Development and validation of a generic scale for use in transition programmes to measure self-management skills in adolescents with chronic health conditions: the TRANSITION-Q.

AIM: To develop a generic self-management skills scale for use with adolescents diagnosed with a chronic health condition who are aged 12 to 18 years. BACKGROUND: There is a lack of methodologically sound scales for healthcare teams to use to measure self-management skills in adolescents with chronic conditions transitioning to adult care. METHODS: Adolescents aged 12 to 18 years with a broad range of chronic health conditions, including neurodevelopmental conditions, were recruited from May to August 2013 from nine outpatient clinics at McMaster Children's Hospital (Canada). Thirty-two participated in a cognitive interview, and 337 completed a questionnaire booklet. Interviews were used to develop the TRANSITION-Q. Rasch measurement theory (RMT) analysis was used to identify items that represent the best indicators of self-management skills. Traditional psychometric tests of measurement performance were also conducted. RESULTS: The response rate was 92% (32/32 cognitive; 337/371 field test). RMT analysis resulted in a 14-item scale with three response options. The overall fit of the observed data to that expected by the Rasch model was non-significant, providing support that this new scale measured a unidimensional construct. Other tests supported the scale as scientifically sound, e.g. Person Separation Index = 0.82; good item fit statistics; no differential item function by age or gender; low residual correlations between items; Cronbach's alpha = 0.85; test-retest reliability = 0.90; and tests of construct validity that showed, as hypothesized, fewer skills in younger participants and in participants who required assistance to complete the scale. Finally, participants who agreed they are ready to transfer to adult healthcare reported higher TRANSITION-Q scores than did participants who disagreed. CONCLUSIONS: The TRANSITION-Q is a short, clinically meaningful and psychometrically sound scale. This generic scale can be used in research and in paediatric and adolescent clinics to help evaluate readiness for transition.

Quality of life in childhood epilepsy: what is the level of agreement between youth and their parents?

Children and parents evaluate the child's quality of life (QOL) from their own perspectives; therefore, responses may differ, especially in abstract domains. We examined differences between self- and proxy-reported QOL of children with epilepsy. Children with active epilepsy (N=375) and their parents (N=378) separately completed the CHEQOL-25, a condition-specific QOL measure. The intraclass correlation coefficient was used to determine interrater agreement. Concordance on the Total CHEQOL-25 was 0.45 (P<0.01). Discrepancies were greatest for the subscales of Secrecy (0.24, P<0.01) and Present Concerns (0.32, P<0.01). School placement correlated with discrepancy in the Intrapersonal/Emotional subscale (r=0.19, P<0.05), and the child's age at testing correlated with discrepancy of the Total measure (r=0.15, P<0.01). This study demonstrates that parent perspectives alone are insufficient to measure their child's QOL. The CHEQOL-25 is a practical tool, with complementary parent and child versions, which can be used to determine health-related quality of life in children with epilepsy.

Andreas Rett and benign familial neonatal convulsions revisited.

In 1964 Andreas Rett published the first account of a family with benign familial neonatal convulsions (BFNC). The authors retraced Rett's family and report that the clinical and genetic features of this original family fit the currently accepted definitions of BFNC. They also consider the career of Dr. Rett, a researcher and social reformer as well as an advocate for the rights of children with developmental disabilities.

Long-term valproate and lamotrigine treatment may be a marker for reduced growth and bone mass in children with epilepsy.

PURPOSE: To determine whether long-term treatment with valproate (VPA) and/or lamotrigine (LTG) in children with epilepsy is associated with altered growth and/or bone metabolism. METHODS: Twenty-seven boys and 26 girls, aged 3 to 17 years (9.2 +/- 3.9, mean +/- SD), with epilepsy treated with VPA and/or LTG for > or =2 years were evaluated for growth, nutrient intakes, physical activity, bone mineral density (BMD), and blood biochemical indices of mineral and bone metabolism. RESULTS: Twenty-three (43.4%) of the children had a body height below the 10th percentile. Z-scores for BMD below -1.5 occurred in 24.4% of the children. When patients were divided into two groups according to daily activity score, a significantly lower Z-score for total body BMD (p = 0.007), percentile for body height (p = 0.05), and plasma parathyroid hormone (PTH; p = 0.04), osteocalcin (p = 0.04) and 25-hydroxyvitamin D (25OHD) (p = 0.01) were found in the inactive compared with the active group. Z-score for total body BMD was correlated with daily activity score (r = 0.43, p = 0.008). Plasma intact osteocalcin and intact PTH values correlated significantly (r = 0.36, p = 0.02). Plasma 1,25-dihydroxyvitamin D was within normal range for all subjects. When patients were divided into LTG-alone, VPA-alone, and LTG-plus-VPA treatment groups, significantly lower (p < 0.05) plasma osteocalcin and percentile for body height were found in the VPA-plus-LTG treatment group. CONCLUSIONS: Long-term VPA and LTG therapy, particularly when combined, is associated with short stature, low BMD, and reduced bone formation. These alterations may be mediated primarily through reduced physical activity rather than through a direct link to the VPA and/or LTG therapy.

Health-related quality of life in childhood disorders: a modified focus group technique to involve children.

OBJECTIVES: Qualitative methodology has been under-utilized in child health research due to lack of a specific set of instruments. The objective of this study was to develop a child-centred qualitative research methodology to facilitate direct exploration of health-related quality of life (HRQL) issues and to identify the quality of life elements in pre-adolescent children with a chronic medical condition. STUDY DESIGN: Purposeful stratified sampling of children, ages 6-12, who function in a regular school class, with active epilepsy who were assembled in small focus groups. The groups met in four phases and were led by moderators who probed preset open questions and activities. RESULTS: The study demonstrated that our modified focus groups process was a powerful exploratory experience eliciting meaningful and important issues in quality of life beyond what parents and health professionals expected, and helped identify HRQL elements in childhood epilepsy. CONCLUSION: Modified focus groups are appropriate and suitable to explore quality of life issues in pre-adolescent children with a chronic medical condition. The process is feasible and trustworthy.

Can sodium valproate improve learning in children with epileptiform bursts but without clinical seizures?

This study aimed to determine whether sodium valproate (VPA) improves cognitive performance and behaviour in children with learning and behavioural problems associated with electrographic epileptiform discharges but without clinical seizures. A randomized, double-blind, single-crossover trial was carried out with VPA or placebo on eight participants with different learning and behaviour problems. Participants also underwent neuropsychological testing under video EEG and the parent and teacher Behaviour Check List (CBCL; Achenbach 1991a, b) during each treatment phase. Clinically none of the children improved on VPA. On formal testing children were more distractable, had increased delay in response time, and showed lower memory scores while on VPA. In addition, parents reported higher internalizing scores on the CBCL while children were on VPA. Our data do not support the use of VPA in similar patients.

An alternative pathway to beta -carotene formation in plant chromoplasts discovered by map-based cloning of beta and old-gold color mutations in tomato.

Carotenoid pigments in plants fulfill indispensable functions in photosynthesis. Carotenoids that accumulate as secondary metabolites in chromoplasts provide distinct coloration to flowers and fruits. In this work we investigated the genetic mechanisms that regulate accumulation of carotenoids as secondary metabolites during ripening of tomato fruits. We analyzed two mutations that affect fruit pigmentation in tomato (Lycopersicon esculentum): Beta (B), a single dominant gene that increases beta-carotene in the fruit, and old-gold (og), a recessive mutation that abolishes beta-carotene and increases lycopene. Using a map-based cloning approach we cloned the genes B and og. Molecular analysis revealed that B encodes a novel type of lycopene beta-cyclase, an enzyme that converts lycopene to beta-carotene. The amino acid sequence of B is similar to capsanthin-capsorubin synthase, an enzyme that produces red xanthophylls in fruits of pepper (Capsicum annum). Our results prove that beta-carotene is synthesized de novo during tomato fruit development by the B lycopene cyclase. In wild-type tomatoes B is expressed at low levels during the breaker stage of ripening, whereas in the Beta mutant its transcription is dramatically increased. Null mutations in the gene B are responsible for the phenotype in og, indicating that og is an allele of B. These results confirm that developmentally regulated transcription is the major mechanism that governs lycopene accumulation in ripening fruits. The cloned B genes can be used in various genetic manipulations toward altering pigmentation and enhancing nutritional value of plant foods.

Outcome measures in pediatric neurology: why do we need them?

Outcome measures should include the patient's values and preferences (from the patient's perspective) in addition to performance ratings and physiologic states. Outcome measures can assess relationships between services and interventions and their end results, can clarify which therapies are worth providing and which therapies need more evidence about their effectiveness, and can measure the burdens of different disorders and interventions. Researchers recently have shown the feasibility of creating and using outcome measures for children with neurodevelopmental disorders. Clinicians may wish to familiarize themselves with the concepts of outcome measures and health-related quality of life in order to understand the rationale, utility, properties, and various types of outcome measures in order to select the most appropriate instruments that will best serve their patient populations. Ongoing research efforts are currently using such measures in children with central nervous system tumors, with neural tube defects, and of extremely low birthweight; in childhood and adolescent epilepsy; and in adolescents with headaches.

Topiramate in intractable childhood onset epilepsy--a cautionary note.

OBJECTIVES: To study the effectiveness and safety of topiramate in clinical practice, for a group of patients with childhood onset epilepsy. METHODS: All patients treated with topiramate at the three study centers between November 1995 and December 31, 1997 were analyzed retrospectively, using a standardized study protocol. Data were gathered on demographic features, seizures response and medication related adverse events. RESULTS: Eighty-seven patients were treated with topiramate. Over 90% seizure reduction was achieved in 8 (9%) patients, 50%-90% in 21 (24%), < 50% in 54 (62%) patients. Four patients (5%) had a deterioration in seizure control. Adverse events required topiramate discontinuation in 36 (41%). Of these 27 (31%) complained of unacceptable cognitive dulling. The rate of dose escalation and final dose in mg/kg were similar in those who remained on topiramate and those who were intolerant because of cognitive side effects. CONCLUSIONS: Although topiramate resulted in > 50% seizure reduction in 29 (33%) of this group of patients with difficult epilepsy, its usefulness was limited by a high incidence of adverse effects. Adverse events prevented ongoing therapy for 36 (41%) and cognitive dulling resulted in topiramate discontinuation by 27 (31%) of the group.

Health-related quality of life in childhood epilepsy: the results of children's participation in identifying the components.

Separate groups of children with epilepsy, recruited from a regional pediatric epilepsy database, and their parents were established to discuss their life with epilepsy. Twenty-nine children (aged between 6 years and 10 years 4 months) and 42 of their parents were placed into nine and 17 groups respectively. The participants provided information about their own perceptions of life with epilepsy. Discussions were taped and textual analysis followed to extract, understand, explain, and categorize the health-related quality of life (HRQL) components. The process enabled us to identify the burdens and concerns of children with epilepsy, and to identify five emerging dimensions: (1) the experience of epilepsy, (2) life fulfillment and time use, (3) social issues, (4) impact of epilepsy, and (5) attribution. Identifying and understanding the components of HRQL is crucial for developing an HRQL scale in childhood epilepsy. In addition, this list of elements can help health professionals improve their services by considering and addressing aspects of the epilepsy experience beyond the traditional issues for children with epilepsy and their families.

Regulation of carotenoid biosynthesis during tomato fruit development: expression of the gene for lycopene epsilon-cyclase is down-regulated during ripening and is elevated in the mutant Delta.

The red colour of tomato (Lycopersicon esculentum) fruits is provided by the carotenoid pigment lycopene whose concentration increases dramatically during the ripening process. A single dominant gene, Del, in the tomato mutant Delta changes the fruit colour to orange as a result of accumulation of delta-carotene at the expense of lycopene. The cDNA for lycopene epsilon-cyclase (CrtL-e), which converts lycopene to delta-carotene, was cloned from tomato. The primary structure of CRTL-E is 71% identical to the homologous polypeptide from Arabidopsis and 36% identical to the tomato lycopene beta-cyclase, CRTL-B. The CrtL-e gene was mapped to a single locus on chromosome 12 of the tomato linkage map. This locus co-segregated with the Del gene. In the wild-type tomato, the transcript level of CrtL-e decreases at the 'breaker' stage of ripening to a non-detectable level in the ripe fruit. In contrast, it increases approximately 30-fold during fruit ripening in the Delta plants. The Delta mutation does not affect carotenoid composition nor the mRNA level of CrtL-e in leaves and flowers. These results strongly suggest that the mutation Del is an allele of the gene for epsilon-cyclase. Together with previous data, our results indicate that the primary mechanism that controls lycopene accumulation in tomato fruits is based on the differential regulation of expression of carotenoid biosynthesis genes. During fruit development, the mRNA levels for the lycopene-producing enzymes phytoene synthase (PSY) and phytoene desaturase (PDS) increase, while the mRNA levels of the genes for the lycopene beta- and epsilon-cyclases, which convert lycopene to either beta- or delta-carotene, respectively, decline and completely disappear.

The cognitive and behavioural effects of clobazam and standard monotherapy are comparable. Canadian Study Group for Childhood Epilepsy.

PURPOSE: To compare the cognitive and behavioural effects of clobazam versus standard monotherapy in the treatment of childhood epilepsy. METHODS: A randomized, double-blind, prospective design was carried out at three Canadian pediatric epilepsy centres. This study was part of a larger multi-centre study on the efficacy of clobazam. Children with newly diagnosed epilepsy were assigned randomly to receive clobazam or carbamazepine. Children who had failed previous treatment with carbamazepine were assigned randomly to clobazam or phenytoin. Children who had failed on any other antiepileptic drug were assigned randomly to receive clobazam or carbamazepine. In a subset of patients neuropsychological assessments were carried out at 6 weeks and 12 months after initiation of medication. Intelligence, memory, attention, psychomotor speed, and impulsivity were assessed. RESULTS: There were no differences between the clobazam and standard monotherapy groups on any of the neuropsychological measures obtained at 6 weeks or 12 months. There was no evidence for a deterioration in performance for those children who remained on clobazam for the entire 12-month study period. CONCLUSION: The cognitive and behavioural effects of clobazam appear to be similar to those of standard monotherapy.

The epidemiology of clinical neonatal seizures in Newfoundland: a population-based study.

OBJECTIVE: To study the incidence, clinical features, etiologic distribution, and day of seizure onset by etiology in neonates with seizures. DESIGN: Prospective, population-based study involving all the obstetric and neonatal units across the province of Newfoundland, Canada. All units were given educational sessions on neonatal seizure symptomatology. SUBJECTS: Detailed questionnaires were prospectively collected for all infants with probable neonatal seizures for a period of 5 years. RESULTS: The incidence rate was 2. 6 per 1000 live births, 2.00 for term neonates, 11.1 for preterm neonates, and 13.5 for infants weighing <2500 g at birth. Seizures lasting 30 minutes or longer were present in 5%, and the neonatal death rate among infants with seizures was 9%. Hypoxic-ischemic encephalopathy was the presumed cause in 40%, infections in 20%, and metabolic abnormalities in 19%. CONCLUSIONS: Clinical neonatal seizures occur 6 times more often in preterm infants than in term infants. Hypoxic-ischemic encephalopathy continues to be a major marker of the likelihood of seizures.

A novel potassium channel gene, KCNQ2, is mutated in an inherited epilepsy of newborns.

Idiopathic generalized epilepsies account for about 40% of epilepsy up to age 40 and commonly have a genetic basis. One type is benign familial neonatal convulsions (BFNC), a dominantly inherited disorder of newborns. We have identified a sub-microscopic deletion of chromosome 20q13.3 that co-segregates with seizures in a BFNC family. Characterization of cDNAs spanning the deleted region identified one encoding a novel voltage-gated potassium channel, KCNQ2, which belongs to a new KQT-like class of potassium channels. Five other BFNC probands were shown to have KCNQ2 mutations, including two transmembrane missense mutations, two frameshifts and one splice-site mutation. This finding in BFNC provides additional evidence that defects in potassium channels are involved in the mammalian epilepsy phenotype.

Clobazam for intractable pediatric epilepsy.

We report our experience with add-on clobazam therapy over a 5-year period in 63 children with refractory epilepsy. The mean duration of epilepsy was 6.7 years. Children were followed for 15 to 64 months. Of 63 children, 57 were developmentally delayed, and 54 had a symptomatic/cryptogenic epilepsy. Forty-one percent became either seizure free or had a greater than 90% reduction in seizure frequency. Seizure frequency was reduced 50% to 90% in another 24%. The average daily dose of clobazam was 0.8 mg/kg. Thirty-five percent had the medication withdrawn for persistent or unacceptable side effects or the development of tolerance (seven patients). Side effects included severe aggressive outbursts, hyperactivity, insomnia, and depression with suicidal ideation. Clobazam is a useful add-on medication for 65% of children with epilepsy. Clinical utility may be limited by behavioral side effects in some patients.

Arthrogryposis multiplex congenita due to congenital myasthenic syndrome.

Two children, now 5 1/2 and 6 years of age, presented as neonates with hypotonia, multiple joint contractures, ptosis, extraocular weakness, bulbar symptoms, and respiratory distress. Fluctuations and episodic exacerbations of weakness necessitated respiratory support. Both children are developmentally delayed and cannot walk independently, although one child underwent bilateral tenotomies. Biochemical investigations and electromyography, including slow-rate, repetitive nerve stimulation, were normal. Acetylcholine receptor antibodies in serum were absent. Single-fiber electromyography with axonal stimulation revealed prolonged mean jitter in the tibialis anterior and extensor digitorum muscles, with more than 2 abnormal individual jitter values in each muscle. Muscle biopsy demonstrated normal pattern and morphology of muscle fibers; immunohistochemical staining for cholinesterase was positive. Electron microscopy revealed abnormalities in motor endplates: atrophy, flattening of primary synaptic clefts, and paucity of side branches. These findings represent one of the postsynaptic abnormalities (i.e., acetylcholine receptor deficiency or paucity of synaptic folds). Both children improved clinically on pyridostigmine therapy. Arthrogryposis congenital multiplex due to congenital myasthenic syndrome, as diagnosed in our patients, has been reported once before. The diagnosis can be established by clinical history, neurologic examination, and electrophysiologic and pathologic findings. Clinical improvement can be achieved with high-dose anticholinesterase therapy.

Occipital paroxysmal discharges suppressed by eye opening: variability in clinical and seizure manifestations in childhood.

The EEG in childhood epilepsy with occipital paroxysms (CEOP) was termed "distinctive" by Gastaut (1985) and Talwar et al. (1992) and "characteristic" by Herranz Tanarro et al. (1984), which suggests that the EEG is specific and diagnostic for CEOP. However, this hypothesis has been challenged (Newton and Aicardi, 1983; Beaumanoir and Grandjean, 1987). To test this, we reviewed 5,291 EEG reports made in 5 1/2 years in the only tertiary pediatric center in Newfoundland and Labrador. We identified 31 children who had one or more EEGs with occipital spike/sharp waves showing suppression of discharges with eye opening and normal background activity. Six had CEOP, 17 had benign nocturnal childhood occipital epilepsy, 5 had symptomatic epilepsy, 3 had unusual complex partial seizures (CPS), 4 had only provoked seizures, and 2 had no definite seizures. Overlap between seizure types was common. The EEG criteria for CEOP are not very specific.

Aggression in children treated with clobazam for epilepsy.

Seven of 63 children (11%) treated with clobazam (CLB) for refractory epilepsy developed a severe behavior disorder. This disorder was characterized by aggressive agitation, self injurious behavior, insomnia, and incessant motor activity occurring between 10 and 55 days after initiation of drug therapy. The affected children were relatively young (mean age 6.4 years) and developmentally disabled (four were autistic and two had isolated mental retardation). The disorder occurred with a short latency after initiation of therapy and at a relatively low dosage of CLB. Serum levels of other coadministered antiepileptic drugs were unchanged by the administration of CLB. One child was taking CLB monotherapy. This behavioral deterioration required the discontinuation of CLB, after which patients returned to their previous behavior within 3 weeks. After > 3 years of follow-up all children continue to require multiple antiepileptic drugs but have not had a recurrence of this aggressive agitation. The mechanism of the behavioral change is unclear.