ZKV and Guillain-Barré Syndrome. Silvia N. Tenembaum Pediatric Neurologist

Transcription

1 ZKV and Guillain-Barré Syndrome Silvia N. Tenembaum Pediatric Neurologist

2 ZIKA VIRUS- BACKGROUND INFORMATION Arbovirus (Arthropod-borne virus) 1- Flaviviridae family: Dengue (DENV) West Nile (WNV) Yellow Fever (YFV) Japanese Encephalitis (JEV) 2- Togaviridae family: Chikungunya (CHIKV) Evidence ZKV is neurotropic Transmitted by infected mosquitoes of the Aedes species (ZKV, DENV, CHIKV)

3 ZIKA VIRUS- BACKGROUND INFORMATION Clinical manifestations ZKV-associated diseases Non-specific acute febrile illness: Self-limited exanthematic disease Neurological manifestations 1. Congenital: Microcephaly- transmitted through transplacental infection (Mother to child) 2. Acquired: Vectorial transmission Guillain-Barré Syndrome Encephalitis - Meningoencephalitis (Carteaux et al, 2016) Acute myelitis (Mecharles et al, 2016)

4 GUILLAIN-BARRÉ SYNDROME and ZIKA VIRUS GBS: Autoimmune neurologic complex embracing several diseases with different underlying pathogenesis and clinical manifestations Global incidence 1-4/ persons-years 2/3 of GBS cases: Triggered by a prior infection Upper respiratory infections (influenza, pseudo-influenza) Gastro-intestinal infections (Campylobacter jejuni) GBS has been associated with a prior infection by: Dengue (DENV) (Solomon et al, 2000) Chikungunya virus (CHIKV) (Wielanek et al, 2007) Zika virus (ZKV) (Cao-Lormeau et al, 2016)

5 GBS and ZKV : French Polynesian case-control study Oct 2013 to Apr 2014: largest ZKV outbreak ever described > suspected cases of ZKV infection 42 cases of GBS Reliable information on the diagnostic criteria used to identify GBS cases Case-control design Rate of SGB after ZKV infection 1 per 4,000 infections Cao-Lormeau et al, The Lancet 2016

6 GBS and ZKV : French Polynesian case-control study Cao-Lormeau et al, The Lancet 2016

7 Main characteristics of ZKV-associated GBS in 42 patients n (%) or Median Age (years) 42 (36-56) Men 32 (74%) Previous viral clinical syndrome 37 (88) Time between viral syndrome and onset of neurol symptoms (days) 6 (4-10) Time between onset of neurol symptoms and peak of illness (days) 6 (4-9) Neurological syndrome Muscle weakness Facial palsy Incapacity to walk Trouble swallowing Treatment IVIg PLEX Respiratory assistance 31 (74) 27 (64%) 18 (44) 10 (24) 42 (100) 1 (2) 12 (29) Cao-Lormeau et al, The Lancet 2016

8 Main characteristics of ZKV-associated GBS in 42 patients n (%) or Median Duration of hospital stay (days) 11 (7-20) CSF Increased protein level Cells (per mm3) 39 (93) 4 (1-7) Outcome at 3 months Able to walk 57% Cao-Lormeau et al, The Lancet 2016

9 EMG examination in 42 patients with ZKV-associated GBS EMG at 1st week Motor Nerve Conduction 37/42 patients Prolonged distal latencies Reduction of distal CMAP amplitude SEVERE CONDUCTION ABNORMALITY IN DISTAL NERVE SEGMENTS Sensitive Nerve Conduction Normal amplitude Normal conduction velocity EMG 4 months later Motor Nerve Conduction 19/37 patients Reduction of the prolonged distal latencies Near normalization of CMAP amplitudes ACUTE MOTOR AXONAL NEUROPATHY Cao-Lormeau et al, The Lancet 2016

10 Differences between ZKV-associated GBS and classical AMAN ZKV-associated GBS Facial Palsy 79% Fatalities -- Full recovery 57% Antigenic mimicry ZKV-Ag and Glycolipid GA1 -- Cao-Lormeau et al, The Lancet 2016 Concomitant massive peptide overlap between ZIKV polyprotein and human proteins linked to myelin, (de)myelination, and axonal neuropathy provides an robust argument for a crossreactivity mechanism as a link between ZIKV infection and GBS Lucchese & Kanduc, 2016

11 Postulated ZIKV mechanisms underlying Guillain Barré syndrome Humoral response Ab-dependent enhancement of ZKV infection T-cell immunoreactivity Direct viral neurotropism and cytotoxicity Muñoz et al, 2016

12 Detection of ZKV acute /past infection and possible past-dengue infection GBS and ZKV N= 42 Control Group 1 Patients with nonfebrile illness N= 98 Control Group 2 Pat. with ZKV but no neurol symptoms N= 70 IgM-against ZKV by IFA 39 (93%) 17 (17%) ND IgG-against ZKV by MIA 29 (69%) 25 (26%) 5 (7%) Viral RNA by RT-PCR (serum) 0 (0) ND 70 (100%) ZKV IgM/IgG positive 41 (98%) 35 (36%) ND Neutralising Antibodies 42 (100%) 54 (56%) ND IgG-against Dengue ( 2 serotypes) 36 (86%) 65 (66%) 46 (66%) No Dengue infection 2 (5%) 11 (11%) 12 (17%) Cao-Lormeau et al, The Lancet 2016

13 GBS associated with ZKV infection: Neuroimaging findings 1) Post-contrast enhancement of cranial nerves, such as V and VII nerves 2) Post-contrast enhancement of the conus medullaris and cauda equina nerve roots, more prominent involving ventral roots 3) T2-hyperintensity and contrast-enhancement of the lumbar spinal ganglia bilaterally No significant imaging difference between ZIKV related GBS and GBS in other settings has been reported Oehler et al, 2014; Fontes et al, 2016; Mehrjardi et al, 2016

14 High incidence of GBS during local ZKV outbreaks Country Reference Brazil Campos, 2015; Do Rosario, Araujo, Barcellos et al, 2016 Puerto Rico Thomas et al, 2016 Colombia Arias et al, 2016; Parra et al, 2016 Dominican Republic El Salvador French Guinea Haiti Honduras Martinique Panama Suriname Venezuela PAHO- WHO-Epidemiological Update, 2016 Pan American Health Organization, 2016

15 Hospitalization rate for GBS in the Northeast region (Brazil) Until May 2015: 0.05/100,000 residents Jun 2015-Feb 2016: 0.11/100,000 residents Approximate distribution of areas of local spread of ZKV in Brazil, 2014 and 2015 Barcellos et al, Emerg Infect Dis 2016 Jul 2015-Oct 2015: GBS hospitalizations - Excess of 240 hospitalizations in the region

16 Future Research Use of standardized clinical criteria for GBS (Brighton Collaboration GBS Working Group) Rule out mimickers: Acute myelitis, Lyme disease, Tick paralysis Acute polymyositis, myasthenia gravis, Botulism Consider current risk: GBS outbreak overwhelm the health systems Priorities for future research: Development of a vaccine against 1zKV Development of new therapeutic approaches Priority interventions: new methods for vector control Araujo et al, Brain 2016

17 Global distribution of Aedes aegypti To enhance monitoring, AFP surveillance officers in areas where Aedes aegypti is present Immediately notify the detection of clusters of AFP cases diagnosed as GBS, or Notify if there is an increase in the number of AFP/GBS cases above the previous baseline for the area. Using polio surveillance systems for Zika. Kandel et al, 2016

18 Hospital Nacional de Pediatría Dr. J.P. Garrahan Buenos Aires, Argentina

19