Most Vaccination-Onset Epilepsy Has Genetic, Structural Cause

Pauline Anderson

September 24, 2014

In most children whose epilepsy started following a standard vaccination, there's a genetic or structural cause, and about a third of cases of epilepsy triggered by a vaccine are relatively benign, a new study suggests.

These results indicate that vaccination-related epilepsy doesn't necessarily have a poor prognosis, said lead author Nienke Verbeek, MD, clinical geneticist, Department of Medical Genetics, Division of Biomedical Genetics, University Medical Centre Utrecht, the Netherlands.

The findings, added Dr. Verbeek, should come as a relief to clinicians and parents and increase their confidence in vaccination.

"For physicians it might be easier to explain to parents that vaccinations, although they may trigger a seizure, are not the cause of epilepsy, and for parents, it may give them faith in the safety of vaccinations."

The study may also support the detection of underlying causes in children who have epilepsy with onset following vaccination, said Dr. Verbeek. "A genetic diagnosis is important for appropriate antiepileptic drug treatment, prognosis, and genetic counselling. "

Dr. Nienke Verbeek

The study was published online September 15 in Pediatrics.

Possible Epileptic Seizures

Fever is a common adverse effect of vaccinations, with the incidence of febrile seizures increased 2 to 5 times after an inoculation. In absolute numbers, this may be the highest following a measles-mumps-rubella (MMR) vaccine. The peak incidence of febrile seizures is around age 1.5 years, when this vaccine is administered in most countries, said Dr. Verbeek.

Researchers looked at cases of possible epileptic seizures after vaccination in the first 2 years of life as reported to the safety surveillance system of the Dutch national Immunization Program from January 1, 1997, to December 31, 2006. The vaccination schedule for these youngsters included 4 doses of diphtheria, tetanus, pertussis, inactivated polio vaccine and Haemophilus influenzae type B vaccine in the first year of life, as well as 1 dose of the live attenuated MMR vaccine at age 14 months.

During the study period, 1.9 million infants received more than 7.5 million diphtheria, tetanus, pertussis, inactivated polio vaccine and Haemophilus influenzae type B combination vaccines, and 1.8 million toddlers received their first MMR vaccine.

Within the 10-year period, 990 children were reported with 1022 possible epileptic seizures occurring in a temporal relation to an inactivated vaccine (68.0%) or live attenuated vaccine (32.0%). Seizures with a temporal relation to vaccination are defined by occurrence within 24 hours of administration of an inactivated vaccine or 5 to 12 days after a live attenuated vaccine such as MMR.

Of the 990 reported children, 945 children had febrile, afebrile, or atypical seizures but were not diagnosed with epilepsy during follow-up.

Of the remaining 45 children, 19 had seizure onset before the vaccination, and in 26 children, the reported seizure was the first of an epilepsy syndrome.

These 26 children had a median age at epilepsy diagnosis of 11.5 months and were older at follow-up than the other children. They also more often had subsequent vaccination-related seizures.

Parents of 23 of these 26 children (13 females and 10 males) consented to retrieval of extended follow-up information from medical files. Mean age of the 23 children was 10.6 years. Genetic testing was performed on 14 of these 23 children.

Epileptic Encephalopathy

Three (13%) of the 23 children already had developmental delay before seizure onset, developed mild to severe intellectual disability, and were presumed to have pre-existing encephalopathy. Twelve (52%) of the 23 children were considered to have epileptic encephalopathy and of these, 8 had Dravet syndrome due to a neuronal sodium channel 1 subunit (SCN1A) gene mutation.

Dravet syndrome is a rare epilepsy syndrome with seizure onset in the first year of life that is often triggered by fever, infectious disease, or vaccinations.

Eight (35%) of the 23 children were considered to have relatively benign epilepsy. Seven of them were seizure-free without use of antiepileptic drugs at follow-up. The median age at their last seizure was 4 years. An underlying genetic etiology was identified or was plausible on the basis of the family history in 3 of these 8 children.

"This is important for clinicians and parents because previous studies focused mainly on epileptic encephalopathy with onset after vaccination," said Dr. Verbeek. "This method may have given the false impression that vaccination-related seizure onset in general has a bad prognosis."

The proportion of children with benign epilepsy may have been underestimated because the study used an enhanced passive reporting system. Parents of children with more severe epilepsies may be more likely to consider vaccinations as a cause of their child's epilepsy.

An underlying cause of the epilepsy syndrome was detected in two thirds (65%) of children. The cause was genetic in most cases — including 8 cases of Dravet syndrome — and likely genetic in 2 additional cases because of the presence of cortical malformations, dysmorphic features, and other congenital anomalies.

In children with identified genetic causes, these fully explained the electroclinical syndrome and other clinical features, said the authors.

In the one third of cases where no underlying cause of epilepsy was detected, a genetic basis was still possible, according to the authors. They noted that genetic analyses were incomplete, some children had positive family histories for seizures, and molecular defects underlying many genetically determined epilepsies have yet to be discovered.

"In the past, the absence of a detectable underlying cause in children with vaccination-related seizure onset led to the assumption that the vaccination itself was the cause of the subsequent neurologic deterioration in some," write the authors. "However, the large variability in electroclinical syndromes and corresponding cognitive outcomes in our study further support the hypothesis that predisposing factors within the child, and not the vaccination, cause the observed neurologic deterioration."

Seizure Predisposition

The vaccine could have acted as a trigger for the first seizure, thereby unmasking the genetic seizure predisposition. In the case of Dravet syndrome, and probably also other genetically driven epilepsy syndromes, the seizures would have occurred anyway, with first seizures triggered later, for example by fever, if not the vaccination, said Dr. Verbeek.

In children with pre-existing structural brain defects, it's also very likely that they would have developed epilepsy, vaccine or no vaccine, she said.

One quarter of the cases with vaccination-related epilepsy onset were reported to have seizures after subsequent vaccinations. This, said the authors, raises the question of whether these children should get further immunizations.

Although the current study wasn't designed to test the influence of further vaccinations, a study on Dravet syndrome found no differences in outcomes between children who did and didn't receive further vaccinations. Other studies indicate that vaccination likely doesn't affect cognitive outcome in patients with Dravet syndrome, said Dr. Verbeek.

As for other syndromes, Dr. Verbeek pointed out that many children with epilepsy following vaccination are sensitive to fever; increased body temperature can trigger their seizures. "So with the next vaccination, they will probably have a somewhat increased risk of having another seizure."

But that risk has to be balanced against the risk of getting an infectious disease that may bring on more frequent and longer-lasting fevers, and possibly triggering additional seizures. There is no evidence that refraining from further vaccinations is beneficial for these children.

However, in children with severe types of seizures, such as status epilepticus, which can be life threatening, clinicians should discuss with parents if special precautions are needed to prevent subsequent seizures triggered by vaccinations.

Important Study

Asked for comment on the findings, Amy Brooks-Kayal, MD, chief and Ponzio Family Chair in Pediatric Medicine, Colorado Children's Hospital, and professor of pediatrics, neurology and pharmaceutical sciences at the University of Colorado, Boulder, said the study confirms previous findings.

"I think this is an important study in that it confirms prior work by Berkovic et al (Lancet Neurol. 2006;5:488-492) suggesting that in the majority of cases of vaccine-associated seizures, the etiology is genetic or structural, and not caused by the vaccine itself," Dr. Brooks-Kayal told Medscape Medical News.

"Further, it found that in the one-third of patients with a benign epilepsy syndrome that began with a seizure around the time of vaccination, the prognosis is good," she added. "This should be reassuring to parents as they are counselled on the safety of vaccinations."

Ingrid E. Sheffer, MBBS, PhD, director of pediatrics, Austin Health, professor of pediatric neurology research at the Florey Institute of Neuroscience and Mental Health, Victoria, Australia, and senior author on the 2006 study by Berkovic et al, agreed, suggesting the findings should help with the uptake of vaccination in the wider community.

Dr. Verbeek was supported by the Stichting Vrienden UMC Utrecht on behalf of the Janivo Stichting and by the NutsOhra Fund. The authors have disclosed no relevant financial relationships.

Pediatrics. Published online September 15, 2014. Abstract


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