Measles Vaccines Reactions - SSPE

[Guest guest]

" Although application of new scientific methods, such

as RNA sequencing, could be used to describe more

completely the virus that causes SSPE, the well-known

genetic alterations of the virus from wild-type

measles virus will confound interpretation of the data

and make it unlikely that investigators will be able

to determine whether there is an independent

association between measles vaccine and the

development of SSPE. "

This makes no sense to me. If we know the genetic

alterations that distinguish wild and vaccine measles

RNA, wiuldn't that clear up the confusion over which

caused the SSPE?

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[Guest guest]

Measles Vaccines Reactions - SSPE

Pages 135 - 142

http://books.nap.edu/books/0309048958/html/135.html#pagetop

SUBACUTE SCLEROSING PANENCEPHALITIS

Clinical Description

Subacute sclerosing panencephalitis (SSPE) is a rare subacute

encephalitis accompanied by demyelination. The entire course of SSPE

may be one of slow progressive deterioration, but variable periods of

remission can occur. The usual duration is about 12 to 24 months to a

vegetative state or death. A more complete discussion of SSPE can be

found in Chapter 3.

History of Suspected Association

Laboratory findings implicate a measles-like virus as the cause of

SSPE. Epidemiologic data have also linked SSPE to prior measles infection.

The first report of SSPE in a patient with a negative history for

measles but a positive history of vaccination with live attenuated

measles vaccine was reported in 1968 (Schneck, 1968). The child had

received measles vaccine with immune globulin 3 weeks prior to the

onset of symptoms. The clinical course accelerated 10 weeks after

vaccination, and the child died 18 months after vaccination.

Serologic studies were not performed, but postmortem histologic

examination of the brain supported a diagnosis of SSPE. Several more

case reports of SSPE in children negative by history for measles but

positive for receipt of the measles vaccine followed and are

described in more detail below.

The dramatic decline in the number of measles cases in the United

States from 1964 to 1968 paralleled a decline in the number of cases

of SSPE starting in the early 1970's. Only 4.2 new cases of SSPE per

year, on average, were reported from 1982 to 1986 (Dyken et al.,

1989). This is in contrast to the 48.6 new cases of SSPE per year, on

average, reported from 1967 to 1971. This decline is attributed to

the increased use of measles vaccine, introduced in the United States

in 1963. However, a report of data from the National Registry for

Subacute Sclerosing Panencephalitis showed that the proportion of

newly diagnosed cases of SSPE occurring in children identified by

history as vaccinated against measles increased approximately

threefold from 1967 to 1974 (Modlin et al., 1977). These data are

discussed in more detail below.

The first publication in 1972 of data in the newly established

National Registry for Subacute Sclerosing Panencephalitis in the

United States reported 14 patients (of a total of 219 records in the

registry) who had received a measles vaccine prior to the onset

between 1960 and 1970 of SSPE (Jabbout et al., 1972). Six of the 14

patients were reported to have had measles prior to the onset of SSPE

as well. The interval between vaccination and the onset of SSPE was 1

year or more in all 14 cases. The specific type of measles vaccine

administered is not known.

The committee was charged with investigating a possible causal

relation between measles vaccine only and SSPE.

Evidence for Association

Biologic Plausibility

SSPE is a recognized sequela of measles infection, and it is

biologically plausible that it could occur after administration of

the live attenuated viral vaccine. Identification of the cause of

SSPE as wild-type or vaccine-strain measles virus has not been

possible. The viruses isolated from patients with SSPE differ from

the known measles viruses. The viruses may have become altered by the

prolonged residence in the brains of the patients, or they may have

been different at the time of the original infection.

Case Reports, Case Series, and Uncontrolled Observational Studies

The first published case report of SSPE in a child with a history of

vaccination with live attenuated measles vaccine appeared in 1968 and

was described above (Schneck, 1968). In the following 5 years,

several more reports of SSPE in individuals vaccinated against

measles appeared (Cho et al., 1973; Gerson and Haslam, 1971; Jabbour

et al., 1972; Klajman et al., 1973; Landrigan and Witte, 1973;

et al., 1970; Payne et al., 1969). These reports represented a total

of 22 patients with SSPE, 7 of whom had a history of both measles and

measles vaccination (Gerson and Haslam, 1971; Jabbour et al., 1972).

The other 15 patients had a negative history for measles and a

positive history for receipt of live attenuated measles vaccine (Cho

et al., 1973; Jabbour et al., 1972; Klajman et al., 1973; Landrigan

and Witte, 1973; et al., 1970; Payne et al., 1969; Schneck,

1968). For two of those 15 patients, exposure to measles virus was

probable, but clinical measles was not recorded (Landrigan and Witte,

1973; et al., 1970). The latency between vaccination against

measles and the onset of SSPE symptoms ranged from 3 weeks (Landrigan

and Witte, 1973; Schneck, 1968) to 5 years (Cho et al., 1973).

The absence of prevaccination serology and the inability to

characterize the cause of SSPE as wild-type or vaccine-strain measles

virus in all cases preclude, as discussed below, a determination that

the SSPE was caused by administration of the live attenuated measles

vaccine. A negative history of natural measles disease in unimmunized

persons is always suspect because measles infection can occur

subclinically without rash. No case reports of SSPE definitively show

that the cause of SSPE in a specific patient was the vaccine-strain

virus and not the wild-type virus.

In 1978 the question about SSPE and measles vaccine surfaced again in

response to a report concerning a boy who at age 7 years showed signs

of SSPE, including deterioration in school performance, incontinence,

and forgetfulness (Dodson et al., 1978). Within a few weeks of

receiving live attenuated measles vaccine at age 8 years, the

patient's symptoms progressed. At 2.5 to 3 months after vaccination,

the patient died. SSPE was diagnosed by high measles virus titers in

serum and CSF and a high ratio of immunoglobulin G/albumin in serum

and CSF. At age 13 months he had suffered a mild illness considered

by history to be measles. The authors hypothesized that the measles

vaccine accelerated an already evolving SSPE.

The National Registry for Subacute Sclerosing Panencephalitis was

founded in 1969, in response to an interest in the effects of measles

vaccine on the incidence of SSPE (Schacher, 1968). Originally housed

at the University of Tennessee Center for Health Sciences, it now

resides at the University of South Alabama. The registry now includes

data on more than 575 patients ( R. Dyken, University of South

Alabama, Mobile, personal communication, 1993). The number of new

cases of SSPE documented in the registry decreased from 46 in 1967 to

33 in 1972 to 13 in 1974 (Modlin et al., 1977). The average number of

new reports of SSPE per year from 1982 to 1986 was 4.2 (Dyken et al.,

1989) and is now about 1, although underreporting is suspected (

R. Dyken, University of South Alabama, Mobile, personal communication, 1993).

Analysis of 375 confirmed cases of SSPE that occurred in the United

States from 1960 to 1974 (Modlin et al., 1977) demonstrated a

decreasing incidence of SSPE beginning in the early 1970's. From 1967

to 1970 the proportion of new cases of SSPE associated with measles

vaccine was less than 13 percent, but it increased to 20.6 percent in

1973 and 38.5 percent in 1974. This prompted the authors to note:

Although far from conclusive, the data presented here suggest that

live, attenuated measles vaccine virus may be capable of contributing

to the pathogenesis of SSPE. However, the risk of SSPE following

vaccination, if any, appears less than the risk following natural

measles (Modlin et al., 1977, p. 511).

A review of the data in the registry of patients with SSPE whose

onset occurred up to 1986 (Dyken et al., 1989), which included the

375 patients described by Modlin et al. (1977) in the study described

above and 200 additional patients, confirmed the continuing decline

in the incidence of SSPE and the increase in the proportion of

patients with SSPE who had a history of measles vaccination.

Reports of patients with SSPE from other countries after the

institution of measles immunization campaigns have supported a role

for measles disease in the pathogenesis of SSPE. The very high levels

of hemagglutination inhibition (HAI) antibody in the serum and CSF of

100 patients with SSPE observed in Tehran, Iran, between 1977 and

1982 (Mirchamsy, 1983) compared with the HAI antibody levels in

patients known to have been vaccinated against measles suggest that

these patients had naturally acquired measles. Similarly, all 70

patients with SSPE reported to the Virusdiagnostic Laboratory in

Stuttgart, Germany, between 1967 and 1978 were negative for measles

vaccination by history (Enders-Ruckle, 1978). Of 26 patients with

documented SSPE in Northern Ireland between 1965 and 1985, none had a

history of measles vaccination (Morrow et al., 1986). Beersma and

colleagues (1988) described 77 patients with SSPE in The Netherlands

whose onset of symptoms occurred between 1976 and 1986. Only two of

the patients had received a measles vaccine. One of the two patients

developed clinical measles 1 week after vaccination and SSPE 9 years

later. The other child developed SSPE 1.5 years after vaccination

against measles. Prior measles virus infection could not be ruled

out. Eleven of 215 patients with SSPE identified in Japan between

1966 and 1985 had received measles vaccine but had not had measles

virus infection by history. A total of 184 patients had a history of

measles virus infection but not vaccination against measles (Okuno et

al., 1989).

There are no reports of SSPE in VAERS (submitted between November

1990 and July 1992), nor is there a discussion of SSPE in the

surveillance reports from the data base of the Monitoring System for

Adverse Events Following Immunization (MSAEFI), which preceded VAERS.

Controlled Observational Studies

Because SSPE is such a rare condition, study of its etiology is best

done by using a case-control design. Patients known to have SSPE are

compared with individuals without SSPE to determine whether the

proportions of certain characteristics or factors thought to be

disease related are similar in the two groups. In this way, a number

of possible etiologic factors can be investigated in a single study.

In the years between the two reviews of the data in the SSPE registry

discussed above, a case-control study of patients in the SSPE

registry was reported (Halsey et al., 1980). Fifty-two patients with

SSPE were compared with controls (49 playmates and 49 hospitalized

children) matched for age, sex, and race. Children with SSPE were

more likely than their age-matched controls to have had measles (odds

ratio [OR], 7; 95% confidence interval [95% CI], 2.5 to 19.6), but

they were less likely than controls to have received measles vaccine

(OR, 0.28; 95% CI, 0.11 to 0.70). The age of infection with measles

virus for children with SSPE was significantly less than that for

controls who had measles. There was no difference in age at the time

of vaccination between those subjects and controls who did not have a

prior measles infection. The same proportion of cases as controls had

more than one measles vaccination.

If the etiology of SSPE has changed over the years such that a

proportion of all cases were due to the vaccine, then the demographic

and epidemiologic characteristics of the SSPE cases would be expected

to change as well. Two such ecologic studies have been reported. When

U.S. patients whose SSPE was diagnosed between 1956 and 1975 were

compared with those whose SSPE was diagnosed between 1976 and 1986,

there was no difference in the ratio of males to females or in the

proportion of African Americans with SSPE (Dyken et al., 1989). The

question of latency was assessed by dividing the patients into three

groups: those with a history of measles only, those with a history of

both measles and measles vaccination, and those with a history of

measles vaccination only. The latency to the onset of SSPE for each

of the three groups increased between the periods of 1956-1966 and

1980-1986. The latency to the onset of SSPE for the group with a

history of measles vaccine only was shorter than the latencies for

the groups with a history of measles, but this difference was not

statistically significant.

Similar analyses were done for cases of SSPE in Romania. Cernescu et

al. (1990) compared 50 patients whose SSPE onset was in 1978-1979

with 62 patients whose SSPE onset was in 1988-1989. The patients in

the 1978-1979 cohort were diagnosed before the national measles

immunization program in Romania was implemented in 1979. For the

1988-1989 cohort, they found an increased mean age at the time of

onset (6.1 versus 12.1 years) and a difference in the ratio of males

to females (2.7:1 versus 0.76:1). They also reported that 76 percent

of the cases of SSPE from the 1978-1979 cohort reported a primary

measles infection at less than 2 years of age, compared with only 47

percent of the 1988-1989 cohort. The mean interval from the time of

measles to the onset of SSPE also increased, from 54 to 106 months,

as had the proportion of cases with extreme levels of measles

antibody (36 versus 88.7 percent).

Controlled Clinical Trials

No controlled clinical trials of measles vaccination have provided

data on the incidence of SSPE. The Medical Research Council of the

United Kingdom reported follow-up data on the incidence and

complications of wild-type measles infection from a randomized trial

of 36,000 patients who received either live measles vaccine or killed

vaccine followed later by live measles vaccine or no vaccine.

Follow-up was for up to 4 years and 9 months (Medical Research

Council, 1971). No mention was made of SSPE, indicating either that

there were no cases or that it was not an outcome that was examined.

Because other neurologic events were noted and because SSPE is such a

striking and serious disease, it is likely that any cases of SSPE

would have been reported, if they had occurred.

Causality Argument

There is no question that measles virus is causally related to SSPE.

Therefore, it is biologically plausible that there is a link between

receipt of live attenuated measles vaccine and SSPE. There is strong

evidence that if such an association does exist, it would be very

weak compared with the association between a naturally acquired

measles infection and SSPE. This evidence is mainly temporal; that

is, the incidence of SSPE has decreased dramatically in parallel with

widespread measles immunization. There have been only two new cases

of SSPE in U.S. citizens reported to the National Registry of

Subacute Sclerosing Panencephalitis since 1989 ( R. Dyken,

University of South Alabama, Mobile, personal communication, 1993).

Neither patient had a history of natural measles infection. One

patient was immunized at 15 months of age.

It is likely that at least some patients with SSPE have had

unrecognized measles infection prior to immunization, and that the

SSPE is directly related to this measles infection. Evidence for this

comes from Krugman et al. (1962), who reported that before the use of

measles vaccine, 15 percent of children whose parents reported no

history of measles were found to be immune to the infection. In

addition, data on 375 children in the National Registry for Subacute

Sclerosing Panencephalitis obtained from Modlin et al. (1977)

indicated that four children who had SSPE but no history of measles

or measles vaccination in fact had elevated measles virus antibody titers.

The data of Cernescu et al. (1990) showing that the characteristics

of patients with SSPE onset in 1978-1979 (prior to national measles

immunization) differ from those of patients with SSPE onset in

1988-1989 indicate a possible change in the nature of the disease

since the introduction of measles vaccine and a concurrent decrease

in the incidence of measles. If such a change is confirmed by other

studies (and this will be difficult, because there are so few new

cases of SSPE), it could indicate a different etiology for current

SSPE cases compared with those in the past. It could also merely

indicate a change in the time of life at which a child is infected

with measles and subsequently develops SSPE (e.g., since the

beginning of widespread immunization, perhaps only infants who are

too young for immunization are infected with measles virus and only a

proportion of these develop SSPE).

It will be difficult to obtain other evidence for a causal relation

between measles vaccine and SSPE. First, the number of cases of SSPE

in the United States is now so low that detection of even moderately

strong associations may be difficult. Second, the period of time

between infection with the measles virus and development of SSPE is

quite long, and if an association between measles vaccine and SSPE

exists, a similarly long latency (perhaps 10 years or more) would be

expected. Even if the latencies for the two conditions were different

and the difference were moderately large, the difference would be

difficult to detect because the range of time from measles infection

to SSPE is fairly long and the number of new cases of SSPE is low.

Although application of new scientific methods, such as RNA

sequencing, could be used to describe more completely the virus that

causes SSPE, the well-known genetic alterations of the virus from

wild-type measles virus will confound interpretation of the data and

make it unlikely that investigators will be able to determine whether

there is an independent association between measles vaccine and the

development of SSPE.

There has been some concern as to whether measles vaccine could

exacerbate preexisting SSPE (Dodson et al., 1978) and whether a

second dose of measles vaccine could more often result in SSPE

(Halsey, 1990). After publication of the case report of Dodson et al.

(1978) of an 8-year-old boy with SSPE whose condition appeared to

have been exacerbated by administration of the measles vaccine,

Halsey et al. (1978) reported data suggesting that such a concern was

not warranted. The National Registry for Subacute Sclerosing

Panencephalitis contained records of nine patients who received

attenuated or killed measles vaccine after the onset of SSPE

symptoms. Four of the nine patients died an average of 3.6 years

after the onset of SSPE symptoms and 2.4 years after vaccination. The

remaining five patients on record at that time were still alive an

average of 10.5 years after the onset of SSPE symptoms and 9.3 years

after vaccination. Halsey and colleagues argued that the variability

in the course of SSPE rendered the assertions of Dodson et al. (1978)

questionable. The same data set contained evidence that the

proportion of SSPE patients who received more than one dose of

vaccine was the same as for the control population.

Conclusion

The evidence is inadequate to accept or reject a causal relation

between measles vaccine and SSPE.