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Different distribution of demyelination in chronic inflammatory demyelinating polyneuropathy subtypes
Journal of Neuroimmunology 341 (2020) 577170
Contents lists available at ScienceDirect
Journal of Neuroimmunology journal homepage: www.elsevier.com/locate/jneuroim
Different distribution of demyelination in chronic inflammatory demyelinating polyneuropathy subtypes
T
Kazumoto Shibuya , Atsuko Tsuneyama, Sonoko Misawa, Yukari Sekiguchi, Minako Beppu, Tomoki Suichi, Yo-ichi Suzuki, Keigo Nakamura, Hiroki Kano, Satoshi Kuwabara ⁎
Department of Neurology, Graduate School of Medicine, Chiba University, Chiba, Japan
ARTICLE INFO
ABSTRACT
Keywords: Chronic inflammatory demyelinating polyneuropathy Blood-nerve barrier Nerve conduction study Demyelinating distribution Clinical subtypes Anti-myelin-associated glycoprotein antibodypositive neuropathy
In demyelinating polyneuropathies, distribution patterns of demyelination reflect underlying pathogenesis. Median and ulnar nerve conduction studies were reviewed in 85 typical chronic inflammatory demyelinating polyneuropathy (CIDP) patients and 29 multifocal acquired demyelinating sensory and motor neuropathy (MADSAM). Distal latencies were prolonged in typical CIDP and near normal in MADSAM. Abnormal amplitude reductions in the nerve trunks were more frequent in MADSAM than typical CIDP. Presumably because the blood-nerve barrier is anatomically deficient at the distal nerve terminals, antibody-mediated demyelination is a major pathophysiology in typical CIDP. In contrast, blood-nerve barrier breakdown is likely to be predominant in MADSAM.
1. Introduction Chronic inflammatory demyelinating polyneuropathy (CIDP) is currently classified into typical CIDP and atypical variant such as multifocal demyelinating sensory and motor neuropathy (MADSAM), according to clinical manifestation (Lehmann et al., 2019). Other representative chronic demyelinating neuropathies include anti-myelinassociated glycoprotein (MAG) antibody-positive neuropathy and multifocal motor neuropathy (MMN). Previous electrophysiological studies have shown characteristic patterns of nerve conduction abnormalities in each disorder. Typical CIDP and anti-MAG neuropathy cause conduction slowing and block predominantly in the distal portions of the peripheral nerves, whereas demyelination is frequently found in the nerve trunks with conduction block in MADSAM and MMN (Attarian et al., 2001; Dalakas, 2018; Kuwabara et al., 2015; Vlam et al., 2011). Additionally, uniform demyelination along a longitudinal course of a nerve is reported in hereditary demyelinating neuropathy such as Charcot-Marie-Tooth disease type 1A (CMT1A) (Manganelli et al., 2016). These different distribution patterns of demyelination are likely to reflect the different underlying pathophysiology. Among CIDP subtypes, response to immunomodulating treatment is different (Kuwabara et al., 2006, 2015; Van den Bergh et al., 2010).
Patients with the typical CIDP respond well to immunoglobulin and plasmapheresis, but patients with MADSAM or anti-MAG neuropathy are often refractory to immunoglobulin therapy (Kuwabara et al., 2015). These findings also suggest that different pathomechanisms underlie in each condition. The present study aimed to systematically and directly compare distribution patterns of demyelination and reveal the underlying pathophysiology among CIDP subtypes and anti-MAG neuropathy. 2. Materials and methods 2.1. Subjects A total of 136 patients, who were referred to the Chiba University Hospital and fulfilled European Federation of Neurological Societies/ Peripheral Nerve Society (EFNS/PNS) criteria for probable or definite CIDP, was included into this study (Van den Bergh et al., 2010). They were followed up at least 1 year, to confirm diagnosis of CIDP. Of these, patients complicated with inherited neuropathies, multiple sclerosis and other neurological comorbidities were excluded. According to EFNS/PNS criteria, the remaining patients were classified into several clinical subtypes, such as typical, MADSAM, DADS and others. We also
Abbreviations: CIDP, chronic inflammatory demyelinating polyneuropathy; MADSAM, multifocal demyelinating sensory and motor neuropathy; MAG, myelinassociated glycoprotein; CMT1A, Charcot-Marie-Tooth disease type 1A; EFNS/PNS, European Federation of Neurological Societies/Peripheral Nerve Society; NC, normal control; AAR, abnormal amplitude reduction ⁎ Corresponding author at: Department of Neurology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan. E-mail address: [email protected] (K. Shibuya). https://doi.org/10.1016/j.jneuroim.2020.577170 Received 4 January 2020; Received in revised form 19 January 2020; Accepted 23 January 2020 0165-5728/ © 2020 Elsevier B.V. All rights reserved.
Journal of Neuroimmunology 341 (2020) 577170
K. Shibuya, et al.
Fig. 1. Normalized conduction slowing of demyelinating polyneuropathies. Conduction slowing is express as percentages of normal mean values in nerve conduction studies. Conduction slowing in the distal and proximal portions of the median and ulnar nerves was prominent in typical chronic inflammatory demyelinating polyneuropathy (CIDP). In MADSAM, distal slowing was mild, and the nerve trunk slowing from the arm to proximal segments was varied. In anti-myelin-associated glycoprotein (MAG) antibody-positive neuropathy, the distal segments were predominantly involved. In CMT1A, all segments were uniformly and prominently affected, compared with other neuropathies. Data are presented as mean + SEM.
included patients with anti-MAG or sulfated glucuronyl paragloboside antibodies, measured with enzyme-linked immunosorbent assay and Western blot, and those with genetically-confirmed CMT1A (Dalakas, 2018). Normal control values (NC) of neurophysiological parameters were obtained from 115 healthy subjects. Patients were clinically evaluated at their first visits. Functional disability was assessed, using the Hughes functional grading scale: 0, normal; 1, able to run; 2, able to walk 5 m independently; 3, able to walk 5 m with aids; 4, and chair or bed bound (Kuwabara et al., 2015). Muscle strength was also investigated, using Medical Research Council (MRC) scales. In this study MADSAM was defined as typical mononeuropathy multiplex or asymmetric weakness with one or more MRC scale differences in the homonymous muscles (Kuwabara et al., 2006).
conduction findings in the median and ulnar motor nerves were divided into the 4 (distal, forearm, arm and plexus/root) and 5 (distal, forearm, elbow, arm and plexus/root) segments, respectively, according to stimulation sites. Nerve conduction studies in the lower extremity were excluded from the analysis, because compound muscle action potentials were not evoked in a lot of patients. Extent of conduction slowing was normalized based on the normal mean values. In the distal portions, distal latencies were normalized. In the forearm, elbow and arm portions, extent of conduction slowing (i.e. conduction velocity ratios) was calculated, using conduction velocity. Plexus/root (i.e. proximal) conduction time was calculated as follows (Capasso et al., 2002);
Proximal conduction time F wave latency (ms ) + distal latency (ms ) = 2
2.2. Electrophysiological studies
1 (ms )
latency measured at axilla (ms ).
Nerve conduction studies were performed within 1 month from their first visits in the severely affected side. Motor nerve conduction and F-wave studies were assessed in the median, ulnar, peroneal and tibial nerves, using conventional procedures. Distal latencies of the median and ulnar nerves were measured after stimulation 3 cm distal from the wrist crease. The median nerve stimulation was applied at the cubital fossa and axillary fossa, and the ulnar nerve stimulation was applied at below and above the cubital tunnel and axillary fossa. Sensory nerve conduction studies were conducted in median, ulnar, radial and sural nerves, antidromically. EFNS/PNS electrodiagnostic criteria for demyelination was applied to determine the presence of demyelinative conduction abnormalities (Van den Bergh et al., 2010). To analyze the distribution pattern of demyelination, nerve
Normalized conduction slowing across the plexus/root (i.e. proximal) portions was calculated. Abnormal amplitude reduction (conduction block or abnormal temporal dispersion) was assessed in the nerve trunks. Over 30% amplitude reduction in each segment (i.e. forearm and arm in the median nerve and forearm, elbow and arm in the ulnar nerve) was judged as abnormal (Van den Berg-Vos et al., 2000). 2.3. Statistical analysis All statistical analyses were performed by one of the authors (KS) using SPSS Version 24 software. Only patients with typical and 2
Journal of Neuroimmunology 341 (2020) 577170
K. Shibuya, et al.
MADSAM subtypes were included into this study and analyzed, to reveal neurophysiological and pathogenic differences in CIDP, because the number of patients with other subtypes was small. To investigate clinical and neurophysiological differences in demyelinating polyneuropathies, unpaired t-test or Fisher's exact test were applied. Data are presented as mean ± SD. In 3 disease group comparison, MADSAM was compared with typical CIDP and anti-MAG neuropathy, and Bonferroni's correction for multiple testing was taken into account. As such, the level of statistical significance was established at p < .025.
longer than typical CIDP, but differences did not reach statistical differences (p = .09), probably due to substantial variabilities. The distribution and extent of nerve conduction slowing are shown in Fig. 1. In typical CIDP, conduction slowing was prominent in the distal and proximal portions of the median and ulnar nerves. In MADSAM, distal slowing was mild, and the nerve trunks from the arm to proximal segments were variably affected. In anti-MAG neuropathy, the pattern was similar to that in typical CIDP; but the distal segments were predominantly involved. In CMT1A, all segments were uniformly affected, and the extent of nerve conduction slowing was most prominent, compared with other neuropathies. Fig. 2 shows comparison of nerve conduction slowing in each segment of typical CIDP, MADSAM, and anti-MAG neuropathy. Distal latency prolongation was most prominent in anti-MAG neuropathy, moderate in typical CIDP and mild in MADSAM. Compared with MADSAM, distal latency prolongation was prominent in the median and ulnar nerves of antiMAG neuropathy (p < .025 and p < .01, respectively) and typical CIDP (both p < .01). Nerve conduction slowing in the nerve trunks and proximal segments was similar among the 3 disorders, whereas conduction slowing across the elbow segment of the ulnar nerve was more prominent in typical CIDP and anti-MAG neuropathy than in MADSAM.
3. Results A total of 125 CIDP patients were classified as having typical CIDP (n = 85), MADSAM (n = 29), DADS (n = 3), and others (n = 8). Of 85 typical CIDP patients, 76 patients met definite electrodiagnostic criteria, 9 met probable (Van den Bergh et al., 2010). Similarly, of 29 MADSAM, 26 met define, and 3 met probable. Additionally, all of 3 DADS met define criteria. We included typical CIDP and MADSAM patients in analyses. Anti-MAG neuropathy (n = 16) and CMT1A (n = 26) patients were also included. Their clinical characteristics are shown in Supplementary table1. Disease duration of MADSAM was
Fig. 2. Normalized conduction slowing in each portion of CIDP and anti-MAG neuropathies. Normalized conduction slowing in each portion of CIDP and anti-MAG neuropathies are expressed. Conduction slowing in the median (A) and ulnar nerves (B) of typical CIDP (both **p < .01) and anti-MAG neuropathy (*p < .025 and **p < .01, respectively) was prominent in distal portions, compared with MADSAM.
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Journal of Neuroimmunology 341 (2020) 577170
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bind these regions in antibody-mediated neuropathies. Whereas autoantibodies in typical CIDP have not been identified, our previous study using MR neurography has shown nerve root-predominant enlargement in patients with typical CIDP (Shibuya et al., 2015). Additionally, a previous study demonstrated higher protein levels in cerebrospinal fluid in typical CIDP, compared to MADSAM, probably reflecting preferential nerve root lesions (Ikeda et al., 2019). These findings may also support the hypothesis. Moreover, the present study showed distal nerve conduction slowing was most prominent in anti-MAG neuropathy, and this raises the possibility that IgM antibodies preferentially bind the distal nerve terminals, rather than the nerve roots. Demyelination over the nerve trunks must be associated with breakdown of the BNB in immune-mediated neuropathies (Kanda, 2013), because the nerve trunk is tightly protected by the BNB and cannot be easily accessed by autoantibodies, and this was the exactly case in MADSAM patients. As such, activated T cells would disrupt the BNB, invade the nerve parenchyma, and thereby cause demyelination in the nerve trunks. The present study identified prominent demyelination, abnormal amplitude reductions, across the nerve trunks in MADSAM. Moreover, our previous MRI study demonstrated multifocal fusiform nerve hypertrophy in the nerve trunks in MADSAM (Shibuya et al., 2015). Furthermore, previous studies disclosed that MADSAM is refractory to immunoglobulin therapy and plasmapheresis (Kuwabara et al., 2015). Findings of the present study may suggest that local activation of cell-adhesion molecules, inflammatory cytokines, matrix metalloproteinases or other inflammatory substances with cellular immunity underlies in MADSAM (Shimizu et al., 2014), similar to those of multiple sclerosis (Reich et al., 2018). Additionally, prolonged distal latencies in MADSAM was much milder than typical CIDP. We speculate the structure and expressed molecules on vessel walls could be different in the distal nerve terminals and nerve trunks. CIDP potentially has heterogenous pathogenesis. Typical CIDP had not only distal nerve and root lesions but also decreased conduction velocities in the nerve trunk. Moreover, MADSAM also had mild distal nerve and root lesions. Additionally, a few patients with typical CIDP occasionally had MADSAM like electrophysiological findings. Multiple pathophysiologies probably underlie in CIDP, such as cytokines and even antibodies could partly contribute to development of MADSAM. However, previously mentioned pathogenesis may be main mechanisms, because prolonged distal latencies in typical CIDP and conduction blocks in MADSAM were the most conspicuous findings in most of patients. A previous pathological study may support our speculation (Ikeda et al., 2019). While sural nerve biopsy in typical CIDP showed unremarkable or uniform findings, MADSAM demonstrated patchy reduction of myelinated fibres. Sural nerve biopsy is performed in the nerve trunk. As such, these findings may be compatible with our hypothesis. The underlying heterogenous mechanisms in CIDP have to be revealed in the future study. This study has several limitations. Paranodal antibodies, such as autoantibodies against Neurofascin (NF) 155, NF186 and Contactin-1, and M-protein were not extensively examined in this cohort (Lehmann et al., 2019). However, previous studies revealed CIDP patients with these antibodies have typical or DADS phenotypes (Kadoya et al., 2016). These may be compatible with our hypothesis. Additionally, both side NCS was not performed in all of patients, but NCS was performed at least in the severely affected side, based on clinical evaluations. As such, if another side NCS was also performed, results may be additional. Different treatment strategy should be established among CIDP subtypes and anti-MAG neuropathy, according to each pathophysiology. The EFNS/PNS guideline has recommended different treatment protocols for paraproteinemic demyelinating neuropathies, including anti-MAG neuropathy Society EFoNSPN, (2010). In this guideline, fludarabine, rituximab and others are described as potentially efficacious drugs for immune-mediated neuropathy with IgM paraproteinemia. Moreover, therapeutic approach for immune-mediated neuropathy with
Fig. 3. Abnormal amplitude reduction in demyelinating neuropathies. Abnormal amplitude reduction (AAR) (ratio > 30%) was the most frequent at all segments in MADSAM, compared with typical CIDP and anti-MAG neuropathy. Especially in the median nerve, frequencies of AAR in MADSAM was prominent, compared with typical CIDP (p < .025) and anti-MAG neuropathy (p < .01).
Fig. 3 shows the frequency of abnormal amplitude reduction (AAR; conduction block or abnormal temporal dispersion) in each nerve segment of the median and ulnar nerves. AAR was most frequently found in MADSAM patients (Median; 76%, Ulnar; 50%). Typical CIDP patients also frequently showed AAR (Median; 49%, Ulnar; 42%), and anti-MAG neuropathy rarely had AAR (Median; 26%, Ulnar; 15%). AAR was frequent in the median nerve of MADSAM, compared with typical CIDP (p < .025) and anti-MAG neuropathy (p < .01). Raw data of neurophysiological findings are shown in Supplementary Table 1. 4. Discussion Our results showed that demyelination in the distal nerve segments was prominent in typical CIDP and anti-MAG neuropathy, and mild in MADSAM. Along with previous reports, demyelination was profusely and uniformly distributed in CMT1A. Conduction block in the nerve trunks was suggested to be most frequently in MADSAM patients, and rarely in anti-MAG neuropathy. These findings presumably reflect the different pathomechanims among immune-mediated neuropathies. The blood-nerve barrier (BNB) is anatomically deficient at the distal nerve terminals and spinal nerve roots (Kanda, 2013). While the of IgG varies depending on the species, the typical value cited is 150 kDa molecular weight (Alberts et al., 2002). In anti-MAG neuropathy, the M-proteins are of IgM class, and IgM, a pentamer of immunoglobulins, has a molecular weight of 970 kDa. Such large molecule substances cannot access the nerve trunks because of the barrier but may easily 4
Journal of Neuroimmunology 341 (2020) 577170
K. Shibuya, et al.
References
IgA and IgG paraproteinemia is recommend as similar to those of CIDP without a paraprotein. The present study implies different underlying pathomechanisms among CIDP subtypes. We suggest that clinical trials may have to be planed for each subtype of CIDP, and treatment strategy should be established according to the pathophysiology.
Alberts, B., Johnson, A., Lewis, J., Raff, M., Roberts, K., Walter, P., 2002. Molecular biology of the cell 4th edn (New York: Garland Science). Ann. Bot. 91, 401. Attarian, S., Azulay, J.P., Boucraut, J., Escande, N., Pouget, J., 2001. Terminal latency index and modified F ratio in distinction of chronic demyelinating neuropathies. Clin. Neurophysiol. 112, 457–463. Capasso, M., Torrieri, F., Di Muzio, A., De Angelis, M.V., Lugaresi, A., Uncini, A., 2002. Can electrophysiology differentiate polyneuropathy with anti-MAG/SGPG antibodies from chronic inflammatory demyelinating polyneuropathy? Clin. Neurophysiol. 113, 346–353. Dalakas, M.C., 2018. Advances in the diagnosis, immunopathogenesis and therapies of IgM-anti-MAG antibody-mediated neuropathies. Ther. Adv. Neurol. Disord. 11, 1756285617746640. Ikeda, S., Koike, H., Nishi, R., Kawagashira, Y., Iijima, M., Katsuno, M., et al., 2019. Clinicopathological characteristics of subtypes of chronic inflammatory demyelinating polyradiculoneuropathy. J. Neurol. Neurosurg. Psychiatry 90, 988–996. Kadoya, M., Kaida, K., Koike, H., Takazaki, H., Ogata, H., Moriguchi, K., et al., 2016. IgG4 anti-neurofascin155 antibodies in chronic inflammatory demyelinating polyradiculoneuropathy: clinical significance and diagnostic utility of a conventional assay. J. Neuroimmunol. 301, 16–22. Kanda, T., 2013. Biology of the blood-nerve barrier and its alteration in immune mediated neuropathies. J. Neurol. Neurosurg. Psychiatry 84, 208–212. Kuwabara, S., Misawa, S., Mori, M., Tamura, N., Kubota, M., Hattori, T., 2006. Long term prognosis of chronic inflammatory demyelinating polyneuropathy: a five year follow up of 38 cases. J. Neurol. Neurosurg. Psychiatry 77, 66–70. Kuwabara, S., Isose, S., Mori, M., Mitsuma, S., Sawai, S., Beppu, M., et al., 2015. Different electrophysiological profiles and treatment response in ‘typical’ and ‘atypical’ chronic inflammatory demyelinating polyneuropathy. J. Neurol. Neurosurg. Psychiatry 86, 1054–1059. Lehmann, H.C., Burke, D., Kuwabara, S., 2019. Chronic inflammatory demyelinating polyneuropathy: update on diagnosis, immunopathogenesis and treatment. J. Neurol. Neurosurg. Psychiatry 981–987. Manganelli, F., Pisciotta, C., Reilly, M.M., Tozza, S., Schenone, A., Fabrizi, G.M., et al., 2016. Nerve conduction velocity in CMT1A: what else can we tell? Eur. J. Neurol. 23, 1566–1571. Reich, D.S., Lucchinetti, C.F., Calabresi, P.A., 2018. Multiple sclerosis. N. Engl. J. Med. 378, 169–180. Shibuya, K., Sugiyama, A., Ito, S., Misawa, S., Sekiguchi, Y., Mitsuma, S., et al., 2015. Reconstruction magnetic resonance neurography in chronic inflammatory demyelinating polyneuropathy. Ann. Neurol. 77, 333–337. Shimizu, F., Omoto, M., Sano, Y., Mastui, N., Miyashiro, A., Tasaki, A., et al., 2014. Sera from patients with multifocal motor neuropathy disrupt the blood-nerve barrier. J. Neurol. Neurosurg. Psychiatry 85, 526–537. Society EFoNSPN, 2010. European Federation of Neurological Societies/Peripheral Nerve Society Guideline on management of paraproteinemic demyelinating neuropathies. Report of a Joint Task Force of the European Federation of Neurological Societies and the Peripheral Nerve Society–first revision. J. Peripher. Nerv. Syst. 15, 185–195. Van den Bergh, P.Y., Hadden, R.D., Bouche, P., Cornblath, D.R., Hahn, A., Illa, I., et al., 2010. European Federation of Neurological Societies/Peripheral Nerve Society guideline on management of chronic inflammatory demyelinating polyradiculoneuropathy: report of a joint task force of the European Federation of Neurological Societies and the Peripheral Nerve Society - first revision. Eur. J. Neurol. 17, 356–363. Van den Berg-Vos, R.M., Franssen, H., Wokke, J.H., Van Es, H.W., Van den Berg, L.H., 2000. Multifocal motor neuropathy: diagnostic criteria that predict the response to immunoglobulin treatment. Ann. Neurol. 48, 919–926. Vlam, L., van der Pol, W.L., Cats, E.A., Straver, D.C., Piepers, S., Franssen, H., et al., 2011. Multifocal motor neuropathy: diagnosis, pathogenesis and treatment strategies. Nat. Rev. Neurol. 8, 48–58.
Contributors KS and SK designed the study. KS, AT, SM, YuS, MB, TS, YoS, KN and HK collected clinical and neurophysiological data, provided technical advice and interpreted data. KS and SK drafted the manuscript. KS performed statistical analyses. SK supervised this study. Ethics approval This study was approved by the Ethics Committee of Chiba University School of Medicine. Ethical publication statement All of the authors 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. Originality of submitted research The content is not published or under review at any other publication. Declaration of Competing Interest None declared. Acknowledgment Drs. Shibuya, Misawa, Sekiguchi, Suzuki and Kuwabara receive research support from the Ministry of Education, Culture, Sports, Science, and Technology of Japan. Dr. Kuwabara receives research support from the Ministry of Education, Culture, Sports, Science, and Technology of Japan, and Grants-in-Aid from the Research Committee of CNS Degenerative Diseases, the Ministry of Health, Labour and Welfare of Japan. Appendix A. Supplementary data Supplementary data to this article can be found online at https:// doi.org/10.1016/j.jneuroim.2020.577170.
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Contents lists available at ScienceDirect
Journal of Neuroimmunology journal homepage: www.elsevier.com/locate/jneuroim
Different distribution of demyelination in chronic inflammatory demyelinating polyneuropathy subtypes
T
Kazumoto Shibuya , Atsuko Tsuneyama, Sonoko Misawa, Yukari Sekiguchi, Minako Beppu, Tomoki Suichi, Yo-ichi Suzuki, Keigo Nakamura, Hiroki Kano, Satoshi Kuwabara ⁎
Department of Neurology, Graduate School of Medicine, Chiba University, Chiba, Japan
ARTICLE INFO
ABSTRACT
Keywords: Chronic inflammatory demyelinating polyneuropathy Blood-nerve barrier Nerve conduction study Demyelinating distribution Clinical subtypes Anti-myelin-associated glycoprotein antibodypositive neuropathy
In demyelinating polyneuropathies, distribution patterns of demyelination reflect underlying pathogenesis. Median and ulnar nerve conduction studies were reviewed in 85 typical chronic inflammatory demyelinating polyneuropathy (CIDP) patients and 29 multifocal acquired demyelinating sensory and motor neuropathy (MADSAM). Distal latencies were prolonged in typical CIDP and near normal in MADSAM. Abnormal amplitude reductions in the nerve trunks were more frequent in MADSAM than typical CIDP. Presumably because the blood-nerve barrier is anatomically deficient at the distal nerve terminals, antibody-mediated demyelination is a major pathophysiology in typical CIDP. In contrast, blood-nerve barrier breakdown is likely to be predominant in MADSAM.
1. Introduction Chronic inflammatory demyelinating polyneuropathy (CIDP) is currently classified into typical CIDP and atypical variant such as multifocal demyelinating sensory and motor neuropathy (MADSAM), according to clinical manifestation (Lehmann et al., 2019). Other representative chronic demyelinating neuropathies include anti-myelinassociated glycoprotein (MAG) antibody-positive neuropathy and multifocal motor neuropathy (MMN). Previous electrophysiological studies have shown characteristic patterns of nerve conduction abnormalities in each disorder. Typical CIDP and anti-MAG neuropathy cause conduction slowing and block predominantly in the distal portions of the peripheral nerves, whereas demyelination is frequently found in the nerve trunks with conduction block in MADSAM and MMN (Attarian et al., 2001; Dalakas, 2018; Kuwabara et al., 2015; Vlam et al., 2011). Additionally, uniform demyelination along a longitudinal course of a nerve is reported in hereditary demyelinating neuropathy such as Charcot-Marie-Tooth disease type 1A (CMT1A) (Manganelli et al., 2016). These different distribution patterns of demyelination are likely to reflect the different underlying pathophysiology. Among CIDP subtypes, response to immunomodulating treatment is different (Kuwabara et al., 2006, 2015; Van den Bergh et al., 2010).
Patients with the typical CIDP respond well to immunoglobulin and plasmapheresis, but patients with MADSAM or anti-MAG neuropathy are often refractory to immunoglobulin therapy (Kuwabara et al., 2015). These findings also suggest that different pathomechanisms underlie in each condition. The present study aimed to systematically and directly compare distribution patterns of demyelination and reveal the underlying pathophysiology among CIDP subtypes and anti-MAG neuropathy. 2. Materials and methods 2.1. Subjects A total of 136 patients, who were referred to the Chiba University Hospital and fulfilled European Federation of Neurological Societies/ Peripheral Nerve Society (EFNS/PNS) criteria for probable or definite CIDP, was included into this study (Van den Bergh et al., 2010). They were followed up at least 1 year, to confirm diagnosis of CIDP. Of these, patients complicated with inherited neuropathies, multiple sclerosis and other neurological comorbidities were excluded. According to EFNS/PNS criteria, the remaining patients were classified into several clinical subtypes, such as typical, MADSAM, DADS and others. We also
Abbreviations: CIDP, chronic inflammatory demyelinating polyneuropathy; MADSAM, multifocal demyelinating sensory and motor neuropathy; MAG, myelinassociated glycoprotein; CMT1A, Charcot-Marie-Tooth disease type 1A; EFNS/PNS, European Federation of Neurological Societies/Peripheral Nerve Society; NC, normal control; AAR, abnormal amplitude reduction ⁎ Corresponding author at: Department of Neurology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan. E-mail address: [email protected] (K. Shibuya). https://doi.org/10.1016/j.jneuroim.2020.577170 Received 4 January 2020; Received in revised form 19 January 2020; Accepted 23 January 2020 0165-5728/ © 2020 Elsevier B.V. All rights reserved.
Journal of Neuroimmunology 341 (2020) 577170
K. Shibuya, et al.
Fig. 1. Normalized conduction slowing of demyelinating polyneuropathies. Conduction slowing is express as percentages of normal mean values in nerve conduction studies. Conduction slowing in the distal and proximal portions of the median and ulnar nerves was prominent in typical chronic inflammatory demyelinating polyneuropathy (CIDP). In MADSAM, distal slowing was mild, and the nerve trunk slowing from the arm to proximal segments was varied. In anti-myelin-associated glycoprotein (MAG) antibody-positive neuropathy, the distal segments were predominantly involved. In CMT1A, all segments were uniformly and prominently affected, compared with other neuropathies. Data are presented as mean + SEM.
included patients with anti-MAG or sulfated glucuronyl paragloboside antibodies, measured with enzyme-linked immunosorbent assay and Western blot, and those with genetically-confirmed CMT1A (Dalakas, 2018). Normal control values (NC) of neurophysiological parameters were obtained from 115 healthy subjects. Patients were clinically evaluated at their first visits. Functional disability was assessed, using the Hughes functional grading scale: 0, normal; 1, able to run; 2, able to walk 5 m independently; 3, able to walk 5 m with aids; 4, and chair or bed bound (Kuwabara et al., 2015). Muscle strength was also investigated, using Medical Research Council (MRC) scales. In this study MADSAM was defined as typical mononeuropathy multiplex or asymmetric weakness with one or more MRC scale differences in the homonymous muscles (Kuwabara et al., 2006).
conduction findings in the median and ulnar motor nerves were divided into the 4 (distal, forearm, arm and plexus/root) and 5 (distal, forearm, elbow, arm and plexus/root) segments, respectively, according to stimulation sites. Nerve conduction studies in the lower extremity were excluded from the analysis, because compound muscle action potentials were not evoked in a lot of patients. Extent of conduction slowing was normalized based on the normal mean values. In the distal portions, distal latencies were normalized. In the forearm, elbow and arm portions, extent of conduction slowing (i.e. conduction velocity ratios) was calculated, using conduction velocity. Plexus/root (i.e. proximal) conduction time was calculated as follows (Capasso et al., 2002);
Proximal conduction time F wave latency (ms ) + distal latency (ms ) = 2
2.2. Electrophysiological studies
1 (ms )
latency measured at axilla (ms ).
Nerve conduction studies were performed within 1 month from their first visits in the severely affected side. Motor nerve conduction and F-wave studies were assessed in the median, ulnar, peroneal and tibial nerves, using conventional procedures. Distal latencies of the median and ulnar nerves were measured after stimulation 3 cm distal from the wrist crease. The median nerve stimulation was applied at the cubital fossa and axillary fossa, and the ulnar nerve stimulation was applied at below and above the cubital tunnel and axillary fossa. Sensory nerve conduction studies were conducted in median, ulnar, radial and sural nerves, antidromically. EFNS/PNS electrodiagnostic criteria for demyelination was applied to determine the presence of demyelinative conduction abnormalities (Van den Bergh et al., 2010). To analyze the distribution pattern of demyelination, nerve
Normalized conduction slowing across the plexus/root (i.e. proximal) portions was calculated. Abnormal amplitude reduction (conduction block or abnormal temporal dispersion) was assessed in the nerve trunks. Over 30% amplitude reduction in each segment (i.e. forearm and arm in the median nerve and forearm, elbow and arm in the ulnar nerve) was judged as abnormal (Van den Berg-Vos et al., 2000). 2.3. Statistical analysis All statistical analyses were performed by one of the authors (KS) using SPSS Version 24 software. Only patients with typical and 2
Journal of Neuroimmunology 341 (2020) 577170
K. Shibuya, et al.
MADSAM subtypes were included into this study and analyzed, to reveal neurophysiological and pathogenic differences in CIDP, because the number of patients with other subtypes was small. To investigate clinical and neurophysiological differences in demyelinating polyneuropathies, unpaired t-test or Fisher's exact test were applied. Data are presented as mean ± SD. In 3 disease group comparison, MADSAM was compared with typical CIDP and anti-MAG neuropathy, and Bonferroni's correction for multiple testing was taken into account. As such, the level of statistical significance was established at p < .025.
longer than typical CIDP, but differences did not reach statistical differences (p = .09), probably due to substantial variabilities. The distribution and extent of nerve conduction slowing are shown in Fig. 1. In typical CIDP, conduction slowing was prominent in the distal and proximal portions of the median and ulnar nerves. In MADSAM, distal slowing was mild, and the nerve trunks from the arm to proximal segments were variably affected. In anti-MAG neuropathy, the pattern was similar to that in typical CIDP; but the distal segments were predominantly involved. In CMT1A, all segments were uniformly affected, and the extent of nerve conduction slowing was most prominent, compared with other neuropathies. Fig. 2 shows comparison of nerve conduction slowing in each segment of typical CIDP, MADSAM, and anti-MAG neuropathy. Distal latency prolongation was most prominent in anti-MAG neuropathy, moderate in typical CIDP and mild in MADSAM. Compared with MADSAM, distal latency prolongation was prominent in the median and ulnar nerves of antiMAG neuropathy (p < .025 and p < .01, respectively) and typical CIDP (both p < .01). Nerve conduction slowing in the nerve trunks and proximal segments was similar among the 3 disorders, whereas conduction slowing across the elbow segment of the ulnar nerve was more prominent in typical CIDP and anti-MAG neuropathy than in MADSAM.
3. Results A total of 125 CIDP patients were classified as having typical CIDP (n = 85), MADSAM (n = 29), DADS (n = 3), and others (n = 8). Of 85 typical CIDP patients, 76 patients met definite electrodiagnostic criteria, 9 met probable (Van den Bergh et al., 2010). Similarly, of 29 MADSAM, 26 met define, and 3 met probable. Additionally, all of 3 DADS met define criteria. We included typical CIDP and MADSAM patients in analyses. Anti-MAG neuropathy (n = 16) and CMT1A (n = 26) patients were also included. Their clinical characteristics are shown in Supplementary table1. Disease duration of MADSAM was
Fig. 2. Normalized conduction slowing in each portion of CIDP and anti-MAG neuropathies. Normalized conduction slowing in each portion of CIDP and anti-MAG neuropathies are expressed. Conduction slowing in the median (A) and ulnar nerves (B) of typical CIDP (both **p < .01) and anti-MAG neuropathy (*p < .025 and **p < .01, respectively) was prominent in distal portions, compared with MADSAM.
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bind these regions in antibody-mediated neuropathies. Whereas autoantibodies in typical CIDP have not been identified, our previous study using MR neurography has shown nerve root-predominant enlargement in patients with typical CIDP (Shibuya et al., 2015). Additionally, a previous study demonstrated higher protein levels in cerebrospinal fluid in typical CIDP, compared to MADSAM, probably reflecting preferential nerve root lesions (Ikeda et al., 2019). These findings may also support the hypothesis. Moreover, the present study showed distal nerve conduction slowing was most prominent in anti-MAG neuropathy, and this raises the possibility that IgM antibodies preferentially bind the distal nerve terminals, rather than the nerve roots. Demyelination over the nerve trunks must be associated with breakdown of the BNB in immune-mediated neuropathies (Kanda, 2013), because the nerve trunk is tightly protected by the BNB and cannot be easily accessed by autoantibodies, and this was the exactly case in MADSAM patients. As such, activated T cells would disrupt the BNB, invade the nerve parenchyma, and thereby cause demyelination in the nerve trunks. The present study identified prominent demyelination, abnormal amplitude reductions, across the nerve trunks in MADSAM. Moreover, our previous MRI study demonstrated multifocal fusiform nerve hypertrophy in the nerve trunks in MADSAM (Shibuya et al., 2015). Furthermore, previous studies disclosed that MADSAM is refractory to immunoglobulin therapy and plasmapheresis (Kuwabara et al., 2015). Findings of the present study may suggest that local activation of cell-adhesion molecules, inflammatory cytokines, matrix metalloproteinases or other inflammatory substances with cellular immunity underlies in MADSAM (Shimizu et al., 2014), similar to those of multiple sclerosis (Reich et al., 2018). Additionally, prolonged distal latencies in MADSAM was much milder than typical CIDP. We speculate the structure and expressed molecules on vessel walls could be different in the distal nerve terminals and nerve trunks. CIDP potentially has heterogenous pathogenesis. Typical CIDP had not only distal nerve and root lesions but also decreased conduction velocities in the nerve trunk. Moreover, MADSAM also had mild distal nerve and root lesions. Additionally, a few patients with typical CIDP occasionally had MADSAM like electrophysiological findings. Multiple pathophysiologies probably underlie in CIDP, such as cytokines and even antibodies could partly contribute to development of MADSAM. However, previously mentioned pathogenesis may be main mechanisms, because prolonged distal latencies in typical CIDP and conduction blocks in MADSAM were the most conspicuous findings in most of patients. A previous pathological study may support our speculation (Ikeda et al., 2019). While sural nerve biopsy in typical CIDP showed unremarkable or uniform findings, MADSAM demonstrated patchy reduction of myelinated fibres. Sural nerve biopsy is performed in the nerve trunk. As such, these findings may be compatible with our hypothesis. The underlying heterogenous mechanisms in CIDP have to be revealed in the future study. This study has several limitations. Paranodal antibodies, such as autoantibodies against Neurofascin (NF) 155, NF186 and Contactin-1, and M-protein were not extensively examined in this cohort (Lehmann et al., 2019). However, previous studies revealed CIDP patients with these antibodies have typical or DADS phenotypes (Kadoya et al., 2016). These may be compatible with our hypothesis. Additionally, both side NCS was not performed in all of patients, but NCS was performed at least in the severely affected side, based on clinical evaluations. As such, if another side NCS was also performed, results may be additional. Different treatment strategy should be established among CIDP subtypes and anti-MAG neuropathy, according to each pathophysiology. The EFNS/PNS guideline has recommended different treatment protocols for paraproteinemic demyelinating neuropathies, including anti-MAG neuropathy Society EFoNSPN, (2010). In this guideline, fludarabine, rituximab and others are described as potentially efficacious drugs for immune-mediated neuropathy with IgM paraproteinemia. Moreover, therapeutic approach for immune-mediated neuropathy with
Fig. 3. Abnormal amplitude reduction in demyelinating neuropathies. Abnormal amplitude reduction (AAR) (ratio > 30%) was the most frequent at all segments in MADSAM, compared with typical CIDP and anti-MAG neuropathy. Especially in the median nerve, frequencies of AAR in MADSAM was prominent, compared with typical CIDP (p < .025) and anti-MAG neuropathy (p < .01).
Fig. 3 shows the frequency of abnormal amplitude reduction (AAR; conduction block or abnormal temporal dispersion) in each nerve segment of the median and ulnar nerves. AAR was most frequently found in MADSAM patients (Median; 76%, Ulnar; 50%). Typical CIDP patients also frequently showed AAR (Median; 49%, Ulnar; 42%), and anti-MAG neuropathy rarely had AAR (Median; 26%, Ulnar; 15%). AAR was frequent in the median nerve of MADSAM, compared with typical CIDP (p < .025) and anti-MAG neuropathy (p < .01). Raw data of neurophysiological findings are shown in Supplementary Table 1. 4. Discussion Our results showed that demyelination in the distal nerve segments was prominent in typical CIDP and anti-MAG neuropathy, and mild in MADSAM. Along with previous reports, demyelination was profusely and uniformly distributed in CMT1A. Conduction block in the nerve trunks was suggested to be most frequently in MADSAM patients, and rarely in anti-MAG neuropathy. These findings presumably reflect the different pathomechanims among immune-mediated neuropathies. The blood-nerve barrier (BNB) is anatomically deficient at the distal nerve terminals and spinal nerve roots (Kanda, 2013). While the of IgG varies depending on the species, the typical value cited is 150 kDa molecular weight (Alberts et al., 2002). In anti-MAG neuropathy, the M-proteins are of IgM class, and IgM, a pentamer of immunoglobulins, has a molecular weight of 970 kDa. Such large molecule substances cannot access the nerve trunks because of the barrier but may easily 4
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References
IgA and IgG paraproteinemia is recommend as similar to those of CIDP without a paraprotein. The present study implies different underlying pathomechanisms among CIDP subtypes. We suggest that clinical trials may have to be planed for each subtype of CIDP, and treatment strategy should be established according to the pathophysiology.
Alberts, B., Johnson, A., Lewis, J., Raff, M., Roberts, K., Walter, P., 2002. Molecular biology of the cell 4th edn (New York: Garland Science). Ann. Bot. 91, 401. Attarian, S., Azulay, J.P., Boucraut, J., Escande, N., Pouget, J., 2001. Terminal latency index and modified F ratio in distinction of chronic demyelinating neuropathies. Clin. Neurophysiol. 112, 457–463. Capasso, M., Torrieri, F., Di Muzio, A., De Angelis, M.V., Lugaresi, A., Uncini, A., 2002. Can electrophysiology differentiate polyneuropathy with anti-MAG/SGPG antibodies from chronic inflammatory demyelinating polyneuropathy? Clin. Neurophysiol. 113, 346–353. Dalakas, M.C., 2018. Advances in the diagnosis, immunopathogenesis and therapies of IgM-anti-MAG antibody-mediated neuropathies. Ther. Adv. Neurol. Disord. 11, 1756285617746640. Ikeda, S., Koike, H., Nishi, R., Kawagashira, Y., Iijima, M., Katsuno, M., et al., 2019. Clinicopathological characteristics of subtypes of chronic inflammatory demyelinating polyradiculoneuropathy. J. Neurol. Neurosurg. Psychiatry 90, 988–996. Kadoya, M., Kaida, K., Koike, H., Takazaki, H., Ogata, H., Moriguchi, K., et al., 2016. IgG4 anti-neurofascin155 antibodies in chronic inflammatory demyelinating polyradiculoneuropathy: clinical significance and diagnostic utility of a conventional assay. J. Neuroimmunol. 301, 16–22. Kanda, T., 2013. Biology of the blood-nerve barrier and its alteration in immune mediated neuropathies. J. Neurol. Neurosurg. Psychiatry 84, 208–212. Kuwabara, S., Misawa, S., Mori, M., Tamura, N., Kubota, M., Hattori, T., 2006. Long term prognosis of chronic inflammatory demyelinating polyneuropathy: a five year follow up of 38 cases. J. Neurol. Neurosurg. Psychiatry 77, 66–70. Kuwabara, S., Isose, S., Mori, M., Mitsuma, S., Sawai, S., Beppu, M., et al., 2015. Different electrophysiological profiles and treatment response in ‘typical’ and ‘atypical’ chronic inflammatory demyelinating polyneuropathy. J. Neurol. Neurosurg. Psychiatry 86, 1054–1059. Lehmann, H.C., Burke, D., Kuwabara, S., 2019. Chronic inflammatory demyelinating polyneuropathy: update on diagnosis, immunopathogenesis and treatment. J. Neurol. Neurosurg. Psychiatry 981–987. Manganelli, F., Pisciotta, C., Reilly, M.M., Tozza, S., Schenone, A., Fabrizi, G.M., et al., 2016. Nerve conduction velocity in CMT1A: what else can we tell? Eur. J. Neurol. 23, 1566–1571. Reich, D.S., Lucchinetti, C.F., Calabresi, P.A., 2018. Multiple sclerosis. N. Engl. J. Med. 378, 169–180. Shibuya, K., Sugiyama, A., Ito, S., Misawa, S., Sekiguchi, Y., Mitsuma, S., et al., 2015. Reconstruction magnetic resonance neurography in chronic inflammatory demyelinating polyneuropathy. Ann. Neurol. 77, 333–337. Shimizu, F., Omoto, M., Sano, Y., Mastui, N., Miyashiro, A., Tasaki, A., et al., 2014. Sera from patients with multifocal motor neuropathy disrupt the blood-nerve barrier. J. Neurol. Neurosurg. Psychiatry 85, 526–537. Society EFoNSPN, 2010. European Federation of Neurological Societies/Peripheral Nerve Society Guideline on management of paraproteinemic demyelinating neuropathies. Report of a Joint Task Force of the European Federation of Neurological Societies and the Peripheral Nerve Society–first revision. J. Peripher. Nerv. Syst. 15, 185–195. Van den Bergh, P.Y., Hadden, R.D., Bouche, P., Cornblath, D.R., Hahn, A., Illa, I., et al., 2010. European Federation of Neurological Societies/Peripheral Nerve Society guideline on management of chronic inflammatory demyelinating polyradiculoneuropathy: report of a joint task force of the European Federation of Neurological Societies and the Peripheral Nerve Society - first revision. Eur. J. Neurol. 17, 356–363. Van den Berg-Vos, R.M., Franssen, H., Wokke, J.H., Van Es, H.W., Van den Berg, L.H., 2000. Multifocal motor neuropathy: diagnostic criteria that predict the response to immunoglobulin treatment. Ann. Neurol. 48, 919–926. Vlam, L., van der Pol, W.L., Cats, E.A., Straver, D.C., Piepers, S., Franssen, H., et al., 2011. Multifocal motor neuropathy: diagnosis, pathogenesis and treatment strategies. Nat. Rev. Neurol. 8, 48–58.
Contributors KS and SK designed the study. KS, AT, SM, YuS, MB, TS, YoS, KN and HK collected clinical and neurophysiological data, provided technical advice and interpreted data. KS and SK drafted the manuscript. KS performed statistical analyses. SK supervised this study. Ethics approval This study was approved by the Ethics Committee of Chiba University School of Medicine. Ethical publication statement All of the authors 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. Originality of submitted research The content is not published or under review at any other publication. Declaration of Competing Interest None declared. Acknowledgment Drs. Shibuya, Misawa, Sekiguchi, Suzuki and Kuwabara receive research support from the Ministry of Education, Culture, Sports, Science, and Technology of Japan. Dr. Kuwabara receives research support from the Ministry of Education, Culture, Sports, Science, and Technology of Japan, and Grants-in-Aid from the Research Committee of CNS Degenerative Diseases, the Ministry of Health, Labour and Welfare of Japan. Appendix A. Supplementary data Supplementary data to this article can be found online at https:// doi.org/10.1016/j.jneuroim.2020.577170.
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