No clinical evidence of hidden vCJD in UK children.

Between May 1997 and November 2004 this national prospective surveillance study identified 1007 children with "progressive intellectual and neurological deterioration" (PIND). In most cases specific diagnoses were made, but of 92 undiagnosed children with PIND 46 had died and only four underwent full necropsy. There was no clinical evidence of variant Creutzfeldt-Jakob disease (vCJD) in these undiagnosed cases, but without necropsy it is not possible to exclude vCJD completely.

Human herpesviruses-6 and -7 each cause significant neurological morbidity in Britain and Ireland.

BACKGROUND: Primary human herpesvirus-6 and -7 (HHV-6/-7) infections cause febrile illness sometimes complicated by convulsions and rarely encephalopathy. AIMS: To explore the extent of such HHV-6 and -7 induced disease in young children. METHODS: In a three year prospective study in Britain and Ireland, 205 children (2-35 months old) hospitalised with suspected encephalitis and/or severe illness with fever and convulsions were reported via the British Paediatric Surveillance Unit network. Blood samples were tested for primary HHV-6 and -7 infections. RESULTS: 26/156 (17%) of children aged 2-23 months had primary infection (11 HHV-6; 13 HHV-7; two with both viruses) coinciding with the acute illness; this was much higher than the about three cases expected by chance. All 26 were pyrexial; 25 had convulsions (18 status epilepticus), 11 requiring ventilation. Median hospital stay was 7.5 days. For HHV-6 primary infection the median age was 53 weeks (range 42-94) and the distribution differed from that of uninfected children; for HHV-7, the median was 60 weeks (range 17-102) and the distribution did not differ for the uninfected. Fewer (5/15) children with primary HHV-7 infection had previously been infected with HHV-6 than expected. CONCLUSIONS: Primary HHV-6 and HHV-7 infections accounted for a significant proportion of cases in those <2 years old of severe illness with fever and convulsions requiring hospital admission; each virus contributed equally. Predisposing factors are age for HHV-6 and no previous infection with HHV-6 for HHV-7. Children with such neurological disease should be investigated for primary HHV-6/-7 infections, especially in rare cases coinciding by chance with immunisation to exclude misdiagnosis as vaccine reactions.

Is variant Creutzfeldt-Jakob disease in young children misdiagnosed as Alpers' syndrome? An analysis of a national surveillance study.

BACKGROUND: There has been concern that children with variant Creutzfeldt-Jakob disease (vCJD) might be misdiagnosed as cases of Alpers' syndrome, as a spongiform degeneration of the brain is seen in both conditions. OBJECTIVE: To report a national prospective surveillance study of children with progressive intellectual and neurological deterioration, designed to detect any children in the United Kingdom with vCJD, to see whether this misdiagnosis is occurring. METHODS: A monthly surveillance card is sent by the British Paediatric Surveillance Unit to all consultant paediatricians in the UK. The card lists the disorders currently under surveillance. Paediatricians are asked to return the card, reporting cases seen in the previous month. The BPSU office informs the surveillance groups about reported cases, and they obtain clinical information from the notifying paediatrician. RESULTS: After 5 years and 8 months of surveillance, 1244 children had been reported to the study. Alpers' syndrome was confirmed in two, although this was the suggested diagnosis in 11 children at the time of initial notification. CONCLUSIONS: The results show that Alpers' syndrome is rare and it is unlikely that vCJD cases are being misdiagnosed as Alpers' syndrome.

Variations in neurodegenerative disease across the UK: findings from the national study of Progressive Intellectual and Neurological Deterioration (PIND).

AIMS: To identify any UK children with variant Creutzfeldt-Jakob disease (vCJD) and obtain information about the causes of progressive intellectual and neurological deterioration (PIND) and the geographical distribution of cases. METHODS: The PIND Study uses the monthly surveillance card that is sent to all UK paediatricians by the British Paediatric Surveillance Unit. Case details are obtained from the reporting paediatricians by telephone interview, site visit, or self completion of a questionnaire. A paediatric neurology expert group then classifies the anonymised cases. The Communicable Disease Surveillance Centre (CDSC) provides mapping support. RESULTS: After five years and five months of surveillance, 1400 children had been reported. In the UK the majority of PIND cases had a confirmed diagnosis (comprising 99 different conditions); 505 "no cases" and 97 "outstanding" cases were excluded. A total of 798 PIND cases were included as follows: 577 with a confirmed underlying diagnosis; six with definite or probable vCJD, 51 who had undiagnosed PIND but were not thought to have vCJD, and 164 cases who were still under investigation. In some districts there were unexpectedly high numbers of PIND cases with a heterogeneous mixture of underlying diagnoses. In the five districts with the largest numbers of resident cases the majority not only came from a particular ethnic group but also had high reported rates of consanguinity. CONCLUSIONS: In districts with large numbers of PIND cases there are major resource implications. These children and their families have complex problems and they need access to diagnostic facilities and appropriate service provision.

Variant Creutzfeldt-Jakob disease in UK children: a national surveillance study.

BACKGROUND: Variant Creutzfeldt-Jakob Disease (vCJD) was first reported in 1996; the youngest patient developed symptoms at 16 years of age. We have done 3 years of prospective active surveillance for progressive intellectual and neurological deterioration (PIND) in UK children, and have searched for vCJD among the children who were reported. METHODS: Since May, 1997, there has been active surveillance for patients younger than 16 years old with PIND by means of a monthly card sent to all UK consultant paediatricians by the British Paediatric Surveillance Unit. Clinical'details of cases of PIND are obtained from reporting paediatricians by telephone interview or site visit, and an expert group of paediatric neurologists then classifies the cases. FINDINGS: After 3 years, 885 patients with suspected PIND have been reported. Among them were two fatal cases of definite vCJD and one case of probable vCJD; all were reported in 1999. One girl was age 12 years at onset--the youngest ever case of vCJD. No other children with the clinical features of vCJD were identified. The expert group has discussed 655 cases, of which 360 have a confirmed underlying cause, being categorised into 88 known neurodegenerative diseases. INTERPRETATION: That this prospective active surveillance in the UK has found few children with suspected vCJD is relatively reassuring. However, 3 years is a short time to survey a disease with an unknown incubation period. Since one probable and two definite cases of vCJD were reported to the study in 1999, there is concern that more childhood cases may appear.

Mutations in the skeletal muscle alpha-actin gene in patients with actin myopathy and nemaline myopathy.

Muscle contraction results from the force generated between the thin filament protein actin and the thick filament protein myosin, which causes the thick and thin muscle filaments to slide past each other. There are skeletal muscle, cardiac muscle, smooth muscle and non-muscle isoforms of both actin and myosin. Inherited diseases in humans have been associated with defects in cardiac actin (dilated cardiomyopathy and hypertrophic cardiomyopathy), cardiac myosin (hypertrophic cardiomyopathy) and non-muscle myosin (deafness). Here we report that mutations in the human skeletal muscle alpha-actin gene (ACTA1) are associated with two different muscle diseases, 'congenital myopathy with excess of thin myofilaments' (actin myopathy) and nemaline myopathy. Both diseases are characterized by structural abnormalities of the muscle fibres and variable degrees of muscle weakness. We have identified 15 different missense mutations resulting in 14 different amino acid changes. The missense mutations in ACTA1 are distributed throughout all six coding exons, and some involve known functional domains of actin. Approximately half of the patients died within their first year, but two female patients have survived into their thirties and have children. We identified dominant mutations in all but 1 of 14 families, with the missense mutations being single and heterozygous. The only family showing dominant inheritance comprised a 33-year-old affected mother and her two affected and two unaffected children. In another family, the clinically unaffected father is a somatic mosaic for the mutation seen in both of his affected children. We identified recessive mutations in one family in which the two affected siblings had heterozygous mutations in two different exons, one paternally and the other maternally inherited. We also identified de novo mutations in seven sporadic probands for which it was possible to analyse parental DNA.

Long-term intellectual and behavioral outcomes of children with febrile convulsions.

BACKGROUND: Hospital-based studies have reported that children with febrile convulsions have subsequent mental retardation and behavior problems. In contrast, population-based studies have reported a better outcome. METHODS: We identified 398 children with febrile convulsions among 14,676 children enrolled in the Child Health and Education Study, a national population-based study in the United Kingdom of children born in one week in April 1970. The children were comprehensively assessed at the age of 10. After excluding 16 children who had neurodevelopmental problems before their first febrile convulsion and 1 child whose case was atypical, we studied 381 children, 287 with simple febrile convulsions and 94 with complex febrile convulsions. We compared them with the rest of the cohort using measures of academic progress, intelligence, and behavior that included questionnaires, standardized tests, and formal tests. RESULTS: At the 10-year assessment, only 4 of 102 measures of academic progress, intelligence, and behavior differed significantly between the entire group of children with febrile convulsions and the group without febrile convulsions -- no more than would be expected by chance. Similar results were found when children with simple febrile convulsions and those with complex febrile convulsions were analyzed separately. The children with recurrent episodes of febrile convulsions had outcomes similar to those of the children with only one episode each. Special schooling was required for more children who had febrile convulsions in the first year of life than for those who had had them later in life (5 of 67, or 7.5 percent, vs. 4 of 265, or 1.5 percent; P=0.02), but these numbers were small. CONCLUSION: Children who had febrile convulsions performed as well as other children in terms of their academic progress, intellect, and behavior at 10 years of age.

A multicentre comparative trial of sodium valproate and carbamazepine in paediatric epilepsy. The Paediatric EPITEG Collaborative Group.

The long-term efficacy and adverse-event profiles of sodium valproate and carbamazepine in children with newly diagnosed primary generalised or partial epilepsy were compared at 63 outpatient clinics. Children with two or more generalised tonic-clonic or partial seizures in the previous six months were randomised to oral sodium valproate (N = 130) or oral carbamazepine (N = 130) and followed for three years as outpatients. Dosages were increased as needed until seizures were controlled or toxicity developed. Sodium valproate and carbamazepine were equally effective in achieving high levels of seizure control in both primary generalised seizures and partial seizures with or without generalisation. Adverse events were mostly mild, few necessitating drug withdrawal. Those particularly associated with valproate were weight increase, alopecia and appetite increase, and with carbamazepine, rashes, somnolence, diplopia and abnormal gait/ataxia.

Outcome of childhood status epilepticus and lengthy febrile convulsions: findings of national cohort study.

OBJECTIVE: To study outcome after lengthy febrile convulsions and status epilepticus in children. DESIGN: Population based birth cohort study. SETTING: The child health and education study (16,004 neonatal survivors born in one week in April 1970). SUBJECTS: Information available for 14,676 children. OUTCOME MEASURES: Clinical information and tests of intellectual performance at five and 10 years after birth. RESULTS: 19 children had lengthy febrile convulsions and 18 had status epilepticus. Two children with status epilepticus died (one at 5 years old); neither death was directly due to the status epilepticus. Four of the 19 (21%) developed afebrile seizures after lengthy febrile convulsions compared with 14 of the 17 (82%) survivors after status epilepticus. Measures of intellectual performance were available for 33 of the 35 survivors: 23 were normal and 10 were not normal but eight of them had preceding developmental delay or neurological abnormality. CONCLUSION: The outcome in children after lengthy febrile convulsions and status epilepticus is better than reported from studies of selected groups and seems determined more by the underlying cause than by the seizures themselves.

Epilepsy in the first 10 years of life: findings of the child health and education study.

OBJECTIVES: To identify children with afebrile seizures in a national cohort, classify the seizures, and document progress in the first 10 years of life. DESIGN: Population based birth cohort study. SETTING: The child health and education study, which includes 16,004 neonatal survivors (98.5% of infants born in the United Kingdom during one week of April 1970). SUBJECTS: 14,676 children for whom relevant information was available. MAIN OUTCOME MEASURES: Responses to parental and general practitioner questionnaires and hospital records at 5 and 10 years after birth. RESULTS: 84 children (42 boys, 42 girls) had had one or more afebrile seizure (incidence 5.7/1000). 63 children (31 boys, 32 girls) had epilepsy (incidence 4.3/1000). 49 of 55 children had a second seizure within a year of the first. The commonest seizure types were tonic-clonic (42) and complex partial (25). A greater proportion of children with complex partial seizures had recurrences. Children who had infantile spasms or a mixed seizure disorder had a poor outcome. All six children who died had symptomatic seizures in the first year, but seizures were not the direct cause of death. CONCLUSIONS: The results of this study are probably representative of seizure patterns in the general population. Outcome after seizures is determined more by the underlying disease than by the seizures themselves.

Risk of epilepsy after febrile convulsions: a national cohort study.

OBJECTIVE: To identify children with febrile convulsions, classify their febrile convulsions into simple and complex, and determine the number and type of subsequent afebrile seizures in those children. DESIGN: National population based study. SETTING: United Kingdom. SUBJECTS: 16,004 neonatal survivors born during one week in April 1970. MAIN OUTCOME MEASURES: Information about febrile and afebrile seizures obtained from questionnaires at 5 and 10 years of age and from hospital records. RESULTS: Information was available for 14,676 of the cohort children. 398 (2.7%) of them had had at least one febrile convulsion. 16 children were known to be neurologically or developmentally abnormal before the first attack. Of the remaining 382 children, 305 had had a simple first febrile convulsion and 77 a complex first febrile convulsion. Thirteen of the 382 had had one or more afebrile seizures, nine of whom had developed epilepsy (recurrent afebrile seizures). A higher proportion of children with complex febrile convulsions (6/95) rather than simple febrile convulsions (3/287) developed epilepsy, the risk being highest for those who had had focal febrile convulsions (5/17; chi 2 = 39.9, p less than 0.001). Three of the 32 children who had prolonged febrile convulsions developed afebrile complex partial seizures. CONCLUSIONS: The risk of epilepsy after febrile convulsions is much less than reported in many hospital studies, and if febrile convulsions cause brain damage that leads to later epilepsy this is a rare occurrence.

Do visual evoked potentials detect neural damage in children treated for cancer?

Abnormal visual evoked potentials (VEPs) have been reported in children treated for acute lymphoblastic leukaemia (ALL), which suggests that VEPs may be useful in screening for toxicity. The authors investigated this by recording flash and pattern VEPs in a control group of 34 siblings of patients, a group of six children studied longitudinally during the early stages of treatment for ALL, and three other follow-up groups. In only three follow-up patients were VEP results outside the normal range and the six ALL patients did not develop new abnormalities during early treatment. Although differences were detected between the groups, there was no evidence of VEPs being a useful means of monitoring the treatment of individual patients.