cb MPA 2011

Methods	Person‐time cohort study, based on a case inventory of narcolepsy cases observed in the 6 Swedish countries between 2009 and 2010 in order to assess its possible association with exposure to pandemic flu monovalent vaccine (PANDREMIX) in children and adolescents, conducted by Medical Product Agency (MPA)
Participants	Cases of narcolepsy with cataplexy were identified from: departments of neurology, paediatrics, paediatric neurology, or paediatric psychiatry of hospitals, sleep laboratories and laboratories of clinical physiology, which perform multiple sleep latency tests (MSLT), MPA database on spontaneous ADR reports on narcolepsy Medical records were collected for cases which had been diagnosed or were under review during 2009 through 2010 2 external clinical experts in neurology/sleep disorders were commissioned by the MPA to review the medical records of all the collected cases and to classify (independently of each other) the diagnosis according to the American Academy of Sleep Medicine criteria for narcolepsy with catalepsy (see Safety) and to assess the onset of the narcolepsy disease through dating of the first symptom of narcolepsy. For the case of discrepancy a third review was performed by an external expert in paediatric neurology. In the preliminary study only cases occurred in Stockholm, Västra Götaland, Östergötland and Skåne countries in participants aged below 19 were considered, whereas the whole Swedish “under 19” age class was included in the whole study
Interventions	Immunisation with pandemic H1N1 vaccine “Pandremix” in the vaccination campaign that took place in Sweden between mid‐October 2009 and March 2010 Incident exposed cases occurred during the pandemic period (after October 1st, 2009) were defined vaccinated if they had the date of vaccination before the date of first symptom of narcolepsy (at least 1 vaccine dose). Cases were classified as non‐exposed when there was no exposure to vaccination or when vaccination had occurred after onset of symptoms or during the same month as onset of symptoms
Outcomes	Laboratory Not assessed Effectiveness Not assessed Safety Incidence of narcolepsy with catalepsy was compared between vaccinated and not vaccinated participants. Diagnosis in medical records was reviewed by 2 neurologists accordingly to the American Academy of Sleep Medicine diagnostic criteria for narcolepsy with catalepsy: Excessive daytime sleepiness occurring almost daily for at least 3 months Definite history of cataplexy, defined as sudden and transient (less than 2 minutes) episodes of loss of muscle tone, generally bilateral, triggered by emotions (usually laughing and joking) Diagnosis should, whenever possible, be confirmed by nocturnal polysomnography (with a minimum of 6 hours sleep) followed by a daytime MSLT: Mean daytime sleep latency 8 minutes or shorter, with 2 or more sleep onset in REM periods (the time from sleep onset to REM sleep should be less than 15 minutes in at least 2 naps) Alternatively, hypocretin‐1 concentrations in the cerebrospinal fluid 110 pg/ml or lower, or a third of mean control values The hypersomnia is not better explained by another sleep disorder, medical or neurological disorder, mental disorder, medication use, or substance use disorder Altogether 87 cases of narcolepsy with catalepsy were confirmed after review of the 135 cases initially identified. Out of them, 69 were vaccinated before onset of the first symptom, 7 were not vaccinated or had symptoms onset before vaccination, a further 6 were also not vaccinated and thus had onset of first symptoms before January 1st, 2009 and were therefore excluded from the study. A further 5 cases were classified under “unknown vaccination status” because they had vaccination during the same month of onset
Funding Source	Government
Notes	In the preliminary registry‐based study, carried out on the population of four counties (Stockholm, Västra Götaland, Östergötland and Skåne) within which vaccination register and health care data were accessible and available, all participants registered in the respective county on October 1st 2009 without a known diagnosis of narcolepsy were followed until December 31st 2010, date of narcolepsy diagnosis, death or migration from the county, whichever came first. In the cohort of vaccinated participants the follow‐up time was defined as exposure from the date of vaccination until the end of follow‐up. Vaccinated participants contributed with exposure time in the UV cohort from October 1st to the date of vaccination. The incidence rates in the vaccinated and UV cohorts, respectively, were calculated as the number of persons diagnosed with an incident registration for narcolepsy in the health data bases, divided by the person years at risk. The relative risk, vaccinated versus UV cohorts, was calculated as the corresponding ratio of incidence rates. Exact CIs for relative risk were calculated through exact CIs for binomial proportions. Since there is no nationwide vaccination register, it was not possible to calculate the risk time directly for the total vaccinated and non‐vaccinated cohorts in all of Sweden. However, risk time was extrapolated from the registry based study, using data from four counties/regions of Sweden. It is not clear how the 5 cases with symptom onset and vaccination within the same month has been considered. They has been initially classified as not vaccinated (see page 5, lines 4 to 5 from the top, i.e. 9 vaccinated cases vs 7+5 not vaccinated cases), has been simply excluded from the main analysis (69 vaccinated cases vs 7 not vaccinated cases), then authors considers, erroneously, these 5 as part of the 7 unexposed in the “sensitivity analysis” (see page 6, 3rd paragraph from the top and page 7, 4th paragraph from the bottom). It would be useful to complete the sensitivity analysis considering the 5 with uncertain vaccine exposure among vaccinated first and among not vaccinated. The authors conclude that “These new results provide strengthened evidence that vaccination with Pandemrix during the pandemic period was associated with an increase in the risk for narcolepsy with cataplexy in children/adolescents 19 years and younger. Further research is urgently needed to explain the possible causative mechanisms”
Risk of bias
Bias	Authors' judgement	Support for judgement
PCS/RCS‐Selection Exposed cohort	Low risk	Secure record
PCS/RCS‐Selection Non Exposed cohort	Low risk	Secure record
PCS/RCS‐Comparability	Unclear risk	Retrospective study
PCS/RCS‐Assessment of Oucome	Low risk	Secure record
Summary assessments	Low risk