Phenotypic and genetic spectrum of epilepsy with myoclonic atonic seizures.

OBJECTIVE: We aimed to describe the extent of neurodevelopmental impairments and identify the genetic etiologies in a large cohort of patients with epilepsy with myoclonic atonic seizures (MAE). METHODS: We deeply phenotyped MAE patients for epilepsy features, intellectual disability, autism spectrum disorder, and attention-deficit/hyperactivity disorder using standardized neuropsychological instruments. We performed exome analysis (whole exome sequencing) filtered on epilepsy and neuropsychiatric gene sets to identify genetic etiologies. RESULTS: We analyzed 101 patients with MAE (70% male). The median age of seizure onset was 34 months (range = 6-72 months). The main seizure types were myoclonic atonic or atonic in 100%, generalized tonic-clonic in 72%, myoclonic in 69%, absence in 60%, and tonic seizures in 19% of patients. We observed intellectual disability in 62% of patients, with extremely low adaptive behavioral scores in 69%. In addition, 24% exhibited symptoms of autism and 37% exhibited attention-deficit/hyperactivity symptoms. We discovered pathogenic variants in 12 (14%) of 85 patients, including five previously published patients. These were pathogenic genetic variants in SYNGAP1 (n = 3), KIAA2022 (n = 2), and SLC6A1 (n = 2), as well as KCNA2, SCN2A, STX1B, KCNB1, and MECP2 (n = 1 each). We also identified three new candidate genes, ASH1L, CHD4, and SMARCA2 in one patient each. SIGNIFICANCE: MAE is associated with significant neurodevelopmental impairment. MAE is genetically heterogeneous, and we identified a pathogenic genetic etiology in 14% of this cohort by exome analysis. These findings suggest that MAE is a manifestation of several etiologies rather than a discrete syndromic entity.

Fifteen-minute consultation: an approach to a child presenting to the emergency department with acute psychotic symptoms.

Presentation of a child in the A&E with altered behaviour including psychotic features is not unusual. New-onset psychotic symptoms in children pose a significant diagnostic challenge due to several reasons. First, primary psychotic conditions are uncommon in pre-pubertal children. Second, differentiating between delirium and psychosis can be difficult in children, more so in infants, toddlers and young children. Third, intervening and managing a secondary cause of psychosis can significantly optimise outcome. Prompt recognition of a possible underlying cause for a child's psychotic behaviour is essential, and at the same time challenging, in the emergency department. This article attempts to present a systematic approach to a child with acute onset of psychotic symptoms in an emergency setting.

Carers' express positive views on the acceptability, efficacy and safety of buccal midazolam for paediatric status epilepticus.

AIM: Buccal midazolam has emerged as an effective alternative to rectal diazepam in the management of paediatric status epilepticus. This study aimed to identify carers' views on the safety, efficacy and acceptability of buccal midazolam in the management of this common neurological emergency. METHODS: Community-based, face-to-face interviews were carried out with 34 carers to evaluate the effectiveness, adverse effects and convenience of buccal midazolam as a rescue treatment for prolonged seizures. All children received 2.5 to 10 mg of Epistatus, a proprietary oral solution (10 mg/mL). We evaluated therapeutic success, time taken for seizures to cease and the need to attend the emergency department, together with the development of side effects, namely respiratory depression and sedation. RESULTS: Most of the families (91%) found that buccal midazolam was always, or usually, effective in stopping seizures and it prevented hospital admission in 65% of cases. The majority (96%) of those who had used both buccal midazolam and rectal diazepam preferred the former as it was easier to administer, more socially acceptable and did not sedate the child as much. CONCLUSION: Carers felt that buccal midazolam was an effective, safe and more acceptable alternative to rectal diazepam in the management of paediatric status epilepticus.

Long term outcome in non-multiple sclerosis paediatric acquired demyelinating syndromes.

OBJECTIVES: We aimed to study the risks of relapse and long term disability in children with non-MS acquired demyelinating syndromes (ADS). METHODS: In this prospective, multi-centre study, from the 14 UK pediatric neurology centres, children (<16 years) experiencing a first episode of ADS were recruited from 2010 to 2014. Case report forms were collected prospectively. RESULTS: A total of 269 children were recruited and followed up for a median of 7.2 years. Median age at onset was 9y (IQR 9.5-14.5, 126 females). At last follow-up, 46 (18 %) had MS, 4 AQP4-Ab NMOSD and 206 (80 %) had other ADS, of which 27 (13 %) relapsed. Relapsing MOGAD was the diagnosis in 12/27, 6 were seronegative and 9 did not have antibodies tested. Frequency of relapse differed according to first presentation in non-MS ADS, being least likely in transverse myelitis (p = 0.025). In the non-MS group, MOG-Ab was predictive of relapse (HR = 8.42; p < 0.001) occurring 8 times as often decreasing over time. Long-term difficulties did not differ between children with monophasic vs relapsing diseases. CONCLUSION: The risk of relapse in non-MS ADS depends on initial diagnosis, and MOG-Ab positivity. Long-term difficulties are observed regardless of relapses and are determined by presenting phenotype.

Transition of children with epilepsies to adult care.

UNLABELLED: Young people aged between 10 and 20 years will account for nearly 23% of the UK's total population by the end of 2012. This fact, coupled with an increasing number of children with chronic illness surviving into adulthood, means that the transition of children with chronic illness into adult care is becoming an increasingly important issue. Epilepsies are pervasive disorders that consist not only of recurrent epileptic seizures that can change over time, but also of evolving behavioural, academic and social difficulties. Many of these young individuals feel 'dumped' or 'left in the dark' once they are 'transferred' to adult care. CONCLUSION: Therefore, it is essential to acknowledge that 'transition of care' in children with epilepsies is not a 'step' but a 'process'. It is a very challenging time with increased stress and anxiety, for both the individual and their families. This article will discuss the various factors associated with the complex topic and aim to establish a framework for the successful transition of children with epilepsy into adult care.

MICrocephaly, disproportionate pontine and cerebellar hypoplasia syndrome: A clinico-radiologic phenotype linked to calcium/calmodulin-dependent serine protein kinase gene mutation.

MICrocephaly, disproportionate pontine and cerebellar hypoplasia (MICPCH) syndrome, a rare X-linked disorder, generally seen in girls, is characterized by neurodevelopmental delay, microcephaly, and disproportionate pontine and cerebellar hypoplasia. It is caused by inactivating calcium/calmodulin-dependent serine protein kinase (CASK) gene mutations. We report a 2-year-old girl with severe neurodevelopmental delay, microcephaly, minimal pontine hypoplasia, cerebellar hypoplasia, and normal looking corpus callosum, with whom the conventional cytogenetic studies turned out to be normal, and an array-comparative genomic hybridization (a-CGH) analysis showed CASK gene duplication at Xp11.4. Our case highlights the importance of using clinico-radiologic phenotype to guide genetic investigation and it also confirms the role of a-CGH analysis in establishing the genetic diagnosis of MICPCH syndrome, when conventional cytogenetic studies are inconclusive.

Facial Dysmorphism, Hirsutism, and Failure to Thrive as Manifestation of Leigh Syndrome in a Child with SURF1 Mutation.

Leigh syndrome (or subacute necrotizing encephalomyelopathy) is a rare neurodegenerative disorder characterized by psychomotor retardation or regression, typically occurring in stepwise decrements. Onset is typically between ages 3 and 12 months. Neurological manifestations include hypotonia, spasticity, movement disorders (including chorea), cerebellar ataxia, and peripheral neuropathy, whereas extraneurological manifestations may include hypertrophic cardiomyopathy, hypertrichosis, anemia, renal tubulopathy, liver involvement, ptosis, and muscle weakness. Approximately 50% of affected individuals die by age 3 years, most often as a result of respiratory or cardiac failure. We report a case of 22-month-old female child presenting to us with severe failure to thrive, dysmorphic features, hirsutism, external ophthalmoplegia epilepsy, and neuroregression with characteristic findings of Leigh's syndrome on neuroimaging and her muscle biopsy revealed evidence of mitochondrial respiratory chain defect involving complex IV and SURF1 mutation.

Neuropsychological Difficulties Associated with Dopa Responsive Dystonia.

A young girl with L-dopa responsive dystonia showed significant improvements in motor function but had ongoing complaints of neuropsychological difficulties. A neuropsychological evaluation was undertaken to understand the nature of her difficulties. Intellectual function, attention, executive function, and academic attainment were assessed using published psychometric tests. Verbal and non-verbal reasoning was found to be age appropriate. Particular difficulties were identified with working memory, visual selective attention, dual attention, and processing speed which were having a significant impact upon the child and her family. The importance of a thorough neuropsychological evaluation is discussed in helping to appropriately manage and support the child with this chronic but rare health condition.

Phenotypical Variation with Same Genetic Mutation in Familial Hypokalemic Periodic Paralysis.

Hypokalemic periodic paralysis is a genetic neuromuscular disorder characterized by episodes of painless muscle paralysis associated with low serum potassium, exclusively, during the attack. This may be precipitated by heavy exercise, fasting, or high-carbohydrate meals. We report two siblings, presenting at different ages with varying symptomatology-older sibling with episodic weakness in the morning associated with reduced physical exercise and consumption of large carbohydrate meal, whereas younger sibling complained of muscle stiffness following large carbohydrate meal and at the end of physical exercise. Molecular genetic study showed both siblings and their father were positive for calcium channel alpha-1S subunit (CACNA1S) C3716G>A; p.Arg1239His mutation. It is important to check serum potassium in a child presenting with muscle stiffness or weakness after a carbohydrate meal or vigorous exercise. This condition responds with potassium supplement. Often relevant family history and trigger factors with clinical correlation and blood results can lead to its diagnosis.

Dystonia during feeding as an early sign of dopa-responsive dystonia.

A 21/2-month-old girl presented with feeding difficulties of 8 weeks' duration. She cried, vomited, arched, and became rigid during every feeding. She was suspected of having gastroesophageal reflux disease. Dystonia and developmental delay became apparent at age 8 months. Nasogastric tube feeding and gastrostomy with Nissen's fundoplication were performed at age 7 and 12 months, respectively. She was treated with baclofen, trihexyphenidyl, and antireflux therapy, without benefit. She became severely developmentally delayed with marked head lag, dystonia, and rigidity. Levodopa therapy was initiated at age 21 months. She manifested dramatic improvement over the next year. Dystonia, rigidity, and retching disappeared soon after treatment. She experienced good catch-up in development. She exhibited poor head control and an inability to reach out at age 21 months, but bottom shuffling was observed at age 26 months, and walking and speaking three-word sentences at age 2 years and 10 months. Pertinent issues relating to signs, pathophysiology, genetics, and biochemical defects are discussed briefly.

Aetiology, course and outcome of children admitted to paediatric intensive care with convulsive status epilepticus: a retrospective 5-year review.

A retrospective case note study of the aetiology and course of children in convulsive status epilepticus (CSE) admitted to a large paediatric intensive care unit (PICU) was undertaken between January 1999 and April 2004. Status epilepticus was defined as a prolonged (>30 min) tonic-clonic seizure irrespective of whether the seizure had stopped prior to admission to PICU. During this period, 137 (74 male) children aged 1 month to 15 years were admitted to PICU with 147 episodes of status epilepticus. Forty-seven of the 137 children (34%) were admitted following a prolonged febrile seizure. Thirty-eight of the 137 children (28%) had a remote symptomatic cause for the CSE, 24 (18%) were admitted for an acute symptomatic cause and 15 (11%) were admitted with an acute exacerbation of a pre-existing idiopathic/cryptogenic epilepsy. Six children had a progressive encephalopathy and no cause was identified in the remaining 7 of the 137 children (5%). Forty-nine (36%) of the 137 children had pre-existing epilepsy. The mean duration of CSE was 44 min. Forty-nine (36%) children admitted to PICU who had received a benzodiazepine with either phenobarbital or phenytoin, required further treatment to terminate the presenting episode of CSE. Forty-two of these 49 were treated with thiopentone anaesthesia and the remaining 7 with a continuous infusion of midazolam, successfully terminating status in all. No child died. Of the 70 children considered to be previously neurologically and developmentally normal prior to admission, only 1 child demonstrated a new gross neurological abnormality at the time of latest follow-up. Seven patients (5%) developed new or de novo epilepsy.

Prolonged expiratory apnoea with cyanosis in Arnold Chiari II malformation.

Apnoea associated with Arnold Chiari malformation is a known entity and can be obstructive or central. Differentiating between two types is vital to deciding management pathway and prognosticating disease process.

Neuroimaging in Menkes Disease.

Menkes disease (MD) is a rare infantile onset neurodegenerative disorder due to mutations in the X linked ATP7A gene. These patients can present with failure to thrive, severe psychomotor retardation, seizures and hypopigmented hair, which is characteristic of this condition. A number of neuro-radiological findings have been reported in this condition. We report the spectrum of neuro-radiological findings in three affected boys being treated at our centre. We suggest that magnetic resonance imaging (MRI) and, in particular magnetic resonance angiography (MRA) when taken in the context of the clinical presentation may be helpful in making an early diagnosis of this devastating condition.

A structured approach to the assessment of a floppy neonate.

Hypotonia in a newborn presents a diagnostic challenge for clinicians. It is an important clinical feature that may indicate an underlying systemic illness or neurological problem at the level of the central or peripheral nervous system. It is important to know the different presentations of hypotonia and to have the knowledge of the diagnostic work up which requires multidisciplinary assessment and input and the prognostic implications of these disorders. This review article presents a structured approach highlighting initial assessment, examination, and management of a neonate with generalized hypotonia.