Research presented yesterday (April 10, 2016) in Vancouver, Canada at the American Academy of Neurology conference by a Brazilian research team suggests that “there is strong evidence that this epidemic [Zika virus] has different neurological manifestations” beyond what is already documented in the literature. The scientists from Brazil discovered that a brain disorder called Acute Disseminated Encephalomyelitis or ADEM for short may be associated with the Zika virus infection in adults.

ADEM is an autoimmune disease. ADEM is a disorder that attacks the central nervous system, specifically the brain and spinal cord. The buzz from the conference presentation is the result of the Brazilian researchers suggesting a new finding, which may show an association between the Zika virus and ADEM, where the Zika virus may trigger an immune attack on the central nervous system. The findings may add to the understanding we are gaining about neurological damage associated with the Zika virus.

Recently we’ve heard a lot about Zika and microcephaly in the news. According to the World Health Organization, there is a strong consensus among scientists that the Zika virus is related to birth defects such as microcephaly. Microcephaly is a birth defect that causes the head of children to be abnormally small, which can lead to problems in the area of intellectual and physical development. Brazil has confirmed more than 940 cases of microcephaly cases and state that most of them are related to virus infections from Zika among expectant mothers. The South American country is investigating almost 4,300 other alleged cases of microcephaly.

Specifically, regarding Acute Disseminated Encephalomyelitis or ADEM mentioned at the conference, it can occur quite suddenly in children, who have had some form of a fever illness. This should not be confused with multiple sclerosis or MS, which more typically occurs after two or more illnesses in adolescence or young adulthood and importantly usually involves a period of time where no illness may be detected. In both instances, there is an immune system problem. ADEM is an immune system disorder characterized by inflammation and a demyelinating condition that largely affects the white matter of the brain and spinal cord. Demyelinating is a term used to describe the process where the covering around nerve fibers are damaged and result in the nerve impulses or the communication along the nerve pathways being disrupted. Most commonly we think of demyelinating as associated with multiple sclerosis or MS.

 

Epidemiology of ADEM

Few studies have specifically provided incidence (or new case) data concerning ADEM, thus little is known about the actual occurrence of ADEM around the world. What we do know is that in Canada, the yearly estimate is approximately 0.2 in 100,000  people will acquire ADEM. Similarly, data from Germany suggest an incidence rate of 0.07 per 100,000. Most common areas of pathology are visual, motor, autonomic, and behavioral or intellectual issues along with epilepsy are all associated with ADEM. To-date, data show individuals with ADEM will make a full recovery in approximately 57-92% of the time. Finally, age is related to ADEM and among cases in children, over 80% of patients are younger than 10 years of age. Conversely, less than 20% of all cases occur among individuals in their 20’s and even less understood is adult onset ADEM with estimates being less than 3% of all reported cases.

It is difficult to get an accurate picture of adult cases because ADEM can be very difficult to diagnose separate from MS (MS and ADEM may also exist together). A difference between child and adult cases is that in adults there are very large white matter lesions compared to childhood cases where the gray-white matter of the forebrain is often affected (Menge et al., 2007) (Sejvar et al., 2007) (Huynh, Cordato, Kehdi, Masters, & Dedousis, 2008).

 

Mosquitos ~ Viruses ~Vaccinations

In terms of being critical consumers of health research information, we want to pause for a moment and clearly point out there is a distinct and important difference among various terms such as association, correlation versus causation in research. It can be very confusing when initially learning how to interpret research to not get carried away with overstating the true relationship among variables. Often you will see a statement that says one variable, such as a virus CAUSES a disease when really we mean there is something related between  variables.

Regarding the Zika virus, we cannot say Zika causes microcephaly in babies or ADEM in people because we simply do not know. What was detected in Brazil initially regarding the Zika virus was the possibility that there is a relationship, some sort of association between the Zika virus and microcephaly. Not only is it incorrect to state the Zika virus causes microcephaly, many researchers, clinicians and like ourselves epidemiologists are still examining if in fact there is an association. Many researchers are not ready to make such a claim based on the current scientific evidence. It certainly does appear there is a possibility.

 

Furthermore, the latest research regarding ADEM is also shedding light on the possibility there is association or relationship between the Zika virus and ADEM and certainly not suggesting the Zika virus causes ADEM. In fact, the Brazilian research presented yesterday is the result of a study with a very small n size or study population that was examined as part of their reserach. The true value of the latest research lies in its ability to inform or suggest further avenues of study and is very important for clinicians, who can be informed to look for ADEM among patients with a history of a Zika infection. The study quoted from the conference involved 151 patients, who were all infected with an arbovirus (a whole grouping of viruses that includes the Zika virus and others such as Chikungunya) and who also went to the hospital. Of those 151 patients, 6 patients did have some sort of autoimmune disease. Specifically, 4 patients had Guillain-Barre and 2 patients had ADEM. Each of the 6 patients showed positive results for a Zika infection.

In exceedingly rare occurrences, ADEM is seen as a complication associated with vaccinations. Vaccinations and ADEM have been associated with several vaccines, including rabies, diphtheria, tetanus, polio, smallpox, measles, and mumps with the most common vaccinations associated with ADEM being influenza and human papilloma” (Huynh et al., 2008). Post-vaccination encephalomyelitis explains less than 5% of present cases of ADEM. Research indicated that the cases of ADEM are most often caused by some sort of pre-existing viral infection and there is a pathway where a vaccine may mediate the process (Sejvar et al., 2007)(Ussel, Boer, Parizel, Cras, & Jorens, 2014). It may be well worth further investigating  vaccination programs in Brazil. We must stop our obsessiveness about vaccines either being all good or all bad. The reality is that in some instances vaccines do cause complications even when they prove extremely effective.

Similarly, both microcephaly and ADEM and other possible conditions may prove to have an association with the Zika virus but certainly are not caused by mosquitoes. The mosquitoes connection has had most of the media coverage regarding the Zika virus. On April 4^th, Angela Crane (Grant) posted a very good piece titled: The Problem is NOT Mosquitoes but Viruses. Clearly mosquitoes transfer viruses to human hosts and we are often most familiar with the connection between mosquitoes and malaria. However, mosquitoes do not cause the virus. We must be careful here as Crane so carefully points out in her article,  viruses infect human-beings through a number of pathways including our skin, airways, and bites such as those from a mosquito.

So What Does All This Really Mean?

We are in the early stages of understanding the Zika virus despite it being identified in the late 1940’s.  Complications that may result from a viral infection such as the Zika virus are likely to be complex and multi-factorial. It also means that mosquitoes may transmit the Zika virus but they do not cause it. We are also learning that Zika can be transmitted through sexual contact and this brings the issue of the Zika virus to parts of the globe where the mosquitoes associated with the Zika virus will never travel. Thus ridding ourselves of the mosquito transmitters will not solve the entire issue.

We know that there has been an increase in the number of cases of microcephaly in Brazil. And, we also know there is some sort of relationship between an expected mother having a viral infection and the possibility of developing complications in their unborn babies along with children and adults showing signs of different complications from the Zika virus; however, what and how those complications manifest, we simply do not understand at this time. We also need more understanding of the process of infections and vaccines.

In closing, there are much more unanswered questions than evidence-based answers concerning the Zika virus. The real appreciation comes in realizing the dedication of resources and researchers around the globe, who are committed to further understanding the Zika virus. We need as much information as possible for clinicians, who must treat patients who are sick now and in need of help rather than spreading fear about a virus we do not yet understand.

 

References

Huynh, W., Cordato, D. J., Kehdi, E., Masters, L. T., & Dedousis, C. (2008). Post-vaccination encephalomyelitis: Literature review and illustrative case. Journal of Clinical Neuroscience, 15(12), 1315–1322. http://doi.org/10.1016/j.jocn.2008.05.002

Menge, T., Kieseier, B. C., Nessler, S., Hemmer, B., Hartung, H.-P., & Stüve, O. (2007). Acute disseminated encephalomyelitis: an acute hit against the brain. Current Opinion in Neurology, 20(3), 247–54. http://doi.org/10.1097/WCO.0b013e3280f31b45

Sejvar, J. J., Kohl, K. S., Bilynsky, R., Blumberg, D., Cvetkovich, T., Galama, J., … Wiznitzer, M. (2007). Encephalitis, myelitis, and acute disseminated encephalomyelitis (ADEM): Case definitions and guidelines for collection, analysis, and presentation of immunization safety data. Vaccine, 25(31), 5771–5792. http://doi.org/10.1016/j.vaccine.2007.04.060

Ussel, I. Van, Boer, W., Parizel, P., Cras, P., & Jorens, P. G. (2014). Encephalitis related to a H1N1 vaccination: case report and review of the literature. Clinical Neurology and Neurosurgery, 124, 8–15. http://doi.org/10.1016/j.clineuro.2014.06.003