How to cite this article: Del Carpio-Orantes L. [Zika, a neurotropic virus?]. Rev Med Inst Mex Seg Soc 2016 Jul-Aug;54(4):540-3.
Received: February 15th 2016
Accepted: February 19th 2016
Luis Del Carpio-Orantesa
aDepartamento de Medicina Interna, Hospital General de Zona 71, Instituto Mexicano del Seguro Social, Veracruz, Veracruz, México
Communication with: Luis del Carpio-Orantes
Telephone: (229) 223 7032
In this paper, the neurotropism potential Zika virus is discussed, by comparison with viruses both RNA and DNA are neurotropic known, also it is said that compared with the new viruses that have affected the Americas, as the chikungunya, Zika has shown great affinity by brain tissue, manifested by a high incidence of acute neurological conditions, such as Guillain-Barré syndrome, among others, as well as the reported incidence of microcephaly that is abnormally high compared with the previous incidence, which, in a stillborn subject necropsied significant alterations demonstrated in brain tissue, identifying viral material and live virus in the fetoplacental complex, and demonstrating the impact both white matter and gray matter as well as basal ganglia, corpus callosum, ventricles and spinal cord, which could explain the microcephaly that concerns him. Although not a direct cause-effect relationship is demonstrated, however current evidence supports that relationship, hoping to be supported scientifically.
Keywords: Arboviruses; Arbovirus infections; Epidemiological surveillance; Epidemiology
A neurotropic virus is one that has high affinity and avidity for both central and peripheral nervous tissue, causing signs of meningitis, meningoencephalitis, acute flaccid paralysis, demyelinating diseases, and others. The action mechanism appears to be direct viral replication in brain tissue, mainly seen in viral DNA, with subsequent neuronal destruction and formation of immune complexes that affect the brain tissue. Similarly, it has been shown that some neurotropic viruses, after initial infection, remain latent in nerve tissue, especially in the ganglia of the cranial nerve pairs (or dorsal root ganglion), and can be reactivated in conditions of immunosuppression.
Classic examples of these viruses are polio and the rabies virus (viral RNA), which have caused pandemics and deadly symptoms, respectively; they can also cause subacute and chronic conditions such as subacute sclerosing panencephalitis (SSPE), associated with the measles virus. Similarly, all viruses of the Herpesviridae family have high affinity for the nervous system, with six types of this virus standing out: herpes simplex virus type 1 and 2, varicella zoster, cytomegalovirus, human herpes virus type 6, and Epstein-Barr virus; in the era of HIV / AIDS, immunosuppression, and transplantology, the JC virus has gained importance, which generates progressive multifocal leukoencephalopathy, causing central nervous system degeneration and even leading to sudden death.1-3
Other viruses, such as rubella, hepatitis B and C, and influenza, among others, can also cause symptoms of encephalitis as well as acute flaccid paralysis, Guillain-Barré syndrome, and its variant Miller Fisher, demonstrating trophism on the central nervous system.
Arboviruses, mainly the flavivirus type, can similarly cause severe acute neurological conditions such as acute flaccid paralysis, Guillain-Barré syndrome, transverse myelitis, and more. The most frequent are West Nile virus, St. Louis encephalitis virus, yellow fever, dengue, chikungunya, and Zika.
Regarding dengue, as the best-known model of arbovirus, it is known that up to 5.4% of patients affected by this virus develop neurological involvement, which varies from headache, the most significant and present symptom in 94% of patients, to seizures, encephalopathy, encephalitis, meningitis, polyneuropathy, mononeuropathy, acute flaccid paralysis, transverse myelitis, tonsillar herniation, subarachnoid hemorrhage, Guillain-Barré syndrome and its variant Miller Fisher, and perivenous leukoencephalitis, etc.1
On the other hand, electroencephalographic changes have been shown in dengue patients without neurological manifestations, showing subclinical involvement of viral infection, just as postmortem studies have shown the presence of edema, vascular congestion, and hemorrhagic areas.
The mechanism of pathogenesis appears to be that previously mentioned, neuronal involvement by viral replication and immune complex formation; however, infected CD68+ macrophage migration to the brain has been shown, which could be the vehicle used by the dengue virus (DENV) to reach the nervous system.1
Chikungunya, likewise, showed some affinity for the nervous system, causing reports of isolated cases and outbreaks of Guillain-Barré syndrome, as reported in French Polynesia between 2014 to 2015, before its arrival in America, where a series of 9 patients is described, all with serologic confirmation of IgM, and evidence of viral meningitis in the cerebrospinal fluid, which speaks of viral invasion of the central nervous system, triggering symptoms of Guillain-Barré syndrome.
In a 2006 outbreak in the Reunion Islands, where 40% of the population was affected by CHIKV, an outbreak of Guillain-Barré syndrome was reported in 3 patients with the same characteristics (low incidence). During the outbreak in America (from the Asian lineage), similarly, there were multiple reports of cases of Guillain-Barré syndrome, flaccid paralysis, meningitis, and encephalitis. Similarly, monocytes have been implicated as vehicles of viral transport to inaccessible organs like the brain.4
Perinatal involvement of arboviruses can cause near miscarriage, preterm labor, incomplete and complete miscarriage, and intrauterine growth retardation and in utero malnutrition in the first two trimesters of pregnancy.
Currently, the vertical transmission of dengue from mother to child has been demonstrated, with an average incidence of 1.6%, and variability in the series from 5.6 to 10%, in mothers who had acute viral infection in the third trimester of pregnancy, resulting in a living child, most of the time with leukopenia and thrombocytopenia, but who, after a variable period of observation, was discharged asymptomatic and healthy with no neurological complications.5
Maternal-fetal chikungunya transmission has a higher incidence than that reported with dengue, up to 49%, and more fetal involvement, in the form of generalized bullous dermatosis in addition to fever, anorexia, arthritis, and hemorrhage. Thrombocytopenia occurs in up to 89% of cases of vertical transmission. There is rarely neurological involvement.6
The recent outbreak of Zika in the Americas highlighted the presence of more severe cases with neurological involvement, and even reports of mortality in areas of Africa and Asia where this had not been demonstrated, and where the mildness of Zika had even been remarked on, in the lack of mortality from this cause. However, countries like Colombia and Brazil have reported high incidences of Guillain-Barré syndrome (increase of 19% in 2015 compared with 2014) and deaths from Zika. In the state of Bahia, Brazil, 46 cases of Guillain-Barré syndrome (GB) associated with Zika were reported in July 2015. Honduras has reported 35 cases of GB out of 4785 cases of Zika through February 2016. Venezuela reported 252 GB cases out of 5221 cases through February 2016.
Regarding maternal-fetal vertical transmission, Zika, unlike dengue and chikungunya, is causing exponentially more cases of microcephaly (up to 20-fold over normal incidence), which was detected primarily in Brazil, the country most affected by Zika, reporting an average of 1.3 million native cases through December 2015.
In addition to microcephaly, there have been several changes in the nervous system, such as calcification, agenesis of the corpus callosum, dilated lateral ventricles, midbrain and spinal cord hypoplasia, and Wallerian degeneration in the descending spinal tracts. Evidence of viral material in brain tissue, as well as placental and amniotic fluid, further increases the causal suspicion of Zika and microcephaly, although it is not yet confirmed or supported by global health organizations.
In Brazil, 4180 suspected cases of microcephaly were reported, of which 270 cases were confirmed (6 of them had the virus, two were stillborn, 4 were born alive, and of these, 3 died); brain damage was ruled out in 462 cases, and the study of the remaining 3448 cases is ongoing.
It is striking that in countries like Colombia, second in Zika incidence in South America, there are no reported cases of microcephaly, calling into question the causal relationship, however this is still being debated; the World Health Organization says it is a circumstantial link that is not scientifically demonstrated.7-9
Given the above, it can be concluded that viruses, both DNA and RNA, mainly arboviruses, may have increased affinity and avidity for the nervous system, manifested in various ways, but that, with each outbreak in a virgin or non-endemic area, can cause the appearance of atypical or severe cases of its previously known manifestations, probably because of the lack of primary infection or immunological memory, which makes our immune system not defend itself as usual, generating higher a incidence and prevalence of cases with complications.
Current concerns are that the vectors are highly prevalent throughout the Americas, including species of the genus Aedes aegypti and albopictus, and to a lesser extent the genus Culex could be involved in the viral transfer to all known regions, encouraging the current pandemic.
Similarly, the spectrum of manifestations that may be due to Zika virus is not yet fully known, especially the severe neurological conditions, rarely seen previously, as well as the high incidence of microcephaly which suggests the hypothesized neurotropism of the Zika virus.
Having been declared by the World Health Organization as a public health emergency of international concern, tools of discriminant diagnosis for various flavivirus are currently being worked on, as well as planning murine models to assess the viral effect on the nervous system and fetal development, and new products for vector control and effective treatment strategies, in addition to preventative vaccines.10
As a final note, the increasing causal relationship of Zika with Guillain-Barré syndrome and microcephaly is highlighted, which suggests a major neurotropism yet to be scientifically proven and recognized worldwide.
Conflict of Interest Statement: el autor completó y envió la forma traducida al español de la declaración de conflictos potenciales de interés del Comité Internacional de Editores de Revistas Médicas, y no reportó alguno que tuviera relación con este artículo.