Christopher M Verity

The United Kingdom Infantile Spasms Study (UKISS) comparing hormone treatment with vigabatrin on developmental and epilepsy outcomes to age 14 months: a multicentre randomised trial

BACKGROUND Infantile spasms is a severe infantile seizure disorder that is difficult to treat and has a high morbidity. Absence of spasms on days 13 and 14 after randomisation is more common in infants allocated hormone treatments than in those allocated vigabatrin. We sought to assess whether early control of spasms is associated with improved developmental or epilepsy outcomes. METHODS Infants enrolled in the United Kingdom Infantile Spasms Study (UKISS) were randomly assigned hormone treatment (n=55) or vigabatrin (n=52) and were followed up until clinical assessment at 12-14 months of age. We assessed neurodevelopment with the Vineland adaptive behaviour scales (VABS) at 14 months of age on an intention to treat basis. FINDINGS Of 107 infants enrolled, five died and 101 survivors reached both follow-up assessments. Absence of spasms at final clinical assessment (hormone 41/55 [75%] vs vigabatrin 39/51 [76%]) was similar in each treatment group (difference 1.9%, 95% CI -18.3% to 14.4%; chi(2)=0.05; p=0.82). Mean VABS score did not differ significantly (hormone 78.6 [SD 16.8] vs vigabatrin 77.5 [SD 12.7]; difference 1.0, 95% CI -4.9 to 7.0; t(99)=0.35, p=0.73). In infants with no identified underlying aetiology, the mean VABS score was higher in those allocated hormone treatment than in those allocated vigabatrin (88.2 [17.3] vs 78.9 [14.3]; difference 9.3, 95% CI 1.2 to 17.3; t(95)=2.28, p=0.025). INTERPRETATION Hormone treatment controls spasms better than does vigabatrin initially, but not at 12-14 months of age. Better initial control of spasms by hormone treatment in those with no identified underlying aetiology may lead to improved developmental outcome.

Risk of narcolepsy in children and young people receiving AS03 adjuvanted pandemic A/H1N1 2009 influenza vaccine: retrospective analysis

Objective To evaluate the risk of narcolepsy in children and adolescents in England targeted for vaccination with ASO3 adjuvanted pandemic A/H1N1 2009 vaccine (Pandemrix) from October 2009. Design Retrospective analysis. Clinical information and results of sleep tests were extracted from hospital notes between August 2011 and February 2012 and reviewed by an expert panel to confirm the diagnosis. Vaccination and clinical histories were obtained from general practitioners. Setting Sleep centres and paediatric neurology centres in England. Participants Children and young people aged 4-18 with onset of narcolepsy from January 2008. Main outcome measures The odds of vaccination in those with narcolepsy compared with the age matched English population after adjustment for clinical conditions that were indications for vaccination. The incidence of narcolepsy within six months of vaccination compared with the incidence outside this period measured with the self controlled cases series method. Results Case notes for 245 children and young people were reviewed; 75 had narcolepsy (56 with cataplexy) and onset after 1 January 2008. Eleven had been vaccinated before onset; seven within six months. In those with a diagnosis by July 2011 the odds ratio was 14.4 (95% confidence interval 4.3 to 48.5) for vaccination at any time before onset and 16.2 (3.1 to 84.5) for vaccination within six months before onset. The relative incidence from the self controlled cases series analysis in those with a diagnosis by July 2011 with onset from October 2008 to December 2010 was 9.9 (2.1 to 47.9). The attributable risk was estimated as between 1 in 57 500 and 1 in 52 000 doses. Conclusion The increased risk of narcolepsy after vaccination with ASO3 adjuvanted pandemic A/H1N1 2009 vaccine indicates a causal association, consistent with findings from Finland. Because of variable delay in diagnosis, however, the risk might be overestimated by more rapid referral of vaccinated children.

The underlying etiology of infantile spasms (West syndrome): Information from the United Kingdom Infantile Spasms Study (UKISS) on contemporary causes and their classification

Purpose:  To examine the underlying etiology of infantile spasms from the United Kingdom Infantile Spasms Study (UKISS), using the pediatric adaptation of ICD 10.

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.

The effect of lead time to treatment and of age of onset on developmental outcome at 4 years in infantile spasms: Evidence from the United Kingdom Infantile Spasms Study

Purpose:  Infantile spasms is a severe infantile seizure disorder. Several factors affect developmental outcome, especially the underlying etiology of the spasms. Treatment also affects outcome. Both age at onset of spasms and lead time to treatment (the time from onset of spasms to start of treatment) may be important. We investigated these factors.

Developmental and epilepsy outcomes at age 4 years in the UKISS trial comparing hormonal treatments to vigabatrin for infantile spasms: a multi-centre randomised trial

Background Infantile spasms is the name given to a difficult to treat, severe infantile epilepsy with high morbidity. The United Kingdom Infantile Spasms Study (UKISS) showed that absence of spasms on days 13 and 14 after randomisation was more common in infants allocated hormonal treatments than vigabatrin. At 12–14 months, those with no identified aetiology allocated hormonal treatment had better development. However, epilepsy outcome was not affected by treatment allocated. It is not known if the difference in development persists as the infants grow. Methods Infants in UKISS were followed up blind to treatment allocation by telephone at a mean age of 4 years using the Vineland Adaptive Behaviour Scales (VABS) and an epilepsy questionnaire. Findings 9 of 107 enrolled infants had died. 77 were traced and consented to take part. The median (quartile) VABS scores were 60 (42, 97) for the 39 allocated hormonal treatment and 50 (36, 67) for the 38 allocated vigabatrin (Mann–Whitney U=575; p=0.091; median difference (95% CI): 8 (−1 to 19)). For those with no identified aetiology, VABS scores were 96 (52, 102) for the 21 allocated hormonal treatment and 63 (37, 92) for the 16 allocated vigabatrin (U=98.5; p=0.033; median difference (95% CI): 14 (1 to 42)).The proportions in each treatment group with epilepsy were similar. Interpretation For all 77 infants, development and epilepsy outcomes were not significantly different between the two treatment groups. The better development seen at 14 months in those with no identified aetiology allocated hormonal treatment was seen again at 4 years in this study.

The epidemiology of progressive intellectual and neurological deterioration in childhood

Objective To study the epidemiology of diseases that cause progressive intellectual and neurological deterioration (PIND) in UK children. Design Since May 1997, the authors have performed active surveillance to search for variant Creutzfeldt–Jakob Disease (vCJD) among the many diseases that cause neurological deterioration in children, using the monthly surveillance card sent to all UK consultant paediatricians by the British Paediatric Surveillance Unit. The authors obtain clinical details from reporting paediatricians by questionnaire or site visit, and an Expert Group then independently classifies the cases. Results After 12 years, 2636 patients less than 16 years old with suspected PIND had been reported, of whom 1114 had a confirmed diagnosis to explain their deterioration: in these children, there were 147 different diseases. These were the six commonest diagnostic groups: leukoencephalopathies (183 cases), neuronal ceroid lipofuscinoses (141 cases), mitochondrial diseases (122 cases), mucopolysaccharidoses (102 cases), gangliosidoses (100 cases) and peroxisomal disorders (69 cases). Relatively large numbers of PIND children were reported from parts of the UK where there are high rates of consanguinity. Only six children with vCJD (four definite, two probable) had been identified. Conclusions Although this study does not ascertain all UK cases, it provides a novel insight into the epidemiology of the neurodegenerative diseases that cause PIND in children. It is reassuring that in general these children are carefully investigated and that active surveillance has found only six children with vCJD. However, there is concern that more childhood vCJD cases may appear, possibly with a different genotype from those identified so far.

Risk of Serious Neurologic Disease After Immunization of Young Children in Britain and Ireland

OBJECTIVE. We sought to investigate the risk of serious neurologic disease after immunization in early childhood. METHODS. The results of a 3-year prospective study of children (2–35 months old) in Britain and Ireland with encephalitis and/or severe illness with convulsions and fever were linked to each childs vaccine history. Cases were reported via the British Paediatric Surveillance Units network. The self-controlled case-series method was used to investigate associations between immunization and acute potential adverse events. The risk periods investigated were 0 to 3 and 0 to 7 days post–diphtheria, tetanus, whole cell pertussis, Haemophilus influenzae type b or meningococcal C conjugate vaccine and 6 to 11 and 15 to 35 days post–measles, mumps, rubella vaccine. RESULTS. A total of 157 disease episodes from 155 children met the analytical case definition. There were 11 cases of herpes simplex encephalitis and 23 cases of primary human herpesvirus 6 and/or 7 infection. There was no evidence of a raised relative incidence of serious neurologic disease in any of the specified risk periods with the exception of a raised relative incidence of 5.68 in the 6–11 days after measles, mumps, rubella vaccine. Based on this relative incidence, between 3 and 6 of the 6 cases in this period were estimated to be attributable to the vaccine with a best estimate of 5. The 6 cases all had fever with convulsions lasting >30 minutes; in all but 1, there was complete recovery by discharge from hospital. Of the 5 patients who recovered, 1 had a concurrent primary human herpesvirus 6 infection and one a primary human herpesvirus 7. CONCLUSIONS. Six to 11 days after measles, mumps, rubella vaccine there is an increased risk of fever and convulsions lasting >30 minutes. All 6 of the episodes temporally related to immunization met the criteria for complex febrile convulsions. The estimated attributable risk of serious neurological disease was similar to that previously found for measles vaccine.

GM2 gangliosidosis in a UK study of children with progressive neurodegeneration: 73 cases reviewed

Aim  To report the demographic, phenotypic, and time‐to‐diagnosis characteristics of children with GM2 gangliosidosis referred to the UK study of Progressive Intellectual and Neurological Deterioration.

Clinical features of narcolepsy in children vaccinated with AS03 adjuvanted pandemic A/H1N1 2009 influenza vaccine in England.

The aim of this study was to investigate whether children in England with narcolepsy who received the ASO3 adjuvanted pandemic A/H1N1 2009 influenza vaccine (Pandemrix) differed clinically from unvaccinated patients.