Lesley Stellitano

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 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.

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.

The clinical presentation of mitochondrial diseases in children with progressive intellectual and neurological deterioration: a national, prospective, population-based study

Aim  Our aim was to study the clinical presentation, mode of diagnosis, and epidemiology of mitochondrial disorders in children from the UK who have progressive intellectual and neurological deterioration (PIND).

Pandemic A/H1N1 2009 influenza vaccination, preceding infections and clinical findings in UK children with Guillain–Barré syndrome

Objective To record clinical findings in all new cases of Guillain–Barré syndrome (GBS) or Fisher syndrome (FS) in UK children in the 2 years following September 2009 and determine the proportion temporally associated with recent infections, pandemic H1N1 (2009) strain influenza vaccination or seasonal influenza vaccination. Design A prospective UK-wide epidemiological study using the British Paediatric Surveillance Unit system. Patients Children aged 16 years or less meeting the Brighton Collaboration criteria for GBS or FS. Results 112 children with GBS (66 boys and 46 girls) and 3 boys with FS were identified in 2 years. All but one recovered sufficiently to go home. The annual UK incidence rate of GBS in patients less than 15 years old was 0.45/100 000, similar to other countries. There was evidence of infection in the 3 months preceding onset in 92/112 GBS and 3/3 FS cases. Of those living in England, 7 cases received pandemic A/H1N1 2009 influenza vaccination before GBS symptom onset (3/7 were within 6 months including 1 within 3 months); 2 children received 2010/2011 seasonal influenza vaccination within 6 months of GBS onset. The numbers vaccinated were not significantly greater than expected by chance. Conclusions The outcome for childhood GBS and FS after 6 months was better than reported in adults. Most UK GBS and FS cases had infections in the preceding 3 months. When considering the children living in England, there was no significantly increased risk of GBS after pandemic A/H1N1 2009 influenza vaccination or 2010/2011 seasonal influenza vaccination.

The PIND study found no association between vaccination and autism in mitochondrial disease – correction

We noted that in two children with progressive intellectualand neurological deterioration there was a reported temporalassociation between immunization and the onset of clinicalsymptoms attributed to mitochondrial disease. In one casethese symptoms commenced in the same week as administra-tion of triple vaccine (diphtheria⁄pertussis⁄tetanus);* in theother case symptoms occurred 2 weeks after MMR vaccina-tion in a child with a Norwalk virus infection.In three other children with mitochondrial disease causingPIND there were reports of autistic features. In none of thesethree cases was there any mention of deterioration in associa-tion with a vaccination.The PIND study questionnaire asked about presentingsymptoms and the subsequent clinical course of childrenreported to the study, which is how we obtained the relevantclinical information. However, the questionnaire did notspecifically ask about an association between vaccination andthe onset of clinical symptoms, nor did it ask about autism, soour conclusions about these data have to be guarded.In the same issue of DMCN there was an excellent com-mentary on our paper by Mark Sharrard.

I5 Swine ‘flu vaccination – the good news and the bad news

Background Guillain-Barré syndrome (GBS) can be associated with ‘swine ‘flu’ vaccination, so in 2009 surveillance for GBS and Fisher syndrome (FS) was established via the British Paediatric Surveillance Unit (BPSU) before UK immunisation against pandemic H1N1 influenza commenced. Then in 2010 there were reports from Scandinavia of an association between narcolepsy and Pandemrix (a monovalent pandemic strain ‘flu vaccine containing the oil-in-water adjuvant AS03). To investigate this in the UK it was necessary to identify retrospectively children who had been diagnosed with narcolepsy from before the 2009 pandemic: the BPSU system was not suitable for this. Results BPSU GBS study: 112 children with GBS (66 boys and 46 girls) and 3 boys with FS were identified between September 2009 and September 2011 inclusive. There was an infection in the 3 months preceding onset in 92/112 GBS and 3/3 FS cases. In England, 7 had received pandemic A/H1N1 seasonal influenza vaccine before GBS onset (3/7 within 6 months, including 1 within 3 months). The number of GBS cases who had been vaccinated was no greater than expected by chance. Narcolepsy study: 16 sleep centres and paediatric neurology centres in England identified 75 cases aged 4–18 years with narcolepsy onset after January 1 st 2008. Eleven were vaccinated before onset; seven within 6 months. The odds ratio for vaccination at any time prior to onset in cases diagnosed by July 2011 was 14·4 (95% confidence intervals 4·3 to 48·5) and 16·2 (3·1 to 84·5) for vaccination within 6 months of onset. The relative incidence in a self-controlled case series analysis with onset from October 2008 to December 2010 was 9·9 (2·1 to 47·9). The attributable risk was between 1 in 57 500 and 1 in 52 000 doses. Conclusion The BPSU GBS study found no increased risk of GBS in those children living in England after pandemic A/H1N1 2009 influenza vaccine or 2010/2011 seasonal influenza vaccine. In contrast, the narcolepsy study indicated that there was a causal association between vaccination with AS03 adjuvanted pandemic A/H1N1 vaccine and narcolepsy, confirming reports from Finland and Sweden.

The clinical presentation and diagnosis of juvenile neuronal ceroid lipofuscinosis: a prospective national study

Aims This prospective study performs active surveillance for progressive intellectual and neurological deterioration (PIND) among children in the UK via the British Paediatric Surveillance Unit system. Methods Data were obtained between January 1995 and December 2009 via reporting paediatricians. The authors analysed the clinical presentation and mode of diagnosis of PIND cases with juvenile neuronal ceroid lipofuscinosis (JNCL). Results 47 JNCL patients had been identified by the study (27 female, 20 male). Median age at first symptom: 5 years 11 months. Median age at presentation to the reporting paediatrician: 7 years 9 months. Presenting symptoms were visual failure 40 (85%), developmental delay/learning difficulties 28 (60%), behavioural problems 17 (36%), seizures 10 (21%), memory loss 8 (17%), extrapyramidal signs 6 (13%) and gait disturbance/ataxia 5 (11%). Seizures and gait disturbance became evident in more cases later. MRI brain imaging was carried out in 18, with atrophy in five and subtle white matter changes in two. EEGs were performed in 2521 had abnormalities, usually slow wave and spike/wave discharges. 35 patients had ERGs: all were abnormal. 31 had VEPs: all were abnormal. Genetic Results Out of the 47, 31 had genetic studies that were positive: 30 had CLN3 mutations (24 homozygous and two heterozygous, four not known) and one had CLN5 mutations (compound heterozygote). 19/31 had the characteristic fingerprint or curvilinear inclusions on histological examination of biopsy specimens. Of the 16 who did not have genetic studies, 13 had characteristic histological findings on rectal, skin or muscle biopsy, three had a characteristic clinical picture plus vacuolated lymphocytes. Conclusion This population-based study provides helpful information about JNCL. The clinical presentation was quite characteristic, with early visual failure in the majority of cases. Paediatricians saw cases about 2 years after symptoms first developed. MRI scans were abnormal in a minorityhowever, ERG/VEP studies were abnormal in all cases where results were available. An increasing number are diagnosed by DNA studies: this trend is likely to continue, resulting in re-classification of cases by genetic abnormality rather than by clinical/biopsy findings.