Subacute sclerosing panencephalitis (SSPE) is a progressive neurological disorder of childhood and early adolescence. It is caused by persistent defective measles virus. Brain biopsies or postmortem histopathological examination show evidence of astrogliosis, neuronal loss, degeneration of dendrites, demyelination, neurofibrillary tangles, and infiltration of inflammatory cells. Patients usually have behavioral changes, myoclonus, dementia, visual disturbances, and pyramidal and extrapyramidal signs. The disease has a gradual progressive course leading to death within 1-3 years. The diagnosis is based upon characteristic clinical manifestations, the presence of characteristic periodic EEG discharges, and demonstration of raised antibody titre against measles in the plasma and cerebrospinal fluid. Treatment for SSPE is still undetermined. A combination of oral isoprinosine (Inosiplex) and intraventricular interferon alfa appears to be the best effective treatment. Patients responding to treatment need to receive it life long. Effective immunisation against measles is the only solution presently available to the problem of this dreaded disease.

https://pmj.bmj.com/content/postgradmedj/78/916/63.full.pdf

Subacute sclerosing panencephalitis

A recombinant measles virus (MV) which expresses enhanced green fluorescent protein (EGFP) has been rescued. This virus, MVeGFP, expresses the reporter gene from an additional transcription unit which is located prior to the gene encoding the measles virus nucleocapsid protein. The recombinant virus was used to infect human astrocytoma cells (GCCM). Immunocytochemistry (ICC) together with EGFP autofluorescence showed that EGFP is both an early and very sensitive indicator of cell infection. Cells that were EGFP-positive and ICC-negative were frequently observed. Confocal microscopy was used to indirectly visualize MV infection of GCCM cells and to subsequently follow cell-to-cell spread in real time. These astrocytoma cells have extended processes, which in many cases are intimately associated. The processes appear to have an important role in cell-to-cell spread, and MVeGFP was observed to utilize them in the infection of surrounding cells. Heterogeneity was seen in cell-to-cell spread in what was expected to be a homogeneous monolayer. In tissue culture, physical constraints govern the integrity of the syncytia which are formed upon extensive cell fusion. When around 50 cells were fused, the syncytia rapidly disintegrated and many of the infected cells detached. Residual adherent EGFP-positive cells were seen to either continue to be involved in the infection of surrounding cells or to remain EGFP positive but no longer participate in the transmission of MV infection to neighboring cells.

Observation of measles virus cell-to-cell spread in astrocytoma cells by using a green fluorescent protein-expressing recombinant virus

Main Outcome Measures:Net present value (net savings) and benefit-cost ratios of routine immunization. Results:Routinechildhoodimmunizationwiththe7vaccines was cost saving from the direct cost and societal perspectives, with net savings of $9.9 billion and $43.3 billion, respectively. Without routine vaccination, direct and societal costs of diphtheria, tetanus, pertussis, H influenzae type b, poliomyelitis, measles, mumps, rubella, congenital rubella syndrome, hepatitis B, and varicella would be $12.3 billion and $46.6 billion, respectively.Directandsocietalcostsforthevaccinationprogram were an estimated $2.3 billion and $2.8 billion, respectively. Direct and societal benefit-cost ratios for routine childhood vaccination were 5.3 and 16.5, respectively. Conclusion: Regardless of the perspective, the current routinechildhoodimmunizationscheduleresultsinsubstantial cost savings. Arch Pediatr Adolesc Med. 2005;159:1136-1144

https://jamanetwork.com/journals/jamapediatrics/articlepdf/486191/POA50071.pdf

Economic evaluation of the 7-vaccine routine childhood immunization schedule in the United States, 2001

Background When measles vaccines were widely introduced in the 1970s, there were concerns that they might cause subacute sclerosing panencephalitis (SSPE): a very rare, late-onset, neurological complication of natural measles infection. Therefore, SSPE registries and routine measles immunization were established in many countries concurrently. We conducted a comprehensive review of the impact of measles immunization on the epidemiology of SSPE and examined epidemiological evidence on whether there was any vaccine-associated risk. Methods Published epidemiological data on SSPE, national SSPE incidence, measles incidence and vaccine coverage, reports of SSPE in pregnancy or shortly post partum were reviewed. Potential adverse relationships between measles vaccines and SSPE were examined using available data. Results Epidemiological data showed that successful measles immunization programmes protect against SSPE and, consistent with virological data, that measles vaccine virus does not cause SSPE. Measles vaccine does not: accelerate the course of SSPE; trigger SSPE or cause SSPE in those with an established benign persistent wild measles infection. Evidence points to wild virus causing SSPE in cases which have been immunized and have had no known natural measles infection. Perinatal measles infection may result in SSPE with a short onset latency and fulminant course. Such cases are very rare. SSPE during pregnancy appears to be fulminant. Infants born to mothers with SSPE have not been subsequently diagnosed with SSPE themselves. Conclusions Successful measles vaccination programmes directly and indirectly protect the population against SSPE and have the potential to eliminate SSPE through the elimination of measles. Epidemiological and virological data suggest that measles vaccine does not cause SSPE.

/pdf/review-of-the-effect-of-measles-vaccination-on-the-2ff0bo0oko.pdf

Review of the effect of measles vaccination on the epidemiology of SSPE

Background. Parents and physicians are understandably concerned about the causes and treat- ment of autism, a devastating disease that affects the entire family. Although much has been learned about autism, there are many gaps in our knowledge about what causes the disorder and how it can be prevented. Autistic symptoms occur along a spectrum, often referred to as autistic spectrum disorder (ASD). Concern has been raised about a possible association between measles- mumps-rubella (MMR) vaccine and inflammatory bowel disease (IBD) and ASD, especially autism with regres- sion. Also, increased requests for educational services related to ASD have raised concerns about possible in- creases in the incidence of ASD. Methods. On June 12-13, 2000, the American Acad- emy of Pediatrics (AAP) convened a conference titled "New Challenges in Childhood Immunizations" in Oak Brook, Illinois. At this conference, parents, practitioners, and scientists presented information and research on MMR vaccine and ASD. Attendees included representa- tives from select AAP committees and sections as well as federal and other organizations that address related is- sues. The multidisciplinary panel of experts reviewed data on what is known about the pathogenesis, epidemi- ology, and genetics of ASD and the available data on hypothesized associations with IBD, measles, and MMR vaccine. Supplemental information was requested from authors who have proposed the hypotheses and other experts in relevant areas. Results. Autism is a complex disorder of uncertain and probably multiple etiologies. Genetic predisposition to ASD may involve as many as 10 genes. Many experts believe that the abnormal brain development in autism occurs before 30 weeks' gestation in most instances. In utero rubella is a known cause of autism. Animal model data support the biologic plausibility that exposure to yet unrecognized infectious or other environmental agents could cause ASD. Several factors may contribute to apparent increases in incidence of ASD in recent years. Most data indicate increased recognition and reporting as primary factors, but the epidemiologic data are insufficient to determine if there has been a true increase in the incidence of ASD. Increased reporting of ASD in recent years has occurred long after the introduction of MMR vaccine in the United States in 1971 and widespread use of this vaccine in the 1970s for routine immunization of children at 12 to 15 months of age. Appropriate detailed studies are needed to define the true incidence and prevalence of ASD. Epidemiologic studies in Europe indicate no association between MMR vaccine and ASD. Some children with ASD have gastrointestinal symp- toms, but an increased rate of any specific gastrointesti- nal disorder in children with ASD has not been estab- lished. Studies to detect evidence of measles virus in intestinal tissue specimens from patients with IBD or autism with gastrointestinal symptoms have not used uniform techniques. Several laboratories have found no evidence of measles viruses in tissue specimens from patients with IBD, but 2 groups have found evidence of measles virus using different techniques. A group that found evidence of measles virus in affected tissue spec- imens from patients with IBD has also reported detecting portions of measles virus in peripheral blood lympho- cytes and intestinal tissue specimens from patients with autism and gastrointestinal disorders. Finding a portion of a virus using molecular techniques does not constitute evidence for a causal relationship, because some viruses persist in unaffected hosts. Additional controlled studies in several laboratories are needed to determine if por- tions of measles virus persist in intestinal and other tissues of people with and without gastrointestinal dis- ease and/or ASD. Conclusions. Although the possible association with MMR vaccine has received much public and political attention and there are many who have derived their own conclusions based on personal experiences, the available evidence does not support the hypothesis that MMR vaccine causes autism or associated disorders or IBD. Separate administration of measles, mumps, and rubella vaccines to children provides no benefit over administra- tion of the combination MMR vaccine and would result in delayed or missed immunizations. Pediatricians need to work with families to ensure that children are pro- tected early in the second year of life from these prevent- able diseases. Continued scientific efforts need to be directed to the identification of the causes of ASD. Pediatrics 2001;107(5). URL: http://www.pediatrics.org/ cgi/content/full/107/5/e84; autism, measles-mumps-ru- bella vaccine, autistic spectrum disorder, inflammatory bowel disease, measles, measles vaccine, epidemiology.

Measles-mumps-rubella vaccine and autistic spectrum disorder: report from the New Challenges in Childhood Immunizations Conference convened in Oak Brook, Illinois, June 12-13, 2000.

J. Lyle Conrad

Papers

Epidemiology of subacute sclerosing panencephalitis