12. Safety: encephalitis or encephalopathy.

Study ID and design	Population	Outcome definition	Exposure MMR/MMRV vaccine	Findings	Crude data	Estimate (95% CI)
bb‐Ray 2006 Case‐control	Cases: (n = 452) children aged 0 to 6 years with outcome of interest. Controls: (n = 1280) matching for HMO, location, age within 7 days, sex, and length of enrolment in health plan	1. Encephalopathy: acute generalised disturbance of brain function requiring hospitalisation and consisting of coma or stupor that cannot be attributed to medication or postictal state. Such cases must have altered consciousness, delirium, obtundation and/or confusion. 2. Reyes syndrome: clinical symptoms of acute encephalopathy with altered level of consciousness as well as: absence of inflammatory changes in cerebrospinal fluid as indicated by 5 white blood cells/mm3 or brain histology showing cerebral oedema without perivascular or meningeal inflammation, plus evidence of hepatitis or liver failure documented by a 3‐fold or greater elevation in serum glutamic oxaloacetic transaminase, serum glutamate pyruvate transaminase or serum ammonia or fatty changes of hepatocytes on liver biopsy or autopsy, plus absence of other aetiologies for cerebral or hepatic abnormalities. 3. Encephalitis/encephalomyelitis: evidence of acute neurologic disease presenting with non‐specific signs such as fever, seizures, altered consciousness, headache, vomiting, meningismus, or anorexia. Multifocal involvement of the central nervous system and evidence of cerebrospinal fluid inflammation (7 white blood cells/mm3) were required. Diseases with other known aetiologies were excluded. For data analysis, all cases were stratified on the basis of their aetiology: known, unknown, suspected but unconfirmed (this last when a diagnosis was not confirmed by a diagnostic test). Hospitalisation cases for encephalopathy, Reyes syndrome, or encephalitis (primary or secondary diagnosis) in children aged 0 to 6 years, members of the health plan of 4 HMOs in the USA, and occurred between 1 January 1981 and 31 December 1995, were considered as possible cases. Hospital charts were reviewed by abstracter (not blind to vaccination status of the cases) who included in first instance encephalitis diagnoses by a neurologist with clear aetiology and excluded all cases with a condition other than encephalopathy. All other neurologic cases were reviewed by a neurologist (blind to vaccination status of the cases) and included as cases if they met case definition (see column on the right).	Vaccine exposure time interval relative to onset of encephalopathy (a) 7 to 14 days (b) 0 to 14 days (c) 0 to 30 days (d) 0 to 60 days (e) 0 to 90 days MMR type not reported. Vaccination status of both cases and controls was ascertained from medical records.	The findings do not support a conclusion that there is an increased risk of encephalitis or encephalopathy after MMR vaccination. Although this study is large, encephalopathy is rare and thus it is not possible to exclude completely a small increase in the risk of encephalopathy after MMR vaccination. However, if such an increased risk exists, the absolute risk is extremely small and it is much lower after vaccination than after measles. This corresponds roughly to an all‐cause incidence (not an attributable risk) of 1 in 200,000 after MMR, a rate that is not statistically different from background. Consequently, our results support the continued use of DTP and MMR vaccines.	N cases vaccinated/ N cases versus N controls vaccinated/ N controls (a) 1/452 versus 6/1280 (b) 1/452 versus 7/1280 (c) 4/452 versus 13/1280 (d) 8/452 versus 33/1280 (e) 15/452 versus 44/1280	OR (95% CI) ‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐ (a) 0.40 (0.05 to 3.46) (b) 0.35 (0.04 to 2.95) (c) 0.85 (0.27 to 2.68) (d) 0.64 (0.27 to 1.50) (e) 0.98 (0.47 to 2.01) adjusted estimates
db‐Makela 2002 Person‐time cohort	Children immunised aged 1 to 7 years old. Between November 1982 and September 1986 n = 535,544 n = 119 children hospitalised for encephalitis (MMR vaccine was administered before the disease), and only 97 between 0 and 24 months after MMR vaccination.	Encephalitis: acute or subacute onset of neurologic symptoms. Presence of neurologic symptoms or findings (clinical or laboratory, e.g. microbiological, electroencephalographic, computed tomographic) indicative of involvement of the brain parenchyma, such as coma, seizures, focal neurologic findings, or mental function impairment. Absence of evidence of other diagnoses, including non‐inflammatory conditions, and no microbiological or other laboratory findings suggestive of a non‐viral infection. When pleocytosis in CSF is present, the term encephalitis is used, implying an inflammatory response within the brain. The presence of normal CSF findings does not preclude the diagnosis if the other criteria are satisfied. Encephalopathy: clinically resembles encephalitis but no inflammatory response is evident. Chronic encephalopathy: persistence of acute findings usually over several months. The National Hospital Discharge Register was consulted by using the following ICD‐8 codes: 065.99, 066.01, 066.02, 072.01, 292.20, 292.38, 292.39, 323.00, 323.01, 323.08, 323.09, 781.70, 999, 999.10. Medical records of hospitalised participants were reviewed (in order to evaluate possible other causes of the event) and their correspondence to diagnostic criteria (see column on the right) examined.	Exposure risk period: (a) 0 to 3 months after vaccination Control period: (b) 4 to 24 months Observation period: (c) 0 to 24 months MMR II vaccine (Merck & Co, West Point, PA) measles: Enders‐Edmonston mumps: Jeryl Lynn rubella: Wistar RA 27/3 Vaccination data were assessed through vaccination register.	Not significant excess of hospitalisation within 3 months of vaccination (P = 0.28) Incidence of encephalitis of undefined cause amongst 1‐ to 7‐year‐old children decreased from 19.9 per 100,000 in 1983 to 13.0 per 100,000 in 1985.	(a) 9 cases (3 months) (b) 88 cases (21 months) (c) 97 cases (24 months)	rr (95% CI)* 0.72 (0.36 to 1.42) (*)rate ratio amongst risk period (b) and control period (a)
db‐Ward 2007 Self‐controlled case series	Children aged 2 to 35 months (immunised with MMR; NK) with outcome of interest diagnosed between October 1998 and September 2001 (n = 107)	Onset of illness: day of hospital admission Fever: temperature of 37.5 °C; the questionnaire asked whether there was a fever and also for the maximum temperature recorded at any site by any method Encephalopathy: a depressed or altered level of consciousness Case definition of serious neurologic disease: any child 2 to 35 months old with a severe illness with fever and convulsions (see Table 35) and/or encephalitis was included Encephalitis: encephalopathy for at least 24 hours and at least 2 of the following: fever, convulsions, focal neurologic findings (≥ 24 h), pleocytosis (> 5 leukocytes per μL CSF), characteristic abnormal results of neuroimaging (computerised tomography or MRI), herpes simplex virus nucleic acid (or nucleic acid of any other virus proven to cause encephalitis) in CSF; or postmortem histologic evidence of encephalitis Exclude: viral (aseptic) meningitis without encephalopathy the following confirmed causes were excluded: hypoxic/ischaemic; vascular; toxic; metabolic, neoplastic, traumatic and pyogenic infections uncomplicated convulsions or a series of convulsions lasting < 30 min immunocompromised children Cases of suspected encephalitis and/or severe illness with fever and convulsion occurring in children aged between age 2 and 35 months through Britain and Ireland were identified by consultant paediatricians taking part in a survey (October 1998 to September 2001) and notified to the British Paediatric Surveillance Unit. Details about neurologic illnesses were collected by reporting paediatricians by means of a detailed questionnaire. For diagnostic purposes, saliva, blood, and cerebrospinal samples were also collected. Questionnaires were reviewed by study investigators in order to assess whether reported cases corresponded to an analytical case definition taking into account severe illness with fever and convulsion and encephalitis (see column on the right).	Exposure risk period: 15 to 35 days after immunisation, because this is the incubation period for postinfectious encephalitis induced by wild‐type measles and for aseptic meningitis induced by the Urabe vaccine strain mumps MMR vaccine type, not reported. Immunisation history of cases was obtained by the Immunisation Department of the Health Protection Agency (other than MMR vaccine, the study also considers DTP, Hib, and MenC vaccines). Only cases with known vaccination history were included in the analysis.	Regarding MMR vaccine, there was no evidence of a raised relative incidence of serious neurologic disease 15 to 35 days after immunisation.	Within 15 to 35 days with concurrent primary HHV‐6 or HHV‐7 infection (a) all (5 cases) (b) no (4 cases) (c) yes (1 case)	rr (95% CI) (a) 1.34 (0.52 to 3.47) (b) 1.52 (0.52 to 4.41) (c) 0.86 (0.10 to 7.23)

incidence: cases/PT
CI: confidence interval
CSF: cerebrospinal fluid
DTP: diphtheria, tetanus, pertussis vaccine
Hib: Haemophilus influenzae b vaccine
HHV: human herpes virus
HMO: health maintenance organisation
ICD: International Classification of Diseases
MenC: meningococcus C vaccine
MMR: measles, mumps, rubella vaccine
MMRV: measles, mumps, rubella, and varicella vaccine
MRI: magnetic resonance imaging
PT: person‐time
OR: odds ratio
RR: risk ratio (relative risk)
rr = rate ratio (relative incidence; incidence rate ratio)