Zika Virus: What the Neurologist Wants to Know

Just as Neurology: Without Borders launched last week, news coverage about the Zika virus epidemic in Latin America with Brazil at ground zero began to reach even the popular press. 1-4 Photos of devastated parents and microcephalic, dysmorphic infants have captured the public’s attention. Recent articles in the New England Journal of Medicine 5 and Lancet 6-8 among others have outlined some of what is known about the epidemiology of this arbovirus and how we believe it made its way from Africa (identified in 1947), to Southeast Asia (mid-twentieth century), to Micronesia (2007), to French Polynesia (2014) and most recently to Latin America in 2015.9

Arrival of the Zika virus into a tropical climate with ample mosquito vectors and large populations of non-immune individuals many of whom live in crowded, urban spaces without air conditioning or screens to limit exposure to the aggressive, indoor daytime bites of the Aedes has resulted in ~500,000 infections since April 2015.10 Clinical suspicion of a “microcephaly epidemic” in Brazil and two cases of RT-PCR diagnosed Zika in microcephalic neonates led to the initiation of a registry of incident microcephaly with ~4,000 cases reported in the past 9 months. Officials are careful to point out that causality has not been definitively established though Zika virus has been detected in amniotic fluid and fetal brain tissue of some affected fetuses. The role, if any, of the coincident outbreaks of dengue and Chikungunya remains unclear. So what is known about the impact of Zika on the nervous system?

Neurobiology

Basic Science

Zika was first identified in 1947 in the Zika (meaning “overgrown”) Forest of Uganda in rhesus monkeys during a yellow fever investigation. Initial reports of Zika were published in the TRSTMH in 1952 and the Royal Society has made the full text of these early papers freely available online until 29 February. 11 This early work clearly delineated viral tropism to brain in intraperitoneally infected mice with the virus crossing the blood brain barrier and infecting both neurons and glia. Intracytoplasmic inclusions, which were then referred to as “virus factories”, are now known to be the result of the virus hijacking the process of autophagy for its own replication. 12-14Another potential mechanism for the neurodevelopmental anomalies associated with Zika is the amplification of centrosomes due to the dual role of some proteins in autophagy and centrosome stability. In mice, increased numbers of centrosomes causes delayed mitosis, increased apoptosis, neural stem cell disorientation, premature neuronal differentiation, and decreased numbers of progenitor cells—all of which could result in microcephaly.15

Clinical Findings

Previous studies of Zika in Africa and Southeast Asia characterized it as an endemic virus causing self-limited infections with fevers, myalgias, arthralgias, a maculopapuar rash and conjunctivitis that largely affected children with 80% of infections being asymptomatic. 12 When Zika spread to French Polynesia in 2007 concurrently with an outbreak of dengue, reports of neurologic and autoimmune phenomena began to surface. Guillain-Barre Syndrome (GBS) incidence reached 20 times the number of expected cases based upon the population size and a retrospective review suggested a similar magnitude increase in neurologic fetal anomalies in infants born in 2014-2015. 16 A report from the European Centre for Disease Prevention and Control (EDCD) indicated that in addition to increased numbers of GBS cases, Zika was thought to be associated with encephalitis, meningoencephalitis, facial paralysis and myelitis. 17

Clinical Management

CSF is not required for diagnosis, but definitive diagnosis can be challenging. RT-PCR may only be positive during active viremia which is as brief as the 3rd-5th day post infection. IgM and neutralizing antibody levels are low early in the disease and these as well as plaque-reduction neutralization testing (PRNT) can cross react with dengue. There is no vaccine and treatment is limited to supportive care with the notable advice that aspirin and NSAIDS be avoided in possible Zika infection due to the common co-occurrence of dengue and the difficulty distinguishing the two infections—these medications are avoided in dengue due to the increased risk of bleeding associated with their use. 10

Ultrasound can be diagnostic of fetal Zika infection as early as 18-20 weeks of gestational age. Key findings beyond microcephaly (occipitofrontal circumference of less than 3rd percentile for age, sex, and gestational age) include intracranial and intraocular calcifications, corpus callosal and vermian dysgenesis, an enlarged cisterna magna, severe unilateral ventriculomegaly, agenesis of the thalami, cataracts, and neuronal migration disorders including lissencephaly and pachygyria. 10

US Guidelines18, 19

The CDC is recommending that pregnant woman postpone travel to any Zika-infected regions. A travel history should be obtained from all pregnant women and pregnant women who have traveled to a Zika-affected area and who have also experienced 2 or more clinical symptoms of Zika within 2 weeks of their travel should be tested through local health authorities or the CDC as no commercial testing is available. Amniocentesis for RT-PCR may aid in diagnosis and decision-making.

Where there is evidence of potential maternal Zika exposure, live births should undergo placental histopathology, as well as cord blood for RT-PCR, IgM and neutralizing antibodies and PRNT for both Zika and dengue. Similar tissue assessments are warranted in tissue recovered from fetal losses. Surviving infants should undergo cranial ultrasound, ophthalmological assessments and hearing screens with repeat hearing evaluations at 6-months even if initial hearing at birth appears normal.

Epidemiology

The incubation period in humans is unknown but in other primates it is ~10 days.The infection is amplified via humans with mosquito-human-mosquito transmission well-established. Perinatal 20 and sexual transmission 21are also described and virus is detectable in saliva, urine, semen, and breast milk.22, 23 Although no reported cases to date, there are concerns that Zika could be transmitted iatrogenically via blood products.24

From a localized problem to a global threat–What lies ahead?

The United Nations health agency held a meeting on Thursday (28 Jan 16) and the World Health Organization is similarly meeting tomorrow (Monday, 1 Feb 2016). Global attention is coming none too soon for the thousands of Zika-affected children. Bogoch et al.used Aedes habitat and volume of air travel to model the risk of spread of Zika from Latin America to the rest of the Americas and concluded that 22.7 million people in the US live in regions with possible year-round transition. These are gross underestimates if unconfirmed reports from Brazil on Thursday (28 Jan 16) that Zika transmission by the Culex is now occurring are substantiated. 25 Culex mosquitoes, which also carry West Nile Virus, are 20 times more common than Aedes and are distributed in broad swaths of North America. This global health issue may soon become all too local for US pediatric neurologists and neonatalologists.

References

  1. McCarthy M. First US case of Zika virus infection is identified in Texas. Bmj 2016;352:i212.
  2. Garcia-Navarro G. Zika virus likely affected her baby, and she feels brazil doesn’t care. 2016.
  3. Dyer O. Jamaica advises women to avoid pregnancy as Zika virus approaches. Bmj 2016;352:i383.
  4. Dyer O. Sixty seconds on . . . Zika virus. Bmj 2016;352:i467.
  5. Fauci AS, Morens DM. Zika Virus in the Americas – Yet Another Arbovirus Threat. The New England journal of medicine 2016.
  6. Enfissi A, Codrington J, Roosblad J, Kazanji M, Rousset D. Zika virus genome from the Americas. Lancet 2016.
  7. Bogoch, II, Brady OJ, Kraemer MU, et al. Anticipating the international spread of Zika virus from Brazil. Lancet 2016.
  8. Triunfol M. A new mosquito-borne threat to pregnant women in Brazil. The Lancet Infectious diseases 2015.
  9. Hayes EB. Zika virus outside Africa. Emerging infectious diseases 2009;15:1347-1350.
  10. CDC. Zika Virus. 2016. Available at: http://www.cdc.gov/zika/prevention/index.html. Accessed 31Jan15.
  11. RSTMH. Zika virus first described in TRansactions! 2016. Available at: https://rstmh.org/blog/2016/jan/26/zika-virus-first-described-transactions.
  12. Ioos S, Mallet HP, Leparc Goffart I, Gauthier V, Cardoso T, Herida M. Current Zika virus epidemiology and recent epidemics. Medecine et maladies infectieuses 2014;44:302-307.
  13. Dick GW. Zika virus. II. Pathogenicity and physical properties. Transactions of the Royal Society of Tropical Medicine and Hygiene 1952;46:521-534.
  14. Dick GW, Kitchen SF, Haddow AJ. Zika virus. I. Isolations and serological specificity. Transactions of the Royal Society of Tropical Medicine and Hygiene 1952;46:509-520.
  15. Tetro JA. Zika and microcephaly: Causation, correlation, or coincidence? Microbes and infection / Institut Pasteur 2016.
  16. Oehler E, Watrin L, Larre P, et al. Zika virus infection complicated by Guillain-Barre syndrome–case report, French Polynesia, December 2013. Euro surveillance : bulletin Europeen sur les maladies transmissibles = European communicable disease bulletin 2014;19.
  17. ECDC. Rapid Risk Assessment, Zika Virus Outbreak, French Polynesia. 2014.
  18. Petersen EE, Staples JE, Meaney-Delman D, et al. Interim Guidelines for Pregnant Women During a Zika Virus Outbreak – United States, 2016. MMWR Morbidity and mortality weekly report 2016;65:30-33.
  19. Staples JE, Dziuban EJ, Fischer M, et al. Interim Guidelines for the Evaluation and Testing of Infants with Possible Congenital Zika Virus Infection – United States, 2016. MMWR Morbidity and mortality weekly report 2016;65:63-67.
  20. Besnard M, Lastere S, Teissier A, Cao-Lormeau V, Musso D. Evidence of perinatal transmission of Zika virus, French Polynesia, December 2013 and February 2014. Euro surveillance : bulletin Europeen sur les maladies transmissibles = European communicable disease bulletin 2014;19.
  21. Musso D, Roche C, Robin E, Nhan T, Teissier A, Cao-Lormeau VM. Potential sexual transmission of Zika virus. Emerging infectious diseases 2015;21:359-361.
  22. Musso D, Nilles, E.J., Cao-Vormeau, C. Rapid spread of emerging Zika virus in the Pacific area. Clinical Microbiology and Infection 2014;20:O595-O596.
  23. Musso D. Zika Virus Transmission from French Polynesia to Brazil. Emerging infectious diseases 2015;21:1887.
  24. Marano G, Pupella S, Vaglio S, Liumbruno GM, Grazzini G. Zika virus and the never-ending story of emerging pathogens and transfusion medicine. Blood transfusion = Trasfusione del sangue 2015:1-6.
  25. Zika Virus may have spread to common mosquito. SkyNews2016.
Gretchen L. Birbeck, MD, MPH

Gretchen L. Birbeck, MD, MPH

Gretchen Birbeck is a neurologist who divides her time between the US and Africa. Her US academic home is the University of Rochester where she is the Rykenboer Professor of Neurology and Research Director for the Strong Epilepsy Center with adjunct appointments in the Center for Human Experimental Therapeutics and the Department of Public Health. Her additional skills in epidemiology, health services research, and tropical medicine are brought to bear during the 6-months annually she spends in Africa where she serves as Director for the Chikankata Epilepsy Care Team in rural Mazabuka, Zambia, an Honorary Lecturer at the University of Zambia and a consultant for the Paediatric Research Ward at Queen Elizabeth Central Hospital in Blantyre, Malawi. Gretchen’s research programs are aimed at identifying opportunities to prevent or ameliorate the medical and social morbidities of common neurologic conditions in low-income, tropical settings with the ultimate goal of developing successful interventions feasible for scale up and broad implementation. She has been recognized as an Ambassador for Epilepsy by the International League against Epilepsy, a Global Health Research Ambassador by the US Paul Rogers Society, a National Outreach Scholar by the WK Kellogg Foundation and a Leader in Medicine by the American Medical Students Association.

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