Demographic, clinical, and service-use characteristics related to the clinician's recommendation to transition from child to adult mental health services.

PURPOSE: The service configuration with distinct child and adolescent mental health services (CAMHS) and adult mental health services (AMHS) may be a barrier to continuity of care. Because of a lack of transition policy, CAMHS clinicians have to decide whether and when a young person should transition to AMHS. This study describes which characteristics are associated with the clinicians' advice to continue treatment at AMHS. METHODS: Demographic, family, clinical, treatment, and service-use characteristics of the MILESTONE cohort of 763 young people from 39 CAMHS in Europe were assessed using multi-informant and standardized assessment tools. Logistic mixed models were fitted to assess the relationship between these characteristics and clinicians' transition recommendations. RESULTS: Young people with higher clinician-rated severity of psychopathology scores, with self- and parent-reported need for ongoing treatment, with lower everyday functional skills and without self-reported psychotic experiences were more likely to be recommended to continue treatment. Among those who had been recommended to continue treatment, young people who used psychotropic medication, who had been in CAMHS for more than a year, and for whom appropriate AMHS were available were more likely to be recommended to continue treatment at AMHS. Young people whose parents indicated a need for ongoing treatment were more likely to be recommended to stay in CAMHS. CONCLUSION: Although the decision regarding continuity of treatment was mostly determined by a small set of clinical characteristics, the recommendation to continue treatment at AMHS was mostly affected by service-use related characteristics, such as the availability of appropriate services.

Admissions to paediatric intensive care units (PICU) with refractory convulsive status epilepticus (RCSE): A two-year multi-centre study.

AIMS: To obtain national epidemiological data on the aetiology, management and outcome of refractory convulsive status epilepticus (RCSE) in children. METHODS: Data on children admitted with RCSE between 01.01.2008 and 31.12.2009, to eight paediatric intensive care units (PICUs) were retrospectively collected using a standard proforma designed with and co-ordinated by PICANet. RESULTS: Data were collected on 245 (male, 179) patients aged between <1 month and 16.5 years (median 2.8 years, IQR 1-7.43 years), of which: One hundred and fifty-one patients (male, 89) aged between <1 month and 16.5 years (median 2.3 years, IQR 1-7.17 years) met the study criteria for a diagnosis of RCSE. Causes included acute symptomatic (15.2%), remote symptomatic (29.0%), epilepsy-related (10.6%), progressive encephalopathy (10.6%) febrile seizures (18.2%); no cause was identified in 16.4%. First line treatments included lorazepam (118 patients, 78.1%), diazepam (72, 47.7%) and midazolam (37, 24.5%). Second-line treatments included phenytoin (125 patients, 82.8%) and phenobarbital (seven patients, 4.6%). Third-line treatments included a thiopentone bolus (99 patients, 65.6%), thiopentone infusion (20, 13.2%) midazolam infusion (56, 37.1%) phenobarbital (18, 11.9%), propofol (6, 4.0%) and clonazepam (2, 1.3%). Deviation from the national advanced paediatric life support (APLS) protocol was noted in approximately one quarter of all patients. Six patients died (4.0%). Seventeen patients (11.3%) developed a new neurological deficit on discharge from PICU, of which eight (5.3%) continued to show this deficit at a 30-day follow-up and 12 patients (7.9%) developed de novo epilepsy. CONCLUSIONS: Thiopentone was the most commonly used anticonvulsant to treat RCSE on admission to PICU. Mortality was low and approximately 1 in 25 showed a new neurological deficit at the 30-day follow-up.

Outpatient anti-epileptic drug prescribing errors in a Children's Hospital: an audit and literature review.

PURPOSE: Prescription errors are a common and potentially hazardous problem and may cause patient harm. This review evaluates all new anti-epileptic drug (AED) outpatient prescriptions over one year and reviews the subject literature. METHODS: A 12-month retrospective review of all outpatient prescriptions of AEDs within a large Children's Hospital. Copies of all prescriptions were obtained from the Trust's Pharmacy. The evaluation included the completeness of the required information, prescribing errors and the need for pharmacist intervention before the drug could be dispensed. It did not address the severity of prescribing errors or the potential harm to the patient. RESULTS: Two hundred and sixty two new prescriptions were evaluated. Incomplete prescriptions (that omitted at least one piece of required information) were found in 72.1%. The most common omission was the dose strength (mg/ml) or actual dose (mg) of the AED. No clinical diagnosis was documented in 62.6% and in 22%, only the word 'epilepsy', was stated with no reference to the epilepsy syndrome or seizure type. Pharmacist intervention was required in approximately 17% (approximately 1 in 6) of all prescriptions before the AED could be dispensed. CONCLUSION: This review highlights the importance of clinical information on prescriptions and that incomplete or poor documentation may contribute to prescribing errors. It also emphasises the importance of pharmacists in the identification and correction or resolution of potential prescribing errors. There is a need to develop a well-validated measure to assess the severity of prescribing errors that will better address their clinical significance and risk.

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.

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.

Intravenous levetiracetam in acute repetitive seizures and status epilepticus in children: experience from a children's hospital.

PURPOSE: To report the effectiveness and safety of intravenous levetiracetam in the treatment of children with acute repeated seizures, and status epilepticus in a children's hospital. METHODS: This two-year observational study evaluated all in-patients who received intravenous levetiracetam to treat acute repeated seizures (ARS) or convulsive and non-convulsive status epilepticus (SE). Information was collected on seizure type, epilepsy syndrome and underlying cause, the initial loading dose of intravenous levetiracetam, its effectiveness and safety and whether the patient remained on the drug at final follow-up. Analysis was descriptive. RESULTS: Fifty-one patients aged 0.2-18.8 (mean 7.1) years were evaluated, including 45 with acute ARS or SE and six unable to continue their usual orally administered anti-epileptic medication. The median initial dose of levetiracetam was 14.4 (range 5-30)mg/kg in the 45 patients treated for acute seizures and SE. Twenty three of the 39 (59%) patients with ARS became and remained seizure-free. Levetiracetam terminated status in three of four (75%) patients with convulsive, and the two patients with non-convulsive status epilepticus. Aggressive behaviour occurred in three children, one of whom discontinued treatment. Forty-two patients (81%), including 34 of the 45 patients (76%) treated for ARS or SE remained on levetiracetam at the time of final follow-up, between two and 18 months after receiving the drug. CONCLUSION: This observational study has confirmed previous data that intravenous levetiracetam seems to be effective and safe in the treatment of acute repeated seizures and status epilepticus. A randomised clinical trial is justified to determine whether intravenous levetiracetam should replace intravenous phenytoin as the first long-acting anticonvulsant in the management of acute repetitive seizures and status epilepticus.

Treatment of difficult epilepsy.

Most of the epilepsies that occur in children are relatively straightforward to manage, including suppression of the seizures. However, in at least 30% of children, seizures will not be fully controlled by one or two antiepileptic drugs (AEDs); these children may also have additional physical, educational or behavioural problems. This population is often labelled as having a "difficult" or an "intractable" epilepsy. The approach to these children must always begin with ensuring that the diagnosis of epilepsy is accurate, that the correct seizure type or types and epilepsy syndrome have been identified and that an underlying cause has been considered. Treatment must be holistic, considering the child as a person and not just someone having seizures; the AED regimen must be appropriate and not excessive; and surgery must always be considered a viable option.

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.

Administration of melatonin mixed with soft food and liquids for children with neurodevelopmental difficulties.

It is sometimes necessary for the contents of medication capsules to be mixed with certain foods and drinks because children are not always able to swallow the capsules. The compatibility and short-term stability (6h) of melatonin capsules mixed in a variety of liquids and foodstuffs (water, orange juice, semi-skimmed milk, strawberry yogurt, and strawberry jam) were analyzed for degradation. Extraction of melatonin from these common administration vehicles and an analytical assay for the drug and its potential degradation products were developed and validated. The results showed good recovery of melatonin from low- and high-strength capsules for all administration vehicles (between 89% minimum and 111% maximum). The drug was found to be stable in the common liquids and foods tested for up to 6 hours at room temperature (no degradation peak); hence it is unlikely to compromise the results of the Use of Melatonin in Children with Neurodevelopmental Disorders and Impaired Sleep trial.

A randomised controlled trial examining the longer-term outcomes of standard versus new antiepileptic drugs. The SANAD trial.

OBJECTIVES: To compare clinicians' choice of one of the standard epilepsy drug treatments (carbamazepine or valproate) versus appropriate comparator new drugs. DESIGN: A clinical trial comprising two arms, one comparing new drugs in carbamazepine and the other with valproate. SETTING: A multicentre study recruiting patients with epilepsy from hospital outpatient clinics. PARTICIPANTS: Patients with an adequately documented history of two or more clinically definite unprovoked epileptic seizures within the last year for whom treatment with a single antiepileptic drug represented the best therapeutic option. INTERVENTIONS: Arm A was carbamazepine (CBZ) versus gabapentin (GBP) versus lamotrigine (LTG) versus oxcarbazepine (OXC) versus topiramate (TPM). Arm B valproate (VPS) versus LTG versus TPM. MAIN OUTCOME MEASURES: Time to treatment failure (withdrawal of the randomised drug for reasons of unacceptable adverse events or inadequate seizure control or a combination of the two) and time to achieve a 12-month remission of seizures. Time from randomisation to first seizure, 24-month remission of seizures, incidence of clinically important adverse events, quality of life (QoL) outcomes and health economic outcomes were also considered. RESULTS: Arm A recruited 1721 patients (88% with symptomatic or cryptogenic partial epilepsy and 10% with unclassified epilepsy). Arm B recruited 716 patients (63% with idiopathic generalised epilepsy and 25% with unclassified epilepsy). In Arm A LTG had the lowest incidence of treatment failure and was statistically superior to all drugs for this outcome with the exception of OXC. Some 12% and 8% fewer patients experienced treatment failure on LTG than CBZ, the standard drug, at 1 and 2 years after randomisation, respectively. The superiority of LTG over CBZ was due to its better tolerability but there is satisfactory evidence indicating that LTG is not clinically inferior to CBZ for measures of its efficacy. No consistent differences in QoL outcomes were found between treatment groups. Health economic analysis supported LTG being preferred to CBZ for both cost per seizure avoided and cost per quality-adjusted life-year gained. In Arm B for time to treatment failure, VPS, the standard drug, was preferred to both TPM and LTG, as it was the drug least likely to be associated with treatment failure for inadequate seizure control and was the preferred drug for time to achieving a 12-month remission. QoL assessments did not show any between-treatment differences. The health economic assessment supported the conclusion that VPS should remain the drug of first choice for idiopathic generalised or unclassified epilepsy, although there is a suggestion that TPM is a cost-effective alternative to VPS. CONCLUSIONS: The evidence suggests that LTG may be a clinical and cost-effective alternative to the existing standard drug treatment, CBZ, for patients diagnosed as having partial seizures. For patients with idiopathic generalised epilepsy or difficult to classify epilepsy, VPS remains the clinically most effective drug, although TPM may be a cost-effective alternative for some patients. Three new antiepileptic drugs have recently been licensed in the UK for the treatment of epilepsy (levetiracetam, zonisamide and pregabalin), therefore these drugs should be compared in a similarly designed trial.

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.

GAMT deficiency: features, treatment, and outcome in an inborn error of creatine synthesis.

BACKGROUND: Guanidinoactetate methyltransferase (GAMT) deficiency is an autosomal recessive disorder of creatine synthesis. The authors analyzed clinical, biochemical, and molecular findings in 27 patients. METHODS: The authors collected data from questionnaires and literature reports. A score including degree of intellectual disability, epileptic seizures, and movement disorder was developed and used to classify clinical phenotype as severe, moderate, or mild. Score and biochemical data were assessed before and during treatment with oral creatine substitution alone or with additional dietary arginine restriction and ornithine supplementation. RESULTS: Intellectual disability, epileptic seizures, guanidinoacetate accumulation in body fluids, and deficiency of brain creatine were common in all 27 patients. Twelve patients had severe, 12 patients had moderate, and three patients had mild clinical phenotype. Twenty-one of 27 (78%) patients had severe intellectual disability (estimated IQ 20 to 34). There was no obvious correlation between severity of the clinical phenotype, guanidinoacetate accumulation in body fluids, and GAMT mutations. Treatment resulted in almost normalized cerebral creatine levels, reduced guanidinoacetate accumulation, and in improvement of epilepsy and movement disorder, whereas the degree of intellectual disability remained unchanged. CONCLUSION: Guanidinoactetate methyltransferase deficiency should be considered in patients with unexplained intellectual disability, and urinary guanidinoacetate should be determined as an initial diagnostic approach.

Corticosteroids in the management of the paediatric epilepsies.

Corticosteroids (predominantly prednisolone and hydrocortisone) and adrenocorticotropic hormone (ACTH) have been used in the treatment of the epilepsies for over 50 years. Over the past 30 years most reports have focused on epilepsy syndromes and epileptic encephalopathies resistant to treatment with the more conventional anticonvulsant and antiepileptic drugs (AEDs) and specifically West syndrome. There has been relatively little attention on the role of corticosteroids in treating other epilepsies.

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.

Attention deficit and hyperactivity disorder, methylphenidate, and epilepsy.

Attention deficit hyperactivity disorder (ADHD) is characterised by inattention, impulsivity, and hyperactivity. The DSM-IV diagnosis of ADHD requires the presence of six of nine items or features that must have been present for at least six months, to have had an onset before 7 years of age, and to have resulted in significant distress or impairment.1 In the general population, the prevalence of ADHD is approximately 5%.2 There is a high co-morbidity of epilepsy and attentional and behavioural problems,3,4 including ADHD, and it has been estimated that at least 20% of patients with epilepsy may present with features of ADHD.5.