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June 13, 2017; 88 (24) Clinical/Scientific Notes

Zika virus infection–associated acute transient polyneuritis

Osvaldo J.M. Nascimento, Jennifer A. Frontera, Daniel A. Amitrano, Ana M. Bispo de Filippis, Ivan R.F. Da Silva
First published May 12, 2017, DOI: https://doi.org/10.1212/WNL.0000000000004026
Osvaldo J.M. Nascimento
From the Universidade Federal Fluminense (O.J.M.N., D.A.A.), Niteroi, Brazil; Cerebrovascular Center of the Neurological Institute (J.A.F.), Cleveland Clinic, OH; the Flavivirus Laboratory (A.M.B.d.F.), Oswaldo Cruz Foundation, Rio de Janeiro, Brazil; and Rush University Medical Center (I.R.F.D.S.), Chicago, IL.
MD, PhD
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Jennifer A. Frontera
From the Universidade Federal Fluminense (O.J.M.N., D.A.A.), Niteroi, Brazil; Cerebrovascular Center of the Neurological Institute (J.A.F.), Cleveland Clinic, OH; the Flavivirus Laboratory (A.M.B.d.F.), Oswaldo Cruz Foundation, Rio de Janeiro, Brazil; and Rush University Medical Center (I.R.F.D.S.), Chicago, IL.
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Daniel A. Amitrano
From the Universidade Federal Fluminense (O.J.M.N., D.A.A.), Niteroi, Brazil; Cerebrovascular Center of the Neurological Institute (J.A.F.), Cleveland Clinic, OH; the Flavivirus Laboratory (A.M.B.d.F.), Oswaldo Cruz Foundation, Rio de Janeiro, Brazil; and Rush University Medical Center (I.R.F.D.S.), Chicago, IL.
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Ana M. Bispo de Filippis
From the Universidade Federal Fluminense (O.J.M.N., D.A.A.), Niteroi, Brazil; Cerebrovascular Center of the Neurological Institute (J.A.F.), Cleveland Clinic, OH; the Flavivirus Laboratory (A.M.B.d.F.), Oswaldo Cruz Foundation, Rio de Janeiro, Brazil; and Rush University Medical Center (I.R.F.D.S.), Chicago, IL.
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Ivan R.F. Da Silva
From the Universidade Federal Fluminense (O.J.M.N., D.A.A.), Niteroi, Brazil; Cerebrovascular Center of the Neurological Institute (J.A.F.), Cleveland Clinic, OH; the Flavivirus Laboratory (A.M.B.d.F.), Oswaldo Cruz Foundation, Rio de Janeiro, Brazil; and Rush University Medical Center (I.R.F.D.S.), Chicago, IL.
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Citation
Zika virus infection–associated acute transient polyneuritis
Osvaldo J.M. Nascimento, Jennifer A. Frontera, Daniel A. Amitrano, Ana M. Bispo de Filippis, Ivan R.F. Da Silva
Neurology Jun 2017, 88 (24) 2330-2332; DOI: 10.1212/WNL.0000000000004026

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Zika virus (ZIKV) has been associated with various neurologic complications in adults, including Guillain-Barré syndrome (GBS), transverse myelitis, meningoencephalitis, and ophthalmologic manifestations. Though some of these syndromes may be due to a postinfectious (molecular mimicry) mechanism, a direct viral pathogenic mechanism may be responsible in others. We present 3 cases of a newly described syndrome of ZIKV-associated acute transient polyneuritis.

Methods.

This article describes a case series of 3 patients admitted to a tertiary hospital in Rio de Janeiro during the 2016 outbreak of Zika virus infection in Brazil.

Standard protocol approvals, registrations, and patient consents.

This study was approved by the HUAP-UFF institutional review board. All patients or their surrogates were consented for participation in this study.

Zika virus diagnosis.

Blood and CSF collected at admission were tested in duplicate using real-time reverse transcriptase PCR (rRT-PCR) for ZIKV following published methods at the Oswaldo Cruz Foundation Flavivirus Laboratory. Urine rRT-PCR was tested in one case.

Other diagnostics.

Electrophysiology studies (EMG and nerve conduction studies) were performed by certified neurologists with specialty training in neuromuscular disease using criteria endorsed by the European Federation of Neurological Societies/Peripheral Nerve Society and American Association of Neuromuscular and Electrodiagnostic Medicine (e-Methods at Neurology.org). All examinations included nerve testing in both upper and lower extremities and F wave testing. Nerve ultrasound was performed of the bilateral median nerves (1–2 cm proximal to the carpal tunnel) and bilateral superficial peroneal nerves (5 cm above the medial malleolus). Brain and spine 3T MRI with gadolinium administration and nerve ultrasound were interpreted by independent, board-certified neuroradiologists. Other blood testing was conducted to rule out alternative causes of muscular/peripheral nerve disease (e-Methods).

Results.

Three patients presented to the Antonio Pedro University Hospital of Universidade Federal Fluminense in Rio de Janeiro, Brazil, with signs and symptoms of distal pain, stocking-glove hypoesthesia, mild distal weakness, and hyporeflexia within 1–2 days of ZIKV symptom onset. Clinical examination, imaging, electrophysiologic, and outcome findings for these patients are delineated in the table. Nerve ultrasound demonstrated bilaterally enlarged median nerves in patients 1 and 2 (figure e-1). Mental status, cranial nerves, and cerebellar examination were normal for all patients, as were muscle enzyme testing, inflammatory serology testing, and other routine laboratory studies. No patient met Brighton1 or electrophysiologic criteria for GBS.

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Table

Clinical and laboratory findings in patients with Zika virus–associated polyneuritis

Discussion.

We report acute ZIKV infection accompanied by clinical findings consistent with a mild, self-limited, distal, sensorimotor neuropathy. Because nerve ultrasound in 2 patients demonstrated enlargement of symptomatic nerves, followed by concomitant improvement in symptoms and nerve diameter on serial ultrasound, the mechanism of this syndrome may be related to nerve swelling. It has been described that some forms of infections might result in segmental nerve inflammation with edema, compromising nerve function in an acute fashion.2,3 For the most part, the Schwann cells are the target of the infectious agent resulting in demyelination, which could evolve into a rapid resolution or further progress, depending on the host's immune response.2,3 Since symptoms and imaging findings tracked closely with ZIKV viremia, we hypothesize that there may be a direct neuropathic effect of ZIKV leading to inflammation and nerve swelling. Others have published reports of weakness developing soon after the first few days of ZIKV infection symptoms, considered early for postinfectious molecular mimicry mechanism of nerve injury, but in this case series the patients developed clinical, laboratory, and electrophysiologic findings highly suggestive of GBS.4 We report 3 cases that do not fit the usual criteria for GBS, as weakness was mild and limited to the extremities, a predominance of sensory symptoms was observed, and rapid improvement of symptoms within the first 7–10 days with associated unrevealing electrophysiologic and CSF testing (repeated weeks later) was noted.

Preliminary research using human neural progenitor cells have shown that ZIKV infection increases cell death and dysregulates cell cycle progression.5 Other flaviviruses, such as West Nile virus, can lead to direct neurotropic injuries as well.

Though nerve conduction studies were normal, mild syndromes with clinical manifestations may manifest with minimal electrophysiologic abnormalities.6,7 Since the syndrome we describe primarily involves distal nerves, normal electrophysiologic studies are not inconsistent with an acute neuropathy. Negative serum and CSF laboratory studies and normal gadolinium-enhanced MRI of the brain and spine diminish the likelihood of a brain, spinal cord, or muscular etiology for our patients' clinical presentations.

Our cases suggest a newly described ZIKV-associated acute transient polyneuritis. It will be important for practitioners to recognize this benign syndrome and differentiate it from other ZIKV-related complications.

Acknowledgments

Acknowledgment: The authors thank Dr. Richard Hughes for his comments on this manuscript and acknowledge coauthor Dr. Daniel A. Amitrano who died prior to publication of this article.

Footnotes

  • Coinvestigators are listed at Neurology.org.

  • Supplemental data at Neurology.org

  • Author contributions: Dr. Nascimento contributed with study design, data analysis, and manuscript writing. Dr. Frontera contributed with study design, data analysis, and manuscript writing. Dr. Amitrano contributed with study design, data analysis, and manuscript writing. Dr. Bispo de Filippis contributed with study design and samples testing. Dr. Da Silva contributed with data collection, study design, data analysis, and manuscript writing. The authors wrote on behalf of the RIO-GBS-ZIKV Research Group (see supplemental data).

  • Study funding: This study was funded by the Cleveland Clinic Foundation, award RPC194-S2.

  • Disclosure: O. Nascimento, J. Frontera, and D. Amitrano report no disclosures relevant to the manuscript. A. Bispo de Fillipis receives grants from Conselho Nacional de Desenvolvimento e Pesquisa (CNPq), Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ). I. Da Silva reports no disclosures relevant to the manuscript. Go to Neurology.org for full disclosures.

  • Received November 2, 2016.
  • Accepted in final form March 22, 2017.
  • © 2017 American Academy of Neurology

References

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    . Evolving pattern of Guillain-Barre syndrome in a community hospital in Israel. Acta Neurol Scand 2008;117:347–350.
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