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									Neurologic Disorders After Measles, Mumps-Rubella Vaccination
Pediatric Journal Club Dr. Khalid Yarouf 11 Nov 2002
4MedStudents.com

Overview
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Title: Neurologic Disorders After Measles, Mumps-Rubella Vaccination Journal: Pediatrics 5 November 2002. Center: Hospital for Children and Adolescents, Helsinki, Finland

Dr. Khalid Yarouf

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Outline
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Introduction of the study. Methods.
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Results. Discussion. Limitations of the study. Conclusion.

Subjects. Data collection. Definition of the risk interval. Statistical methods.

Dr. Khalid Yarouf

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Introduction
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Worldwide, the incidences of measles, mumps, and rubella have been significantly reduced by MMR vaccination. Concurrently, the severe Cx of these diseases have become less apparent, and more attention has been focused on vaccine-related adverse events.

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Why are we afraid of measles and mump?
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Measles virus causes a variety of CNS syndromes = meningitis, encephalitis, measles inclusion body encephalitis (MIBE), subacute sclerosing panencephalitis (SSPE), & acute disseminated encephalomyelitis. Before the introduction of vaccination, mumps was the most common cause of viral encephalitis in children in several countries.
Dr. Khalid Yarouf 4

Introduction (Con’t)
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Why this research?
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Cases of meningitis, encephalitis, MIBE, and acute disseminated encephalomyelitis have been reported after MMR vaccinations, but in most cases the link has remained unclear. An association was suggested on the basis of clustering of cases of encephalitis after vaccination, but the report rates were indistinguishable from the background rates (i.e. the rates of unvaccinated children). More recently, MMR vaccine has been suggested as one reason for the increasing incidence of autistic disorder.
Dr. Khalid Yarouf 5

Methods (Subjects)
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In Finland, MMR vaccination of children aged 14 to 18 months and 6 years began in 1982. From November 1982 to June 1986, 561 089 vaccines were enrolled in a surveillance study by the National Public Health Institute. Of the enrolled vaccines, 535 544 (95%) were 1 to 7 years old at the time of vaccination and are included in the current analysis. MMR was the only vaccine in use in Finland during the enrollment. This vaccine contains the more attenuated Enders-Edmonston strain of measles virus, the Jeryl Lynn strain of mumps, and the Wistar RA 27/3 strain of rubella virus.
Dr. Khalid Yarouf 6

Methods (Data collection)
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Vaccination data of every 1- to 7-year-old child in the vaccination register was linked individually with data from the hospital discharge register. Hospitalizations because of encephalitis, encephalopathies, aseptic meningitis, or autistic disorder were identified. Exclusion criteria: Patients hospitalized for encephalitis or meningitis with a defined cause unrelated to measles, mumps, or rubella infections or to MMR vaccination. For autism, only the first hospital visit during the study period was included in the survey. In addition, hospitalizations because of IBD during 1982-1995 were evaluated for children with autism.
Dr. Khalid Yarouf 7

Methods (Con’t)
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Of the patients hospitalized because of encephalitis or meningitis within 3 months of MMR vaccination, the exact dates of immunization were collected from the patients' medical records or personal vaccination cards filed at health centers. Cases meeting the diagnostic criteria listed in Table 2 were analyzed.
Dr. Khalid Yarouf

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Methods (Con’t)
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Definition of the Risk Interval
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Incubation periods of measles (8-12 days), mumps, and rubella (both 16-18 days) are expected to be similar for the vaccine viruses. To enable sufficient follow-up for encephalitis and aseptic meningitis, a 3-month period postvaccination was used as the risk interval. Because of the undefined latency until manifestation of the symptoms of autistic disorders, the follow-up was extended to the end of the study period for every vaccine, irrespective of the date of immunization. The data were analyzed using the x2 test, and the P values of < 0.05 were considered significant.
Dr. Khalid Yarouf 9

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Statistical Methods
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Results
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Of the 535 544 vaccinees, 199 were hospitalized for encephalitis, 161 for aseptic meningitis, and 352 for autistic disorders.

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Encephalitis:
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Of the 199 children who were hospitalized:
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9 had encephalitis within 3 months of vaccination. 80 got the disease then received MMR vaccine. 110 were hospitalized during the interval between vaccination & hospitalization which exceeded 3 months.

Dr. Khalid Yarouf

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Results (Con’t)
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In 8 of the 9 cases, a very short interval of 2 days or an interval exceeding 1 month between vaccination & hospitalization makes an association with immunization very unlikely. The incidence of encephalitis of undefined cause among all 1- to 7- year-old children decreased by 35% from 19.9 / 100 000 in 1983 to 13 / 100 000 in 1995.
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Results (Aseptic meningitis)
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Of the 161 children hospitalized, the following developed aseptic meningitis:
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Of the unvaccinated children, 30 were hospitalized also for aseptic meningitis. No significant increase in the number of meningitis cases was observed within 3 months post-vaccination (P = 0.57). As with encephalitis, as association between vaccination and meningitis occurring on day 2 or over 1 month after vaccination in 7 patients seems very unlikely.
Dr. Khalid Yarouf 12

10 within 3 months of MMR vaccination. 41 vaccinated after hospitalization. 110 hospitalized after the 3-month interval.

Resuls (Con’t)
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The incidence of meningitis of undefined cause in 1- to 7-year-old children decreased by 25% during the study period from 10.17 / 100 000 in 1983 to 7.71 / 100 000 in 1985

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Autistic disorders
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309 were hospitalized after vaccination. When the shortest possible intervals between MMR vaccination & the day of hospitalization were assessed, these ranged from 3 days to 12 years and 5 months. No distinguishable clustering was detected in the intervals from vaccination to the hospitalization.
Dr. Khalid Yarouf 13

Results (Con’t)
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Figure 3
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The number of hospital admissions remained relatively steady during the first 3 years  then gradually decreased, because of the increasing age of the vaccinees.

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Of the children hospitalized for autism, none made hospital visits because of IBD in 1982-1995.
Dr. Khalid Yarouf 14

Discussion
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Linkage of vaccination records of over 500 000 children with a national hospital discharge register found NO EVIDENCE of an increased risk of encephalitis or aseptic meningitis associated with MMR vaccination. On the contrary, during 1983-1985 the incidence of encephalitis of undefined cause among 1- to 7-yearold children decreased by 35% and the incidence of aseptic meningitis by 24%. In addition, there is NO EVIDENCE for the hypothesized link between MMR vaccination, autism, and IBD. Compared to a study from the US and Canada, a definite link between the vaccine and encephalitis was not established.
Dr. Khalid Yarouf 15

Discussion (Con’t)
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Several case reports of encephalitis occurring after monovalent or combination MMR vaccination exist, but in most cases causality has not been proved. However, measles virus with a nucleotide sequence identical to the more attenuated EndersEdmonston vaccine strain was isolated from brain tissue of immunodeficient patient developing MIBE 8 months after MMR vaccination. Development of SSPE has been described 3 weeks after live measles vaccination in a child with no Hx of measles. Reassuringly, measles immunization has dramatically diminished the incidence of SSPE.
Dr. Khalid Yarouf 16

Discussion (Con’t)
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Rare cases of meningitis have been reported after vaccination with the Jeryl Lynn mumps strain, but causality has not been proved in any of the cases! Other studies from the US and the UK showed NO definite link between the vaccine and autism. Although the first symptoms are typically manifested at the age of MMR vaccination, there's NO epidemiologic evidence that immunization causes autism.
Dr. Khalid Yarouf 17

Limitations of the study
1. 2. No access to data of outpatient visits. Exact incidence of autism could not be defined with their approach, because autism develops insidiously over long periods of time, or the disorder is present at birth but not obvious until later, and the first hospitalization does not indicate the timing of the occurrence of symptoms. As the coverage of MMR vaccination register was not complete, some children regarded as unvaccinated may actually have been immunized during the study period.
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Conclusion
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No association between MMR vaccine and encephalitis, aseptic meningitis, and autism.

Dr. Khalid Yarouf

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