:Over 6 months, 348 children were screened - most lived too far from centres or were enrolled in other trials. Twelve (30% of target) were randomised to AT (n = 8) or control (n = 4). People in the AT (n = 8) and control (n = 2: attrition because of parental report) arms contributed outcome data. The mean change in NSAA score at 6 months was -5.5 [standard deviation (SD) 7.8] for LBT and -2.8 (SD 4.1) in the AT arm. One boy suffered pain and fatigue after AT, which resolved the same day. Physiotherapists and parents valued AT and believed that it should be delivered in community settings. The independent rater considered AT optimised for three out of eight children, with other children given programmes that were too extensive and insufficiently focused. The estimated NHS costs of 6-month service were between £1970 and £2734 per patient. LIMITATIONS:The focus on delivery in hospitals limits generalisability. CONCLUSIONS:Neither a full-scale frequentist randomised controlled trial (RCT) recruiting in the UK alone nor a twice-weekly open-ended AT course delivered at tertiary centres is feasible. Further intervention development research is needed to identify how community-based pools can be accessed, and how families can link with each other and community physiotherapists to access tailored AT programmes guided by highly specialised physiotherapists. Bayesian RCTs may be feasible; otherwise, time series designs are recommended. TRIAL REGISTRATION:Current Controlled Trials ISRCTN41002956. FUNDING:This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 21, No. 27. See the NIHR Journals Library website for further project information.

Standard treatment of Duchenne muscular dystrophy (DMD) includes regular physiotherapy. There are no data to show whether adding aquatic therapy (AT) to land-based exercises helps maintain motor function. We assessed the feasibility of recruiting and collecting data from boys with DMD in a parallel-group pilot randomised trial (primary objective), also assessing how intervention and trial procedures work.

OBJECTIVE: We describe a child with post-anoxic myoclonus of the reticular reflex type and discuss the classification of post-anoxic myoclonus. PATIENT DESCRIPTION: A nine-year-old boy with severe hypoxic-ischemic encephalopathy due to submersion developed early epileptic spasms followed by stimulus sensitive multifocal generalized myoclonus and later dystonia. Video electromyography (EMG) polygraphy performed before treatment demonstrated that the discharges associated with the myoclonus lasted less than 50 milliseconds. Cortical myoclonus was excluded by jerk-locked averaging using arm muscles, which showed no cortical correlates. The recruitment order on EMG polygraphy was consistent with a brainstem generator for the myoclonus, characteristic of reticular reflex myoclonus. Both myoclonus and dystonia responded to clonazepam. He remains in a persistent vegetative state. CONCLUSIONS: Reticular reflex myoclonus can be demonstrated by detailed neurophysiological assessment in children as in adults, and it has a similar poor prognosis in children. Post-anoxic myoclonus can have several mechanisms and should not be considered synonymous with Lance-Adams myoclonus.

In the February 2015 issue of DMCN, Mrs Michele Shusterman argued from a mother’s perspective that the diagnosis ‘cerebral palsy’ (CP) is misleading and unhelpful. She suggests it should be replaced by a term that more accurately reflects the multiple problems a child with an early brain impairment can experience: ‘early developmental brain injury/interference’ or EDBI. Subsequent correspondence has supported this proposal. Cerebral palsy was originally coined by William Osler in the late 1880s, mainly to distinguish weakness due to brain damage from weakness due to poliomyelitis. At that time there were no paediatric neurologists and the specialties of neurology and paediatrics were in their infancy. Pathology could only be confirmed by post-mortem examination. Since then clinical experience and observation has accumulated, while neuroimaging and functional technologies now allow sequential assessment of what is happening in the living brain, not to mention the spinal cord and peripheral nervous system as well. The nature, site, and severity of the wide range of different pathologies which are currently recognized determine which or to what extent cerebral functions are impaired, such as cognition, learning, behaviour, vision, hearing, motor abilities, as well as the risk of problems such as hydrocephalus or epilepsy. Preventative measures also vary according to the underlying cause. From a neurological perspective using CP as an umbrella term for a mixed group of unrelated pathologies with differing clinical effects has rightly been questioned, especially as it can also lead to diagnostic complacency. What, for example, is the cause in a child with normal neuroimaging? By definition, the features that distinguish CP are the exclusion of progressive pathology and the timing, in that the disturbance must affect the fetal or infant brain, which means that developing rather than established function is impaired. Even here there is a problem, since the development of motor and other functions does not stop after infancy but continues throughout childhood and beyond. At present a motor impairment due to a brain injury at 6 months of age is classified as CP, but not if it is due to a brain injury at 30 months of age. However, the term still has a very important function. The effects of an insult on the developing brain do need to be highlighted and separated from those on the developed brain, although this applies to all the cerebral functions listed above, not just the motor aspects. The causes are individually rare, so in isolation would become yet more orphan diseases. Putting them together under the same umbrella is enormously helpful when it comes to treatment, support, and research funding. As stated in the annotation to the 2007 definition, the term CP ‘is established in the literature and is used universally by clinicians, therapists, epidemiologists, researchers, policy makers, health care funding organization and laypersons’, and ‘has been retained to relate future research in CP to existing published work’. Parents regularly report that saying their child has CP, rather than for example spastic hemiplegia, unlocks previously unavailable educational resources and social services. Research funding from both government and charitable sources would be more difficult to obtain without a well-recognized term. That research has given better insight into causal pathways and possible preventative interventions, and helped decide which treatments are effective and which are less so. Over 40 years ago Dr Ronald MacKeith was arguing that children with CP need comprehensive management. Since then a holistic approach has become the expectation, as detailed in the recent book published by Mac Keith Press. Good clinical practice is already recognized to encompass an aetiological diagnosis, a detailed description of all the impairments affecting a child, the associated limitations of activities and participation, and appropriate management. If a new term is considered, one such as ‘developmental brain (or cerebral) impairment’ would be a broader concept since it would cover a wider age range and include additional pathologies not typically associated with motor problems, such as the sequelae of neonatal hypoglycaemia. However, if we continue to use ‘cerebral palsy’, we must ensure all the possible implications for a child are emphasized to the same degree as the motor problems if we are to address Mrs Shusterman’s justified concerns.

In the immediate aftermath of a severe brain injury survivors are usually in coma, which is characterised as a state of unresponsiveness without any understanding or purposeful functions, although reflex responses can still be elicited. If the injury is severe enough but not fatal, the coma can persist for days or weeks, but it is nonetheless recognised to be a transient condition which evolves into other defined conscious states. Consciousness may be regained, but if not signs of a persistent vegetative state (also called unresponsive wakefulness syndrome) or a minimally conscious state develop. Both the latter are characterised by spontaneous or induced eye opening and sleep wake cycles, with additional responses such as apparent crying, laughing, or smiling. In the minimally conscious state there are also reproducible if inconsistent visual, verbal, or gestural responses to particular stimuli. In both these states, signs depend on relatively intact brain stem function, contrasting with the locked-in syndrome, a condition in which brain stem dysfunction prevents a conscious person from demonstrating their awareness.1, 2 Recognition of the two states of reduced consciousness has informed treatment and management decisions. Families and others who can see obvious signs of improvement, in that a person is no longer completely unresponsive or comatose, often expect further recovery. Standard advice is that in adults and children the potential for recovery from the persistent vegetative state, and the time to allow, depends on the cause: significant improvement can still occur up to 12 months after traumatic injury, but only up to 3 months after a non-traumatic injury, such as near-drowning. The potential for recovery from a minimally responsive state may be better, but it is not clear by how much, or if the time scales differ. One group reported that in the first 3 months there is a good chance of reasonable recovery but this falls sharply with longer durations, especially after non-traumatic injuries. In the latter groups survivors may continue to improve in terms of responsiveness but most remain severely disabled.1, 3, 4 However, problems remain. Detailed definitions of the clinical features of the two states differ.3 Distinguishing the two states is clinically difficult, although specific scales increase diagnostic precision.2 It seems logical to expect that in some patients with additional brain stem damage a state of reduced consciousness might co-exist with a degree of locked-in syndrome. In addition, from personal experience some patients do not show spontaneous eye opening or sleep-wake cycles despite other responses suggestive of a minimally conscious state. Such cases are not defined or studied in the medical literature. Finally over the last few years functional neuroimaging studies, mostly in adults, have shown that some patients have much more cortical responsiveness than clinically suspected, meaning that some thought to be in a persistent vegetative state may be at least minimally conscious.5 In one study 13 out of 41 patients classified by a standard scale as being in the vegetative state showed activity compatible with a minimally conscious state on neuroimaging between 3 weeks and 8 years after the injury. Twelve months later some clinical improvement in consciousness had occurred in most, usually to a minimally conscious state. One, assessed approximately 5 weeks after a traumatic injury, had recovered fully but the other survivors were still severely disabled.5 Ideally perhaps patients should now all be assessed by functional neuroimaging, but that may be impractical. The predictive value of more accessible modalities such as EEG and transcranial magnetic stimulation are still being explored. For all these, it would be clinically helpful if outcome studies followed a standard format to report the state and how it was assessed at fixed times after the injury, such as 3 months and 6 months, and the prognosis at 12 months or thereafter, subdivided into traumatic and non-traumatic groups. In the meantime all patients in such states should be assumed to have some awareness some of the time, which means for example that there must be adequate analgesia for painful conditions or procedures, and that further discussion is needed on the relationship between responsiveness and awareness. In children these difficulties are even more marked. There is limited data on both the accuracy of clinical diagnosis and outcome, especially in the very young age groups.1 Clinical scales have not been validated in children. Some studies of functional imaging have included children or young people but do not always report their data separately. Patient and medical groups should lobby for standardized outcome studies in children, which should be large enough to provide useful data for smaller subgroups.

BackgroundScoliosis in patients with Duchenne muscular dystrophy (DMD) is usually progressive and is treated with surgery. However, it is unclear whether the existing evidence is sufficiently scientifically rigorous to support a recommendation for spinal surgery for most patients with DMD and scoliosis. This is an updated review, and an updated search was undertaken in which no new studies were found for inclusion.ObjectivesTo determine the effectiveness and safety of spinal surgery in patients with DMD with scoliosis. We intended to test whether spinal surgery is effective in increasing survival and improving respiratory function, quality of life, and overall functioning, and whether spinal surgery is associated with severe adverse effects.Search methodsOn 16 June 2015 we searched the Cochrane Neuromuscular Disease Group Specialized Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, and CINAHL Plus. We also searched ProQuest Dissertation and Thesis database (January 1980 to June 2015), the National Institutes of Health Clinical Trials Database (6 January 2015), and the WHO International Clinical Trials Registry Platform (17 June 2015), and checked references. We imposed no language restrictions.Selection criteriaWe planned to include controlled clinical trials using random or quasi-random allocation of treatment evaluating all forms of spinal surgery for scoliosis in patients with DMD in the review. The control interventions would have been no treatment, non-operative treatment, or a different form of spinal surgery.Data collection and analysisWe used standard methodological procedures expected by The Cochrane Collaboration. Two review authors independently examined the search results and evaluated the study characteristics against inclusion criteria in order to decide which studies to include in the review.Main resultsOf the 49 relevant studies we found, none met the inclusion criteria for the review because they were not clinical trials, but prospective or retrospective reviews of case series.Authors' conclusionsSince no randomized controlled clinical trials were available to evaluate the effectiveness of scoliosis surgery in patients with DMD, we can make no good evidence-based conclusion to guide clinical practice. Patients with scoliosis should be informed as to the uncertainty of benefits and potential risks of surgery for scoliosis. Randomized controlled trials are needed to investigate the effectiveness of scoliosis surgery, in terms of quality of life, functional status, respiratory function, and life expectancy.

BACKGROUND:Seventy-five percent of patients with pyridoxine-dependent epilepsy (PDE) due to Antiquitin (ATQ) deficiency suffer from developmental delay and/or intellectual disability (IQ < 70) despite seizure control. An observational study showed that adjunct treatment with a lysine-restricted diet is safe, results in partial normalization of lysine intermediates in body fluids, and may have beneficial effects on seizure control and psychomotor development.METHODS:In analogy to the NICE guideline process, the international PDE Consortium, an open platform uniting scientists and clinicians working in the field of this metabolic epilepsy, during four workshops (2010-2013) developed a recommendation for a lysine-restricted diet in PDE, with the aim of standardizing its implementation and monitoring of patients. Additionally, a proposal for a further observational study is suggested.RESULTS:(1) All patients with confirmed ATQ deficiency are eligible for adjunct treatment with lysine-restricted diet, unless treatment with pyridoxine alone has resulted in complete symptom resolution, including normal behavior and development. (2) Lysine restriction should be started as early as possible; the optimal duration remains undetermined. (3) The diet should be implemented and the patient be monitored according to these recommendations in order to assure best possible quality of care and safety.DISCUSSION:The implementation of this recommendation will provide a unique and a much needed opportunity to gather data with which to refine the recommendation as well as improve our understanding of outcomes of individuals affected by this rare disease. We therefore propose an international observational study that would utilize freely accessible, online data sharing technologies to generate more evidence.

We describe four children with an apparently unique form of easily treatable early onset epilepsy. All had an unremarkable family history, pregnancy and delivery. One child presented with neonatal seizures. None of them had neonatal jaundice. They presented with developmental impairment, cortical visual agnosia or squint, and clusters of epileptic spasms [3] beginning in infancy. Electroencephalogram showed features of modified (atypical) hypsarrhythmia. Neuroimaging in infancy showed unilateral or bilateral signal changes in the globus pallidus. All infants were treated with high dose vigabatrin (VGB). The seizure disorder responded well to treatment and VGB was discontinued. Repeat magnetic resonance imaging brain scan showed complete resolution of the signal changes in the globus pallidi. All remained seizure free but continued to show severe intellectual disability. We suggest that VGB treatment was associated with "reversible" signal changes in the globus pallidi in these children.

Some large-scale cooling studies in term infants with encephalopathy of presumed asphyxial origin are now publishing longer-term results with interesting, if at times contradictory, results. In 2012 Shankaran et al.1 reported that out of 208 child participants in the US National Institute of Child Health and Human Development (NICHD) study, 190 were assessed at the ages of 6 to 7 years. The main outcome of death and/or an IQ below 70, while lower in the cooled group, was not significantly different from the control group. The difference had been significant at 18 to 22 months of age, but just lost statistical significance at the later age. However, at the older age there was still a significant reduction in the risk of death, death or severe disability (defined as an IQ score below 55, Gross Motor Function Classification System [GMFCS] level of IV or V, and/or bilateral blindness) and death or cerebral palsy (CP). There was no significant difference in survivors for CP rates or levels of disability. In those who were followed up, survival without disability (i.e. an IQ above 85 and no neurological problems) was 29% in the cooled versus 23% in the control group. In 2014 Azzopardi et al.2 reported data from 280 of 325 newborn infants originally enrolled in the European Total Body Hypothermia for Neonatal Encephalopathy (TOBY) trial, followed to the same age. Their prime outcome, survival with an IQ score of 85 or more, was significantly better in the cooled group, as were the chances of avoiding neurological abnormalities, including CP and moderate or severe disability. Yet there was no difference in deaths in the two groups. In those who were followed up, survival without disability (i.e. an IQ above 85 and no neurological problems) was 45% in the cooled versus 27% in the control group. Apart from different primary outcome measures, both studies were very similar in design. As well as showing increasingly convincing benefits from cooling in terms of reducing motor and intellectual disability, they also allay fears that survivors of cooling might have increased rates of disability. This information builds on a larger number of shorter-term outcome studies which were the subject of a 2013 Cochrane Review.3 This concluded that there are benefits from cooling in terms of death, cognitive development, and CP. When comparing outcomes in neonates with moderate or severe encephalopathy, there was a clear reduction in mortality in both groups but survival without severe disability was only significantly improved in those with moderate encephalopathy. In both groups seven (range 4–17) and six (range 4–11) children respectively needed to be cooled to prevent one from dying or surviving with severe disability. Finally, it remained unclear whether whole body cooling differs in effectiveness from selective head cooling with milder body cooling. Other useful results from the longer-term studies are the comparisons of outcomes at 18 to 22 months and 6 to 7 years, which corroborates previously published data.4 A survivor's IQ classification could change but not the severity of their CP if they already had a GMFCS level of III to V, indicating that the diagnosis of more severe CP can be reasonably confident by 18 months of age. However, they did not give information on changes between these levels. Another important finding was that while the 10-minute Apgar score correlated closely with outcome, three out of 24 infants with a score of zero (i.e. who were technically dead even at that stage) could still survive without disability.5 As always there are now further questions to answer. The first is whether the results from these trials can be replicated in real life and, even more importantly, in countries with less well-resourced health services. Other questions include dosage (e.g. 48 vs 72h of cooling); timing (e.g. could infants still benefit if cooling is introduced after 6h of age?); whether preterm infants could benefit; and whether adjunctive therapy makes a difference. However, it is very heartening that in this group of infants one intervention is now proved to reduce the risk of the rightly feared outcomes of death and disability.

In 2013, rapid technological improvement in DNA methods has radically changed paediatric neurology. Advances have made exome sequencing more reliable and affordable, revolutionising the diagnostic process in much of paediatric neurology. This change has also enabled the recognition of novel disorders, expansion of the phenotype of previously known ones, and has led to new treatments, belying the old adage that neurology is concerned only with diagnosis; as a corollary, it is also providing fresh clinical challenges.

While the pre-eminent causes of autism are genetic, environmental factors are still likely to be influential. In 2013 a large Danish population-based study reported that the cumulative incidence of all autism spectrum disorders over a 10-year period in children born to mothers taking valproate during pregnancy was significantly increased, from 1.53% to 4.42%.1 In mothers with epilepsy the risk was increased from 2.44% to 4.15%. Analyses of the subgroup of children with childhood autism showed a similarly increased risk. There was no comparable increase in children born to mothers taking other anticonvulsants, or to those who discontinued valproate before pregnancy. The effect of valproate was unrelated to the dose, polytherapy, whether it was taken throughout pregnancy or started during pregnancy (but numbers of the latter were low), and remained after adjustments for congenital malformations and parental psychiatric disorders. The study relied on national databases, so precise details about therapy such as dosage, other drugs including alcohol, and independent corroboration of the diagnosis were not available. Like many similar studies, the absolute numbers in some subgroups were still quite low. Experience in the UK National Childhood Encephalopathy Study showed that rechecking the clinical diagnoses in these small groups can be important. In addition, the prevalence by birth year increased steadily from 0.2% to 1.2% with age, so the comparisons had to take this into account. Furthermore, IQ was not assessed as a possible confounding factor, which could be important in view of the suggested link with learning difficulties. Nonetheless, it is the most robust data set so far and supports previous studies with lower levels of evidence that described the same risk association. In contrast, there is also some evidence that folate started before conception could have a protective effect. In 2012 a case-control study in the USA found that greater than 600 μg daily in the first month of pregnancy was associated with a reduced risk of autism spectrum disorder in mothers or children with certain MTHFR genotypes.2 In 2013 the Norwegian Mother and Child Cohort Study2 looked at a national group with formally confirmed diagnoses of autism and found that childhood autism occurred in 0.21% of those whose mothers did not take folate, significantly more than the 0.10% in those who took 400 μg or more daily over the 4 weeks before conception and 8 weeks after.3 This effect was not present for folate use in mid-pregnancy, nor for fish oil consumption. There was no association with other autism spectrum disorders but there was more limited power to detect an effect in these groups. While the cohort is not fully representative of the Norwegian population, analysis of a nationwide data file showed the same association. Nonetheless, effects from confounders such as socio-economic status, and non-response bias, could not be completely ruled out. Again, IQ was not assessed. The same group previously reported an association between peri-conception folate treatment and a reduced risk of severe language delay at the age of 3 years. However, it is unclear why the benefit should occur so early in fetal development. In addition there is no obvious difference in autism prevalence between countries with and without routine folate supplementation of food, or before and after its introduction, even though the latter appears to reduce the risk of neural tube defects. Dosage may be important, since in the USA the effective mean daily intake from fortified food is around 100 μg.2 This intriguing data only reveal associations, not proof of cause. In Denmark 85% of mothers taking valproate had epilepsy but in other countries such as the USA the majority of valproate treatment is for other indications, such as migraine or bipolar disorder. When considering valproate therapy in adult and adolescent females of child-bearing age, or younger females who are likely to need to continue treatment into their child-bearing years, it seems best to advise that there is a clear association with some congenital malformations, especially neural tube defects, and some evidence of links with learning difficulties and now autism in their offspring. Hence, if possible, an equally effective alternative would be preferable. The next questions are whether younger females who are already stably maintained on valproate should be switched to an alternative medication once they pass through puberty, or if valproate is prescribed, should folate supplementation be routinely given as well and if so, in what dose? As usual, more studies are needed before we can give our patients clear guidance.

Developmental Medicine & Child NeurologyVolume 55, Issue 11 p. 972-972 EditorialFree Access Service provision for people with learning disability Peter Baxter, Peter Baxter Editor in ChiefSearch for more papers by this author Peter Baxter, Peter Baxter Editor in ChiefSearch for more papers by this author First published: 04 October 2013 https://doi.org/10.1111/dmcn.12279Citations: 1AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Embarrassingly, the English National Health Service discovered earlier this year that the service it provides for people with learning (or intellectual) disability is not up to the standard it should be and that there is an excess of premature deaths due to avoidable factors. This is the conclusion of a confidential enquiry commissioned by the government in response to previously expressed concerns, including a trigger article published in DMCN.1 The Confidential Inquiry into Premature Deaths of People with Learning Disability (CIPOLD) covered a population of nearly 1.7 million in the South West of England and investigated the deaths of people aged over 4 years with learning disability.2 The first striking finding was that there were more than twice the expected number of deaths in this group, nearly all in adults. The second important finding was that the median age at death was reduced whatever the IQ level, in contrast to epidemiological data from Finland which showed that people with mild or moderate intellectual disability did not have a reduced life expectancy.3 Many of the people investigated had additional impairments such as physical disability, but no separate analysis was provided based on additional clinical features except that as in other studies, those with Down syndrome had a significantly earlier age of death than those with learning disability from other causes. Overall, the major causes of death, cancer, heart and circulatory disorders, and the proportion of unexpected deaths (i.e. unanticipated in the 24h before death [e.g. due to stroke]) was the same as in the general population. However, more deaths were classified as premature, due to delays in assessment, investigation, or treatment, and to problems with identifying needs. In trying to understand why this happens, the inquiry looked at professional data and family perspectives. While premature death was more likely in people who were socially isolated, the majority were still in people living in residential care homes. Most had had annual health checks, but the quality was very variable. A major issue was that during acute events families felt they were not listened to appropriately, particularly by doctors. In addition, guidelines on end of life care were not followed correctly, although this has been the subject of separate recent concerns in the wider population.4 Overall, the CIPOLD report identified inadequate adherence to established care pathways, fragmented care between medical specialties, and difficulties at the interface between health and social care, but most of all attitudinal problems. While there are a number of publications on the effects of education on the attitudes of healthcare students to disabled people, there is surprisingly little on the attitudes of qualified professionals or whether, where less than positive attitudes exist, training can improve or change them.5, 6 It is difficult to find similar information from other countries. In the UK, coordination of care, especially for adults, relies on doctors in general practice who are responsible for coordination of care and, where needed, refer patients to medical and non-medical specialist care providers. In children, paediatricians often take this role. Pathways of care obviously vary in other countries with different healthcare systems. In the USA the recent Affordable Care Act recognized and banned discrimination in provision of healthcare on the basis of medical history or genetic information. Many countries with a nationally organized healthcare system state that they pay special attention to people with all forms of disabilities, but it is not clear whether or how the provision of care is audited.7 Hopefully, the problems identified in the CIPOLD report are purely an English phenomenon and people with learning disability or those caring for them elsewhere do not need to be concerned, but it would be reassuring to confirm this in other countries. In the meantime, in England at least the best way to help people with learning disability does not appear to be through further research into medical problems, but through ensuring the delivery of what are already recognized to be good models of care. References 1Hollins S, Attard MT, von Fraunhofer N, McGuigan S, Sedgwick P. Mortality in people with learning disability: risks, causes, and death certification findings in London. Dev Med Child Neurol 1998; 40: 50– 6. 2 University of Bristol. CIPOLD: Confidential Inquiry into Premature Deaths of People with Learning Disabilities. http://www.bris.ac.uk/cipold (accessed 23 July 2013). 3Patja K, Iivanainen M, Vesala H, Oksanen H, Ruoppila I. Life expectancy of people with intellectual disability: a 35-year follow-up study. J Intellect Disabil Res 2000; 44: 591– 9. 4 GOV.UK. Review of Liverpool Care Pathway for Dying Patients. https://www.gov.uk/government/publications/review-of-liverpool-care-pathway-for-dying-patients (accessed 23 July 2013). 5Satchidanand N, Gunukula SK, Lam WY, et al. Attitudes of healthcare students and professionals toward patients with physical disability: a systematic review. Am J Phys Med Rehabil 2012; 91: 533– 45. 6Hannon F. National Disability Authority (Údarás Náisiúnta Míchumais). Literature Review on Attitudes towards Disability. http://www.ucd.ie/issda/static/documentation/nda/nda-literature-review.pdf (accessed 23 July 2013). 7Holt G, Costello H, Bouras N, et al. BIOMED-MEROPE project: service provision for adults with intellectual disability: a European comparison. J Intellect Disabil Res 2000; 44: 685– 96. Citing Literature Volume55, Issue11November 2013Pages 972-972 ReferencesRelatedInformation