Genetics and the myth of vaccine encephalopathy

VACCINES AND NEUROLOGICAL DISEASE

Safety is often cited as the major concern by families who refuse vaccines (5) and, in particular, worries about the risk of neurological disease. The potential for vaccines to cause autism is a significant concern of families, whether through the vaccine itself or the perceived ‘mercury toxicity’ through thimerosal, a compound used to preserve some vaccines. There is significant evidence to suggest no causal effect or association between receipt of vaccinations and autism, and this has been reviewed extensively elsewhere (6).

The possibility that immunizations may cause seizures or epilepsy is another potential concern, and indeed febrile seizures have been shown to occur at an increased rate after vaccination (7). However, there is no evidence to suggest that the fever caused by vaccines predisposes a person to seizures, any more than fevers from other causes (8). This is reinforced by the fact that children with seizures after vaccination are no more likely to go on to have afebrile seizures or developmental problems than children who have febrile seizures from other causes (7). Overall, there is no evidence to suggest that vaccines cause central nervous system injury, epilepsy or infantile spasms (8).

Despite this, children who experience an onset of neurological illness after immunization are often placed in the category of so-called ‘vaccine encephalopathy’. Although there is no agreed on definition for vaccine encephalopathy, in this disorder, children commonly experience developmental regression and seizures within one to 14 days after administration of a vaccine. Despite data from well-constructed studies (8) failing to show an association between receipt of vaccines and neurological illness or encephalopathy (8), it remains difficult to explain the lack of cause and effect to parents, especially when it is they who witness their child undergoing developmental regression. The question they invariably pose is ‘If the vaccines were not the cause, what was?’.

SEVERE MYOCLONIC EPILEPSY OF INFANCY (DRAVET SYNDROME) AND VACCINE ENCEPHALOPATHY

The initial clues to unravelling the etiology of vaccine encephalopathy lay in its clinical similarity to severe myoclonic epilepsy of infancy (SMEI), also known as Dravet syndrome. In this disorder, seizures present at approximately six months of age, usually with hemiclonic or generalized status epilepticus, often associated with fever. Children remain neurologically normal until the second year of life, whereupon they frequently experience developmental regression. Other seizure types then appear, including myoclonic, partial and absence seizures (8), and the epilepsy is usually refractory to treatment.

In 2001, Claes et al (9) found that mutations in the sodium channel alpha 1 subunit gene, SCN1A, were causative in 80% of children with SMEI, and that 95% of mutations arise de novo. Knowing this, Berkovic et al (10) studied 14 patients with alleged vaccine encephalopathy who had onset of seizures within 72 h of vaccination. They found that 11 of 14 patients (78%) had mutations in the SCN1A gene, with the majority of these mutations having arisen spontaneously. Thus, despite these patients previously being labelled as having vaccine encephalopathy, the majority of patients studied had a clear genetic cause for their disease.

In vaccine encephalopathy, many parents cite a lack of family history as a reason to why vaccines may be causative in their children’s neurological problems. However, because of the high rate of de novo SCN1A mutations, this genetic abnormality likely occurs either in the gametes or very early postfertilization, thus making a family history of seizures extremely unlikely in patients with SCN1A mutations.

Others argue that the temporal association with immunizations proves that the vaccines themselves are causative. We know, however, that fever is the most common complication of immunization, and that patients with SMEI often have an exacerbation in seizures with fever. Thus, it could simply be that the fever associated with the vaccine and not the vaccine itself is what provokes the initial seizure in some patients with SCN1A mutations.

Avoidance of vaccines as a potential ‘trigger’ in patients who harbour a SCN1A mutation does not make biological sense (10). First, there are many patients with the SMEI phenotype who have onset of symptoms unrelated to vaccinations. Second, the mutations seen in these patients have not been reported in healthy subjects (10), implying that it is unlikely that many of us harbour a ‘silent’ mutation, only needing a vaccine trigger to set it off. Finally, if the perceived mechanism is an inflammatory or autoimmune attack on the brain secondary to vaccination, one might expect abnormalities to be seen on neuroimaging. None of Berkovic’s patients had neuroimaging evidence of an inflammatory or destructive process.

VACCINES AND MITOCHONDRIAL ENCEPHALOPATHY

Recent media attention has been focused on the case of Hannah Poling, a young girl with mitochondrial encephalopathy and autistic features, whose parents won compensation under the United States National Vaccine Injury Compensation Program (11). The lack of scientific reasoning behind the decision is expertly critiqued in a recent commentary (12) in The New England Journal of Medicine. A scientific report on Hannah Poling’s case has been published by her father (13), and documents that the patient had a previous history of recurrent infections – thus, her immunizations were delayed. Shortly after multiple immunizations were given on a single day, she developed fever, rash, irritability and a regression in developmental milestones. Bloodwork revealed persistently high lactic acid, aspartate aminotransferase and creatine kinase levels, and thus, a muscle biopsy was performed. This revealed abnormal mitochondrial enzyme function. The authors state that children with mitochondrial enzyme dysfunction may be prone to autistic regression due to immunizations or infections.

Mitochondrial enzyme abnormalities are rare inborn errors of metabolism demonstrating defects in oxidative phosphorylation, and are often associated with mutations in nuclear or mitochondrial DNA. Patients can display a wide variety of features including acute and chronic encephalopathy, seizures, weakness, systemic symptoms, growth retardation, regression of developmental milestones and, rarely, autistic features. Most patients with mitochondrial disorders will have a constellation of neurological and systemic findings, and will not demonstrate autistic features alone. Some authors caution that even when mitochondrial abnormalities are found in a child with autistic features, the results should be interpreted with caution because these changes may be secondary to technical inaccuracies or may be due to another genetic disorder, such as Rett syndrome (14).

Similarly to diseases associated with mutations in the SCN1A gene, children with mitochondrial dysfunction often have an exacerbation in symptomatology (for example, encephalopathy or regression in milestones) with febrile illnesses. No clear evidence is available to suggest that vaccines can cause similar regression (12). Despite this, if regression or encephalopathy did develop in a patient with mitochondrial dysfunction, it could be that the fever itself, and not the vaccine, is the real cause of exacerbation, as is seen in SMEI. If this is the case, it may be even more prudent to immunize children with mitochondrial disorders to decrease their risk of acquiring febrile illnesses in early childhood. Additionally, as in SMEI, it is unlikely that those with mitochondrial disease simply require a vaccine ‘trigger’ to set off the disease process because most patients with mitochondrial disease do not have an onset of symptoms associated with vaccination.

IMPLICATIONS FOR PRACTICE

Testing for mutations in the SCN1A gene is possible, although testing is expensive and needs to be sent to laboratories outside of Canada. As a result, should a practitioner encounter a patient in whom they suspect a diagnosis of SMEI (or ‘vaccine encephalopathy’), a referral should be made to a paediatric neurologist and/or geneticist for further evaluation and testing. Mitochondrial disorders represent a rare cause of autism, and most children will present with other systemic and neurological signs and symptoms (14). Testing for mitochondrial disorders is usually not necessary, unless these other features are present. With respect to inborn errors of metabolism as a whole, testing for these in autism should only be considered if other clinical findings are present, including lethargy, cyclic vomiting, early onset seizures, dysmorphic features, mental retardardation and an abnormal neurological examination (15).

A recent survey (16) found that 39% of paediatricians would dismiss a family if the parents refused vaccines for their child. This is a concerning finding, especially because most families rely on health care practitioners as their most important source of information on immunizations (14). Thus, it is imperative that paediatricians and family physicians enter into an open and honest dialogue with parents regarding vaccines, vaccine safety and their children’s health. The risks and benefits of individual vaccines need to be discussed with parents, and their specific concerns need to be addressed.

The discovery of SCN1A mutations in patients with alleged vaccine encephalopathy provides us with a solid, scientifically proven alternate explanation for the cause of these children’s neurological disorder. The example of SCN1A mutations in vaccine encephalopathy should be mentioned in conversations with parents when discussing vaccine side effects and vaccine refusal. It is much easier to proactively explain to families this plausible, alternate cause for vaccine-associated neurological illness, than to cite negative epidemiological studies which fail to support a causal association between vaccines and neurological disease. One can explain to parents that, with further scientific inquiry, more and more explanations may arise to explain neurological disorders that may have previously been thought to be due to immunizations.

In the course of these discussions with families, reassurance should be given regarding the rarity of both SMEI and mitochondrial diseases. In explaining the idea of ‘de novo’ mutations in SMEI to families, it is important to emphasize that these mutations occur around the time of fertilization, well before children have received any immunizations.

By using examples such as these with patients and families, we, as health care practitioners, can calm fears, facilitate discussion and improve vaccine adherence, resulting in an improvement in both individual patient health, as well as the health of the population at large.