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What you need to know Chiari malformations are a heterogeneous group of hindbrain anomalies. Six different malformations are described. Most common are Chiari 1 malformation (CM1) and Chiari 2 malformation (CM2, also termed “Arnold-Chiari malformation”) and are the focus of this review. These are rare conditions, but symptoms may impair quality of life in both adults and children,1 causing disruption to work or education and social exclusion. The diagnosis is often delayed or missed as symptoms may be mistaken for other neurological conditions or attributed as psychogenic.2 Not enough information or explanation from healthcare professionals3 can aggravate patients’ fears on being diagnosed. Although some patients improve after surgery, others experience lifelong symptoms, progression of deficits, need for re-operation, and complications. Non-specialists can play an important role in early diagnosis and referral, counselling, and supporting long term care for these patients. In this clinical update, we summarise the definitions, epidemiology, and …

ObjectivesTo report investigations performed in children with progressive neurodegenerative diseases reported to this UK study.DesignSince 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.SettingThe PIND Study obtains case details from paediatricians who notify via the British Paediatric Surveillance Unit.ParticipantsBetween May 1997 and October 2017, a total of 2050 cases meeting PIND criteria had been notified and investigated.ResultsSix 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.ConclusionsMost 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.

ObjectiveOnset of symptoms in severe sporadic neurofibromatosis type 2 (NF2) is typically within childhood; however, there is poor awareness of presenting features in young children, potentially resulting in delayed diagnosis and poorer outcome. We have reviewed presentation of sporadic paediatric NF2 to raise awareness of early features, highlighting those requiring further investigation.DesignPatients diagnosed with NF2 at age ≤16 and seen between 2012 and 2015 were notified via the British Paediatric Neurology Surveillance Unit or identified through the English NF2 service.ResultsEpidemiological data estimate that 1 in 110 611 births are affected with childhood-onset NF2. Notes of 32 patients with sporadic NF2 were reviewed. Of those presenting under the age of 5, 89% (17/19) had ocular, 74% (14/19) dermatological and 58% (11/19) neurological signs; in 84% (16/19) features were multisystemic. Sixty-six per cent (21/32) had ≥1 atypical feature, including cerebellar hypoplasia in three cases (9%) and focal cortical dysplasia in five out of seven seizure-related presentations. Five cases presented with a sometimes transient or intermittent cranial nerve mononeuropathy. The mean delay to diagnosis was 3.16 years; in eight cases (25%) this exceeded 6 years. Most significant delay occurred in mononeuropathy, ophthalmological and/or seizure presentations, with a mean delay of 3, 4.5 and 6 years, respectively. Eighty-four per cent (27/32) of cases needed intervention in childhood.ConclusionsAll non-vestibular schwannoma NF2 presentations in childhood had significant diagnostic delay. We emphasise the importance of detailed assessment of skin and eyes in unusual presentations and propose an aide to prompt timely referral to specialist services.

Objective To identify neuronal surface antibodies in opsoclonus myoclonus ataxia syndrome (OMAS) using contemporary antigen discovery methodology. Methods OMAS patient serum immunoglobulin G immunohistochemistry using age-equivalent rat cerebellar tissue was followed by immunoprecipitation, gel electrophoresis, and mass spectrometry. Data are available via ProteomeXchange (identifier PXD009578). This generated a list of potential neuronal surface cerebellar autoantigens. Live cell-based assays were used to confirm membrane-surface antigens and adsorb antigen-specific immunoglobulin Gs. The serologic results were compared to the clinical data. Results Four of the 6 OMAS sera tested bound rat cerebellar sections. Two of these sera with similar immunoreactivities were used in immunoprecipitation experiments using cerebellum from postnatal rat pups (P18). Mass spectrometry identified 12 cell-surface proteins, of which glutamate receptor δ2 (GluD2), a predominately cerebellar-expressed protein, was found at a 3-fold-higher concentration than the other 11 proteins. Antibodies to GluD2 were identified in 14/16 (87%) OMAS samples, compared with 5/139 (5%) pediatric and 1/38 (2.6%) adult serum controls (p < 0.0001), and in 2/4 sera from patients with neuroblastoma without neurologic features. Adsorption of positive OMAS sera against GluD2-transfected cells substantially reduced but did not eliminate reactivity toward cerebellar sections. Conclusion Autoantibodies to GluD2 are common in patients with OMAS, bind to surface determinants, and are potentially pathogenic.

AIM: Paediatric opsoclonus-myoclonus syndrome (OMS) is a poorly understood condition with long-term cognitive, behavioural, and motor sequelae. Neuroimaging has indicated cerebellar atrophy in the chronic phase, but this alone may not explain the cognitive sequelae seen in many children with OMS. This study aimed to determine the extent of structural change throughout the brain that may underpin the range of clinical outcomes. METHOD: Nine participants with OMS (one male, eight females; mean age [SD] 14y, [6y 5mo], range 12-30y) and 10 comparison individuals (three males, seven females; mean age 12y 6mo, [4y 9mo], range 10-23y) underwent magnetic resonance imaging to acquire T1-weighted structural images, diffusion-weighted images, and magnetic resonance spectroscopy scans. Neuroblastoma had been present in four participants with OMS. Voxel-based morphometry was used to determine changes in grey matter volume, tract-based spatial statistics to analyze white matter integrity, and Freesurfer to analyze cortical thickness across visual and motor cortices. RESULTS: Whole-brain analysis indicated that cerebellar grey matter was significantly reduced in the patients with OMS, particularly in the vermis and flocculonodular lobe. A region-of-interest analysis indicated significantly lower cerebellar grey matter volume, particularly in patients with the greatest OMS scores. Diffusion-weighted images did not show effects at a whole brain level, but all major cerebellar tracts showed increased mean diffusivity when analysis was restricted to the cerebellum. Cortical thickness was reduced across the motor and visual areas in the OMS group, indicating involvement beyond the cerebellum. INTERPRETATION: Across individuals with OMS, there is considerable cerebellar atrophy, particularly in the vermis and flocculonodular lobes with atrophy severity associated with persistent symptomatology. Differences in cerebral cortical thickness indicate disease effects beyond the cerebellum.

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

Objective: Changing trends in multiple sclerosis (MS) epidemiology may first be apparent in the childhood population affected with first onset acquired demyelinating syndromes (ADSs). We aimed to determine the incidence, clinical, investigative and magnetic resonance imaging (MRI) features of childhood central nervous system ADSs in the British Isles for the first time. Methods: We conducted a population active surveillance study. All paediatricians, and ophthalmologists ( n = 4095) were sent monthly reporting cards (September 2009–September 2010). International Paediatric MS Study Group 2007 definitions and McDonald 2010 MS imaging criteria were used for acute disseminated encephalomyelitis (ADEM), clinically isolated syndrome (CIS) and neuromyelitis optica (NMO). Clinicians completed a standard questionnaire and provided an MRI copy for review. Results: Card return rates were 90%, with information available for 200/222 positive notifications (90%). After exclusion of cases, 125 remained (age range 1.3–15.9), with CIS in 66.4%, ADEM in 32.0% and NMO in 1.6%. The female-to-male ratio in children older than 10 years ( n = 63) was 1.52:1 ( p = 0.045). The incidence of first onset ADS in children aged 1–15 years old was 9.83 per million children per year (95% confidence interval [CI] 8.18–11.71). A trend towards higher incidence rates of ADS in children of South Asian and Black ethnicity was observed compared with White children. Importantly, a number of MRI characteristics distinguished ADEM from CIS cases. Of CIS cases with contrast imaging, 26% fulfilled McDonald 2010 MS diagnostic criteria. Conclusions: We report the highest surveillance incidence rates of childhood ADS. Paediatric MS diagnosis at first ADS presentation has implications for clinical practice and clinical trial design.

Aim Opsoclonus–myoclonus syndrome (OMS) is a rare, poorly understood condition that can result in long-term cognitive, behavioural, and motor sequelae. Several studies have investigated structural brain changes associated with this condition, but little is known about changes in function. This study aimed to investigate changes in brain functional connectivity in patients with OMS. Method Seven patients with OMS and 10 age-matched comparison participants underwent 3T magnetic resonance imaging (MRI) to acquire resting-state functional MRI data (whole-brain echo-planar images; 2mm isotropic voxels; multiband factor ×2) for a cross-sectional study. A seed-based analysis identified brain regions in which signal changes over time correlated with the cerebellum. Model-free analysis was used to determine brain networks showing altered connectivity. Results In patients with OMS, the motor cortex showed significantly reduced connectivity, and the occipito-parietal region significantly increased connectivity with the cerebellum relative to the comparison group. A model-free analysis also showed extensive connectivity within a visual network, including the cerebellum and basal ganglia, not present in the comparison group. No other networks showed any differences between groups. Interpretation Patients with OMS showed reduced connectivity between the cerebellum and motor cortex, but increased connectivity with occipito-parietal regions. This pattern of change supports widespread brain involvement in OMS.

All 253 children receiving neurosurgical intervention for hydrocephalus (HCP) at a single British Neurosurgical Unit over a decade were investigated by retrospective case note review. Referral rates and mean age at presentation remained stable throughout, as did proportions of children presenting due to myelomeningocoele or meningitis. Comparing the first and second halves of the decade, the predominant aetiologies (intraventricular haemorrhage [IVH] at

Localized hypertrophic neuropathy, also termed intraneural perineurioma, is a rare disorder of unknown etiology that produces a slowly progressive painless focal lesion of a peripheral nerve. It is characterized histologically by concentric whorls (“onion bulbs”) of epithelial membrane antigen-reactive, S-100 protein-negative perineurial cells surrounding nerve fibers. We report a radial nerve palsy in a child aged 2 years in whom the diagnosis of localized hypertrophic neuropathy was made by biopsy. Resection of the affected nerve segment and sural nerve grafting produced no useful recovery after 3 years, probably because of the long duration of denervation. When this mononeuropathy presents in early childhood, uncertainty over the time of onset can lead to difficulty in distinguishing this potentially treatable lesion from congenital and other causes of nerve palsy. ( J Child Neurol 2004;19:71—75).

Neurexin 1 (NRXN1) is a cell adhesion protein, the normal function of which is critical for effective neurotransmission. It forms a trans-synaptic complex in the central nervous system with neuroligin. There has been one case in the literature of a patient with a heterozygous deletion in NRXN1 on one allele and a nonsense mutation on the other allele, reported to have a Pitt Hopkins-like phenotype. We report on two daughters of healthy, nonconsanguineous, Caucasian parents with biallelic NRXN1 deletions identified by array CGH. The children presented with severe early onset epilepsy, profound developmental delay, gastroesophageal reflux disease, constipation, and early onset puberty. Our report confirms that biallelic NRXN1 mutations result in a severe recessive mental retardation syndrome and broadens the range of phenotypes associated with this gene. © 2011 Wiley-Periodicals, Inc.

Alice is referred by her general practitioner (GP) for a paediatric neurology opinion with a history of episodes of her legs giving way. The referral letter from her GP mentions that when Alice is picked up when she has one of these episodes, she cannot control her legs, which move abnormally. Alice is seen by the registrar. Her parents' say that these episodes are occurring at a frequency of one every month, and they describe non-rhythmic jerky movements involving her legs lasting approximately 20 min. She falls and cannot walk or stand when these happen. Recovery occurs without intervention. She has experienced a total of five episodes, and they all occurred in the evening following exertion. Her consciousness is not impaired during these events, and between the episodes Alice is well. The prenatal and perinatal history are normal, and her development is in keeping with her chronological age. An interesting aspect of Alice's family history is the fact that her father had experienced similar episodes when he was 8 years old, and they had lasted until he was 13. He described episodic paroxysmal movements involving both his upper and lower limbs, and he recalled needing to sit down when these episodes occurred. He had been given the diagnosis of Sydenham's chorea by his GP. Alice's head circumference and neurological examination are normal. The paediatric registrar discusses Alice with the neurology consultant, and given the history of Alice's father having similar episodes in childhood, they consider the possibility of a familial movement disorder such as a ‘Benign hereditary chorea.’ Since Alice is clinically well, the decision is made not to investigate further at that point but to keep her under review. The neurologist suggests a video recording of the event should it happen again. ### Comment Chorea is characterised by frequent, random, unpredictable …

Glucose transporter type 1 deficiency syndrome (GLUT1DS) is a treatable condition resulting from impaired glucose transport into the brain. The classical presentation is with infantile-onset epilepsy and severe developmental delay. Non-classical phenotypes with movement disorders and early-onset absence epilepsy are increasingly recognized and the clinical spectrum is expanding. The hallmark is hypoglycorrhachia (cerebrospinal fluid [CSF] glucose

Phospholipase associated neurodegeneration (PLAN) comprises a heterogeneous group of autosomal recessive neurological disorders caused by mutations in the PLA2G6 gene. Direct gene sequencing detects ∼85% mutations in infantile neuroaxonal dystrophy. We report the novel use of multiplex ligation-dependent probe amplification (MLPA) analysis to detect novel PLA2G6 duplications and deletions. The identification of such copy number variants (CNVs) expands the PLAN mutation spectrum and may account for up to 12.5% of PLA2G6 mutations. MLPA should thus be employed to detect CNVs of PLA2G6 in patients who show clinical features of PLAN but in whom both disease-causing mutations cannot be identified on routine sequencing.

Objective The aim of this study is to describe the long-term neurological, neuropsychological and neuroradiological sequelae and to determine prognostic factors for neurological outcome in children with neuroblastoma-associated opsoclonus-myoclonus-ataxia (OMA) syndrome. Methods Data on medical history were collected for the study patients. Examinations with grading of neurological signs, neuropsychological tests and brain magnetic resonance imaging with spectroscopy were performed during a follow-up clinic. Results Fourteen subjects entered the study. All had localized neuroblastoma and they were evaluated after a median of 7.8 years. Patients with a chronic/multiphasic neurological course received steroids combined with intravenous immunoglobulins in the majority of cases. 71% presented neurological sequelae and 62% had a full-scale IQ below the normal range. All patients showed at least some deficit in the neuropsychological functions assessed (language, visual-motor integration, memory, attention and motor ability). Long-term deficits were more frequently detected in patients with an interval of more than 2 months between OMA onset and its diagnosis, even if in most comparisons statistical significance was not reached. Cerebellar atrophy, observed in 36% of patients, was not associated with the neurological outcome. Conclusions Persisting disability is present in most children with neuroblastoma-associated OMA. However, our results support the role of an early diagnosis of OMA in reducing sequelae and encourage the use of new immunosuppressive therapies.

The use of extreme freeform illumination conditions and multi patterning processes used to generate sub 40nm images can result in significant intra-field overlay errors. When levels with differing illumination conditions are aligned to each other, these intra-field distortions can result in overlay errors which are uncorrectable using normal linear feedback corrections. We use a double exposure method, previously described by Minghetti [1] et al. to isolate and measure intra-field overlay distortions caused by tool lens signatures and different illumination conditions. A full field test reticle is used to create a dual level expose pattern. The same pattern is exposed twice, but with two different illumination conditions. The first exposure is done with a standard reference illumination. The second exposure is the target illumination condition. The test reticle has overlay target pairs that are measurable when the 2nd exposure is offset in the Y direction by the designed amount. This allows for a high density, 13x13, intra-field overlay measurement to be collected and modeled to determine 2 nd and 3 rd order intra-field terms. Since the resulting illumination and scanner lens specific intra field corrections are independent of field size, the sub-recipes can be applied to any product exposure independent of field size, which use the same illumination conditions as the test exposures. When the method is applied to all exposure levels in a product build cycle, the overlay errors contributed by the reference illumination condition cancel out. The remaining errors are due exclusively to the impact of the illumination condition on that scanner lens. Actual results correlated well with the model with more than 80% of the predicted overlay improvement being achieved.

Synaptotagmin-1 (SYT1) is a calcium-binding synaptic vesicle protein that is required for both exocytosis and endocytosis. Here, we describe a human condition associated with a rare variant in SYT1. The individual harboring this variant presented with an early onset dyskinetic movement disorder, severe motor delay, and profound cognitive impairment. Structural MRI was normal, but EEG showed extensive neurophysiological disturbances that included the unusual features of low-frequency oscillatory bursts and enhanced paired-pulse depression of visual evoked potentials. Trio analysis of whole-exome sequence identified a de novo SYT1 missense variant (I368T). Expression of rat SYT1 containing the equivalent human variant in WT mouse primary hippocampal cultures revealed that the mutant form of SYT1 correctly localizes to nerve terminals and is expressed at levels that are approximately equal to levels of endogenous WT protein. The presence of the mutant SYT1 slowed synaptic vesicle fusion kinetics, a finding that agrees with the previously demonstrated role for I368 in calcium-dependent membrane penetration. Expression of the I368T variant also altered the kinetics of synaptic vesicle endocytosis. Together, the clinical features, electrophysiological phenotype, and in vitro neuronal phenotype associated with this dominant negative SYT1 mutation highlight presynaptic mechanisms that mediate human motor control and cognitive development.

Process-induced overlay errors are a growing problem in meeting the ever-tightening overlay requirements for integrated circuit production. While uniform process-induced stress is easily corrected, non-uniform stress across the wafer is much more problematic, often resulting in non-correctable overlay errors. Measurements of the wafer geometry of free, unchucked wafers give a powerful method for characterization of such non-uniform stress. We will describe a Patterned Wafer Geometry (PWG) tool, which uses optical methods to measure the geometry of in-process wafers. PWG data can be related to In-Plane Distortion (IPD) of the wafer through the PIR (Predicted IPD Residual) metric. This paper will explore the relationship between the PIR data and measured overlay data on Engineered Stress Monitor (ESM) wafers containing various designed stress variations. The process used to fabricate ESM wafers is quite versatile and can mimic many different stress variation signatures. For this study, ESM wafers were built with strong across-wafer stress variation and another ESM wafer set was built with strong intrafield stress variation. IPD was extensively characterized in two different ways: using standard overlay error metrology and using PWG metrology. Strong correlation is observed between these two independent sets of data, indicating that the PIR metric is able to clearly see wafer distortions. We have taken another step forward by using PIR data from the PWG tool to correct process-induced overlay error by feedforward to the exposure tool, a novel method that we call PWG-FF. We conclude that appropriate wafer geometry measurements of in-process wafers have strong potential to characterize and reduce process-induced overlay errors.

We investigated the features of children with spinal cord insults (SCI) occurring in the pre-, peri-, and neonatal periods by sending 340 questionnaires to all paediatric neurologists, paediatric urologists, and neonatologists in the UK and Ireland. We requested information about timing, nature, and level of SCI in their patients; family and maternal history; pregnancy, delivery, and neonatal period; clinical presentation, imaging, laboratory studies, and outcome. Two-hundred and sixty-one questionnaires were returned with data on 58 patients with SCI. Seven out of the 58 children with SCI had pure dysraphic cord syndromes and were excluded. Fifty-one patients (33 males, 17 females, one unknown), born between 1972 and 1996, remained. Clinical presentations included severe respiratory failure (N=20; five of whom died neonatally) and hypotonia or weakness recognized either during the neonatal period (N=12) or after 28 days (N=10). Data on clinical presentation were not given in nine cases. Lesions were cervical (N=22) and thoraco-lumbar (N=29). SCI was ascribed to ischaemia (N=12), trauma (N=4), and other associated underlying conditions (N=11), whilst the aetiology was unknown in 24 cases. Mean gestational age (36.2 weeks) and birthweight (2.6 kg) were lower than previously reported with the lowest figures associated with thoraco-lumbar and ischaemic lesions. More males were affected by lesions than females and the incidence of preterm delivery, multiple pregnancy, breech presentation, forceps delivery, and caesarean delivery were higher than average. Forceps delivery was associated with cervical lesions. Outcome data were given in 47 children, nine of whom died either neonatally or within the first 20 months of life. Motor disability ranged from a complete recovery in one out of 40 to paraparesis in 26 out of 40, and tetraparesis in 13 out of 40 patients: 17 out of 39 were ambulant. Sphincter dysfunction was present in 22 out of 38 patients and scoliosis in 16 out of 37. Learning difficulties were present in 10 out of 39, behavioural problems in five out of 39 and seizures in four out of 39 patients. SCI in the pre-, peri-, and neonatal periods are rare but probably under-diagnosed and are heterogeneous in aetiology, presentation, and outcome. Boys appear to be more susceptible than girls.

Duchenne muscular dystrophy (DMD) is a progressive muscle disorder associated with an intellectual deficit which is non-progressive. We obtained localised 1H magnetic resonance spectra from the left frontal lobe and left cerebellum of 15 boys with DMD (mean age 106 months+/-32) and 15 similarly aged control boys (mean age 115 months+/-31); all boys underwent a battery of neuropsychological tests. We found a significant (P0.01) increase in the ratio of choline-containing compounds to N-acetylaspartate (Cho/NA) in the left cerebellum in boys with DMD compared with control boys. There was no change in the creatine/NA ratio and a significant increase (P=0.03) in the Cho/creatine ratio, suggesting that the change in Cho/NA ratio was due to an increase in choline-containing compounds; this increase has been previously observed in the brain of the murine model of DMD, the mdx mouse. No significant changes were observed in spectra obtained from left frontal lobe in DMD compared to controls. We also observed a significant association between Cho/NA in the left cerebellum, and the performance of DMD boys on the Matrix Analogies Test (MAT). The MAT is a test of visuo-spatial ability and non-verbal reasoning which requires neither manual dexterity nor a verbal response for an adequate performance. A comparison of DMD boys whose cerebellar Cho/NA fell within 2 standard deviations of the control norm (0.56+/-0.24) with DMD boys whose cerebellar Cho/NA was outside this range (i.e.0.80) revealed a significant difference in ability on the MAT (P0.05). DMD boys whose Cho/NA ratio is more than two standard deviations higher than controls perform significantly better on the MAT than DMD boys whose Cho/NA ratio is within the normal range. This finding suggests that the observed elevation in Cho/NA and Cho/creatine is not associated with intellectual deficit (as sampled by the MAT), and may represent a compensatory mechanism. The possible interpretations of these metabolic changes are discussed.

Opsoclonus-myoclonus syndrome is a very rare disorder with onset usually in the second year of life, and the clinical features of opsoclonus, myoclonus, ataxia, irritability, sleep disturbance, and, often but by no means invariably, an associated neuroblastoma. There is no diagnostic test; brain imaging is normal and other investigations produce nonspecific results; the diagnosis is clinical and the condition is not infrequently mistaken for acute cerebellar ataxia. The pathophysiology is thought to be immunological on the basis of the paraneoplasticity and the symptomatic (though often incomplete) response to immunomodulatory therapies; a number of autoantibodies have been identified to a variety of antigens and cerebrospinal fluid B-cell numbers found to be increased but no diagnostic immunological marker has yet been identified. Therapeutic benefit has been described with steroids, intravenous immunoglobulin, cyclophosphamide, azathioprine, and rituximab, but randomized trials are extremely difficult because of the rarity of the condition. Successful treatment of the tumor, when present, does not usually improve neurological outcome. Disease course may be monophasic or chronic relapsing and children are often left with long-term motor, behavioral, and cognitive sequelae.

Opsoclonus-myoclonus syndrome is a very rare disorder with onset usually in the second year of life, and the clinical features of opsoclonus, myoclonus, ataxia, irritability, sleep disturbance, and, often but by no means invariably, an associated neuroblastoma. There is no diagnostic test; brain imaging is normal and other investigations produce nonspecific results; the diagnosis is clinical and the condition is not infrequently mistaken for acute cerebellar ataxia. The pathophysiology is thought to be immunological on the basis of the paraneoplasticity and the symptomatic (though often incomplete) response to immunomodulatory therapies; a number of autoantibodies have been identified to a variety of antigens and cerebrospinal fluid B-cell numbers found to be increased but no diagnostic immunological marker has yet been identified. Therapeutic benefit has been described with steroids, intravenous immunoglobulin, cyclophosphamide, azathioprine, and rituximab, but randomized trials are extremely difficult because of the rarity of the condition. Successful treatment of the tumor, when present, does not usually improve neurological outcome. Disease course may be monophasic or chronic relapsing and children are often left with long-term motor, behavioral, and cognitive sequelae.

Introduction Infectious and immune-mediated encephalitides are important but under-recognised causes of morbidity and mortality in childhood, with a 7% death rate and up to 50% morbidity after prolonged follow-up. There is a theoretical basis for ameliorating the immune response with intravenous immunoglobulin (IVIG), which is supported by empirical evidence of a beneficial response following its use in the treatment of viral and autoimmune encephalitis. In immune-mediated encephalitis, IVIG is often used after a delay (by weeks in some cases), while diagnosis is confirmed. Wider use of IVIG in infectious encephalitis and earlier use in immune-mediated encephalitis could improve outcomes for these conditions. We describe the protocol for the first ever randomised control trial of IVIG treatment for children with all-cause encephalitis. Methods and analysis 308 children (6 months to 16 years) with a diagnosis of acute/subacute encephalitis will be recruited in ∼30 UK hospitals and randomised to receive 2 doses (1 g/kg/dose) of either IVIG or matching placebo, in addition to standard treatment. Recruitment will be over a 42-month period and follow-up of each participant will be for 12 months post randomisation. The primary outcome is ‘good recovery’ (score of 2 or lower on the Glasgow Outcome Score Extended—paediatric version), at 12 months after randomisation. Additional secondary neurological measures will be collected at 4–6 weeks after discharge from acute care and at 6 and 12 months after randomisation. Safety, radiological, other autoimmune and tertiary outcomes will also be assessed. Ethics and dissemination This trial has been approved by the UK National Research Ethics committee (South Central—Oxford A; REC 14/SC/1416). Current protocol: V4.0 (10/03/2016). The findings will be presented at national and international meetings and conferences and published in peer-reviewed journals. Trial registration numbers NCT02308982, EudraCT201400299735 and ISRCTN15791925; Pre-results.

The use of different illumination source shapes and multipatterning processes used to generate sub–40-nm images can create image placement errors level to level, resulting in significant intrafield overlay errors. These errors arise because of the impact of the different pupil shapes on lens aberrations resolving into image placement errors as well as because different tools will react differently to the same pupil shapes. We compare the impact of two extreme illumination sources on intrafield image placement and its effect on overall pattern overlay. We also discuss a method to empirically isolate and measure the amount of intrafield overlay distortion relative to a reference illumination source and then use the results to correct the resultant image placement errors.

Requirements for ever tightening overlay control are driving improvements in tool set up and matching procedures, APC processes, and wafer alignment techniques in an attempt to address both systematic and non systematic sources of overlay error. Thermal processes used in semiconductor manufacturing have been shown to have drastic and unpredictable impacts on lithography overlay control. Traditional linear alignment can accommodate symmetric and linearly uniform wafer distortions even if these defects vary in magnitude wafer to wafer. However linear alignment cannot accommodate asymmetric wafer distortions caused by variations in film stresses and rapid thermal processes. Overlay improvement techniques such as Corrections per Exposure can be used to compensate for known systematic errors. However, systematic corrections applied on a lot by lot basis cannot account for variations in wafer to wafer grid distortions caused by semiconductor processing. With High Order Wafer Alignment, the sample size of wafer alignment data is significantly increased and modeled to correct for process induced grid distortions. HOWA grid corrections are calculated and applied for each wafer. Improved wafer to wafer overlay performance was demonstrated. How HOWA corrections propagate level to level in a typical alignment tree as well as the interaction of mixing and matching high order wafer alignment with traditional linear alignment used on less overlay critical levels. This evaluation included the evaluating the impact of overlay offsets added by systematic tool matching corrections, product specific corrections per exposure and 10 term APC process control.

Glucose transporter type 1 deficiency syndrome (GLUT1DS) is a treatable condition resulting from impaired glucose transport into the brain. The classical presentation is with infantile-onset epilepsy and severe developmental delay. Non-classical phenotypes with movement disorders and early-onset absence epilepsy are increasingly recognized and the clinical spectrum is expanding. The hallmark is hypoglycorrhachia (cerebrospinal fluid [CSF] glucose2.2 mmol/l) in the presence of normoglycaemia with a CSF/blood glucose ratio of less than 0.4. GLUT1DS is due to a mutation in the solute carrier family 2, member 1 gene (SLC2A1). We present five individuals (four males, one female), all of whom had a mild phenotype, highlighting the importance of considering this diagnosis in unexplained neurological disorders associated with mild learning difficulties, subtle motor delay, early-onset absence epilepsy, fluctuating gait disorders, and/or dystonia. The mean age at diagnosis was 8 years 8 months. This paper also shows phenotypical parallels between GLUT1DS and paroxysmal exertion-induced dyskinesia.

Many clinical features of autosomal centronuclear myopathies (CNM) and X-linked myotubular myopathy (XLMTM) are common to congenital myasthenic syndromes (CMS). We describe three children whose clinical and electrophysiological findings originally suggested CMS, in whom CNM was diagnosed pathologically, though not yet genetically characterised. A fourth case, with XLMTM, also showed electrophysiological features of a neuromuscular transmission defect. Three (including the XLMTM case) showed improved strength with acetylcholinesterase inhibitor treatment. We also studied neuromuscular junction structure and function in the MTM1 knockdown zebrafish model of XLMTM, demonstrating abnormal neuromuscular junction organization; anticholinesterase therapy resulted in marked clinical response. These observations suggest that a neuromuscular transmission defect may accompany CNM and contribute to muscle weakness. Muscle biopsy should be considered in infants suspected to have CMS, especially if treatment response is incomplete, or no CMS gene mutation is identified. Treatment with acetylcholinesterase inhibitors may benefit some CNM patients. This warrants further confirmation.

The work reviewed will describe a particular effort in the area of overlay matching based on the BaseLiner™ package marketed by ASML. BaseLiner relies on the concept of Scanner Baseline Constants (SBCs). Traditionally, optical lithography systems are controlled by many numerical parameters known as Machine Constants (MCs). MCs are typically generated by a lithography system during in situ or other system based tests that generate and optimize the MCs for a very specific test condition set. The concept of SBCs introduces a “middle layer” of offsets that forces tools to be closely matched to one another under general lithography conditions, not just the specific test conditions used for MC generation. The methodology is designed to handle specific product layouts.

More sophisticated corrections of overlay error are required because of the challenge caused by technology scaling faster than fundamental tool improvements. Starting at the 45 nm node, the gap between the matchedmachine- overlay error (MMO) and technology requirement has decreased to the point where additional overlay correction methods are needed. This paper focuses on the steps we have taken to enable GridMapperTM, which is offered by ASML, as a method to reduce overlay error. The paper reviews the basic challenges of overlay error and previous standard correction practices. It then describes implementation of GridMapper into IBM's 300 mm fabrication facility. This paper also describes the challenges we faced and the improvements in overlay control observed with the use of this technique. Specifically, this paper will illustrate several improvements: 1. Minimization of non-linear grid signature differences between tools 2. Optimization of overlay corrections across all fields 3. Decreased grid errors, even on levels not using GridMapper 4. Maintenance of the grid for the lifetime of a product 5. Effectiveness in manufacturing - cycle time, automated corrections for tool grid signature changes and overlay performance similar to dedicated chuck performance

The presence of vertical ocular motor apraxia should prompt a careful assessment to detect an underlying neurometabolic condition. But congenital vertical ocular motor apraxia is a rare entity that may be attributed to perinatal stroke, hypoxia or kernicterus. We report a case of a 5-year old girl with congenital vertical ocular motor apraxia. Her magnetic resonance imaging (MRI) brain showed symmetrical high signal in the inferomedial thalamic nuclei in the distribution of the vessel of Percheron, a rare posterior cerebral artery variant. Awareness of this rare cause of childhood stroke may obviate unnecessary investigation.

Aims To define the incidence, describe presentation, management and outcome and identify prognostic factors in Acquired Transverse Myelopathy (ATM) in children under 16 years. Methods A prospective population-based surveillance study, involving all consultant paediatric neurologists in the United Kingdom from 1 July 2002 to 30 June 2004. Results and discussion Response rate was 91%, and 60 children were reported, of whom 41 were included. Median age was 9 years. The incidence of ATM in children under 16 years in confirmed cases is at least 1.72 per million children per year. There was a previously unrecognised male predominance (M:F 25:16). Early evaluation of bladder function is sometimes omitted. MR imaging should include whole spine and brain to maximise diagnostic information. Despite the use of high dose steroids, 25% of cases were left with significant sequelae. Outcome data was available for 36 children in whom recovery was defined as ‘complete’ in 19, ‘good’ in 8, ‘fair’ in 3 and ‘poor’ in 6. Significant positive prognostic factors were preceding infection, start of recovery within a week of onset, age less than 10 years, and lumbosacral spinal level on clinical assessment. Significant negative predictors were flaccid legs at presentation, sphincter involvement and rapid progression from onset to nadir within 24 h.

A new type of chrome-on-glass (COG) photomask defect was observed in 2006. Absorber material migrated into vias on dark field masks, partially obscuring the incident 193nm light and thereby causing the imaged photoresist to be underexposed. Through detailed characterization of new and defective photomasks and their histories it was determined that the migration is not caused by any unusual line events or faulty mask handling procedures. Rather, it is an inevitable result of mask use under specific conditions. Four essential elements have been identified: the presence of Cr, 193nm light exposure, charge, and water vapor and their roles elucidated through modeling studies and existing literature. We have reproduced Cr migration in the laboratory, demonstrating that these four elements are necessary and sufficient for this type of defect to occur. The only way to avoid Cr migration is to avoid reactions with water vapor.

Opsoclonus-myoclonus syndrome or Dancing Eye Syndrome (OMS/DES) is a rare neurological disorder of children, which associates with neuroblastoma (NB) in approximately 50% of cases. We examined sera from five patients with (OMS-NB(+)) and five without NB (OMS-NB(-)) for autoantibodies. OMS-NB(-) IgG bound to the surface of a NB cell line, whereas IgG from OMS-NB(+) and from NB patients without OMS/DES bound only to permeabilised cells. Both OMS-NB(+) and OMS-NB(-) reduced proliferation of NB cells. We also present a case report of a child with OMS/DES without NB who made a complete recovery without treatment. Serum antibodies at presentation bound to the surface and decreased NB cell proliferation but had decreased 9 weeks later when the child was asymptomatic. These results demonstrate that sera from some OMS/DES patients contain IgG antibodies that are potentially pathogenic.