Electrodiagnosis of reversible conduction failure in Guillain-Barré syndrome

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1 Electrodiagnosis of reversible conduction failure in Guillain-Barré syndrome Yee-Cheun Chan, MBBS, 1 Aubrey M Punzalan-Sotelo, MD, 1 Therimadasamy A Kannan, BSc, 2 Nortina Shahrizaila, DM, 3 Thirugnanam Umapathi, MBBS, 4 Eunice J H Goh, 1 Yuki Fukami, MD, 1 Einar Wilder- Smith, MD, 1 Nobuhiro Yuki, MD, PhD, 1 1 Departments of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 2 Division of Neurology, National University Hospital, Singapore, 3 Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia, 4 National Neuroscience Institute, Singapore. Disclosure of Conflict of Interest: Prof. Yuki serves as an editorial board member of Expert Review of Neurotherapeutics, The Journal of the Neurological Sciences, The Journal of Peripheral Nervous System, Journal of Alzheimer s Disease and Journal of Neurology, Neurosurgery & Psychiatry. The remaining authors have no conflicts of interest. Author contributions: Drafting the manuscript for content; Y.C.C. and A.M.P.S.. Revising the manuscript for content; Y.C.C., N.S., T.U., E.WS, F.Y. and N.Y.. Study concept and design; Y.C.C. and N.Y.. Acquisition of data; A.M.P.S., T.A.K., E.J.H.G., N.S., and Y.F.. Analysis and interpretation of data; Y.C.C., A.M.P.S., T.A.K., E.J.H.G., N.S., Y.F. and N.Y.. We confirm that we have read the Journal s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. Corresponding author: Dr Yee-Cheun Chan, Division of Neurology, University Medicine Cluster, National University Hospital, NUHS Tower Block, Level 10, Singapore yee_cheun_chan@nuhs.edu.sg This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process which may lead to differences between this version and the Version of Record. Please cite this article as an Accepted Article, doi: /mus.25577

2 Page 5 of 23 2 Running title: Diagnosing conduction failure Title, 76 characters with space; Abstract, 146 words; Manuscript, 2100 words; Figures, 3; Table, 1; References 26; Supplementary tables: 5

3 Page 6 of 23 3 ABSTRACT Objective: We proposed electrodiagnostic criteria for early reversible conduction failure (ERCF) in axonal Guillain-Barré syndrome (GBS) and applied 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) 50% increase in amplitude of distal compound muscle action potentials or sensory nerve action potentials, or ii) resolution of proximal motor conduction block with 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 amplitude increase of at least 50%. Discussion: Our proposed criteria identified a group of patients with a characteristic evolution of NCS abnormality that is consistent with ERCF. Keywords: acute inflammatory demyelinating polyneuropathy, acute motor axonal neuropathy, conduction block, Guillain-Barré syndrome, electrodiagnostic criteria, reversible conduction failure

4 Page 7 of 23 4 INTRODUCTION Guillian-Barré syndrome (GBS) can be divided into acute inflammatory demyelinating polyneuropathy (AIDP) and acute motor axonal neuropathy (AMAN). 1 The classic pathological findings in AIDP are segmental demyelination in the motor and sensory nerves. 2 These result in conduction block or slowing. Remyelination occurs over many weeks. 3 In AMAN, IgG antibodies bind to GM1 or GD1a on the axolemma of motor fibers at the nodes of Ranvier, activate complement in situ, resulting in disappearance of voltage-gated sodium channel clusters at the nodes and disruption of axo-glial junctions at the paranodes. 4,5 The nodal and paranodal changes disrupt nerve impulse conduction and result in muscle weakness. Classically, axonal degeneration subsequently occurs. 6 However, in some patients, rapid recovery occurs when conduction failure at the nodes resolve before the development of any axonal degeneration. 7-9 This is believed to be due to the rapid reappearance and re-organization of sodium channels at the nodal lesion. 4 In clinical practice, nerve conduction study (NCS) is the major means by which the axonal and demyelinating subtypes are distinguished. However, recent studies have found that current electrophysiological criteria tend to under diagnose axonal GBS, classifying some cases as AIDP instead. 8,10 This is because nodal conduction failure also manifests as conduction block, decreased conduction velocity (CV) and prolonged distal latency (DL); classically recognized as features of demyelination on NCS, making it difficult to distinguish AMAN from AIDP. 11 However, AMAN and AIDP differ in their evolution of changes on serial NCS. In AMAN, 2 possible patterns of evolution have been observed. Rapid improvement in compound muscle action potential (CMAP) amplitudes and CV from resolution of nodal conduction failure may be seen. The other pattern is decrease of distal CMAP amplitudes due to axonal degeneration. 11 Both patterns are not associated with increase in temporal dispersion (TD). In contrast, with gradual remyelination in AIDP, CV remains decreased and persistently increased TD are seen. 3,12 Such changes can best be demonstrated on serial NCS. Observation of emerging patterns consistent with early reversible conduction failure (ERCF) or distal

5 Page 8 of 23 5 axonal degeneration supports the diagnosis of axonal GBS. 11 However, there have not been any proposed electrodiagnostic criteria for recognition of ERCF. 8,10 We hypothesize that in a cohort of GBS patients, serial NCS will show a group of patients with improvement in amplitudes of muscle and sensory action potentials. Within this group, there may be 2 distinct groups of patients; one where there is occurrence of ERCF and another where recovery occurs with remyelination. We propose tentative criteria for recognition of ERCF based on the understanding that with resolution of conduction failure, amplitudes increase accompanied by improvement in CV and decreased temporal dispersion. For the purpose of comparison in this study we also defined a contrasting criteria based on the observation that with remyelination, CV remained decreased even as amplitudes recover. We applied the criteria retrospectively on the NCS of a cohort of GBS patients and test if they will separate 2 distinct groups of patients.

6 Page 9 of 23 6 METHODS Patients We retrospectively analyzed NCS of GBS patients admitted to National University Hospital in Singapore between years 2010 to 2013, National Neuroscience Institute in Singapore and University Malaya Medical Center in Malaysia between years 2010 to Patients who fulfilled clinical criteria for GBS with 2 or more NCS done within 10 weeks of symptoms onset and initial NCS done within 14 days of symptom onset were included in the study. Patients with Miller Fisher syndrome and its subtypes 13 were excluded. The study protocol was reviewed and approved by the respective institutional review boards. Waiver of consent was granted for this retrospective study in National University Hospital. Patients from National Neuroscience Institute and University Malaya Medical Center were prospectively recruited as part of a study on epidemiology and electrodiagnosis of GBS and gave informed consent. Nerve conduction studies NCSs were performed using standardized techniques as described elsewhere. 16,17,18 Proposed electrodiagnostic criteria for ERCF Table 1 shows the proposed criteria for the presence of ERCF on serial NCSs. For comparison in this study, we defined contrasting criteria as the presence of 50% increase in amplitudes of distal CMAP, distal SNAP or resolution of proximal conduction block due to increase in proximal CMAP amplitude with persistent prolonged DL, dispersion or conduction slowing. We refer to this as amplitude increase with persisting demyelinating feature (AIPDF). Analysis of NCS results NCS abnormalities were determined with reference to respective laboratory normative values and according to GBS neurophysiological criteria by Ho et al. and Hadden et al. (Table S1 [available

7 Page 10 of 23 7 online]). 1,15 NCSs were then classified as indicating diagnoses of AIDP or AMAN. We looked for the presence of ERCF and AIPDF on follow-up NCS. Anti-ganglioside antibody serology IgG antibodies to GM1, GM1b, GD1a, GalNAc-GD1a, GT1a and GQ1b were tested as described elsewhere. 19 Statistical analysis The Chi-square test was performed to determine the associations of either ERCF or AIPDF pattern with anti-ganglioside seropositivity.

8 Page 11 of 23 8 RESULTS Electrophysiological diagnoses Eighty-two patients were included in the study. These included 21 patients treated at National University Hospital in Singapore, 30 patients at National Neuroscience Institute in Singapore and 31 patients at University Malaya Medical Center in Malaysia. Applying Hadden s 15 or Ho s criteria, 1 the initial NCS of 60 patients were classified as AIDP and 9 patients as AMAN. Thirteen patients had initial NCS that did not fulfill criteria for either AIDP or AMAN. Presence of ERCF and AIPDF Applying our proposed criteria, we looked for the presence of ERCF and AIPDF on follow-up NCS of the patients. Of 21 patients treated at National University Hospital in Singapore, ERCF was found in 8 patients (Figure 1, Supplementary table S2, available online) and AIPDF in 5 patients (Figure 2, supplementary table S3, available online). One patient had both (Figure 3, supplementary table S4, available online). Seven patients did not show an amplitude increase of at least 50% within 10 weeks of symptom onset. Of 30 patients treated at National Neuroscience Institute, ERCF was found in 17 patients and AIPDF in 1 patient. Six patients had both. Six patients did not have amplitude increase of at least 50%. Of 31 patients treated at University Malaya Medical Center, ERCF was found in 12 patients and AIPDF in 15 patients. One patient had both. Three patients did not have amplitude increase of at least 50%. In summary, of 82 patients from 3 centers, 37 (45%) had ERCF, 21 (26%) had the AIPDF pattern, and 8 (10%) had both. Sixteen patients did not show amplitude increase of at least 50%. Anti-ganglioside antibodies Patients with ERCF pattern were more likely to be associated with positive antibodies (p = 0.004; odds ratio, 15.9; 95% confidence interval, ). Sera were available from 65 of the 82 patients from 3

9 Page 12 of 23 9 centres (7 of the 21 patients at National University Hospital in Singapore, 27 of the 30 patients at National Neuroscience Institute, and all 31 patients at University Malaya Medical Center). Antiganglioside antibodies were tested in 31 of 37 patients with ERCF pattern, and 18 of 21 patients with AIPDF pattern. In the former, IgG antibodies were positive for GM1 (n = 9), GM1b (n = 4), GD1a (n = 7), GalNAc-GD1a (n = 4), GT1a (n = 2) and GQ1b (n = 4); whereas, in the latter, anti-gq1b antibodies were positive in 1 patient. IgG antibodies against at least a single ganglioside were present in 15 (48%) of the patients with ERCF pattern and 1 (6%) of the patients with AIPDF pattern on NCSs.

10 Page 13 of DISCUSSION We have proposed tentative criteria for recognition of ERCF on serial NCSs based on the current understanding of the underlying pathophysiology. For comparison, we have also defined comparison criteria. When tested in 82 GBS patients, except for 8 patients, the criteria identified 2 distinct groups with improvement in nerve potential amplitudes. The group with ERCF pattern was significantly associated with positive antibodies. This is consistent with the knowledge that ERCF is a feature in AMAN and that AMAN, but not AIDP, is associated with anti-gm1, anti-gm1b, anti-gd1a and anti- GalNAc-GD1a IgG antibodies. 8,20 In the group with AIPDF pattern, amplitude improvement is presumed to have occurred with remyelination. In 8 patients, both ERCF and AIPDF patterns were found. This represented an indeterminate group that reflects the difficult balance between sensitivity and specificity of criteria. Another group of 16 patients had follow-up NCSs that did not show improvement in nerve potential amplitudes. Six of these had normal amplitudes on serial NCS, while 10 had decreased amplitudes that persisted during the 10 weeks study period. Persisting decreased amplitudes reflect axonal degeneration, which may have originated either from an initial axonal nodal pathology or secondary to severe demyelination. Previous studies had suggested that AMAN and AIDP show different evolution of changes on serial NCS. 3,7,8,10 In AIDP, mean DL and CV remained prolonged beyond 2 months of symptom onset even as amplitudes improved. 3,7 Albers et al. showed that in 70 AIDP patients, maximum impairment in CV, terminal CV, TD were noted between Weeks 3 and 10 and these impairments persisted beyond the time taken for significant improvement in CMAP amplitudes. 3 Other studies have also shown that in AMAN patients, prolonged DL and increased CMAP duration were common at Week 1 but they improved towards normal from Week In contrast, the mean DL and CMAP duration of AIDP patients increased to a maximum at Week 4 and remained abnormal at Week 10. Based on these studies, our proposed criteria focused on the NCS changes within 10 weeks of symptom onset.

11 Page 14 of More recent studies have suggested that the serial NCS changes in axonal GBS reflect ERCF at nodes of Ranvier and recognizing an ERCF pattern of NCS changes is important for classifying GBS subtypes. 8,10 Rajabally et al. recently proposed a modified criteria where proximal to distal CMAP amplitude <0.7 without demyelinating features, is recognized as indicative of axonal pathology. 24 However, the criteria does not address the recognition of ERCF on serial NCS. 25 To our knowledge, there has not been any formal criteria that recognizes ERCF pattern of NCS evolution. At the same time, in doing this study, challenges in demonstrating evolution of change in serial NCS were highlighted. It is challenging to determine cut-off values sensitive enough to detect ERCF that, at the same time, represent significant change in amplitude, latency and CV between tests. Based on our experience with serial NCS, 16,17,18 we recognized 50% change in amplitude and 10% change in latency and CV as sensitive markers to significant change. Our test-to-test variability was within these limits (motor amplitude; median 9.6%, ulnar 12%, tibial 13%, peroneal 13.4%, motor latency; median 3.3%, ulnar 5.4%, tibial 4.7%, peroneal 6.6%, motor velocity; median 2.5%, ulnar 5.8%, tibial 7.8%, peroneal 4.1%, sensory amplitudes; median 18.9%, ulnar 12.9%, sensory latency median 3.9%, ulnar 4.1%, sensory velocity median 2.6%, ulnar 6.5%) (Supplementary table S5, available online). 50% difference in amplitude is also the convention for detecting a significant side-to-side difference in amplitude. Nevertheless, we acknowledge that even when strict NCS protocols are followed, test-to-test variability may still confound the interpretation of results. We propose that the changes should be seen in at least 2 nerves to reflect genuine change. It may also be necessary to define a lower limit of amplitude and latency for application of the criteria as the percentage change of a low value may not be significant. Inter-tests variability is more pronounced with SNAP amplitudes and SNAP parameters may be better considered as supportive features. Secondly, in this retrospective study, follow-up NCS were not done at regular short intervals. ERCF changes can appear very early and disappear rapidly. Changes occurring in between NCS may have been missed. It may be necessary to specify that the criteria need to be applied to NCS changes seen within a short time interval with the first NCS done early (e.g. within first 2 weeks). 26 Thirdly, in this study, we did not correlate the NCS changes with prognosis or clinical

12 Page 15 of course of the patients. Our tentative ERCF criteria need to be further defined for specificity and subsequent studies needed for validation. For example, specifying the definition of resolution of proximal conduction block as an increase in proximal to distal amplitude ratio to 0.6 or more. We propose prospective studies with defined NCS protocol, inter-test intervals, correlation with milestones in the clinical course, correlation with serological studies and ideally, validation by histological evidence. Validated criteria will greatly facilitate further research in the management of patients with GBS variants.

13 Page 16 of CONCLUSION This study provides further evidence that serial NCS can identify patients with a characteristic evolution of NCS abnormality that is consistent with current concepts of ERCF. The ability of the criteria to separate 2 groups of patients support the concept of ERCF versus demyelination-remyelination. The challenges highlighted will help in modification of the criteria.

14 Page 17 of ACKNOWLEDGEMENT Study funding: This project was supported by Singapore National Medical Research Council (IRG 10nov086 and CSA/047/2012 to Drs Y C Chan, T Umapathi and N Yuki). Dr. N Shahrizaila receives research support from University of Malaya Research Grant (RG491/13).

15 Page 18 of ABBREVIATIONS AIDP, acute inflammatory demyelinating polyneuropathy; AMAN, acute motor axonal neuropathy; CMAP, compound muscle action potential, CV, conduction velocity; DL, distal latencies; ERCF, early reversible conduction failure; GBS, Guillian-Barré syndrome; NCS, nerve conduction study; TD, temporal dispersion

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17 Page 20 of Wexler I. Sequence of demyelination-remyelination in Guillain-Barré disease. J Neurol Neurosurg Psychiatry 1983;46: Wakerley BR, Uncini A, Yuki N, GBS Classification Group. Guillain-Barré and Miller Fisher syndromes: new diagnostic classification. Nat Rev Neurol 2014;10: Clouston PD, Kiers L, Zuniga G, Cros D. Quantitative analysis of the compound muscle action potential in early acute inflammatory demyelinating polyneuropathy. Electroencephalogr Clin Neurophysiol 1994;93: Hadden RDM, Cornblath DR, Hughes RAC, Zielasek J, Hartung HP, Toyka KV et al. Electrophysiological classification of Guillain-Barré syndrome: clinical associations and outcome. Ann Neurol 1998;44: Umapathi T, Tan EY, Kokubun N, Verma K, Yuki N. Non-demyelinating, reversible conduction failure in Fisher syndrome and related disorders. J Neurol Neurosurg Psychiatry 2012;83: Shahrizaila N, Goh KJ, Kokubun N, Tan AH, Tan CY, Yuki N. Sensory nerves are frequently involved in the spectrum of Fisher syndrome. Muscle Nerve 2014;49: YC Chan, AK Therimadasamy, NM Sainuddin, E Wilder-Smith, N Yuki. Serial electrophysiological studies in a Guillain-Barré subtype with bilateral facial neuropathy. Clin Neurophysiol. Published online: November 19, DOI: /j.clinph Yuki N, Tagawa Y, Irie F, Hirabayashi Y, Handa S. Close association of Guillain-Barré syndrome with antibodies to minor monosialogangliosides GM1b and GM1α. J Neuroimmunol 1997;74: Sekiguchi Y, Uncini A, Yuki N, Misawa S, Notturno F, Nasu S et al. Antiganglioside antibodies are associated with axonal Guillain-Barré syndrome: a Japanese-Italian collaborative study. J Neurol Neurosurg Psychiatry 2012;83: Kokubun N, Shahrizaila N, Hirata K, Yuki N. Reversible conduction failure is distinct from neurophysiological patterns of recovery in mild demyelinating Guillain-Barré syndrome. J Neurol Sci 2013;326:

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19 Page 22 of Table 1. Electrodiagnostic criteria for a reversal of conduction failure pattern on follow-up nerve conduction studies The presence of one of the following on follow-up nerve conduction study within 10 weeks of symptom onset is defined as an early reversible conduction failure pattern: i) 50% increase in distal compound motor action potential (CMAP) amplitude with accompanying decrease ( 10%) in distal motor latencies or distal CMAP duration or distal motor latencies and CMAP duration remaining within normal limits. ii) Resolution of proximal conduction block due to increase of proximal CMAP amplitude with accompanying increase ( 10%) in CV or decrease ( 10%) in proximal CMAP duration. iii) 50% increase in sensory nerve action potential amplitude with accompanying increase ( 10%) in sensory CV or decrease ( 10%) in latencies.

20 Page 23 of FIGURE LEGENDS Figure 1. Examples of serial nerve conduction tracings showing reversal of conduction failure pattern. Increase in amplitudes of nerve action potential was accompanied by decrease in distal latency, action potential duration or increase in conduction velocity. These were seen in 3 motor nerves and 1 sensory nerve in serial recordings of Patient 1 and 7 motor nerves in Patient 3. Figure 2. Examples of serial nerve conduction tracings showing amplitude increase with persistent demyelinating feature pattern change. Increase in amplitudes of nerve action potential was accompanied by persistent prolonged distal latency, dispersion or conduction slowing. These were seen in 2 motor nerves in Patient 2 and 7 motor nerves in Patient 21. Figure 3. Nerve conduction tracings in Patient 6. A. Serial recordings of compound muscle action potential from the abductor digiti minimi after stimulation of the right ulnar nerve at the wrist, below elbow and above elbow showing early reversible conduction failure pattern of change. B. Serial recordings of compound muscle action potential from the abductor hallucis after stimulation of the right tibial nerve at the ankle and knee showing amplitude increase with persisting demyelinating features pattern of change.

21 Page 1 of 23 Figure 1. Examples of serial nerve conduction tracings showing reversal of conduction failure pattern. Increase in amplitudes of nerve action potential was accompanied by decrease in distal latency, action potential duration or increase in conduction velocity. These were seen in 3 motor nerves and 1 sensory nerve in serial recordings of Patient 1 and 7 motor nerves in Patient x145mm (300 x 300 DPI)

22 Page 2 of 23 Figure 2. Examples of serial nerve conduction tracings showing amplitude increase with persistent demyelinating feature pattern change. Increase in amplitudes of nerve action potential was accompanied by persistent prolonged distal latency, dispersion or conduction slowing. These were seen in 2 motor nerves in Patient 2 and 7 motor nerves in Patient x291mm (154 x 154 DPI)

23 Page 3 of 23 Figure 3. Nerve conduction tracings in Patient 6. A. Serial recordings of compound muscle action potential from the abductor digiti minimi after stimulation of the right ulnar nerve at the wrist, below elbow and above elbow showing early reversible conduction failure pattern of change. B. Serial recordings of compound muscle action potential from the abductor hallucis after stimulation of the right tibial nerve at the ankle and knee showing amplitude increase with persisting demyelinating features pattern of change. Figure 3 151x136mm (300 x 300 DPI)

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