The use of MElatonin in children with neurodevelopmental disorders and impaired sleep: a randomised, double-blind, placebo-controlled, parallel study (MENDS).

BACKGROUND: Difficulties in initiating and maintaining sleep are common in children with neurodevelopmental disorders. Melatonin is unlicensed in children yet widely prescribed for sleep problems. OBJECTIVE: To determine whether or not immediate-release melatonin is beneficial compared with placebo in improving total duration of night-time sleep in children with neurodevelopmental problems. DESIGN: Randomised, double-blind, placebo-controlled, parallel study. SETTING: Hospitals throughout England and Wales recruited patients referred by community paediatricians and other clinical colleagues. PARTICIPANTS: Children with neurodevelopmental problems aged from 3 years to 15 years 8 months who did not fall asleep within 1 hour of lights out or who had < 6 hours of continuous sleep. Before randomisation, patients meeting eligibility criteria entered a 4- to 6-week behaviour therapy period in which a behaviour therapy advice booklet was provided. Sleep was measured using sleep diaries and actigraphy. After this period the sleep diaries were reviewed to determine if the sleep problem fulfilled the eligibility criteria. Eligible participants were randomised and followed for 12 weeks. INTERVENTIONS: Melatonin or placebo capsules in doses of 0.5 mg, 2 mg, 6 mg and 12 mg for a period of 12 weeks. The starting dose was 0.5 mg and the dose could be escalated through 2 mg and 6 mg to 12 mg during the first 4 weeks, at the end of which the child was maintained on that dose. MAIN OUTCOME MEASURES: The primary outcome was total night-time sleep time (TST) calculated using sleep diaries at 12 weeks compared with baseline. Secondary outcome measures included TST calculated using actigraphy data, sleep-onset latency (SOL) (time taken to fall asleep), sleep efficiency, Composite Sleep Disturbance Index score, global measure of child's sleep quality, Aberrant Behaviour Checklist, Family Impact Module of the Pediatric Quality of Life Inventory (PedsQL™), the Epworth Sleepiness Scale, number and severity of seizures and adverse events. Salivary melatonin concentrations and association of genetic variants with abnormal melatonin production were also investigated. RESULTS: A total of 275 children were screened to enter the trial; 263 (96%) children were registered and completed the 4- to 6-week behaviour therapy period and 146 (56%) children were randomised, of whom 110 (75%) contributed data for the primary outcome. The difference in TST time between the melatonin and placebo groups adjusted for baseline was 22.43 minutes [95% confidence interval (CI) 0.52 to 44.34 minutes; p = 0.04] measured using sleep diaries. A reduction in SOL, adjusted for baseline, was seen for melatonin compared with placebo when measured by sleep diaries (-37.49 minutes, 95% CI -55.27 to -19.71 minutes; p < 0.0001) and actigraphy (-45.34 minutes, 95% CI -68.75 to -21.93 minutes; p = 0.0003). There were no significant differences between the two groups in terms of the reporting of adverse events. The results of other secondary outcomes favoured melatonin but were not statistically significant. CONCLUSIONS: On average, the children treated with melatonin slept 23 minutes longer than those in the placebo group; however, the upper limit of the confidence interval was less than 1 hour, the minimum clinically worthwhile difference specified at the outset of the trial. Melatonin is effective in reducing SOL in children with neurodevelopmental delay by a mean of 45 minutes; a value of 30 minutes was specified a priori to be clinically important. Future studies should be conducted over longer periods and directly compare different formulations of melatonin with conventional hypnotic and sedative medications. It would also be important to study groups of children with specific neurological disorders. TRIAL REGISTRATION: Current Controlled Trials ISRCTN05534585. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 16, No. 40. See the HTA programme website for further project information.

Review of the efficacy of rectal paraldehyde in the management of acute and prolonged tonic-clonic convulsions.

INTRODUCTION: The aim of this prospective audit was to assess the effectiveness and safety of rectal paraldehyde in the management of acute, including prolonged, tonic-clonic convulsions. There are very limited published data on its effectiveness and safety, and previous data have focused on its intramuscular route of administration. METHODS: Four hospitals participated in the study. Information was collected on each dose of paraldehyde used for the treatment of a tonic-clonic convulsion over 1 year. Data were not included on patients treated with rectal paraldehyde for other seizure types or non-convulsive status epilepticus. RESULTS: Data analysis was undertaken regarding 53 episodes in 30 patients. Patient's ages ranged from 5 months to 16 years (mean 6.12 years, median 5.91 years). A pre-existing diagnosis of epilepsy was recorded in 35 episodes (66%). The mean dose of paraldehyde was 0.65 ml/kg (SD 0.22, 95% CI 0.59 to 0.71) and median dose 0.79 ml/kg. Rectal paraldehyde terminated the convulsion in 33 (62.3%) of the 53 episodes. In the 35 episodes where a pre-existing diagnosis of epilepsy was recorded, paraldehyde stopped the convulsion on 26 (74.3%) occasions. There was no difference in the dose of paraldehyde between the episodes where the convulsion was or was not terminated. There was no recorded respiratory depression in any episode. CONCLUSIONS: This study provides unique evidence that rectal paraldehyde is effective and safe in treating acute prolonged tonic-clonic convulsions. This would appear to confirm that paraldehyde should remain a treatment for the management of prolonged tonic-clonic convulsions, including convulsive status epilepticus.

Neurological disorders presenting mainly in adolescence.

The aim of this review is to discuss some of the neurological diseases that present mainly in the adolescent period. The article focuses on the usual presentation and course of the more common, and some uncommon, epilepsies, neuromuscular disorders, neurodegenerative disorders, inflammatory disorders of the central nervous system and some other, miscellaneous conditions. The article ends with a very brief and general discussion about management issues in this age group.

Guanidinoacetate methyltransferase deficiency masquerading as a mitochondrial encephalopathy.

Guanidinoacetate methyltransferase (GAMT) deficiency is a rare disorder of creatine synthesis. We report a patient who presented at 10 months of age with hypotonia and global developmental delay. Subsequently, she developed seizures and choreoathetosis. Magnetic resonance imaging showed high signal bilaterally in the globus pallidus on T2-weighted images. Mitochondrial respiratory chain studies revealed low complex I activity (in muscle 0.052 nmol NADH oxidized per min per unit citrate synthase, controls 0.166 +/- 0.047; in fibroblasts 0.080 nmol NADH oxidized per min per unit citrate synthase, controls 0.197 +/- 0.034). The true diagnosis was suspected at 21 months of age because of persistent low plasma and urine creatinine concentrations. GAMT activity was undetectable in fibroblasts and compound heterozygous mutations were found in the GAMT gene (c.327G>A and c.522G>A). The patient was treated with creatine, dietary arginine restriction and ornithine supplements. Her movement disorder and seizures resolved but she still has severe cognitive impairment and no expressive language. The occurrence of secondary respiratory chain abnormalities in GAMT deficiency may lead to misdiagnosis, particularly as the clinical and radiological features resemble those seen in mitochondrial encephalopathies. It is important to establish the correct diagnosis because specific treatment is available.

Alternative approaches to conventional antiepileptic drugs in the management of paediatric epilepsy.

Over the last two decades, there has been a rapid expansion in the number and types of available antiepileptic drugs (AEDs), but there is increasing concern amongst parents and carers about their unwanted side effects. Seizure control is achieved in approximately 75% of children treated with conventional AEDs, but non-conventional (or non-standard) medical treatments, surgical procedures, dietary approaches, and other non-pharmacological treatment approaches may have a role to play in those with intractable seizures or AED toxicity. Many of the approaches are largely common sense and are already incorporated into our current practice, including, for example, avoidance techniques and lifestyle advice, while others require further investigation or appear to be impractical in children.

Intranasal immunisation with defective adenovirus serotype 5 expressing the Venezuelan equine encephalitis virus E2 glycoprotein protects against airborne challenge with virulent virus.

There is no vaccine licensed for human use to protect laboratory or field workers against infection with Venezuelan equine encephalitis virus (VEEV). Infection of these groups is most likely to occur via the airborne route and there is evidence to suggest that protection against airborne infection may require high antibody levels and the presence of antibody on the mucosal surface of the respiratory tract. Recombinant defective type 5 adenoviruses, expressing the E3E26K structural genes of VEEV were examined for their ability to protect mice against airborne challenge with virulent virus. After intranasal administration, good protection was achieved against the homologous serogroup 1A/B challenge virus (strain Trinidad donkey). There was less protection against enzootic serogroup II and III viruses, indicating that inclusion of more than one E3E26K sequence in a putative vaccine may be necessary. These studies confirm the potential of recombinant adenoviruses as vaccine vectors for VEEV and will inform the development of a live replicating adenovirus-based VEEV vaccine, deliverable by a mucosal route and suitable for use in humans.

The relationship between treatment with valproate, lamotrigine, and topiramate and the prognosis of the idiopathic generalised epilepsies.

OBJECTIVE: To examine a large population with idiopathic generalised epilepsy (IGE), and estimate the overall remission rates for the IGEs and subsyndromes in a clinic based sample. Remission rates on valproate, lamotrigine, topiramate, and combinations of these antiepileptic drugs were estimated and factors predicting outcome examined. METHODS: All patients with IGE were identified from a computerised database and EEG records at large adult and paediatric epilepsy clinics. Data were recorded retrospectively on demographics and clinical information, seizure types and syndrome diagnosis, antiepileptic drug treatment details, and remission rates. RESULTS: 54.3% of 962 patients had achieved a one year period of remission; this was most likely with valproate monotherapy (52.1%), with lower rates for lamotrigine and topiramate (16.7% and 34.6%, respectively). The combination of valproate and lamotrigine achieved a remission rate of 15.3%. The factor most predictive of a response to a particular antiepileptic drug regimen was the rank order in which it was given. Relapse rate was high (79.9%) after antiepileptic drug withdrawal in remission, particularly with juvenile myoclonic epilepsy (93.6%). CONCLUSIONS: Valproate may be the most effective antiepileptic drug in the treatment of the IGEs. Combination therapy should be initiated if an adequate trial of valproate monotherapy is not effective, rather than switching to alternative monotherapy. Antiepileptic drug treatment needs to be lifelong in many adult patients with IGE.

Mortality in paediatric epilepsy.

The reasons for premature death in paediatric epilepsy are reviewed with reference to recent studies reported in the literature. Ways of informing families of children with epilepsy about the risk of death are discussed, and recommendations for personal practice given.

Post-traumatic epilepsy in children requiring inpatient rehabilitation following head injury.

OBJECTIVE: To study the prevalence of, and identify possible risk factors for, the development of post-traumatic epilepsy in a cohort of children with severe head injury treated in an inpatient rehabilitation unit. METHODS: The hospital and community medical case notes of all children admitted prospectively to the unit and the records of the clinical EEG department over a seven year period were reviewed to identify those children who had developed late epilepsy after head injuries. RESULTS: 102 children received inpatient rehabilitation between 1 June 1991 and 28 February 1998. Follow up of these patients ranged from 18 months to over eight years. Nine patients (9%) developed post-traumatic epilepsy between eight months and over five years after the head injury. Three of the nine patients had experienced early tonic-clonic seizures in the first week after the injury. Other risk factors examined included the age of the patient, the cause of the head injury, initial Glasgow coma scale score, neuroimaging findings, and duration of ventilatory support. Only the presence of early seizures (p = 0.002) and possibly the Glasgow coma scale score (p = 0.043) were found to be specific risk factors for late late epilepsy. CONCLUSIONS: Post-traumatic epilepsy appears to be uncommon, even in children with severe head injuries. Early seizures may indicate increased risk of developing late post-traumatic epilepsy in this study population.

Acute, severe self-limiting dysautonomia and hypertensive encephalopathy.

We describe two unrelated children with almost identical clinical illnesses comprising of severe, burning dysesthesia, allodynia, hypertensive encephalopathy, and laboratory evidence of both sympathetic and parasympathetic autonomic disturbance after a nonspecific viral illness. No underlying etiology was identified. Both patients displayed complete resolution of their clinical and radiologic findings after a number of months, and there was no recurrence over a follow-up period of 17 months to 4 years. Treatment of the patients' dysesthesias proved difficult, requiring multiple analgesics and intensive physiotherapy. We speculate that their illnesses may represent a pure autonomic variant of Guillain-Barré syndrome.

West syndrome: long-term prognosis and social aspects.

West syndrome (WS) is commonly associated with a poor long-term outcome including a small but significant mortality, infantile spasms that are resistant to treatment, the development of other seizure types and impaired cognitive and psychosocial functioning. It is important to understand that the families of these children also experience significant psychosocial morbidity, which is usually, but not invariably, correlated with persisting seizures beyond the first or second year of life. One of the fundamental points about the prognosis of this epilepsy syndrome is that the natural history (i.e. the outcome of spasms without any medical or surgical intervention) is not known. Numerous factors have been implicated as being important in influencing the long-term prognosis of children with WS. However, the majority of these factors have been identified from retrospective and markedly heterogeneous studies, including different populations and different treatment regimes. The most important prognostic factors are generally recognised to be the underlying aetiology of the syndrome and the presence or absence of pre-existing seizures and/or developmental abnormalities. The rapidity with which the diagnosis is made and treatment started from the onset of spasms (often termed the 'treatment lag') is a possible, though controversial and as yet unproven, factor in the prognosis of WS.

Dermatomyositis and Whipple's disease.

A 14-year-old boy presented with a 3-year history of a skin rash typical of juvenile dermatomyositis, and a 2-month history of mild proximal weakness, myalgia, and weight loss. A quadriceps biopsy showed perifascicular fibre atrophy, focal necrosis and regeneration, immunohistochemical labelling for HLA-1 on the surface of the fibres, and focal C5-9 deposition in capillaries. Macrophages with diastase-resistant, PAS-positive cytoplasm were present. Ultrastructural studies showed electron dense and membranous debris. The patient's symptoms responded to intravenous immunoglobulin and oral prednisolone. Four months after discontinuing prednisolone, the patient developed cardiac failure, ventricular tachycardia, and a recurrence of his rash. The 16S ribosomal RNA specific for Tropheryma whippelii was identified by polymerase chain reaction (PCR) analysis in skeletal and cardiac muscle. The myalgia and skin rash responded to prednisolone and oral co-trimoxazole, and the tachycardia is controlled by oral verapamil. This patient appears to have a novel association of juvenile dermatomyositis and Whipple's disease.

Randomised, placebo-controlled study of vigabatrin as first-line treatment of infantile spasms.

PURPOSE: Vigabatrin (VGB) has been shown to be an effective drug in the treatment of infantile spasms (West syndrome) in predominantly retrospective and open but also in prospective studies. This prospective, randomised, and placebo-controlled trial of VGB in infantile spasms was considered to be justified and feasible to confirm or refute these previous findings. METHODS: Forty children with newly diagnosed infantile spasms received either VGB or placebo for 5 days in a double blind, placebo-controlled, parallel-group study, after which all the infants continuing in the study were treated openly with VGB for a minimum of 24 weeks. RESULTS: Compared with baseline, at the end of the double-blind phase, the patients treated with VGB had a 78% (95% confidence interval, 55-89%) reduction in spasms compared with 26% (-56-65%) in the group treated with placebo (p = 0.020). Seven VGB-treated patients and two placebo-treated patients were spasm free on the final day of the double-blind period (p = 0.063). At the end of the study, 15 children (38% of the original 40 patients or 42% of the 36 patients who entered the open phase) were spasm free with VGB monotherapy. No patient withdrew from the study because of an adverse event. CONCLUSIONS: This unique randomized, placebo-controlled study is the first to demonstrate the efficacy of a specific drug in the treatment of West syndrome and supports the results of previously published open and prospective trials. It further confirms that VGB could be considered as the drug of first choice in treating infantile spasms.