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Complement regulatory proteins (CD46, 55 and 59) expressed on Schwann cells: immune targets in demyelinating neuropathies?

Miyaji K, Paul F, Shahrizaila N, Umapathi T, Yuki N

J Neuroimmunol, 2014 Nov 15;276(1-2):172-4.
PMID: 25156074 DOI: 10.1016/j.jneuroim.2014.08.004

Given their localization and important role in regulating complement, complement regulatory proteins may act as target antigens and their antibodies as biomarkers in demyelinating neuropathies. We investigated the binding of autoantibodies to complement regulatory proteins (CD46, 55 and 59) in demyelinating diseases. In 42 acute inflammatory demyelinating polyneuropathy, 23 chronic inflammatory demyelinating polyneuropathy, 13 acute motor axonal neuropathy, 71 multiple sclerosis, and 19 neuromyelitis optica patients as well as 55 healthy controls, we were unable to detect significant titers of antibodies to CD46, CD55 and CD59. These autoantibodies are unlikely to be biomarkers in acute and chronic inflammatory demyelinating polyneuropathies.
Autoantibodies to tetraspanins (CD9, CD81 and CD82) in demyelinating diseases

Miyaji K, Paul F, Shahrizaila N, Umapathi T, Yuki N

J Neuroimmunol, 2016 Feb 15;291:78-81.
PMID: 26857499 DOI: 10.1016/j.jneuroim.2015.12.012

Tetraspanin family proteins, CD9, CD81 and CD82 are expressed in the oligodendrocytes and Schwann cells. We investigated autoantibodies to tetraspanin proteins in patients with demyelinating diseases. Sera were collected from 119 multiple sclerosis patients, 19 neuromyelitis optica, 42 acute inflammatory demyelinating polyneuropathy, 23 chronic inflammatory demyelinating polyneuropathy and 13 acute motor axonal neuropathy as well as 55 healthy controls. Few multiple sclerosis and acute inflammatory demyelinating polyneuropathy patients had autoantibodies that were weakly reactive to CD9 or CD81 but the significance is unclear. It is unlikely that these autoantibodies are pathogenic or serve as potential biomarkers in demyelinating diseases.
Are ERM (ezrin/radixin/moesin) proteins targets for autoantibodies in demyelinating neuropathies?

Miyaji K, Shahrizaila N, Umapathi T, Chan YC, Hirata K, Yuki N

Hum Immunol, 2014 Nov;75(11):1089-91.
PMID: 25286001 DOI: 10.1016/j.humimm.2014.09.010

Ezrin, radixin and moesin, which are strongly expressed in the Schwann cell microvilli, are putative targets for autoantibodies in acute or chronic inflammatory demyelinating polyneuropathy (AIDP or CIDP). An association between anti-moesin IgG antibodies and cytomegalovirus-related AIDP has been postulated. None of 41 AIDP patients, including 8 cytomegalovirus-related AIDP patients, and 23 CIDP had IgG or IgM antibodies to ezrin, radixin and moesin; whereas, one patient with cytomegalovirus-related AIDP had anti-ezrin IgM antibodies. Ezrin, radixin and moesin are unlikely targets for autoantibodies in AIDP and CIDP, and the association of anti-moesin antibodies with cytomegalovirus-related AIDP was not confirmed.
The value of comparing mortality of Guillain-Barré syndrome across different regions

Wong AH, Umapathi T, Shahrizaila N, Chan YC, Kokubun N, Fong MK, et al.

J Neurol Sci, 2014 Sep 15;344(1-2):60-2.
PMID: 24993467 DOI: 10.1016/j.jns.2014.06.021

To study the clinical profile of Guillain-Barré syndrome (GBS) patients who died in 4 Asian countries in order to understand factors underlying any variation in mortality.
Fulltext Antibodies to single glycolipids and glycolipid complexes in Guillain-Barré syndrome subtypes

Shahrizaila N, Kokubun N, Sawai S, Umapathi T, Chan YC, Kuwabara S, et al.

Neurology, 2014 Jul 8;83(2):118-24.
PMID: 24920848 DOI: 10.1212/WNL.0000000000000577

To comprehensively investigate the relationship between antibodies to single glycolipids and their complexes and Guillain-Barré syndrome subtypes and clinical features.
The 2016 Singapore Zika virus outbreak did not cause a surge in Guillain-Barré syndrome

Umapathi T, Kam YW, Ohnmar O, Ng BCJ, Ng Y, Premikha M, et al.

J Peripher Nerv Syst, 2018 09;23(3):197-201.
PMID: 30070025 DOI: 10.1111/jns.12284

Although individuals with Zika virus (ZIKV) antibodies were reported in Malaya in mid-1950s, entomological and human surveillance in Singapore did not identify autochthonous transmission until the outbreak of August-November, 2016. A total of 455 cases from 15 separate clusters were identified. We asked if this ZIKV outbreak increased the incidence of Guillain-Barré syndrome (GBS) and aimed to characterize these cases. Eleven GBS cases, consecutively enrolled into our prospective GBS database from onset to 4 weeks after outbreak, and six controls, comprising three GBS patients enrolled before outbreak and three non-GBS patients, were examined for evidence of recent ZIKV infection. We performed serum, urine ZIKV RT-PCR, ZIKV serology, and virus neutralization assays, accounting for cross-reaction and co-infection with dengue (DENV). We found five GBS cases with only serological evidence of recent ZIKV infection (including one ZIKV-DENV co-infection). A temporal relationship with ZIKV outbreak was unlikely as two cases were GBS controls enrolled 3 months before outbreak. None reported symptoms of ZIKV infection. In addition, compared to last 10 years the national number of GBS hospitalizations did not increase during and immediately after outbreak. We conclude the 2016 Singapore ZIKV outbreak did not cause a change in GBS epidemiology.
The neurological manifestations of Nipah virus encephalitis, a novel paramyxovirus

Lee KE, Umapathi T, Tan CB, Tjia HT, Chua TS, Oh HM, et al.

Ann Neurol, 1999 Sep;46(3):428-32.
PMID: 10482278 DOI: 10.1002/1531-8249(199909)46:3<428::AID-ANA23>3.0.C

A novel Hendra-like paramyxovirus named Nipah virus (NiV) was the cause of an outbreak among workers from one abattoir who had contact with pigs. Two patients had only respiratory symptoms, while 9 patients had encephalitis, 7 of whom are described in this report. Neurological involvement was diverse and multifocal, including aseptic meningitis, diffuse encephalitis, and focal brainstem involvement. Cerebellar signs were relatively common. Magnetic resonance imaging scans of the brain showed scattered lesions. IgM antibodies against Hendra virus (HeV) were present in the serum of all patients. Two patients recovered completely. Five had residual deficits 8 weeks later.
Electrodiagnosis of reversible conduction failure in Guillain-Barré syndrome

Chan YC, Punzalan-Sotelo AM, Kannan TA, Shahrizaila N, Umapathi T, Goh EJH, et al.

Muscle Nerve, 2017 Nov;56(5):919-924.
PMID: 28093784 DOI: 10.1002/mus.25577

INTRODUCTION: In this study we propose electrodiagnostic criteria for early reversible conduction failure (ERCF) in axonal Guillain-Barré syndrome (GBS) and apply them to a cohort of GBS patients.
METHODS: Serial nerve conduction studies (NCS) were retrospectively analyzed in 82 GBS patients from 3 centers. The criteria for the presence of ERCF in a nerve were: (i) a 50% increase in amplitude of distal compound muscle action potentials or sensory nerve action potentials; or (ii) resolution of proximal motor conduction block with an accompanying decrease in distal latencies or compound muscle action potential duration or increase in conduction velocities.
RESULTS: Of 82 patients from 3 centers, 37 (45%) had ERCF, 21 (26%) had a contrasting evolution pattern, and 8 (10%) had both. Sixteen patients did not show an amplitude increase of at least 50%.
CONCLUSION: Our proposed criteria identified a group of patients with a characteristic evolution of NCS abnormality that is consistent with ERCF. Muscle Nerve 56: 919-924, 2017.
Impact of Covid-19 on the therapeutic plasma exchange service within the South East Asian region: Consensus recommendations and global perspectives

Viswanathan S, Hiew FL, Siritho S, Apiwattanakul M, Tan K, Quek AML, et al.

J Clin Apher, 2021 Dec;36(6):849-863.
PMID: 34694652 DOI: 10.1002/jca.21937

INTRODUCTION: Therapeutic plasma exchange (TPE) for neuroimmunological disorders has played an increasingly important role within the Southeast Asian (SEA) region. The South East Asian Therapeutic Plasma exchange Consortium (SEATPEC) was formed in 2018 to promote education and research on TPE within the region. The advent of the Covid-19 pandemic has produced challenges for the development and expansion of this service.
METHODOLOGY: A qualitative and semi-quantitative questionnaire-based survey was conducted by SEATPEC member countries from January to June 2020 (Phase 1) and then from July 2020 to January 2021 in (Phase 2) to assess the impact of Covid-19 on regional TPE.
OBJECTIVES: The study's main objectives were to explore the challenges experienced and adaptations/adjustments taken by SEATPEC countries in order to continue safe and efficient TPE during the Covid-19 pandemic.
RESULTS: The pandemic was found to disrupt the delivery of TPE services in all SEATPEC countries. Contributing factors were multifactorial due to overstretched medical services, staff shortages, quarantines and redeployments, fear of acquiring Covid-19, movement restriction orders, and patient's psychological fear of attending hospitals/testing for Covid-19. All SEATPEC countries practiced careful stratification of cases for TPE (electives vs emergencies, Covid-19 vs non-Covid-19 cases). SEATPEC countries had to modify TPE treatment protocols to include careful preprocedure screening of patient's for Covid-19, use of personal protective equipment (PPE) and post-TPE sanitization of machines and TPE suites.
CONCLUSION: Based on the responses of the survey, SEATPEC countries produced a consensus statement with five recommendations for safe and effective TPE within the region.
Fulltext A call for a global COVID-19 Neuro Research Coalition

Winkler AS, Knauss S, Schmutzhard E, Leonardi M, Padovani A, Abd-Allah F, et al.

Lancet Neurol, 2020 06;19(6):482-484.
PMID: 32470416 DOI: 10.1016/S1474-4422(20)30150-2
Fulltext Effect of Combined Treatment with MLC601 (NeuroAiDTM) and Rehabilitation on Post-Stroke Recovery: The CHIMES and CHIMES-E Studies

Suwanwela NC, Chen CLH, Lee CF, Young SH, Tay SS, Umapathi T, et al.

Cerebrovasc Dis, 2018;46(1-2):82-88.
PMID: 30184553 DOI: 10.1159/000492625

BACKGROUND AND PURPOSE: MLC601 has been shown in preclinical studies to enhance neurorestorative mechanisms after stroke. The aim of this post hoc analysis was to assess whether combining MLC601 and rehabilitation has an effect on improving functional outcomes after stroke.
METHODS: Data from the CHInese Medicine NeuroAiD Efficacy on Stroke (CHIMES) and CHIMES-Extension (CHIMES-E) studies were analyzed. CHIMES-E was a 24-month follow-up study of subjects included in CHIMES, a multi-centre, double-blind placebo-controlled trial which randomized subjects with acute ischemic stroke, to either MLC601 or placebo for 3 months in addition to standard stroke treatment and rehabilitation. Subjects were stratified according to whether they received or did not receive persistent rehabilitation up to month (M)3 (non- randomized allocation) and by treatment group. The modified Rankin Scale (mRS) and Barthel Index were assessed at month (M) 3, M6, M12, M18, and M24.
RESULTS: Of 880 subjects in CHIMES-E, data on rehabilitation at M3 were available in 807 (91.7%, mean age 61.8 ± 11.3 years, 36% female). After adjusting for prognostic factors of poor outcome (age, sex, pre-stroke mRS, baseline National Institute of Health Stroke Scale, and stroke onset-to-study-treatment time), subjects who received persistent rehabilitation showed consistently higher treatment effect in favor of MLC601 for all time points on mRS 0-1 dichotomy analysis (ORs 1.85 at M3, 2.18 at M6, 2.42 at M12, 1.94 at M18, 1.87 at M24), mRS ordinal analysis (ORs 1.37 at M3, 1.40 at M6, 1.53 at M12, 1.50 at M18, 1.38 at M24), and BI ≥95 dichotomy analysis (ORs 1.39 at M3, 1.95 at M6, 1.56 at M12, 1.56 at M18, 1.46 at M24) compared to those who did not receive persistent rehabilitation.
CONCLUSIONS: More subjects on MLC601 improved to functional independence compared to placebo among subjects receiving persistent rehabilitation up to M3. The larger treatment effect of MLC601 was sustained over 2 years which supports the hypothesis that MLC601 combined with rehabilitation might have beneficial and sustained effects on neuro-repair processes after stroke. There is a need for more data on the effect of combining rehabilitation programs with stroke recovery treatments.
Proceedings of the Inaugural Strategy Meeting for the Establishment of a Southeast Asia Regional Therapeutic Plasma Exchange Consortium for Neurological Disorders

Viswanathan S, Appiwatanakul M, Nayak A, Islam B, Khatri B, Pangeran D, et al.

Ther Apher Dial, 2019 Jun;23(3):289-297.
PMID: 30927331 DOI: 10.1111/1744-9987.12806

In conjunction with the third regional Southeast Asian (SEA) therapeutic plasma exchange (TPE) conference in Kuala Lumpur, Malaysia, 25 clinicians and researchers from SEA and South Asian countries attended the inaugural strategy meeting for the establishment of a regional TPE consortium for neurological disorders. The primary objective was to establish regional collaboration to improve delivery of TPE services in SEA. A pre-meeting survey was conducted to gather insights on disease spectrum, contextual practice challenges, and the need for a regional TPE consensus. Challenges identified include limited healthcare funding in support of diagnostic workup, TPE therapy, as well as development of clinical infrastructure and expertise capacity building. There was favorable interest in developing a working plan contextualized to this region. Strategies to overcome challenges were discussed. This included the need for a comprehensive referral system and network of regional TPE centers suited to local needs, supported by innovative TPE delivery programs.
[Evidence based guidelines. Diagnosis and management of Guillain-Barré syndrome in ten steps]

Leonhard SE, Mandarakas MR, de Assis Aquino Gondim F, Bateman K, Brito Ferreira ML, Cornblath DR, et al.

Medicina (B Aires), 2021;81(5):817-836.
PMID: 34633957

Guillain-Barré syndrome (GBS) is a rare, but potentially fatal, immune-mediated disease of the peripheral nerves and nerve roots that is usually triggered by infections. The incidence of GBS can therefore increase during outbreaks of infectious diseases, as was seen during the Zika virus epidemics in 2013 in French Polynesia and in 2015 in Latin America. Diagnosis and management of GBS can be complicated as its clinical presentation and disease course are heterogeneous, and no international clinical guidelines are currently available. To support clinicians, especially in the context of an outbreak, we have developed a globally applicable guideline for the diagnosis and management of GBS. The guideline is based on current literature and expert consensus, and has a ten-step structure to facilitate its use in clinical practice. We first provide an introduction to the diagnostic criteria, clinical variants and differential diagnoses of GBS. The ten steps then cover early recognition and diagnosis of GBS, admission to the intensive care unit, treatment indication and selection, monitoring and treatment of disease progression, prediction of clinical course and outcome, and management of complications and sequelae.
Fulltext Diagnosis and management of Guillain-Barré syndrome in ten steps

Leonhard SE, Mandarakas MR, Gondim FAA, Bateman K, Ferreira MLB, Cornblath DR, et al.

Nat Rev Neurol, 2019 Nov;15(11):671-683.
PMID: 31541214 DOI: 10.1038/s41582-019-0250-9

Guillain-Barré syndrome (GBS) is a rare, but potentially fatal, immune-mediated disease of the peripheral nerves and nerve roots that is usually triggered by infections. The incidence of GBS can therefore increase during outbreaks of infectious diseases, as was seen during the Zika virus epidemics in 2013 in French Polynesia and 2015 in Latin America. Diagnosis and management of GBS can be complicated as its clinical presentation and disease course are heterogeneous, and no international clinical guidelines are currently available. To support clinicians, especially in the context of an outbreak, we have developed a globally applicable guideline for the diagnosis and management of GBS. The guideline is based on current literature and expert consensus, and has a ten-step structure to facilitate its use in clinical practice. We first provide an introduction to the diagnostic criteria, clinical variants and differential diagnoses of GBS. The ten steps then cover early recognition and diagnosis of GBS, admission to the intensive care unit, treatment indication and selection, monitoring and treatment of disease progression, prediction of clinical course and outcome, and management of complications and sequelae.

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