CASE STUDY Longitudinal study on nerve ultrasound and corneal confocal microscopy in NF155 paranodopathy Diamantis Athanasopoulos1 , Jeremias Motte1, Anna Lena Fisse1, Thomas Grueter1, Nadine Trampe2, Dietrich Sturm3,4, Martin Tegenthoff4, Melissa Sgodzai1, Rafael Klimas1, Luis Querol5, Ralf Gold1 & Kalliopi Pitarokoili1 1 Department of Neurology, St. Josef Hospital, Ruhr-University, Bochum, Germany 2 Department of Neurology, Katholische Kliniken Emscher-Lippe, Germany 3 Department of Neurology, Agaplesion Bethesda Hospital, Wuppertal, Germany 4 Department of Neurology, Bergmannsheil University Hospital, Ruhr University, Bochum, Germany 5 Unidad de Enfermedades Neuromusculares, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain Correspondence Abstract Diamantis Athanasopoulos, Department of Neurology, Ruhr University, St. Josef-Hospital, We report the case of a 27-year-old patient with subacute anti-neurofascin-155 Gudrunstr. 56, 44791 Bochum, Germany. neuropathy with bifacial palsy, who showed excellent response to rituximab. Tel: 0049-15237894362; Fax: 0049- We provide longitudinal data of established clinical scores, nerve conduction 2345092414; E-mail: studies, antibody titers, and novel imaging methods (nerve ultrasonography and diamantis.athanasopoulos@ruhr-uni- corneal confocal microscopy). Clinical and electrophysiological improvement bochum.de followed the reduction of serum antibody titer and correlated with a reduction of corneal inflammatory cellular infiltrates whereas the increase in the cross-sec- Funding information tional area of the peripheral nerves remained 12 months after first manifesta- There was no funding source. tion. Our findings suggest that novel techniques provide useful follow-up parameters in paranodopathies. Received: 18 March 2020; Revised: 24 April 2020; Accepted: 24 April 2020 Annals of Clinical and Translational Neurology 2020; 7(6): 1061–1068 doi: 10.1002/acn3.51061 response to IVIg but a good response to rituximab Introduction (RTX). We provide for the first time in the literature lon- Chronic inflammatory demyelinating polyneuropathy gitudinal findings of high-resolution nerve ultrasound (CIDP) is a rare relapsing autoimmune neuropathy with (HRUS) and corneal confocal microscopy (CCM). a multifaceted presentation.1–3 Recently, the description of pathogenic antibodies – predominantly of the IgG4 Case Description and Results class – against nodal and paranodal proteins such as neu- rofascin-186, neurofascin-155, contactin-1, and contactin- A 27-year-old male patient was admitted to the clinic due associated protein-1 has shed new light to a small subset to a subacute, progressive sensorimotor affection of all four of CIDP cases.4–7 extremities. Onset was reported approximately 3 weeks More specifically, antibodies against neurofascin-155 before admission beginning with ascending numbness and (NF155) correlate with a distinct clinical phenotype.8–14 prickling of the feet and hands, which rapidly involved the The response to first-line treatment with intravenous lower extremities up to the groin, followed by a progres- immunoglobulins (IVIg) is poor9–11,13,14 but patients sive, predominantly distal muscle weakness with concomi- show a good response to anti-CD20 targeted therapy.13–16 tant gait disorder. He also reported distal leg pain. No Here, we report the case of a 27-year-old male with difficulty of speech or swallowing was reported. Mild diar- anti-NF155 antibody-positive neuropathy with poor rhea occurred a few weeks before. The past medical and ª 2020 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association 1061 This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. 23289503, 2020, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/acn3.51061 by Readcube (Labtiva Inc.), Wiley Online Library on [10/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License HRUS and CCM in a Case of NF155 Paranodopathy D. Athanasopoulos et al. family history was unremarkable, except from a history of The nerves of the lower extremities remained not exci- 8 pack-years of cigarette consume and penicillin allergy. table after 12 months despite clinical improvement. At On clinical examination, hypoesthesia of the hands and the nerves of the upper extremities DML, F-wave-latencies the lower body with pallanesthesia and areflexia of the and cMAP-duration prolongation was detected with a legs, minor flaccid symmetric distal tetraparesis as well as peak at 2 months, cMAP amplitudes decreased with a limb and gait ataxia were noted. Distally, finger flexion maximum at 5 months. The mCV reduction plateaued at and foot dorsiflexion were grade 4 of the Medical 2 to 5 months. At 12 months mCV, F-wave-latency and Research Council (MRC) sum score on both sides. The cMAP-duration were mostly normalized, cMAP ampli- remainder of the examination was normal. No autonomic tudes and DML also significantly recovered (Figure 1, dysfunction was noted. Table S1). Cerebrospinal fluid (CSF) analysis revealed an albu- Needle electromyography initially showed abnormal minocytologic dissociation with marked increase in pro- spontaneous activity which persisted after 12 months. tein of 319 mg/dl (normal 15-45 mg/dl) and normal cell Chronic neurogenic changes were noted at month 2 and count. Oligoclonal bands were absent. Further laboratory also persisted thereafter. testing for other causes of polyneuropathy revealed no HRUS was performed with the use of an 18 MHz abnormalities. Anti-neurofascin-155 IgG (of the IgG4 sub- ultrasound transducer. The median, ulnar, common class) antibodies were positive in a high titer of 1:3200 radial, tibial, fibular and sural nerves were studied bilater- (detected with cell-based immunofluorescence and con- ally throughout their visualizable courses. The brachial firmed with teased-nerve method in two different labora- plexus was also assessed in the supraclavicular and inter- tories). No further antibodies were detected. scalene spaces. Standardized CSA measurements were per- NCS revealed marked prolongation of distal motor formed at 30 predefined locations according to the latency (DML) and F-wave-latencies symmetrically affect- protocol of our group.17,18 At 2 months after initial diag- ing the nerves of the upper extremities and a less symmet- nosis multifocal peripheral nerve enlargement (median, ric reduction of motor conduction velocity (mCV). The ulnar, and tibial nerve) was noted. The brachial plexus compound muscle action potential (cMAP) amplitudes was enlarged bilaterally. In the following months more were normal. The nerves of the lower extremities were not nerves showed a cross-sectional area (CSA) enlargement excitable (Figure 1, Table S1). The EFNS/PNS criteria for (radial nerve). The Bochum ultrasound score19 (BUS, definite CIDP were fulfilled. MRI studies of the brain and ranging from 0 to 4 points, with 1 point given for the complete spinal axis were unremarkable. increased CSA at each of the four following sites: ulnar The initial treatment, pending results of the serology nerve in Guyons’ canal, ulnar nerve in the upper arm, panel, was five cycles of plasma exchange (PE). A brief radial nerve in the spiral groove, and sural nerve between improvement was followed by a deterioration, including the gastrocnemius muscle), which was developed from bifacial palsy in approximately 1 week. In view of the in our group as a marker of CIDP (if more than two sites the meantime available positive results for NF155 antibod- show increased CSA, score of 2 or more), reached the ies the therapy was immediately escalated to RTX (cumula- maximum of 3 points 12 months after initial presenta- tive 2g). Due to a further relapse with deterioration of tion. A further HRUS marker for clinical progression is muscle weakness 1 month later, the patient was treated the intranerve CSA variability20 (max CSA/min CSA of with IVIg (2 g/kg of body weight) without significant one nerve), which increased for the majority of the nerves improvement. Therefore, a course of intravenous corticos- 2–5 months after the initial presentation and stabilized at teroids (4.5 g prednisolone over 5 days) followed by a fur- high values 12 months after. (Figure 2, Table 2). ther PE session (six cycles) were applied. This led to CCM was performed with a Heidelberg Retina Tomo- clinical stabilization. However, improvement occurred only graph III with a Rostock cornea module, the images were 5 months after disease onset (approximately 3 months analyzed with ACC-Metrics software, version 2.0 (Xin after Rituximab application). During the following months Chen and Mohammad Dabbah, Manchester, UK), the symptoms improved steadily. At 12 months, we noted a average of five images was calculated. Two months after complete recovery of muscle strength, facial weakness, and initial diagnosis CCM showed an increased number of subjective sensory deficits. Minor gait instability and sen- corneal cell infiltrates (121/mm2), but normal corneal sory ataxia persisted, but the patient could walk without nerve fiber density and corneal nerve branch density and aids (Table 1). Repeat treatment with RTX was planned. only a minor reduction in corneal nerve fiber length. The titer of anti-NF155 antibodies started to diminish After 12 months the corneal cell infiltrates were markedly promptly after initiation of treatment already at first reduced (21/mm2). However, there was a progressive month. This decrease preceded the clinical and electro- reduction in the corneal nerve fiber length and density physiological improvement (Table 1). (Figure 3). 1062 ª 2020 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association 23289503, 2020, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/acn3.51061 by Readcube (Labtiva Inc.), Wiley Online Library on [10/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License D. Athanasopoulos et al. HRUS and CCM in a Case of NF155 Paranodopathy Figure 1. Electroneurography traces of the left median nerve at 2 (Panel A), 5 (Panel B), and 12 months (Panel C). cMAPs after stimulation at the wrist and the elbow. At 2 months a marked prolongation of DML and distal cMAP duration as well as CV slowing were observed. Furthermore a conduction block, with reduction of the cMAP amplitudes >50% after proximal stimulation, is noted. At 5 months the distal cMAP amplitudes are also diminished, while DML, CV, and distal cMAP duration are slightly improved. At 12 months an almost full recovery is observed. The distal cMAP amplitude also recovers to normal values, indicating that the previous marked reduction was mainly due to a distal conduction block. DML, distal motor latency; CV, conduction velocity; cMAP, compound muscle action potential. Table 1. Evolution of clinical scores, NF155 antibodies titer and CCM parameters Onset 1 month 2 months 3 months 5 months 12 months MRCss 73 65 64.5 52.5 51 80 INCAT/ODSS 3 5 5 6 6 3 NF155 Antibody Titer 1:3200 1:1000 1:320 1:100 1:32 1:32 CCM (cells/mm2) 121 – – – – 21 INCAT/ODSS, Inflammatory Neuropathy Cause and Treatment Overall Disability Sum Score; MRCss, modified Medical Research Council sum score (max. of 80 with lower scores corresponding to lower muscle strength). and enabled early treatment with RTX, based on prior Discussion small case series.13–16,21 This case demonstrates a thorough longitudinal study of Bifacial palsy was a noteworthy feature in our case. a paranodal neuropathy. Acute presentation and progres- This is a common manifestation of Guillain–Barre syn- sion over 8 weeks in combination with the nerve conduc- drome but rare in CIDP. Cases of NF155 neuropathy with tion studies and CSF findings led to the clinical diagnosis cranial nerve involvement have been reported,22,23 the of a chronic demyelinating inflammatory polyradicu- exact incidence remains unknown. In the case of Miller loneuropathy. Prompt testing for anti-NF155 antibodies Fisher syndrome, Chiba et al24 showed that GQ1b expres- helped to diagnose an anti-NF155 immune neuropathy sion is proportionally higher in oculomotor nerves. ª 2020 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association 1063 23289503, 2020, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/acn3.51061 by Readcube (Labtiva Inc.), Wiley Online Library on [10/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License HRUS and CCM in a Case of NF155 Paranodopathy D. Athanasopoulos et al. Further studies are required to determine the specific expression of NF155 in cranial nerves. As previously reported9–11,13,14 treatment response after IVIg was poor in our patient. Corticosteroid treatment did not infer any relevant improvement either, which is why we escalated to PE after the second relapse. Although at initial presentation PE lead to a minor and only tem- porary improvement, disease progression was stopped after the second PE treatment. Although PE was less effec- tive regarding improvement, it led to a decrease in the antibody titer (1 month later). However, the timing of clinical stabilization and the following robust remission (5 months after initial presentation and 4 months after Rituximab) without need for further interventions argue that the anti-CD20 treatment was mainly responsible. As previously shown25,26 the improvement of electro- physiological parameters correlated with the clinical improvement in a lagged fashion, demonstrating that new methods with better temporal correlation to the clinical development are needed. The anti-NF155 antibodies titer fell promptly after treatment initiation (PE and Rituximab). This trend pre- ceded clinical improvement. Further studies are needed to show if anti-NF155 antibody titers are a useful prognostic and disease monitoring tool.27 To our knowledge, this is the second report13 of HRUS findings in anti-NF155 antibody-positive neuropathy, but a longitudinal study has never reported before yet. We saw a multifocal and asymmetric swelling of the nerves distally as well as proximally. The nerves were hypoe- chogenic, which could imply an inflammatory affection according to previous data.28 The increased CSA of multi- ple peripheral nerves correlated with previous reports10,13 and in accordance with the expected changes in inflam- matory neuropathies.19,29,30 Bochum ultrasound score increased successively from 1 to 3 points in the course of 12 months indicating that acute paranodopathies do not present with typical sonographical BUS characteristics at the beginning of the disease. An increase in intranerve CSA variability for the majority of nerves coincided tem- porally with the active disease phase between months 2 and 5. We have previously shown that the increase in CSA variability and BUS correspond with disease progres- Figure 2. Representative images of high-resolution nerve ultrasound. sion in typical CIDP.20,31,32 At 12 months we did not Transverse images of the left median nerve at the distal upper arm observe a relevant improvement of CSA or its intranerve are shown at 2 (Panel A), 5 (Panel B), and 12 months (Panel C). The variability despite clinical improvement. This could be cross section of the median nerve is outlined with a doted circle, (h) attributed to the follow-up interval, as previous stud- denotes the humerus, (a) the brachial artery, (sc) the subcutaneous ies20,33 show an improvement over a period of more than fat. Asterisks in panel B mark individual nerve fascicles. The initially 12 months. However, there are no previous longitudinal normal CSA increases significantly between months 2 and 5 in the active disease phase (reference range 2,6-14,1 mm2). After clinical ultrasound studies on paranodopathies. stabilization nerve swelling shows a small reduction. Intranerve CSA To our knowledge, this is the first report of the use of variability shows a corresponding course. (s. Table 2). CSA, cross- CCM in a case of anti-NF155 antibody-positive autoim- sectional area. mune neuropathy. CCM is a noninvasive technique which 1064 ª 2020 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association 23289503, 2020, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/acn3.51061 by Readcube (Labtiva Inc.), Wiley Online Library on [10/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License D. Athanasopoulos et al. HRUS and CCM in a Case of NF155 Paranodopathy Table 2. Sonographic mean cross-sectional area values in mm2. 2 Month 5 Month 12 Month Nerve Site Right Left Right Left Right Left Ref. range Median Carpal tunnel 15,1 13,4 13,7 13,7 10,9 11,5 1,3–12,6 Forearm 8 8,2 7,5 7,9 6,73 6,75 3,4–12,6 Upper arm 14,5 13,3 20,0 17,8 21,9 15,9 2,6–14,1 intranerve CSA variability 1,8 1,61 2,66 2,25 3,25 2,35 <1,5 Ulnar Gyuon canal 6,6 5,5 5,03 7,59 9,76 6,16 3,1–7,2 Forearm 7,6 8,5 6,3 6,79 6,83 5,89 2,9–8,0 Elbow 7,7 9,3 7,99 8,78 8,57 11 2,5–8,1 Upper arm 7,7 7,7 9,94 9,43 12,3 9,92 2,9–10,2 intranerve CSA variability 1,16 1,69 1,97 1,39 1,80 1,86 <1,5 Radial Spiral groove 6,2 8,7 12,8 7,1 5,69 8,19 0,2-6,3 Brachial Plexus Intrascalene space 65,1 n/a 20,4 20,1 48,4 35,1 9,3–52,6 Supraclavicular space 144 145 117 99 96,5 91,8 9,6–82,7 Fibular Fibular Head 9,9 11,6 9,35 8,72 17,2 10,7 2,5–11,7 Popliteal fossa 5,2 8,5 11,6 7,69 14,7 10,4 4,0–13,2 intranerve CSA variability 1,9 1,36 1,24 1,13 1,17 1,03 <1,5 Tibial Popliteal fossa 23 25,3 44,1 36,8 39,3 47,9 3,0–13,8 Ankle 14,4 13,6 13,2 15,8 14,5 15,2 3,4–9,2 intranerve CSA variability 1,59 1,86 3,34 2,33 2,71 3,15 <1,5 Sural Between heads of gastrocnemius 2,2 2,5 1,4 1,61 1,79 1,53 0,5–3 CSA, cross-sectional area. has shown its capacity to detect small fiber damage in Conflicts of Interest several types of neuropathies34 and it is used in inflam- matory neuropathies recently.32,35,36 Patients with auto- Athanasopoulos Diamantis has no conflict of interest to nomic neuropathies and CIDP patients with symptoms of report. Jeremias Motte received travel grants from Biogen small fiber damage, such as painful neuropathy, show a idec, Novartis AG, Teva and Eisai GmbH, his research is greater loss of corneal nerve fibers. However, classical funded by Klaus Tschira Foundation and Ruhr-Univer- CIDP patients still show significant abnormalities.35,36 sity, Bochum (FoRUM-program), none related to this The small fiber damage in the cornea may thus mirror an work. Anna Lena Fisse received research funding by Geor- axonal damage of the peripheral nerves. In our patient a gius Agricola Stiftung Ruhr, received honoraria and travel marked decrease in corneal nerve parameters correlated grants from Novartis AG, Sanofi and Eisai GmbH, none with a remaining reduction of the amplitudes of the related to this work. Owns shares of Fresenius SE & Co., nerves in the lower extremities over the course of time. It Gilead Sciences, Medtronic PLC and Novartis AG. Tho- is noteworthy that no signs or symptoms of small fiber mas Grueter received travel reimbursement from Sanofi neuropathy were noted at 12 months and the paraesthe- Genzyme and Biogen Idec, none related to this work. sias the patient had at presentation had resolved. We have Dietrich Sturm received research funding from the Ruhr- recently shown that an increased number of inflammatory University, Bochum (FoRUM-program), none related to corneal cell infiltrates correlates with disease progression this work. Martin Tegenthoff has received speaker hono- in immunoneuropathies.32 Conversely, in this case the raria from Pfizer, Novartis, and Mundipharma. He also reduction in inflammatory cell infiltrates correlated with acknowledges a grant support from Genzyme, none clinical remission. related to this work. Nadine Trampe, Melissa Sgodzai, Concluding, we investigated for the first time further and Rafael Klimas have no conflict of interest to report. CCM and HRUS markers of disease activity in a case of Luis Querol has provided expert testimony for Grifols, paranodopathy. Surely, longitudinal testing in a larger SanofiGenzyme, Novartis, UCB, Roche, CSL Behring, number of patients is needed to better understand the Johnson and Johnson, Alexion and Annexon, has received temporal relation of these alterations but these methods research funds from Novartis Spain, Sanofi-Genzyme, and seem to be promising to determine axonal degeneration Grifols, research support from the GBS-CIDP Foundation and inflammatory activity in paranodopathies. and the Department of Health of the Government of ª 2020 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association 1065 23289503, 2020, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/acn3.51061 by Readcube (Labtiva Inc.), Wiley Online Library on [10/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License HRUS and CCM in a Case of NF155 Paranodopathy D. Athanasopoulos et al. Sanofi-Aventis and TEVA. He also acknowledges grant support from Bayer Schering, Biogen idec, Merck Serono, Sanofi-Aventis and TEVA, none related to this work. Kal- liopi Pitarokoili received travel funding and speaker honoraria from Biogen Idec, Novartis and Bayer Schering Pharma and funding from the Ruhr-University, Bochum (FORUM-Program), none related to this work. Author Contributions All authors have read and approved the manuscript. Athanasopoulos Diamantis and Jeremias Motte were involved in patient treatment, acquisition, analysis and interpretation of data, and drafting/revising the manu- script for content. Anna Lena Fisse, Thomas Grueter, and Dietrich Sturm were involved in acquisition, analysis and interpretation of data, and drafting/revising the manu- script for content. Nadine Trampe was involved in patient treatment, acquisition, analysis and interpretation of data, and revising the manuscript for content. Martin Tegen- thoff, Luis Querol, and Ralf Gold were involved in critical comments during data collection, drafting and manu- script revision. Melissa Sgodzai and Rafael Klimas were involved in acquisition, analysis and interpretation of data, revising the manuscript for content. Kalliopi Pitaro- koili was involved in first idea, patient treatment, acquisi- tion, analysis and interpretation of data, drafting and manuscript revision, and study supervision. Ethical Standards The patient gave written informed consent. References 1. Broers MC, Bunschoten C, Nieboer D, et al. 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