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Neurologic manifestations of Zika virus infection/Manifestaciones neurologicas de la infeccion por el virus zika.

An Fac med. 2017;78(1):83-7 / http://dx.doi.org/10.15381/anales.v78i1.13027

Abstract

Zika virus is a flavivirus transmitted via mosquito bite, blood transfusion, sexual intercourse or from mother-to-child during gestation. Although neurologic complications of Zika virus infection are rare, Guillain-Barre syndrome (GBS) is the most common manifestation and typically develops soon after the initial systemic manifestations of Zika virus infection. This syndrome typically starts in the distal limbs with symmetric sensory abnormalities and progresses to involve weakness and decreased or absent deep tendon reflexes. Severe cases may also involve respiratory and cardiovascular impairment requiring care in an intensive care unit, and ventilator or circulatory support. A review of 166 published cases of GBS associated with Zika virus is notable for lower mortality than seen with sporadic GBS, but limited data regarding long-term outcome. When available, treatment with intravenous IgG (IVIg) or plasmapheresis, can reduce the severity and duration of symptoms.

Keywords: Zika Virus; Neurologic Manifestations; Central Nervous System Infection; Guillain-Barre Syndrome.

Resumen

El virus zika es un flavivirus transmitido a traves de la mordedura de mosquito, transfusion de sangre, la relacion sexual o de madre a hijo durante la gestacion. Aunque las complicaciones neurologicas de la infeccion por el virus zika son raras, el sindrome de Guillain-Barre (GBS) es la manifestacion mas comun y normalmente se desarrolla poco despues de las manifestaciones sistemicas iniciales de la infeccion por el virus. Este sindrome comienza en las extremidades distales con alteraciones sensoriales simetricas y progresa hasta involucrar la debilidad y la disminucion o ausencia de reflejos tendinosos profundos. Los casos graves pueden implicar deterioro respiratorio y cardiovascular, requiriendo atencion en una unidad de cuidados intensivos, asi como ventilador o soporte circulatorio. Una revision de 166 casos publicados de GBS asociados con el virus zika se caracteriza por una menor mortalidad que los observados con GBS esporadica, pero los datos son limitados con respecto a resultados a largo plazo. Cuando este disponible, el tratamiento con IgG intravenoso (IVIg) o plasmaferesis puede reducir la gravedad y duracion de los sintomas.

Palabras clave. Virus Zika; Manifestaciones Neurologicas; Infeccion del Sistema Nervioso Central; Sindrome de Guillain-Barre.

INTRODUCCION

Zika virus is an arthropod-borne RNA virus in the flaviviridae family, a family that includes other neurotropic viruses such as dengue, yellow fever, Japanese encephalitis, West Nile and Saint Louis encephalitis viruses. Although Zika virus was first described in Uganda in 1947, it was not identified as a cause of neurologic disorders until Guillain-Barre syndrome (GBS) was reported in French Polynesia in 2013 (1,2). Since then, Zika virus infection has also been associated with microcephaly, encephalitis and myelopathy. Microcephaly in Brazil was initially reported in early 2016 and will be discussed in a separate manuscript. Encephalitis or meningoencephalitis associated with Zika virus infection has been reported in four patients, with Zika virus detected in cerebrospinal fluid (CSF) of three of the four patients and anti-Zika antibodies detected in CSF of the fourth patient (3-5). Acute myelitis has also been reported in one patient, also confirmed through detection of Zika virus in CSF (6). As GBS associated with Zika virus infection is currently the most common neurologic manifestation in adults, this review will focus on the clinical features, diagnosis and management of GBS.

GUILLAIN-BARRE SYNDROME

Guillain-Barre syndrome (GBS) is a common cause of acute flaccid paralysis throughout the world. The syndrome is rare and most often follows a bacterial or viral infection, or less frequently, vaccination. Symptoms typically include weakness and sensory abnormalities but may also include cranial nerve abnormalities, such as ophthalmoplegia (the Fisher syndrome). Weakness starts in the distal limbs, then progresses proximally, and can progress to paralysis; is typically associated with decreased or absent deep tendon reflexes as well as sensory loss, paresthesia or dysesthesia that starts in the peripheral limbs and ascends proximally.

Guillain-Barre syndrome associated with Zika virus infection

The onset of neurologic symptoms typically follows a prodromal illness that may include rash, fever, arthritis and conjunctivitis. The median onset of neurologic symptoms of GBS following transient illness with Zika virus is 6-10 days, which is similar to the median interval of 9 days reported between onset of neurologic symptoms of GBS and diarrhea due to Camphylobacter jejuni infection (7-10). Given the lack of prior reports of GBS in Uganda, some experts have postulated that prior exposure to another arboviral infection, specifically dengue or chikungunya, is necessary for Zika to produce GBS through an immune-mediated mechanism. In one study, evidence of prior dengue infection was present in 32 (86%) of 37 patients with GBS (9). In this same study, 20 (29.4%) of 68 patients with Zika virus-associated GBS had onset of neurologic symptoms during or immediately following the viral prodrome, suggesting a portion of the GBS symptoms could be due to direct effects of viral infection (9). Neuropathologic studies in human and non-human primate fetuses have detected Zika virus in brain tissue (11,12). Immunohistochemical assays have further localized Zika virus infection to neurons and glial cells (13). Neuropathologic studies of patients with Zika-associated GBS have not been published.

The clinical symptoms associated with GBS due to Zika virus infection are similar to those due to other etiologies of GBS. Table 1 provides an overview and summary of specific symptoms, neurologic findings and frequency of respiratory and intensive care unit support required for patients with Zika-associated GBS. Although there is no particular neurologic finding that would suggest Zika virus over an alternate etiology, clinical symptoms typically appear distally and symmetrically, as opposed to West Nile virus infection, which typically produces an asymmetric flaccid paralysis similar to polio (14).

Diagnosis

Diagnosis of GBS requires confirmation of a peripheral neuropathy by neurophysiologic testing (15). There are multiple potential types of peripheral nerve dysfunction associated with GBS (acute inflammatory demyelinating polyneuropathy, AIDP; acute motor and sensory axonal neuropathy, AMSAN; acute motor neuropathy, AMAN; acute sensory neuronopathy, acute pandysautonomia and overlap syndrome) and criteria for electrodiagnosis vary with the subtype of GBS. Measurement of nerve conduction velocity and needle electromyography are used to characterize and confirm the presence of demyelinating polyradiculoneuropathy or axonal damage in affected limbs. Specific guidelines are available to help diagnose and differentiate between the various forms of GBS (15). The likelihood of detecting abnormalities with neurophysiologic testing is maximal at 7 or more days following onset of illness.

Lumbar puncture in patients with GBS should demonstrate less than 50 white blood cells/[micro]l in CSF and, when CSF is obtained at least two days after symptoms develop, often reveals a "cytoalbuminologic dissociation"--an elevation of CSF protein greater than 45 mg/dL (this level may vary by local laboratory). Lumbar puncture is also useful for excluding other infectious causes of acute flaccid paralysis. The Brighton criteria were developed to provide guidelines for diagnosing GBS with four levels of diagnostic certainty (Table 2) (16). These criteria incorporate clinical, electrodiagnostic and CSF findings and provide a useful tool for case ascertainment of GBS.

As is the case for many viral infections of the central nervous system (CNS), detection of virus in CSF is transient and is often absent by the time neurologic symptoms develop. As GBS is often an immune-mediated response to the CNS initiated by a bacterial or viral infection, detection of Zika virus in CSF is not necessary, but is more likely if neurologic symptoms start during the prodromal stage with systemic symptoms, such as rash and arthralgia. Current assays can directly detect Zika virus RNA or the immune response developed by the immune system against the Zika virus (Table 3) (17).

During the initial viremic period, realtime reverse transcriptase polymerase chain reaction (rRT-PCR) can be used to detect virus in blood, CSF, saliva or urine up to a week after onset of symptoms (18). A positive rRT-PCR confirms the presence of Zika virus infection, but as viremia is transitory, a negative test does not exclude the diagnosis. Presence of Zika virus RNA in urine has been reported to start approximately two weeks after onset of viral symptoms and in one patient persisted for 48 days, suggesting that duration of detection of viral RNA by rRT-PCR may vary across body fluids (9,19).

The detection of specific IgM antibodies or a significant rise in the anti-Zika IgG titer in a pair of samples taken at least two weeks apart provides evidence of an acute infection. Anti-Zika virus IgM can be detected by enzyme-linked immunosorbent assay (ELISA) in CSF or serum following the initial viremic phase until about 12 weeks after infection. Neutralizing antibodies to Zika virus develop following appearance of IgM antibodies, are primarily IgG, and typically persist for years. Unfortunately, Zika virus antibody assay results can be obscured due to cross-reactivity with other flaviviruses, which can prevent identification of the specific infecting virus, especially in a person previously infected with or vaccinated against a related flavivirus (20). The plaque reduction neutralization test (PRNT) allows discrimination of antiZika virus antibodies from other potential cross-reacting antibodies due to other flavivirus infections. Although a PRNT [greater than or equal to] 4-fold titer is typically used to confirm an infection, the U.S. Centers for Disease Control and Prevention has suggested a more conservative approach using a titer of [greater than or equal to] 10 against Zika virus and PRNT < 10 against other flaviviruses to confirm infection (17).

Similar to the Brighton Criteria developed to provide levels of diagnostic certainty for GBS, the World Health Organization has developed criteria to determine level of certainty for diagnostic assays for Zika virus infection (21). These levels of diagnostic certainty have been further modified to include CSF testing by Parra and colleagues (9), with definite infection requiring detection of Zika virus RNA by rRT-PCR assay in blood, CSF or urine; probable infection requiring detection of anti-Zika antibodies by ELISA in the CSF or serum, as well as exclusion of dengue virus serotypes; and suspected infection requiring two or more features of the PAHO case definition without laboratory confirmation (Table 3).

Treatment

Treatment of GBS is often symptomatic, but as respiratory and cardiovascular systems can also be affected, experts recommend monitoring in an intensive care setting where respiratory and blood pressure support are available. In addition to symptomatic treatment, GBS can be treated with plasmapheresis or high dose intravenous immunoglobulins (IVIg). As plasmapheresis requires specialized equipment for plasma exchange, this procedure is often limited to specialized reference centers and to patients affected by respiratory compromise or hypotension. Although IVIg is easier to administer, cost of treatment is high, typically costing over $US10 000 for a five-day course of 0.4 g/kg bodyweight.

Although outcome of GBS is generally quite good, 5-15% of patients die and 20% remain disabled at one year (22). Factors associated with poor prognosis include requiring mechanical ventilation, rapid onset of weakness and severe weakness at nadir of illness (23). Although long-term neurologic outcome following Zika-associated GBS is not yet clear, reports suggest mortality from Zika-associated GBS, when appropriate intensive care services and treatment are available, is less than 5%. Reports of long-term outcome following Zika-associated GBS are few, but suggest the majority of patients recover the ability to walk without assistance (Table 1).

CONCLUSIONS

The neurologic complications of Zika virus infection in adults include Guillain-Barre syndrome (GBS), meningitis, encephalitis and myelitis. The most common of these complications is GBS. The clinical presentation and course of illness of GBS due to Zika virus infection appears to be very similar to GBS caused by other etiologies. Healthcare providers in areas where Zika is endemic, or who evaluate patients who have recently traveled through an endemic area or had sex with a person who may have had Zika infection, should consider Zika virus as a possible etiology of GBS. Treatment frequently requires an intensive care unit to provide support for respiratory and cardiovascular decompensation. In addition, IVIg and plasmapheresis, where available, can reduce duration and severity of symptoms.

ACKNOWLEDGMENT

I would like to thank Mrs. Mallory Erickson for her assistance with developing Tables 1-3.

REFERENCES

(1.) Oehler E, Watrin L, Larre P, Leparc-Goffart I, Lastere S, Valour F, et al. Zika Virus Infection complicated by Guillain-Barre syndrome - case report, French Polynesia, December 2013. Eurosurveillance. 2014;19(4):Pii20720.

(2.) Dick GW, Kitchen SF, Haddow AJ. Zika virus. I. Isolations and serological specificity. Trans R Soc Trop Med Hyg. 1952;46(5):509-20.

(3.) Carteaux G, Maquart M, Bedet A, Contou D, Brugieres P, Fourati S, et al. Zika virus associated with meningoencephalitis. N Engl J Med. 2016;374(16):1595-6. doi: 10.1056/NEJMc1602964.

(4.) Roze B, Najioullah F, Signate A, Apetse K, Brouste Y, Gourgoudou S, et al. Zika virus detection in cerebrospinal fluid from two patients with encephalopathy, Martinique, February 2016. Euro Surveill. 2016;21(16). doi: 10.2807/1560-7917. ES.2016.21.16.30205.

(5.) Soares CN, Brasil P, Carrera RM, Sequeira P, de Filippis AB, Borges VA, et al. Fatal encephalitis associated with Zika virus infection in an adult. J Clin Virol. 2016;83:63-5. doi: 10.1016/j.jcv.2016.08.297.

(6.) Mecharles S, Herrmann C, Poullain P, Tran TH, Deschamps N, Mathon G, et al. Acute myelitis due to Zika virus infection. Lancet. 2016;387(10026):1481. doi: 10.1016/S0140-6736(16)00644-9.

(7.) Arias A, Torres-Tobar L, Hernandez G, Paipilla D, Palacios E, Torres Y, et al. Guillain-Barre syndrome in patients with a recent history of Zika in Cucuta, Colombia: A descriptive case series of 19 patients from December 2015 to March 2016. J Crit Care. 2016;37:19-23. doi: 10.1016/j.jcrc.2016.08.016.

(8.) Cao-Lormeau VM, Blake A, Mons S, Lastere S, Roche C, Vanhomwegen J, et al. Guillain-Barre Syndrome outbreak associated with Zika virus infection in French Polynesia: a case-control study. Lancet. 2016;387(10027): 1531-9. doi: 10.1016/S0140-6736(16)00562-6.

(9.) Parra B, Lizarazo J, Jimenez-Arango JA, Zea-Vera AF, Gonzalez-Manrique G, Vargas J, et al. Guillain-Barre Syndrome associated with Zika virus infection in Colombia. N Engl J Med. 2016. doi: 10.1056/NEJMoa1605564.

(10.) Rees JH, Soudain SE, Gregson NA, Hughes RA. Campylobacter jejuni infection and Guillain-Barre syndrome. N Engl J Med. 1995;333(21):1374-9. doi: 10.1056/NEJM199511233332102.

(11.) Adams Waldorf KM, Stencel-Baerenwald JE, Kapur RP, Studholme C, Boldenow E, Vornhagen J, et al. Fetal brain lesions after subcutaneous inoculation of Zika virus in a pregnant nonhuman primate. Nat Med. 2016. doi: 10.1038/nm.4193.

(12.) Mlakar J, Korva M, Tul N, Popovic M, Poljsak-Prijatelj M, Mraz J, et al. Zika virus associated with microcephaly. N Engl J Med. 2016;374(10):951-8. doi: 10.1016/S0140-6736(16)30883-2.

(13.) Martines RB, Bhatnagar J, de Oliveira Ramos AM, Davi HP, Iglezias SD, Kanamura CT, et al. Pathology of congenital Zika syndrome in Brazil: a case series. Lancet. 2016;388(10047):898-904. doi: 10.1016/S0140-6736(16)30883-2.

(14.) Sejvar JJ, Leis AA, Stokic DS, Van Gerpen JA, Marfin AA, Webb R, et al. Acute flaccid paralysis and West Nile virus infection. Emerg Infect Dis. 2003;9(7):788-93. doi: 10.3201/eid0907.030129.

(15.) Hughes RA, Cornblath DR. Guillain-Barre syndrome. Lancet. 2005;366(9497):1653-66. doi:10.1016/S0140-6736(05)67665-9.

(16.) Fokke C, van den Berg B, Drenthen J, Walgaard C, van Doorn PA, Jacobs BC. Diagnosis of Guillain-Barre syndrome and validation of Brighton criteria. Brain. 2014;137(Pt 1):33-43. doi: 10.1093/brain/awt285.

(17.) Rabe IB, Staples JE, Villanueva J, Hummel KB, Johnson JA, Rose L, et al. Interim Guidance for Interpretation of Zika Virus Antibody Test Results. MMWR Morb Mortal Wkly Rep. 2016;65(21):543-6. doi: 10.15585/mmwr.mm6521e1.

(18.) Musso D, Roche C, Nhan TX, Robin E, Teissier A, Cao-Lormeau VM. Detection of Zika virus in saliva. J Clin Virol. 2015;68:53-5. doi: 10.1016/j. jcv.2015.04.021.

(19.) Roze B, Najioullah F, Ferge JL, Apetse K, Brouste Y, Cesaire R, et al. Zika virus detection in urine from patients with Guillain-Barre syndrome on Martinique, January 2016. Euro Surveill. 2016;21(9). doi: 10.2807/1560-7917.ES.2016.21.9.30154.

(20.) Calisher CH, Karabatsos N, Dalrymple JM, Shope RE, Porterfield JS, Westaway EG, et al. Antigenic relationships between flaviviruses as determined by cross-neutralization tests with polyclonal antisera. J Gen Virol. 1989;70 (Pt 1):37-43. doi: 10.1099/0022-1317-70-1-37.

(21.) Zika: Case Definitions Washington, D.C.: Pan American Health Organization; 2016 [Available from: http://www.paho.org/hq/index.php?option=com_content&view=article&id=11117&Itemid=41532.

(22.) Rees JH, Thompson RD, Smeeton NC, Hughes RA. Epidemiological study of Guillain-Barre syndrome in south east England. J Neurol Neurosurg Psychiatry. 1998;64(1):74-7.

(23.) Singh NK, Jaiswal AK, Misra S, Srivastava PK. Prognostic factors in Guillain-Barre' syndrome. J Assoc Physicians India. 1994;42(10):777-9.

(24.) Dirlikov E, Major CG, Mayshack M, Medina N, Matos D, Ryff KR, et al. Guillain-Barre Syndrome during ongoing Zika virus transmission - Puerto Rico, January 1-July 31, 2016. MMWR Morb Mortal Wkly Rep. 2016;65(34):910-4. doi: 10.15585/mmwr.mm6534e1.

(25.) do Rosario MS, de Jesus PA, Vasilakis N, Farias DS, Novaes MA, Rodrigues SG, et al. Guillain-Barre Syndrome after Zika virus infection in Brazil. Am J Trop Med Hyg. 2016. doi: 10.4269/ajtmh.16-0306.

Joseph R. Zunt (1,2,3,4)

Departments of Global Health (1), Neurology (2), Medicine (Infectious Diseases) (3), and Epidemiology (4), University of Washington, Seattle, USA.

Correspondence

Joseph R. Zunt jzunt@uw.edu

Harborview Medical Center 325 Ninth Ave Box 359775 Seattle, WA 98104

Received, 20 December 2016

Reviewed, 10 January 2017

Accepted, 18 January 2017

Conflict of interest: None

Financing: Own resources

Citar como: Zunt JR. Neurologic manifestations of Zika virus infection. An Fac med. 2017;78(1):83-7.
Table 1. Clinical features of Guillain-Barre Syndrome associated with
Zika virus infection. Compiled from references (1, 7-9, 24, 25).

                                     Publication
Clinical feature               Arias            Dirilikov
                              (n = 19)           (n=34)

Male gender                      12 (63.2%)        14 (41%)
Median onset days (Range)        10 (2-20)          5 (0-17)
Rash                             17 (89%)          18 (56%)
Fever                            15 (79%)          12 (30%)
Arthritis                        14 (74%)           -
Conjunctivitis                    7 (37%)           -
Diarrhea                           -                7/21 (34%)
Facial palsy                      8 (42.1%)        20/32 (63%)

Dysphagia                         5 (26%)          19/32 (59%)
Paresthesias                     14 (73.7%)    Leg 24/32 (75%)
Limb paresis               Upper 13 (68.4%)  Upper 24/32 (75%)
                           Lower 19 (100%)   Lower 31/32 (97%)
Areflexia                        18 (95%)          31/32 (97%)
Increased CSF protein             8 (42.1%)        25/25 (100%)
Respiratory assistance           15 (79%)          12/32 (29%)
Labile blood pressure
Hypotension                      15 (79%)           -
ICU stay                         19 (100%)         21 (62%)
Disability (3 months)             -                 -
Death                             0/19 (0%)         1/34 (3%)

                                 Publication
Clinical feature           Oehler      Cao-Lorameau
                           (n = 1)    (n=42)[degrees]

Male gender                   -          31 (74%)
Median onset days (Range)     7          6 (4-10)
Rash                       1 (100%)     29/36 (81%)
Fever                      1 (100%)     18/31 (58%)
Arthritis                  1 (100%)     23/31 (74%)
Conjunctivitis             1 (100%)     15/31 (48%)
Diarrhea                      -             -
Facial palsy               1 (100%)     33 (79%)
                           Bilateral  Bilateral 25 (60%)
Dysphagia                     -         19 (45%)
Paresthesias               1 (100%)     35 (83%)
Limb paresis               1 (100%)     33 (79%)
                                       Lower 17 (40%)
Areflexia                  1 (100%)     20 (48%)
Increased CSF protein      1 (100%)     39 (93%)
Respiratory assistance        -         12 (29%)
Labile blood pressure
Hypotension                1 (100%)     -
ICU stay                   0 (0%)       16 (30%)
Disability (3 months)         *         24/57
Death                      0/1 (0%)      0/42 (0%)

                                   Publication
Clinical feature            Do Rosario       Parra
                              (n=2)          (n=68)

Male gender                  1 (50%)        38 (565)
Median onset days (Range)    9 (8-10)        7 (3-10)
Rash                         2 (100%)       40 (59%)
Fever                        1 (50%)        47 (69%)
Arthritis                    2 (100%)       15 (22%)
Conjunctivitis                0 (0%)        17 (25%)
Diarrhea                        -             -
Facial palsy                 2 (100%)       34 (50%)
                           All Bilateral  All Bilateral
Dysphagia                    2 (100%)         -
Paresthesias                 2 (100%)       52 (76%)
Limb paresis                 2 (100%)       66 (97%)

Areflexia                    2 (100%)       64 (94%)
Increased CSF protein        2 (100%)       45/55 (82%)
Respiratory assistance       -              21 (31%)
Labile blood pressure
Hypotension                  -              41 (31%)
ICU stay                     0 (0%)         40 (59%)
Disability (3 months)        **              -
Death                        0/2 (0%)        3/68 (4%)

                           Publication
Clinical feature              Total
                            (n = 166)

Male gender                96/165 (58%)
Median onset days (Range)       -
Rash                       107/160 (67%)
Fever                       94/155 (61%)
Arthritis                   55/121 (45%)
Conjunctivitis              40/121 (33%)
Diarrhea
Facial palsy                98/164 (60%)

Dysphagia                   45/95 (47%)
Paresthesias               128/164 (78%)
Limb paresis               152/164 (93%)

Areflexia                  136/164 (83%)
Increased CSF protein      120/144 (83%)
Respiratory assistance      60/161 (37%)
Labile blood pressure
Hypotension                 57/88 (65%)
ICU stay                    56/95 (59%)
Disability (3 months)           -
Death                        4/166 (2.4%)

(*) Day 4: Walking without assistance
(**) Day 28: House-Brackmann Grade 2, Day 47: House-Brackmann Grade 3

Table 2. Key diagnostic criteria and Brighton case definitions for
Guillain-Barre syndrome.

                                       Level of diagnostic certainty
Diagnostic criteria                    1     2          3    4

Bilateral and flaccid weakness
of limbs                               +     +          +  + / -
Decreased or absent deep tendon
reflexes in weak limbs                 +     +          +  + / -
Monophasic course and time
between onset-nadir 12 h to 28
days                                   +     +          +  + / -
CSF cell count <50 white blood
cells/mL                               +     + (a)      -  + / -
CSF protein concentration > 45
mg/dL                                  +     + / - (a)  -  + / -
Nerve conduction study consistent
with one of the subtypes of GBS        +     + / -      -  + / -
No alternative diagnosis for weakness  +     +          +    +

+ present; - absent; + / - present or absent
(a) If CSF results not available, nerve conduction study must be
consistent with diagnosis of Guillain-Barre syndrome

Table 3. Key clinical and laboratory diagnostic criteria for Zika virus
infection with and without Guillain-Barre Syndrome.

                 Zika virus disease
               Clinical AND Laboratory

Suspected (*)

               Patient with rash with two
               or more of the following
Probable       signs or symptoms:

               1) Fever <38.5[degrees] C
               2) Conjunctivitis (non-
               purulent/ hyperemic)

               3) Arthralgia

               4) Myalgia
Confirmed

               5) Peri-articular edema

                       Zika virus disease
                     Clinical AND Laboratory

Suspected (*)       No laboratory confirmation


                Zika IgM antibodies without evidence of
Probable        other flavivirus infection

                RNA or Zika virus antigen detected in
                serum, urine, saliva, tissue or whole blood;
                                 OR
                Positive Zika IgM antibodies AND Plaque
                reduction neutralization (PRNT90) for Zika
Confirmed       virus titers = 20 and [greater than or equal to]
                four times greater
                than titers for other flaviviruses; AND

                exclusion of other flavivirus; OR
                detection of Zika viral genome in
                autopsy specimen (fresh or paraffin
                tissue) by molecular techniques or
                immunohistochemistry

                 Zika associated GBS
               Clinical AND Laboratory

Bilateral and flaccid
weakness of the limbs        No laboratory confirmation
AND
                             Detection of anti-Zika antibodies by
Decreased or absent deep     enzyme-linked immunosorbent assay
tendon reflexes in weak      (ELISA) in CSF, serum, or urine and
limbs                        exclusion of the four dengue virus
AND                          serotypes

Monophasic illness pattern,
with interval between onset
  and nadir of weakness
  between 12 hours and
  28 days, and subsequent    Detection of Zika virus RNA by real-time
   clinical plateau          reverse-transcriptase polymerase
                             chain reaction (RT-PCR) assay in blood,
         AND                 CSF or urine


Absence of identified
alternative diagnosis for
weakness (**)

(*) Adapted from PAHO Zika: Case Definition (7). Suspected case
requires potential exposure through 1) Zika virus disease in geographic
areas with autochthonous transmission and vectors are present; OR 2)
travel to or residing in, a geographic area with known vector presence
or Zika virus transmission within 2 weeks prior to onset of symptoms;
OR 3) un-protected sex, in the 2 weeks prior to onset of symptoms, with
a person who traveled, in the previous 8 weeks, to a geographic area
with (a) known local transmission of the Zika virus or (b) an area with
known vector presence.
(**) See Table 1 for levels of diagnostic certainty.
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