Penny Fallon

Paediatric autoimmune encephalopathies: clinical features, laboratory investigations and outcomes in patients with or without antibodies to known central nervous system autoantigens

Objective To report the clinical and investigative features of children with a clinical diagnosis of probable autoimmune encephalopathy, both with and without antibodies to central nervous system antigens. Method Patients with encephalopathy plus one or more of neuropsychiatric symptoms, seizures, movement disorder or cognitive dysfunction, were identified from 111 paediatric serum samples referred from five tertiary paediatric neurology centres to Oxford for antibody testing in 2007–2010. A blinded clinical review panel identified 48 patients with a diagnosis of probable autoimmune encephalitis whose features are described. All samples were tested/retested for antibodies to N-methyl-D-aspartate receptor (NMDAR), VGKC-complex, LGI1, CASPR2 and contactin-2, GlyR, D1R, D2R, AMPAR, GABA(B)R and glutamic acid decarboxylase. Results Seizures (83%), behavioural change (63%), confusion (50%), movement disorder (38%) and hallucinations (25%) were common. 52% required intensive care support for seizure control or profound encephalopathy. An acute infective organism (15%) or abnormal cerebrospinal fluid (32%), EEG (70%) or MRI (37%) abnormalities were found. One 14-year-old girl had an ovarian teratoma. Serum antibodies were detected in 21/48 (44%) patients: NMDAR 13/48 (27%), VGKC-complex 7/48(15%) and GlyR 1/48(2%). Antibody negative patients shared similar clinical features to those who had specific antibodies detected. 18/34 patients (52%) who received immunotherapy made a complete recovery compared to 4/14 (28%) who were not treated; reductions in modified Rankin Scale for children scores were more common following immunotherapies. Antibody status did not appear to influence the treatment effect. Conclusions Our study outlines the common clinical and paraclinical features of children and adolescents with probable autoimmune encephalopathies. These patients, irrespective of positivity for the known antibody targets, appeared to benefit from immunotherapies and further antibody targets may be defined in the future.

Childhood arterial ischaemic stroke incidence, presenting features, and risk factors: a prospective population-based study

BACKGROUND Arterial ischaemic stroke is an important cause of acquired brain injury in children. Few prospective population-based studies of childhood arterial ischaemic stroke have been undertaken. We aimed to investigate the epidemiology and clinical features of childhood arterial ischaemic stroke in a population-based cohort. METHODS Children aged 29 days to less than 16 years with radiologically confirmed arterial ischaemic stroke occurring over a 1-year period (July 1, 2008, to June 30, 2009) residing in southern England (population denominator 5·99 million children) were eligible for inclusion. Cases were identified using several sources (paediatric neurologists and trainees, the British Paediatric Neurology Surveillance Unit, paediatricians, radiologists, physiotherapists, neurosurgeons, parents, and the Paediatric Intensive Care Audit Network). Cases were confirmed by personal examination of cases and case notes. Details of presenting features, risk factors, and investigations for risk factors were recorded by analysis of case notes. Capture-recapture analysis was used to estimate completeness of ascertainment. FINDINGS We identified 96 cases of arterial ischaemic stroke. The crude incidence of childhood arterial ischaemic stroke was 1·60 per 100 000 per year (95% CI 1·30-1·96). Capture-recapture analysis suggested that case ascertainment was 89% (95% CI 77-97) complete. The incidence of arterial ischaemic stroke was highest in children aged under 1 year (4·14 per 100 000 per year, 95% CI 2·36-6·72). There was no difference in the risk of arterial ischaemic stroke between sexes (crude incidence 1·60 per 100 000 per year [95% CI 1·18-2·12] for boys and 1·61 per 100 000 per year [1·18-2·14] for girls). Asian (relative risk 2·14, 95% CI 1·11-3·85; p=0·017) and black (2·28, 1·00-4·60; p=0·034) children were at higher risk of arterial ischaemic stroke than were white children. 82 (85%) children had focal features (most commonly hemiparesis) at presentation. Seizures were more common in younger children (≤1 year) and headache was more common in older children (>5 years; p<0·0001). At least one risk factor for childhood arterial ischaemic stroke was identified in 80 (83%) cases. INTERPRETATION Age and racial group, but not sex, affected the risk of arterial ischaemic stroke in children. Investigation of such differences might provide causative insights. FUNDING The Stroke Association, UK.

Incidence of neurological complications of surgery for congenital heart disease

A total of 523 cardiac surgical discharge summaries were searched for recorded evidence of adverse neurological events occurring between operation and time of discharge. Neurological events were recorded in 31 and included one or more of seizure disorder (n = 16), pyramidal signs (n = 11), extrapyramidal signs (n = 8), coma (n = 6), and neuro-ophthalmic deficits (n = 6). There were significantly more adverse neurological events after repairs for arch anomalies (16.6% of cases). There was also an association with the length of cardiopulmonary bypass and a period of low perfusion pressure either intraoperatively or postoperatively. Of the 19 out of 23 survivors in whom long term outcome data were available, four were normal and six had persisting neurological problems directly related to the perioperative period. In a further nine of the 19 survivors, established preoperative neurodevelopmental abnormality probably contributed to their present neurological status, in addition to perioperative events. In view of the way these data were collected, this study must represent the minimum incidence of neurological events in children undergoing cardiac surgery.

Measurement of cerebral blood flow during cardiopulmonary bypass with near-infrared spectroscopy

OBJECTIVE A novel noninvasive method for repeatedly measuring cerebral blood flow during cardiopulmonary bypass by near-infrared spectroscopy is described. The reproducibility of the method is investigated and a comparison is made with an established technique. METHODS AND RESULTS The method is derived from the Fick principle and uses indocyanine green dye, injected into the bypass circuit, as an intravascular tracer. Cerebral blood flow was measured in nine children undergoing cardiopulmonary bypass on a total of 49 occasions. Results from this study suggest that an integrating period of 4 seconds provided a consistent measurement of global cerebral blood flow. The values obtained ranged from 3.2 to 32.4 (median 15.9) ml.100 gm-1.min-1. In an additional 10 children in whom repeated measurements were made, the coefficient of variation was 11% +/- 7% (mean +/- standard deviation). In a further study, the method was compared with microsphere injection in five piglets undergoing cardiopulmonary bypass. The comparison within each animal with the linear least squares method gave values for R2 in the range 0.91 to 0.99. The gradients of the fits ranged from 0.5 to 1.8 (median 1.0). The mean difference between the two techniques was 5.7 ml.100 gm-1.min-1 or 7%. The coefficient of variation for the piglets was 14% +/- 9% (mean +/- standard deviation). CONCLUSIONS Indocyanine green and near-infrared spectroscopy allow frequent and repeated measurements of cerebral blood flow during cardiopulmonary bypass. The measurements are reproducible and accurately reflect changes in cerebral blood flow. It may be widely applicable both in research and clinical practice.

CEREBRAL HEMODYNAMICS DURING CARDIOPULMONARY BYPASS IN CHILDREN USING NEAR-INFRARED SPECTROSCOPY

We describe a new noninvasive method using near-infrared spectroscopy for monitoring cerebral hemodynamics during cardiopulmonary bypass in children. All patients were undergoing open heart operations for repair of congenital heart defects. Standardized anesthesia, an alpha-stat method of blood gas management, and nonpulsatile flow were used in all cases. All measurements during bypass were made after steady-state conditions had been reached. Cerebral blood flow was measured on 13 occasions in 4 children, aged between 4 and 10 months (median, 5 months). Values of 15.9 to 53.5 mL x 100 g-1 x min-1 were obtained. Cerebral blood volume was measured in 1 patient, aged 4 months. Volumes of 4.3 to 8.0 mL x 100 g-1 were obtained on bypass at full pump flow (2.4 L.min-1 x m-2). On bypass at half flow, the volume increased to 14.7 mL x 100 g-1. Change in cerebral blood volume with changing carbon dioxide tension (CBVR) was measured in 13 patients aged from 1 to 90 months (median, 13.5 months). Preoperatively, CBVR was 0.12 +/- 0.07 mL x 100 g-1 x kPa-1 and was independent of mean arterial pressure, which remained between 40 and 80 mm Hg in all cases. During hypothermic bypass (25 degrees C), CBVR was significantly reduced to 0.05 +/- 0.02 mL x 100 g-1 x kPa-1. In addition, there were three values at mean arterial pressure of lower than 40 mm Hg in which CBVR was negative (-0.04 +/- 0.01 mL x 100 g-1 x kPa-1). We conclude that near-infrared spectroscopy is useful for the noninvasive investigation of cerebral hemodynamics during cardiopulmonary bypass.

Novel mutations expand the clinical spectrum of DYNC1H1-associated spinal muscular atrophy

Objective: To expand the clinical phenotype of autosomal dominant congenital spinal muscular atrophy with lower extremity predominance (SMA-LED) due to mutations in the dynein, cytoplasmic 1, heavy chain 1 (DYNC1H1) gene. Methods: Patients with a phenotype suggestive of a motor, non–length-dependent neuronopathy predominantly affecting the lower limbs were identified at participating neuromuscular centers and referred for targeted sequencing of DYNC1H1. Results: We report a cohort of 30 cases of SMA-LED from 16 families, carrying mutations in the tail and motor domains of DYNC1H1, including 10 novel mutations. These patients are characterized by congenital or childhood-onset lower limb wasting and weakness frequently associated with cognitive impairment. The clinical severity is variable, ranging from generalized arthrogryposis and inability to ambulate to exclusive and mild lower limb weakness. In many individuals with cognitive impairment (9/30 had cognitive impairment) who underwent brain MRI, there was an underlying structural malformation resulting in polymicrogyric appearance. The lower limb muscle MRI shows a distinctive pattern suggestive of denervation characterized by sparing and relative hypertrophy of the adductor longus and semitendinosus muscles at the thigh level, and diffuse involvement with relative sparing of the anterior-medial muscles at the calf level. Proximal muscle histopathology did not always show classic neurogenic features. Conclusion: Our report expands the clinical spectrum of DYNC1H1-related SMA-LED to include generalized arthrogryposis. In addition, we report that the neurogenic peripheral pathology and the CNS neuronal migration defects are often associated, reinforcing the importance of DYNC1H1 in both central and peripheral neuronal functions.

Diagnostic delays in paediatric stroke

Background Stroke is a major cause of mortality in children. Conditions that mimic stroke also cause severe morbidity and require prompt diagnosis and treatment. We have investigated the time to diagnosis in a cohort of children with stroke. Methods A population-based cohort of children with stroke was prospectively identified in the south of England. Case notes, electronic hospital admission databases and radiology records were reviewed. Timing of symptom onset, presentation to hospital, first neuroimaging, first diagnostic neuroimaging and presenting clinical features were recorded. Results Ninety-six children with an arterial ischaemic stroke (AIS) and 43 with a haemorrhagic stroke (HS) were identified. The median time from symptom onset to diagnostic neuroimaging was 24.3 h in AIS and 2.9 h in HS. The initial imaging modality was CT in 68% of cases of AIS. CT was diagnostic of AIS in 66% of cases. MRI was diagnostic in 100%. If initial neuroimaging was non-diagnostic in AIS, then median time to diagnosis was 44 h. CT was diagnostic in 95% of HS cases. Presentation outside normal working hours resulted in delayed neuroimaging in AIS (13 vs 3 h, p=0.032). Diffuse neurological signs or a Glasgow Coma Scale <9 resulted in more expeditious neuroimaging in both HS and AIS. Conclusions The diagnosis of AIS in children is delayed at every stage of the pathway but most profoundly when the first neuroimaging is CT scanning, which is non-diagnostic. MRI should be the initial imaging modality of choice in any suspected case of childhood AIS.

White matter abnormalities and dystonic motor disorder associated with mutations in the SLC16A2 gene

Aim  Mutations in the SLC16A2 gene have been implicated in Allan–Herndon–Dudley syndrome (AHDS), an X‐linked learning disability * syndrome associated with thyroid function test (TFT) abnormalities. Delayed myelination is a non‐specific finding in individuals with learning disability whose genetic basis is often uncertain. The aim of this study was to describe neuroimaging findings and neurological features in males with SLC16A2 gene mutations.

MECP2 triplication in 3 brothers – A rarely described cause of familial neurological regression in boys

Male patients with large duplications of the methyl CpG-binding protein 2 (MECP2) gene have been identified with a characteristic phenotype consisting of infantile hypotonia replaced by spasticity, developmental delay, severe mental retardation and recurrent respiratory infections. Only one patient with MECP2 triplication, with a more severe phenotype has been reported so far. We report three brothers of unrelated parents with MECP2 triplication. Their phenotypic features include macrocephaly with large ears, infantile hypotonia, developmental delay, significant constipation, recurrent severe respiratory tract infections from early childhood, and seizures followed by neurological regression in late childhood. Our cases indicate that MECP2 triplication is similar to or more severe than that of MECP2 duplication syndrome.

Outcome and recurrence one year after paediatric arterial ischaemic stroke in a population-based cohort

Arterial ischemic stroke (AIS) is an important cause of acquired brain injury in children. Few prospective population‐based studies of childhood AIS have been completed. We aimed to investigate the outcome of childhood AIS 12 months after the event in a population‐based cohort.