Accumulation of Brain Hypointense Foci on Susceptibility-Weighted Imaging in Childhood Ataxia Telangiectasia.

BACKGROUND AND PURPOSE: SWI hypointense cerebral lesions have been reported in adults with the inherited cerebellar neurodegenerative disorder ataxia telangiectasia. This study aims to establish the prevalence, age-dependency, and spatial distribution of these lesions in children and young people with ataxia telangiectasia. MATERIALS AND METHODS: Participants with classic ataxia telangiectasia and matched controls underwent SWI acquisition at 3T at 1 or 2 time points. SWI hypointense lesions were manually labeled according to the Microbleed Anatomical Rating Scale. Differences in prevalence of lesion number between groups with ataxia telangiectasia and without ataxia telangiectasia were tested with the Fisher exact test, and differences in age between participants with ataxia telangiectasia with and without lesions were tested using independent samples Mann-Whitney U test. The relationship between age and lesion number was modeled as an exponential function. RESULTS: Analyzable SWI datasets from 17 participants with ataxia telangiectasia (with median age at first scan of 12.4 years; range, 4.6-20.2 years; 8 [47%] were female) and 22 matched healthy controls showed prevalence of SWI hypointense lesions in 41% of participants with ataxia telangiectasia and 0% in controls (P = .001, Fisher exact test). Lesions were exclusively supratentorial and predominantly lobar. Participants with ataxia telangiectasia with SWI hypointense lesions were older than those without (median age 5.2 years versus 9.3 years, U = 10.5, P = .014). An exponential curve described the relationship between age and lesion number (R 2 = 0.67). CONCLUSIONS: SWI hypointense lesions are common in children and young people with ataxia telangiectasia, accumulating from 12 years of age onward. In contrast to cerebellar-dominant neurodegeneration in ataxia telangiectasia, SWI hypointense lesions were exclusively supratentorial. Further investigation is needed to establish the clinical relevance of these imaging-detected lesions.

Comorbidity in multiple sclerosis: its temporal relationships with disease onset and dose effect on mortality.

BACKGROUND AND PURPOSE: We aimed to determine the burden of comorbidities at the time of diagnosis of multiple sclerosis (MS), the risk of developing new comorbidities after diagnosis and the effect of comorbidities on mortality in patients with MS. METHODS: This study used data from 2526 patients with incident MS and 9980 age-, sex- and physician-matched controls without MS identified from the UK Clinical Practice Research Datalink. RESULTS: Before the MS diagnosis, the adjusted odds ratio for the association between MS and a Charlson comorbidity index score of 1-2, 3-4 or ≥5 was 131 [95% confidence interval (CI), 1.17-1.47], 1.65 (95% CI, 1.20-2.26) or 3.26 (95% CI, 1.58-6.70), respectively. MS was associated with increased risks of cardiovascular and neurological/mental diseases. After diagnosis, the adjusted hazard ratio for the association between MS and an increased risk of developing comorbidities was 1.13 (95% CI, 1.00-1.29). The risk of developing any comorbidity in terms of neoplasms, musculoskeletal/connective tissue diseases or neurological/mental diseases was higher in MS. Patients with MS had a higher mortality risk compared with controls, with a hazard ratio of 2.29 (95% CI, 1.81-2.73) after adjusting for comorbidities. There was a dose effect of pre-existing comorbidities on mortality. CONCLUSIONS: Patients with MS have an increased risk of developing multiple comorbidities both before and after diagnosis and pre-existing comorbidities have an impact on survival.

Epilepsy and associated mortality in patients with multiple sclerosis.

BACKGROUND AND PURPOSE: We aimed to determine the prevalence of epilepsy in patients with multiple sclerosis (MS) at diagnosis, the risk of developing epilepsy after the diagnosis of MS and the relative risk of mortality associated with epilepsy. METHODS: We used the UK Clinical Practice Research Data-link to identify 2526 patients with incident MS and 9980 age-, sex- and index year-matched non-MS controls from 1997 to 2006. Logistic regression was used to estimate odds ratios [95% confidence interval (CI)] for epilepsy and Cox regression was used to estimate hazard ratios (HRs) (95% CI) for epilepsy and mortality. RESULTS: Patients with incident MS were on average 45 years old and 70.9% were female. At diagnosis, the prevalence of epilepsy in patients with MS was 1.30% compared with 0.57% in non-MS controls. At diagnosis, MS was associated with an adjusted odds ratio (95% CI) of 2.11 (1.36-3.27) for pre-existing epilepsy. Among epilepsy-free patients, the cumulative probabilities of developing epilepsy, first recorded within 10 years of the index date, were 2.77% for patients with MS and 0.90% for controls. MS was associated with an adjusted HR (95% CI) of 6.01 (2.94-12.29) for epilepsy. Among patients with MS, epilepsy was associated with an HR (95% CI) of 2.23 (1.02-4.84) for all-cause mortality. CONCLUSIONS: This population-based study found an increased prevalence of epilepsy in patients with MS at diagnosis when compared with non-MS controls and the risk of developing epilepsy was also higher following the MS diagnosis. Patients with MS with epilepsy had a higher risk of mortality compared with those without.

Melatonin for sleep problems in children with neurodevelopmental disorders: randomised double masked placebo controlled trial.

OBJECTIVE: To assess the effectiveness and safety of melatonin in treating severe sleep problems in children with neurodevelopmental disorders. DESIGN: 12 week double masked randomised placebo controlled phase III trial. SETTING: 19 hospitals across England and Wales. PARTICIPANTS: 146 children aged 3 years to 15 years 8 months were randomised. They had a range of neurological and developmental disorders and a severe sleep problem that had not responded to a standardised sleep behaviour advice booklet provided to parents four to six weeks before randomisation. A sleep problem was defined as the child not falling asleep within one hour of lights out or having less than six hours' continuous sleep. INTERVENTIONS: Immediate release melatonin or matching placebo capsules administered 45 minutes before the child's bedtime for a period of 12 weeks. All children started with a 0.5 mg capsule, which was increased through 2 mg, 6 mg, and 12 mg depending on their response to treatment. MAIN OUTCOME MEASURES: Total sleep time at night after 12 weeks adjusted for baseline recorded in sleep diaries completed by the parent. Secondary outcomes included sleep onset latency, assessments of child behaviour, family functioning, and adverse events. Sleep was measured with diaries and actigraphy. RESULTS: Melatonin increased total sleep time by 22.4 minutes (95% confidence interval 0.5 to 44.3 minutes) measured by sleep diaries (n=110) and 13.3 (-15.5 to 42.2) measured by actigraphy (n=59). Melatonin reduced sleep onset latency measured by sleep diaries (-37.5 minutes, -55.3 to -19.7 minutes) and actigraphy (-45.3 minutes, -68.8 to -21.9 minutes) and was most effective for children with the longest sleep latency (P=0.009). Melatonin was associated with earlier waking times than placebo (29.9 minutes, 13.6 to 46.3 minutes). Child behaviour and family functioning outcomes showed some improvement and favoured use of melatonin. Adverse events were mild and similar between the two groups. CONCLUSIONS: Children gained little additional sleep on melatonin; though they fell asleep significantly faster, waking times became earlier. Child behaviour and family functioning outcomes did not significantly improve. Melatonin was tolerable over this three month period. Comparisons with slow release melatonin preparations or melatonin analogues are required. TRIAL REGISTRATION: ISRCT No 05534585.

Retention rate of Gabapentin in children with intractable epilepsies at 1 year.

Gabapentin (GAB) is a newer second-line antiepileptic drug (AED) used in children. This is a multi-centre retrospective observational study of the efficacy, tolerability and retention rate in 105 children, aged 0-17.5 years (mean 10.1) over a 14 year period. The median age of epilepsy onset was 2.5 years (range 0-14.6). 72% started GAB as at least the 3rd AED, with 43% having been withdrawn from at least 2 AEDs. 77% had focal and 52% symptomatic epilepsies. The maintenance doses for GAB ranged 6.0-87.3 mg/kg/day (mean 43.7). The study comprised 157 person-treatment years for GAB. GAB was well tolerated with 55% remaining on treatment beyond 1 year. No serious adverse events were reported whilst on GAB, but 39% reported possibly and probably related adverse events. Seizure improvement (<50% seizure frequency compared to baseline) at more than 12 months of treatment, was reported in 35% of patients starting GAB, including 6% who remained seizure free. The results demonstrated the efficacy and tolerability of GAB in children with difficult to treat epilepsies, and a good response to treatment beyond 12 months, in both focal and generalised epilepsies.

Retention rate of clobazam, topiramate and lamotrigine in children with intractable epilepsies at 1 year.

UNLABELLED: Clobazam (CLB), Topiramate (TOP) and Lamotrigine (LAM) are newer second-line antiepileptic drugs (AEDs) used in children. This is a single-centre retrospective observational study of the efficacy, tolerability and retention rate in 224 separate treatment episodes in 194 children, aged 0.1-16.7 years (median 9.4) over an 8 year period. The median age of epilepsy onset was 3.3 years (range 0-15.1). 79% started CLB, TOP or LAM as at least the 3rd AED, with 39% having been withdrawn from at least 2 AEDs. 53% had generalised and 37% idiopathic epilepsies. The maintenance doses for CLB ranged 0.12-3.50 mg/kg/day (mean 0.7); for TOP 0.45-32.0 mg/kg/day (mean 7.1) and for LAM 1.13-16.0 mg/kg/day (mean 5.6). The study comprised 75 person-treatment years for CLB, 56 for TOP, 124 for LAM. RESULTS: CLB, TOP and LAM were well tolerated with 51%, 37% and 69% remaining on treatment beyond 1 year respectfully. 1 serious adverse event for CLB (inducing seizures) and 2 for LAM (rashes) were reported, and 60%, 47% and 39% had possibly and probably related adverse events for CLB, TOP and LAM respectively. Beyond 12 months seizure improvement (< 50% seizure frequency compared to baseline) was reported in 43%, 35% and 44% on CLB, TOP and LAM, including 5% and 8% remaining seizure free on CLB and LAM respectively. CONCLUSION: Our results demonstrate the efficacy and tolerability of CLB, TOP and LAM in children with difficult to treat epilepsies and a good response in CLB and LAM, and a reasonable response in TOP beyond 12 months.

Personal resuscitation plans and end of life planning for children with disability and life-limiting/life-threatening conditions.

This article discusses the need for person-specific planning for the increasing numbers of disabled children with life-limiting and life-threatening conditions. It describes the system developed in Nottingham for this client group to have a family-held personal resuscitation plan, (PRP) which is developed with the child and family by their lead paediatrician. The PRP is an emergency medical care plan which supports the provision of the most appropriate level of intervention for the child whether they are at home, school, short break unit or hospital. The PRP template is presented with advice on implementation and case examples. Feedback from families, medical and nursing staff is that PRPs are useful and empowering. The system supports timely discussions about appropriate care in an emergency and the communication of decisionsmade jointly by the child, family and medical team to all concerned. A flexible and person-specific PRP stating what interventions to do such as airway clearance, facial oxygen, trial of bag and mask ventilation is preferable to a do not attempt resuscitation form which is an 'all or nothing system' and can seem very negative to families. A PRP in the home can support appropriate action from local rapid response teams set up to review unexpected child deaths.

When to image neurologically normal children with headaches: development of a decision rule.

AIMS: The aim of this study was to develop and refine a decision rule on when to undertake brain imaging (BI) in neurologically normal children with headaches. METHODS: From the literature and a questionnaire study, a list of red flags (RFs) was drawn-up. During the prospective 4-year period, consecutive children with headache were classified according to RFs and the headache diagnosis. RESULT: Three of 709 (0.4%) neurologically normal children had significant brain abnormalities. BI was carried out in 389 of 498 (78%) children with RFs. Significant abnormalities were found in three of 389 children (0.8%), all had unclassified headache (UH). BI was not arranged for the 211 children with no RFs. None of these developed RFs or abnormal signs on follow-up for a mean of 13 months. CONCLUSION: In addition to BI for those with neurological signs, we think BI should be considered for neurologically normal patients with UH and RFs. This would have saved imaging children needlessly: only 101 of 709 (14%) would have had scans arranged, instead of 389 of 709.

Retention rate of levetiracetam in children with intractable epilepsy at 1 year.

UNLABELLED: Levetiracetam (LEV) is a novel antiepileptic drug (AED) that has recently obtained marketing authorisation for use in children. The purpose of this study was to assess the efficacy, tolerability and retention rate of LEV in children with refractory epilepsies. It is a retrospective multicentre observational study reporting the use of LEV in 200 children, aged 0.3-19 years (median 9-years-old) over a 4-year period. All of the patients included in the study had refractory epilepsy with a median age of onset of epilepsy of 3 years (range 0-13 years). The 38% had failed and withdrawn 3 or more AEDs previously and 24% were taking at least 2 other AEDs in addition to LEV. The 47% had focal, and 58% had symptomatic epilepsies. The LEV dose ranged from 8 to 100 mg/kg/day (mean 39 mg/kg). The study comprised 215 person years of LEV exposure. RESULTS: LEV was well tolerated with a retention rate of 49% at 1 year. No serious adverse events were reported with possibly related adverse events reported in only 24% of patients (mainly emotional or behavioural changes). At more than 2, 6 and 12 months, worthwhile improvement (>50% seizure reduction) was noted in 60, 40 and 32%, including seizure freedom in 14, 14 and 5%, respectively. CONCLUSION: Our results confirm the efficacy and tolerability of LEV in children with refractory epilepsies and demonstrate good response and retention rates at 12 months. It represents the largest cohort of paediatric patients published so far on LEV with a 1-year follow-up.

Pyruvate dehydrogenase E3 binding protein (protein X) deficiency.

Pyruvate dehydrogenase (PDH) deficiency is a major cause of neurological dysfunction and lactic acidosis in infancy and early childhood. The great majority of cases (>80%) result from mutations in the X-linked gene for the E1alpha subunit of the complex (PDHA1). Mutations in the genes for the other subunits have all been described, but only dihydrolipoamide dehydrogenase (E3) and E3 binding protein (E3BP) defects contribute significantly to the total number of patients with PDH deficiency. Although previously considered rare, with only 13 reported cases, we have found that mutations in PDX1, the gene for the E3 binding protein, are in fact relatively common. Clinical, biochemical, and genetic features of six new patients (four males, two females; age range 15mo-6y) with mutations in this gene are compared with previously reported cases. All patients with E3BP deficiency identified to date have mutations which completely prevent synthesis of the protein product. However, they are generally less severely affected than patients with PDHA1 mutations, although there is considerable overlap in clinical and neuroradiological features.

Comparison of a dedicated children's seizure clinic to mixed general paediatric clinics.

BACKGROUND: In the light of recent recommendations regarding the current management of children with possible epilepsy in the UK, different models of care are compared using an existing validated audit tool. METHODS: The initial clinical assessment process, investigation, management and communication regarding children referred with suspected epilepsy to general paediatric clinics or a paediatric seizure clinic was compared using the British Paediatric Neurology Association (BPNA) audit tool. Results Ninety-three children were included in the comparison. The history and description of the episodes was better documented in the Seizure Clinic (SC). Children's early development (79% vs. 50%) and school performance (86% vs. 42%) were better documented in the SC. Documentation of possible side effects relating to newly prescribed anti-epileptic drugs was poor in both groups (33% vs. 15%). CONCLUSIONS: Differences between models of epilepsy care can be detected using audit tools although there are some methodological limitations of this particular study. Future similar studies as well as informing local practice can add to the debate on the appropriate way forward in improving the care for children with epilepsy.

Occult carotid pseudoaneurysm following streptococcal throat infection.

Pseudoaneurysm of the internal carotid artery (PAICA) is a rare complication of neck space infection. An 8-year-old girl presented with odynophagia (painful swallowing), trismus and left peritonsillar swelling. Abscess was suspected, but aspiration was dry. The PAICA was diagnosed on computed tomography. The aneurysm and involved left internal carotid artery were occluded endovascularly. She has made an uneventful recovery.