Introduction/Clinical Case

A 34-year-old Canadian-born woman traveled to Nicaragua for tourism in August 2016. On the tenth day of travel, she developed a papular rash across her chest that spread along her arms, legs, and face. She became febrile and complained of muscle fatigue and weakness involving her arms and legs, arthralgia of the wrists and ankles, and global headache with photophobia. Exposures during the trip were notable for several daytime mosquito bites. She had no prior travel history and had not received prior immunization against yellow fever. She was assessed by a physician in Nicaragua who made a presumptive diagnosis of Zika virus (ZIKV) infection but no diagnostic investigations were performed.

She returned home 4 days after the onset of symptoms and was assessed in our unit the following day. On physical examination, the patient was afebrile with normal vital signs, with a macular rash on the lower extremities, and tender non-effusive joints in the hands, wrists, elbows, and feet. Neurologic examination identified global weakness, most pronounced in the left hip flexor (4/5). Deep tendon reflexes were normal (2+) throughout. Sensation was intact but reduced in the left lower extremity. Routine blood work was normal with negative malaria testing. Serologies for travel-related infections were ordered (Table 1) and the patient was discharged home with instructions to rest and return before her 1-week follow-up should any symptoms worsen.

Table 1 Summary of Investigations
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Four days later, she re-presented to our institution with headache, debilitating muscle weakness, and an inability to ambulate independently. On examination, she was afebrile and without rash. Neurologic examination revealed worsening lower extremity muscle weakness in the left hip flexor (3/5) and diminished power (4/5) in the rest of upper and lower extremity muscle groups. Deep tendon reflexes were diminished (1+) and symmetric in the upper and lower extremities. Sensory examination demonstrated decreased light touch, pain, and temperature sensation in a ‘glove-and-stocking’ distribution. Cranial nerve examination revealed decreased sensation (soft touch, pain, and temperature) in the left-sided distributions of cranial nerve V (V1,V2, and V3) and decreased power in the left orbicularis oculi.

Routine investigations were normal (Table 1). Magnetic resonance imaging (MRI) of the brain and spine were normal. Cerebrospinal fluid (CSF) analysis was notable for a white blood cell count of 28/mm3 (85% lymphocytes, reactive) and protein concentration above the upper limit of normal (0.49 g/L). ZIKV RNA was detected from CSF via polymerase chain reaction (PCR). Serum PCR for ZIKV was negative but ZIKV IgM antibody was reactive, with plaque reduction neutralization test (PRNT) titers corroborating the molecular ZIKV diagnosis (Table 1).

The patient received supportive care in hospital over a 5-day admission. She did not receive intravenous immunoglobulin (IVIG). On discharge, she was able to ambulate with the assistance of a walker and continued to report headache, fatigue, weakness, and numbness in the left thigh. She was followed in the outpatient physiatry clinic for rehabilitation support and management of the post-infectious fatigue syndrome. She was prescribed gabapentin and celecoxib for the management of chronic neuropathic pain. After 1 month, she was able to return to work on a modified schedule required to accommodate the on-going muscle fatigue and weakness. At 4 months post-discharge, she was ambulating independently. Six months post-discharge, there was residual left hip flexor weakness (4/5), decreased light touch sensation in the left lower extremity, and on-going paresthesia with chronic neuropathic pain. Nerve conduction studies performed at that time were normal. By 2 years post-discharge, all symptoms and signs had resolved.

Methods

Mini-Review

We performed a non-systematic mini-review of the English language literature using the PubMed database from inception to October 26, 2018, and combinations of the search terms “Zika*”, “neurologic*”, and “Guillain-Barre syndrome” in order to contextualize the demographic, clinical, and laboratory features of our patient with what is already known about the Guillain–Barre syndrome in ZIKV infection. Bibliographies of literature identified by our search strategy were also hand searched for additional relevant reports. We restricted our review to studies reporting primary data on clinical course, diagnosis, and treatment of Guillain–Barre syndrome in Zika and included all observational studies, case series, and case reports.

Discussion

Neurologic Sequelae of Zika Virus Infection

Most people infected with ZIKV suffer mild, if any, symptoms typically consisting of fever, rash, arthralgia, and non-purulent conjunctivitis [1]. The putative association with neurologic disorders was first made in the 2015 ZIKV outbreak in French Polynesia with a study which found that all of the patients diagnosed with Guillain–Barré syndrome during the surveillance period had evidence of ZIKV infection [2•,3]. Since then, several case reports/series and surveillance reports from Latin American, South America, and Oceania have corroborated the association between ZIKV and Guillain–Barré syndrome [4, 5•, 6,7,8, 9••, 10,11,12,13,14, 15••, 16,17,18,19,20,21,22,23]. Zika virus infection has been associated with additional neurologic complications including sensory polyneuropathy, facial paralysis, vestibulitis, encephalitis/meningoencephalitis, myelitis, and a severe congenital ZIKV syndrome characterized by fetal/neonatal microcephaly and other central nervous system (CNS) abnormalities (reviewed in [24••, 25, 26].

The Guillain–Barré Syndrome

The Guillain–Barré syndrome is classically described as an immune-mediated, post-infectious acute polyradiculoneuropathy attributed to molecular mimicry between the antigenic epitopes of the inciting pathogen and ‘self’ neuronal proteins [27]. It is a known complication of many bacterial and viral infections including Campylobacter jejunii, Mycoplasma pneumoniae, Haemophilus influenzae, influenza virus, Epstein–Barr virus, cytomegalovirus, human immunodeficiency virus, and rarely the arboviruses dengue virus, chikungunya virus, and West Nile virus [27,28,29].

The Guillain–Barré syndrome features progressive, symmetric muscle weakness and diminished or absent deep tendon reflexes, but a spectrum of neurologic manifestations including facial muscle weakness and paresthesia of the hands and feet is well described. Symptoms typically evolve over 2 to 4 weeks following a period of latency after an acute infection or vaccination. Cerebrospinal fluid findings include elevated protein concentration with a white blood cell count < 50/mm3 (the albuminocytologic dissociation), while nerve conduction studies (NCS) are useful in identifying specific disease variants.

Zika Virus-Associated Guillain–Barré Syndrome

The patient presented in the clinical vignette had many features consistent with the Guillain–Barré syndrome though the relatively short interval between the onset of ZIKV illness and neurologic symptoms, and the rapid progression to symptomatic nadir, are atypical of classic post-infectious Guillain–Barré syndrome. Emerging reports of Guillain–Barré-like syndromes from ZIKV-affected regions have described similar clinical profiles (Table 2). A case series conducted in Colombia found that almost half of the patients with proven ZIKV infection and Guillain–Barré syndrome manifested neurologic symptoms soon after onset of the viral illness; 40% had concurrent viremia at the time of their admission for management of the Guillain–Barré syndrome and 57% had positive ZIKV studies from CSF [5••]. These findings have led to speculation that neurologic sequelae of ZIKV infection may result from direct viral infection of peripheral nerves (reviewed in [30••]. Zika virus is phylogenetically related to other neurotropic flaviviruses such as West Nile virus and Japanese encephalitis virus, and the neurotropism of ZIKV has been well established in murine models [31]. However, while studies of human tissues are limited, a recent report of a sural nerve biopsy taken from a patient with ZIKV and Guillain–Barré syndrome did not detect ZIKV in nerve tissue [32, 33]. Alternatively, there is evidence of considerable peptide overlap between the ZIKV polyprotein and human neural proteins [34]. The ZIKV incubation period may provide the time required to generate cross-reactive antibodies, thus allowing concurrent manifestation of ZIKV and neurologic symptoms. Serum analyses have confirmed the presence of circulating autoantibodies in patients with ZIKV-associated Guillain–Barré syndrome, but the anti-ganglioside antibodies typically associated with the Guillain–Barré syndrome are rarely apparent [2•]. These observations raise the possibility that a novel host target is implicated ZIKV-induced Guillain–Barré syndrome [33].

Table 2 Similar clinical profiles
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The spectrum of clinical severity associated with Guillain–Barré-like syndrome following ZIKV infection is broad. Case series have reported rates of admission to intensive care units ranging from 38 to 69% and the need for assisted ventilation ranging from 29 to 35% [2•, 6, 7, 9••]. The majority of the patients reported in the literature received IVIG at the time of diagnosis; however, there have been no prospective or randomized clinical trials to evaluate the efficacy of this intervention or other modalities used in the management of classic Guillain–Barré syndrome, such as plasma exchange (PLEX), for the management of ZIKV-associated neurologic complications (Table 2). Nevertheless, the World Health Organization now recommends either IVIG or PLEX therapy for all patients with Guillain–Barré syndrome who have rapidly progressive symptoms, are unable to walk unaided, or who develop progressive bulbar weakness [35].

While patients reach the nadir of neurologic symptoms within a few days of onset, resolution requires a protracted period of recovery in keeping with the time required for repair of demyelinated peripheral nerves. Anaya and colleagues describe 29 patients with confirmed/probable ZIKV infection complicated by Guillain–Barré syndrome, over half of whom were bed- or chair-bound at the time of discharge [6]. Dirlikov and colleagues reported that 45% of patients in their cohort were discharged from hospital to a rehabilitation facility or a skilled nursing facility [23]. Among the cases reviewed in Table 2, most patients with Guillain–Barré syndrome regained independent ambulation several weeks following infection. Neuropathic pain and paresthesia can take longer to resolve.

Conclusions

There has been an exponential rise in the number of reported ZIKV infections among travelers since 2013 [36••, 37,38,39,40]. A wide spectrum of acute ZIKV infection manifestations have been reported in Canadian travelers returning from South America and the Caribbean, including neurologic complications. Currently, the pathogenesis of ZIKV-associated Guillain–Barré syndrome is poorly understood. It may involve the classic mechanisms of immune-mediated polyradiculoneuropathy, or result from direct cytopathic effect of ZIKV infection, or both.

Returned travelers from ZIKV-endemic regions with onset of the Guillain–Barré-like syndrome warrant testing for markers of ZIKV infection, including PCR (serum, urine, CSF) and IgM/IgG serology (serum, CSF), and should be followed carefully until the nadir of the neurologic symptoms is established and the symptoms of active viremia have abated. Progressive neurologic compromise may necessitate monitoring and treatment in an intensive care unit. Zika virus-associated Guillain–Barré syndrome can result in long-term disability. Patients should be counseled to expect a protracted recovery period and may benefit from multidisciplinary rehabilitation therapy as well as pharmacologic therapy to manage neuropathic pain.