Sarah E. Aylett

Genotypic and phenotypic spectrum of pyridoxine-dependent epilepsy (ALDH7A1 deficiency)

Pyridoxine-dependent epilepsy was recently shown to be due to mutations in the ALDH7A1 gene, which encodes antiquitin, an enzyme that catalyses the nicotinamide adenine dinucleotide-dependent dehydrogenation of l-α-aminoadipic semialdehyde/l-Δ1-piperideine 6-carboxylate. However, whilst this is a highly treatable disorder, there is general uncertainty about when to consider this diagnosis and how to test for it. This study aimed to evaluate the use of measurement of urine l-α-aminoadipic semialdehyde/creatinine ratio and mutation analysis of ALDH7A1 (antiquitin) in investigation of patients with suspected or clinically proven pyridoxine-dependent epilepsy and to characterize further the phenotypic spectrum of antiquitin deficiency. Urinary l-α-aminoadipic semialdehyde concentration was determined by liquid chromatography tandem mass spectrometry. When this was above the normal range, DNA sequencing of the ALDH7A1 gene was performed. Clinicians were asked to complete questionnaires on clinical, biochemical, magnetic resonance imaging and electroencephalography features of patients. The clinical spectrum of antiquitin deficiency extended from ventriculomegaly detected on foetal ultrasound, through abnormal foetal movements and a multisystem neonatal disorder, to the onset of seizures and autistic features after the first year of life. Our relatively large series suggested that clinical diagnosis of pyridoxine dependent epilepsy can be challenging because: (i) there may be some response to antiepileptic drugs; (ii) in infants with multisystem pathology, the response to pyridoxine may not be instant and obvious; and (iii) structural brain abnormalities may co-exist and be considered sufficient cause of epilepsy, whereas the fits may be a consequence of antiquitin deficiency and are then responsive to pyridoxine. These findings support the use of biochemical and DNA tests for antiquitin deficiency and a clinical trial of pyridoxine in infants and children with epilepsy across a broad range of clinical scenarios.

Neurobehavioral Comorbidities in Children With Active Epilepsy: A Population-Based Study

BACKGROUND: In addition to recurrent epileptic seizures, children with epilepsy can have coexisting cognitive and behavioral difficulties but the spectrum and prevalence of such difficulties are uncertain. METHODS: The Children with Epilepsy in Sussex Schools study is a prospective, community-based study involving school-aged children (5–15 years) with active epilepsy in a defined geographical area in the United Kingdom. Participants underwent comprehensive psychological assessment, including measures of cognition, behavior, and motor functioning. Consensus neurobehavioral diagnoses were made with respect to Diagnostic and Statistical Manual, Fourth Edition-Text Revision (DSM-IV-TR) criteria. RESULTS: A total of 85 children (74% of eligible population) were enrolled; 80% of children with active epilepsy had a DSM-IV-TR behavioral disorder and/or cognitive impairment (IQ <85). Intellectual disability (ID) (IQ <70) (40%), attention-deficit/hyperactivity disorder (ADHD) (33%), and autism spectrum disorder (ASD) (21%) were the most common neurobehavioral diagnoses. Of those who met criteria for a DSM-IV-TR behavioral disorder, only one-third had previously been diagnosed. Logistic regression revealed that seizures in the first 24 months compared with first seizures at 24 to 60 or 61+ months (odds ratio [OR] 13, 95% confidence interval 2.2–76.9; OR 21.3, 3.2–148.9) and polytherapy (OR 7.7, 1.6–36.3) were independently associated with ID and the presence of ID was associated with a diagnosis of ASD (OR 14.1, 2.3–87.1) after Bonferroni adjustment. Epilepsy-related factors did not independently predict the presence of behavioral disorders. CONCLUSIONS: Screening for neurobehavioral comorbidities should be an integral part of management in children with “active” epilepsy. There is a need for research to identify neurobiological mechanisms underpinning neurobehavioral impairments and studies to evaluate possible treatments.

Complications of congenital melanocytic naevi in children: analysis of 16 years' experience and clinical practice

Background  Congenital melanocytic naevi (CMNs) can be associated with abnormalities of the cental nervous system (CNS) and/or with melanoma. Quoted incidences for these complications vary in the literature, as do recommendations for investigations and follow‐up.

Epilepsy surgery in children under 3 years

PURPOSE Resective epilepsy surgery in early childhood has become an important treatment option for selected infants and children with epilepsy. We describe experience and clinical outcomes of children under 3 years undergoing epilepsy surgery at Great Ormond Street Hospital (GOSH). METHODS All children under 36 months of age who had resective surgery for the purpose of treating epilepsy within the GOSH epilepsy surgery programme were ascertained using a departmental database. Aetiology, post-operative seizure frequency, pre and post-operative cognitive function, long-term complications and re-operation rates were analysed by retrospective examination of clinical records. RESULTS Forty-two children were included in our cohort with a median age at surgery of 20 months (range 3-36 months). Surgical procedures comprised 25 functional hemispherectomies, two anatomical hemispherectomies, four multilobar resections, seven lobar resections and four focal resections. 7/42 (17%, 95% CI 8-31%) children underwent re-operation. 20/42 (48%, 95% CI 33-62%) children achieved seizure freedom. 18/42 (43%, 95% CI 29-58) demonstrated an improvement in seizure frequency and no children had an increase in seizure frequency. Post-operative complications included subsequent shunt procedure in 5/25 (20%, 95% CI 9-39%) children undergoing hemispherectomy. There were no mortalities. In 23 children pre- and post-operative DQ or IQ was determinable allowing longitudinal comparison. Five children had a decrease in DQ/IQ >15 and two children had an increase DQ/IQ >15. DISCUSSION Epilepsy surgery in children under 3 years of age offers suitable candidates a good chance of significantly improved seizure outcome which compares with rates in older cohorts.

Development and validation of a measure of the impact of epilepsy on a young person’s quality of life: Glasgow epilepsy outcome scale for young persons (GEOS-YP)

OBJECTIVE The goal of the work described here was to develop and validate a measure of the impact of epilepsy on an adolescents quality of life that is based on direct exploration of the adolescents views. METHODS Initial scale development was based on data generated through qualitative methods (focus groups) in a previous study [McEwan MJ, Espie CA, Metcalfe J, Brodie MJ, Wilson MT. Seizure 2004;13:15-31]. A draft measure was piloted (n=30) and refined using correlational methods. Psychometric properties were established by means of a preliminary field trial (n=78). RESULTS An initial item pool of 76 was refined to 50. The structure of the measure mirrored the conceptual model derived from focus group study; Part 1 covered issues relating to adolescent development (identity formation) with five subscales, and Part 2 covered epilepsy-related issues with four subscales. The final GEOS-YP had good internal consistency (alpha=0.91) and test-retest reliability (rho=0.75). Concurrent and construct validity was acceptable, and the GEOS-YP discriminated on dimensions of clinical importance. Participant feedback suggested the measure has excellent face validity and potential clinical utility. CONCLUSIONS The GEOS-YP is a direct measure of how adolescents perceive epilepsy impacts their quality of life. The GEOS-YP has sound psychometric properties and provides a relatively brief and potentially useful clinical outcome tool.

Sturge–Weber syndrome: cerebral haemodynamics during seizure activity

The aim of this study was to examine the haemodynamic response to seizures in three infants with Sturge–Weber syndrome by measuring regional cerebral blood flow using transcranial Doppler sonography and 99mTc HMPAO SPECT. Time‐locked video/digital EEG recording was carried out for ictal studies. MRI was performed in all subjects. SPECT showed hemispheric hypoperfusion interictally in all three patients and also ictally in one of the three; a small region of hyperperfusion was seen on the same ictal scan in the latter, ie. the patient with interictal and ictal hypoperfusion. In the two older children middle cerebral artery velocity (MCAV) was reduced by between 29 and 62% in the middle cerebral artery of the predominantly affected hemisphere compared with the contralateral side. During seizures, increases of 6 to 30% in MCAV were recorded for the clinically seizing hemisphere compared with 24 to 170% for the contralateral side in four of the seizures recorded. In one infant, MCAV fell bilaterally during a seizure that generalized (–18 and –43% in the predominantly affected and contralateral side respectively). Sequential recordings in one infant suggested that, with time, the haemodynamic response to seizures of the unaffected hemisphere may decrease. These findings suggest that the venous malformation in SWS is associated with an impairment of the cerebral haemodynamic response to seizure activity.

Pyridoxine-dependent seizures: a family phenotype that leads to severe cognitive deficits, regardless of treatment regime.

The neuropsychological and clinical histories of three male siblings affected by pyridoxine‐dependent seizures with known homozygous antiquitin mutations are presented. Neuropsychological evaluation is reported from when the siblings were 11, 9, and 7 years of age. Two of the siblings had received early pyridoxine treatment (antenatal, 2–4wks into pregnancy) and one had received late treatment (2mo postnatal). However, there was no differential effect on cognitive outcome, with all three siblings having moderate to severe learning disability. Unlike previously reported cases that received early postnatal treatment, none of the siblings had relatively preserved non‐verbal cognitive skills. Equally, their intellectual performance over time did not increase above the 1st centile despite high maintenance doses of vitamin B6 (range 16–26mg/kg/d), and mild sensory neuropathy was reported on nerve conduction studies. The findings in these siblings challenge assumptions that early and high dose pyridoxine treatment can benefit cognition in this population and suggest routine electromyography monitoring may be beneficial.

New vascular classification of port-wine stains: improving prediction of Sturge–Weber risk

Facial port‐wine stains (PWSs) are usually isolated findings; however, when associated with cerebral and ocular vascular malformations they form part of the classical triad of Sturge–Weber syndrome (SWS).

Methylphenidate treatment of attention deficit hyperactivity disorder in young people with learning disability and difficult-to-treat epilepsy: Evidence of clinical benefit

To establish the efficacy and safety of methylphenidate (MPH) treatment for attention deficit hyperactivity disorder (ADHD) in a group of children and young people with learning disability and severe epilepsy.

Hyponatraemia associated with lamotrigine in cranial diabetes insipidus.

We report the cases of two children with cranial diabetes insipidus who were treated with lamotrigine for seizures and who had accompanying changes in desmopressin requirements. Lamotrigine is a new anticonvulsant chemically unrelated to other existing antiepileptic drugs. Studies suggest it acts at voltage-sensitive sodium channels and also decreases calcium conductance. Both of these mechanisms of action are shared by carbamazepine, which can cause hyponatraemia secondary to inappropriate secretion of antidiuretic hormone. It is possible that the effect of lamotrigine on fluid balance in the cases described is also centrally mediated.