646332 research-article2016
TAN0010.1177/1756285616646332Therapeutic Advances in Neurological DisordersS Faissner, J Nikolayczik
Therapeutic Advances in Neurological Disorders
Immunoadsorption in patients with neuromyelitis optica spectrum disorder Simon Faissner, Johanna Nikolayczik, Andrew Chan, Ralf Gold, Min-Suk Yoon and Aiden Haghikia
Original Research
Ther Adv Neurol Disord 2016, Vol. 9(4) 281–286 DOI: 10.1177/ 1756285616646332 © The Author(s), 2016. Reprints and permissions: http://www.sagepub.co.uk/ journalsPermissions.nav
Abstract Introduction: Neuromyelitis optica spectrum disorder (NMOSD) is a neuroinflammatory disorder of the central nervous system, distinct from multiple sclerosis by affecting predominantly the optic nerve and the spinal cord, and mediated by antibodies directed against aquaporin 4 (AQP4-ab) as a possible pathomechanistic hallmark of NMOSD. Therapeutic options include immunosuppression with steroids or B-cell-depleting agents as baseline therapies, as well as plasma exchange (PLEX) and/or immunoadsorption (IA) during relapses. Until now, data concerning the efficacy of IA alone are scarce. Methods: Visual evoked potentials (VEPs), visual acuity and changes of symptoms at relapse leading to admission in NMOSD patients (n = 10) treated with IA in a single-centre setting were evaluated retrospectively. Results: All patients profited from the procedure and showed an amelioration of admission symptoms. Three patients improved in visual acuity, another three patients remained stable, whereas five patients showed an improvement in VEPs. Discussion: In this small cohort, IA constitutes a valid therapeutic option for patients with NMOSD as an equivalent to PLEX. Analysis in larger cohorts is warranted.
Keywords: aquaporin 4 antibodies, immunosuppressive treatment, multiple sclerosis-related disease, plasmapheresis
Introduction Neuromyelitis optica (NMO) is an inflammatory disease of the central nervous system affecting mainly the optic nerve and the spinal cord with a longitudinal transversal myelitis. Originally NMO was considered as a subtype of multiple sclerosis (MS). In 2004, however, the identification of an antibody against the astrocytic aquaporin-4 water channel protein (AQP4-ab) led to a paradigm change of the disease [Lennon et al. 2005]. Today, NMO spectrum disorder (NMOSD) is used as a unifying term according to the revised guidelines from 2015 [Wingerchuk et al. 2015]. Here, NMOSDs with or without detection of AQP4-ab are differentiated. In the case of AQP4-ab negativity, two core clinical characteristics have to be fulfilled such as optic neuritis, acute myelitis, area postrema syndrome or acute brainstem syndrome. Additionally, magnetic resonance imaging (MRI) requirements have to be
fulfilled (i.e. spinal MRI with lesions of ⩾3 vertebral bodies, acute optic neuritis, and acute brainstem lesions) [Wingerchuk et al. 2015]. Treatment options include immunosuppression with steroids as well as B-cell-depleting therapies as baseline treatment [Trebst et al. 2014; Kleiter et al. 2015]. Additionally, procedures such as plasma exchange (PLEX) or immunoadsorption (IA) can be performed to remove pathogenic AQP4-ab and proinflammatory cytokines during relapses. Data regarding the efficacy of IA alone in NMO is scarce. Performing IA alone leads only to a distraction of pathologic antibodies sparing other plasma proteins [Kobayashi et al. 2014], and thus, may avoid potential allergic side effects resulting from albumin substitution, and unselective elimination of other plasma proteins in patients treated with PLEX. Additionally, IA is less challenging for the circulation and there is no risk related to the transmission of human material
Correspondence to: Simon Faissner, MD Aiden Haghikia, MD Department of Neurology, St. Josef-Hospital, RuhrUniversity, Gudrunstr. 56, D-44791 Bochum, Germany [email protected] [email protected] Johanna Nikolayczik Andrew Chan, MD Ralf Gold, MD Min-Suk Yoon, MD Department of Neurology, St. Josef-Hospital, Ruhr-University, Bochum, Germany
http://tan.sagepub.com 281
Therapeutic Advances in Neurological Disorders 9(4) compared with PLEX. IA is also advantageous for patients who do not want to receive human material for religious reasons. Yet IA is a medical procedure which is not licensed in some countries such as the United States. Here, we present a retrospective case series of 10 patients with likely NMOSD treated with IA in a German university centre setting. Methods Extensive clinical and paraclinical data from patients with definite or likely NMOSD filed during hospital treatment were assessed for the retrospective evaluation of IA efficacy. Diagnosis was based on the revised Wingerchuk criteria for NMOSD from 2015 [Wingerchuk et al. 2015]. Testing for AQP4-abs was performed with the indirect immunofluorescent test, performed in the laboratory (EUROIMMUN, Lübeck, Germany). In six patients AQP4-abs were negative but symptoms and radiological findings were suggestive of NMOSD. We included patients who had received IA in the period between January 2011 and November 2014. Patients were 34.6 years old (range 22–49), 6/10 patients were female and the median Expanded Disability Status Scale (EDSS) score was 4.75 (range 2.5– 9). All patients were treated at a single centre and were devoid of acute infections (clinically, white blood cell counts and C-reactive protein). IA was performed after written informed consent of all patients and after placement of a Shaldon´s catheter in the left or right jugular vein. Each exchange session had a mean duration of 2 hours. Patients had 5.2 (range 3–7) cycles of IA. IA treatment was performed using the tryptophan-linked polyvinyl alcohol adsorber TR-350(L) after membrane plasma separation with the polyethylene plasma separator OP-05W (Asahi Kasei Medical Tokyo, Japan) in combination with the Octo Nova technology SW 4.30.5 (DIAMED Medizintechnik, Cologne, Germany). Plasma volume was between 2–2.5 l per session. IA was antibody specific but not AQP4-abs specific. The patients were evaluated clinically and with visual evoked potentials (VEPs) before and after the IA. VEPs were generated using the Keypoint software (Medtronic, Meerbusch, Germany). Follow-up VEPs were performed 0.75 days post IA in the mean (±1.75 days SD). In two patients the follow-up VEP was performed one day before the end of the procedure. Visual acuity was evaluated bedside with an eye chart placed approximately 35 cm in front of the eyes of the patient.
Retrospective evaluation of the patients was permitted by Ruhr University ethics committee (No 15-5268). Results and long-term treatment In eight patients VEPs before and after IA were available. Three patients had improved P-100 latencies of VEPs after IA on the left eye, and two on the right eye (Figure 1). Three patients had longer P-100 latencies on the left eye, and four on the right eye. In two patients a stimulus response was only detected after IA on the left side, and in one patient on the right side. For seven patients, visual acuity was documented and showed amelioration after IA in four of the patients and stable visual acuity in three patients (Figure 1). There was no worsening in visual acuity in any of the patients. Correlation of VEPs with visual acuity was not significant but showed a trend towards better visual acuity (Figure 2). Concerning the initial symptoms which led to admission, all patients showed a benefit with an amelioration of clinical deficits after IA (Table 1). Follow-up treatment was initiated with rituximab (n = 3), tocilizumab (n = 3), fingolimod (n = 1), mitoxantrone (n = 1) and interferon-β1a intramuscularly 1 × 30 µg (n = 1); for one patient no follow-up data were available. Discussion In our current case series, we report on 10 patients diagnosed with NMOSD or clinical and radiological findings suggestive of NMOSD treated with IA alone, which to our knowledge is the first of its kind. While the proportion of patients who had stable or improved latencies of VEPs was similar, most of the patients profited concerning visual acuity. This seemingly controversial finding may be due to the observation that visual acuity improves prior to electrophysiological alterations. The limitations of the study are clearly the low number of patients. However, for rare diseases there is often no class I evidence available. An additional weakness of the current study is that not all patients clearly fulfilled the 2015 revised Wingerchuk criteria for NMOSD but were classified as syndromes likely to be NMOSD. Additionally, as this is a retrospective analysis, there was unfortunately not more information available concerning improvement from treatment than documented in Table 1.
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Figure 1. Latencies of VEPs on the left (A) and right (B) side and visual acuity (left, C; right D). On the left n = 3 patients profited from IA, whereas in 2 patients a stimulus response was only detected after IA. 3 patients showed worsened latencies. On the right n = 2 patients had better VEPs, in 1 patient a stimulus response was only detected after IA, whereas 4 had worsened latencies. Visual acuity was either better (n = 3, left eye; n = 4 right eye) or stable (n = 4 left eye; n = 3 right eye). §, If no stimulus response was detectable VEPs were set to 250 ms. IA, immunoadsorption; VEPs, visual evoked potentials.
Figure 2. Correlation of VEPs (ms) and visual acuity (%) before (A) and after (B) IA is shown (data of left and right eye are shown together). There is a trend towards better visual acuity. §, VEPs without stimulus response were set to 250 ms (A, four data points; B, one data point). IA, immunoadsorption; VEPs, visual evoked potentials.
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2
3
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10
7
6.5
2.5
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3.5
3
2.5
9
6.5
5.5
EDSS
Multiple infratentorial T2 lesions, no Gd enhancing lesion
No current MRI
Right thalamus 5 mm lesion (Gd not applied)
No current MRI
No lesions
3 T2 hyperintense lesions, left supratentorial, no Gd enhancement No current MRI
T2 hyperintense lesions pons and mesencephalon, no Gd enhancement
T2 hyperintense lesions (no Gd enhancement)
Right cerebellum, cerebellar peduncle
Brain
No signs of optic neuritis in MRI
No current MRI
No signs of optic neuritis in MRI
Prominent optic nerve with signal alteration No current MRI
No current MRI
No signs of optic neuritis in MRI
No signs of optic neuritis in MRI
No signs of optic neuritis in MRI
No signs of optic neuritis in MRI
Optic nerve
Region of inflammation
Multiple T2 hyperintense lesions in the thoracic spinal cord. C5–6 Gd enhancement
No current MRI
Gd + lesion C5/6, multiple T2 hyperintense lesions cervical myelon T2 hyperintense lesion C2 without Gd enhancement C1–3 T2 hyperintense lesions, no Gd enhancement, T1–8 hyperintense lesions, no Gd enhancement No lesions
T2 hyperintense lesions from Dens to C7 with Gd enhancement C2-4 Gd enhancement. T2 hyperintense lesions from T5–11, no Gd enhancement Gd enhancing lesion C2
T 2/3, 5–9 hyperintense lesions
Spinal cord
Yes
Positive
No
Yes
Positive
Negative
No
Yes
Positive
Negative
No
No
Negative
Negative
No
Yes
Positive
Negative
Yes
Fulfilled Wingerchuk 2015 criteria
Negative
AQP4-ab status
Unsteady gait
VA left 0.05
Blurred vision on the right, VA 0.8
VA left side only shadowy recognition of fingers Right sided spastic tetraparesis
Hemihypaesthesia right side, VA right
Hypaesthesia, ataxia
Left sided spastic tetraparesis, upper extremities can be moved against gravity
Left sided spastic tetraparesis, unsteady gait
VA affected
Main Symptom before IA
Better
Better
Better
Better
Better, persons can be recognized↑
Hemihypaesthesia absent
Both better
Better, upper extremities proximal can be moved against resistance
Amelioration of tetraparesis
Better
Changes of initial symptoms after IA
VEP, left 112.5 ms, right 105 ms VA left 70.0, VA right 32.0 VEP, left no SR, right no SR VA left 4.0, VA right 85.0
VEP, left 141.3 ms, right 148.0 ms
VA left 75.0 VA right 50.0
VA left 100.0, VA right 0
VEP, left no SR, right no SR VA left 10.0, VA right 5.0
Before
VEP, left 108 ms↓, right 110 ms VA left 75.0↑, VA right 75.0↑ VEP, left 174.3↑, right 178.8↑ VA left 50.0↑, VA right 85.0
VEP, left 163.8 ms, right 157.5 ms
VA left 85.0↑ VA right 85.0↑
VA left 100.0, VA right 20.0↑
VEP, left 180.0 ms, right no SR VA left 10.0, VA right 50.0↑
After
Changes of VEP and VA, if affected
Rebif 22
Aza, GLAT, Mitoxantrone, Rituximab
Avonex, GLAT
Avonex, Interferon alpha, Rebif 22, Rebif 44, GLAT
Rebif 44, GLAT
Rebif 22
Aza, GLAT, NAT
Previous treatments
Rituximab
Tocilizumab
Avonex
Tocilizumab
Fingolimod
Unknown
Mitoxantrone
Rituximab
Tocilizumab
Rituximab
Treatment following IA
Aza, Azathioprine; EDSS, Expanded Disability Status Scale; Gd, gadolinium; GLAT, Glatiramer acetate; IA, immunoadsorption; MRI, magnetic resonance imaging; NAT, Natalizumab; SR, stimulus response; VA, visual acuity; VEP, visual evoked potential. Improvements of VEP P100 latencies (ms) and VA are shown in bold letters.
Age
Patient
Table 1. Clinical data of patients.
Therapeutic Advances in Neurological Disorders 9(4)
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S Faissner, J Nikolayczik et al. Some patients were on drugs following IA which are not recommended for the treatment of NMO such as in patient number 6 (fingolimod). Fingolimod can lead to the development of extensive brain lesions in NMOSD [Min et al. 2012]. Patient number eight was treated with Avonex (Biogen, USA) following IA. In a retrospective analysis from Thailand, in patients with NMO or NMOSD, the EDSS worsened in 53.3% of the cases under interferon beta [Jarernsook et al. 2013], which is therefore not recommended in NMOSD. The reason for the controversial finding that some patients were on MS medications was that they were in the first place categorized as having MS, and in the course the diagnosis was changed to NMOSD. As this was a retrospective analysis, outcome parameters could not be addressed concerning the clinical symptoms, thus VEP and visual acuity seemed the most objective measures that were performed on a routine basis. The EDSS was not used to evaluate the clinical course after IA, as the target symptom was more precise to evaluate the clinical improvement. Levy and colleagues proposed a new severity scale for NMO at the Annual American Neurology meeting in 2015, which may potentially replace the EDSS in a prospective cohort [Levy et al. 2015]. PLEX has been shown previously to be effective in NMOSD [Miyamoto and Kusunoki, 2009; Munemoto et al. 2011]. Recently, it could be shown in one patient with NMOSD positive for AQP4-ab who suffered from acute transverse myelitis that IA is also effective in long term means in NMOSD [Kobayashi et al. 2014]. In an evaluation of 871 attacks by the Neuromyelitis Optica Study group isolated myelitis responded better to the combination of PLEX with IA than to high dose steroids as first treatment course [Kleiter et al. 2015]. Although severe side effects in IA have been less frequently reported than in PLEX there are reliable data available on clinical efficacy such as steroid refractory MS relapses comparing these two procedures. IA leads to immediate antibody elimination, pulsed induction of antibody redistribution, and immunomodulation [Klingel et al. 2013]. IA has been successfully used in other neurological autoimmune diseases, such as corticosteroid nonresponsive MS relapses for decades. In total, 68 MS patients have been published until now of whom >65% had a beneficial clinical response to treatment. In relapses mainly comprising optic neuritis, the response rates were even higher (>75%)
[Klingel et al. 2013]. In natalizumab-associated progressive multifocal leucoencephalopathy a combination of a single cycle of PLEX with two cycles of IA is highly effective in reliably eliminating natalizumab. Furthermore, IA has been used for the treatment of limbic encephalitis and led to a clinical response in about 70% of the patients in a retrospective analysis of 30 patients, irrespective of whether PLEX or IA have been used [Ehrlich et al. 2013]. Summarizing, our study provides evidence for the efficacy of IA as a valid treatment option for NMOSD in the acute phase of disease. Our data provide the basis for further studies regarding the efficacy of IA versus PLEX in larger patient cohorts and to better understand its mechanism of action in the context of NMOSD. Acknowledgements The authors thank DIAMED Medizintechnik (Cologne, Germany) for initial financial support for tryptophan-linked polyvinyl alcohol adsorber TR-350(L). Funding The author(s) received no financial support for the research, authorship, and/or publication of this article. Conflict of interest statement The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: The authors declare the following potential conflicts of interest, none of which are related to the content of the manuscript. Simon Faissner received travel grants from Biogen Idec and Genzyme. Andrew Chan received personal compensation as a speaker or consultant for Bayer Schering, Biogen Idec, Merck Serono, Sanofi-Aventis and Teva Neuroscience. He also received research support from the German Ministry for Education and Research (BMBF, German Competence Network Multiple Sclerosis (KKNMS), CONTROL MS, 01GI0914), Bayer Schering, Biogen Idec, Merck Serono and Novartis. Ralf Gold serves on scientific advisory boards for Teva Pharmaceutical Industries Ltd., Biogen Idec, Bayer Schering Pharma, and Novartis; has received speaker honoraria from Biogen Idec, Teva Pharmaceutical Industries Ltd., Bayer Schering Pharma, and Novartis; serves as editor for Therapeutic Advances in Neurological Diseases, is on the editorial boards of Experimental
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Therapeutic Advances in Neurological Disorders 9(4) Neurology and the Journal of Neuroimmunology; and receives research support from Teva Pharmaceutical Industries Ltd., Biogen Idec, Bayer Schering Pharma, Genzyme, Merck Serono, and Novartis. Min-Suk Yoon received speaker´s honoraria from CSL Behring. Aiden Haghikia received travel grants from Bayer Healthcare and Genzyme.
spectrum disorders long after the acute phase. J Clin Apher 30: 43–45.
References
Min, J., Kim, B. and Lee, K. (2012) Development of extensive brain lesions following fingolimod (FTY720) treatment in a patient with neuromyelitis optica spectrum disorder. Mult Scler 18: 113–115.
Ehrlich, S., Fassbender, C., Blaes, C., Finke, C., Günther, A., Harms, L. et al. (2013) Therapeutische Apherese bei autoimmuner Enzephalitis: eine bundesweite Datenerhebung. Nervenarzt 84: 498–507. Jarernsook, B., Siritho, S. and Prayoonwiwat, N. (2013) Efficacy and safety of beta-interferon in Thai patients with demyelinating diseases. Mult Scler 19: 585–592. Kleiter, I., Gahlen, A., Borisow, N., Fischer, K., Wernecke, K., Wegner, B. et al. (2015) Neuromyelitis optica: Evaluation of 871 attacks and 1,153 treatment courses. Ann Neurol DOI: 10.1002/ana.24554. [Epub ahead of print]. Klingel, R., Heibges, A. and Fassbender, C. (2013) Neurologic diseases of the central nervous system with pathophysiologically relevant autoantibodiesperspectives for immunoadsorption. Atheroscler Suppl 14: 161–165. Visit SAGE journals online http://tan.sagepub.com
SAGE journals
Kobayashi, M., Nanri, K., Taguchi, T., Ishiko, T., Yoshida, M., Yoshikawa, N. et al. (2014) Immunoadsorption therapy for neuromyelitis optica
Lennon, V., Kryzer, T., Pittock, S., Verkman, A. and Hinson, S. (2005) IgG marker of optic-spinal multiple sclerosis binds to the aquaporin-4 water channel. J Exp Med 202: 473–477. Levy, M., Mealy, M., Jarius, S., Paul, F., Aktas, O., Broadley, S. et al. (2015) New Acute Severity Scale for Neuromyelitis Optica Relapses. Presented at the AAN Annual Meeting, 22 April 2015, Washington.
Miyamoto, K. and Kusunoki, S. (2009) Intermittent plasmapheresis prevents recurrence in neuromyelitis optica. Ther Apher Dial 13: 505–508. Munemoto, M., Otaki, Y., Kasama, S., Nanami, M., Tokuyama, M., Yahiro, M. et al. (2011) Therapeutic efficacy of double filtration plasmapheresis in patients with anti-aquaporin-4 antibody-positive multiple sclerosis. J Clin Neurosci 18: 478–480. Trebst, C., Jarius, S., Berthele, A., Paul, F., Schippling, S., Wildemann, B. et al. (2014) Neuromyelitis Optica Study Group (NEMOS). Update on the diagnosis and treatment of neuromyelitis optica: recommendations of the Neuromyelitis Optica Study Group (NEMOS). J Neurol 261: 1–16. Wingerchuk, D., Banwell, B., Bennett, J., Cabre, P., Carroll, W., Chitnis, T. et al. (2015) International consensus diagnostic criteria for neuromyelitis optica spectrum disorders. Neurology 85: 177–189.
286 http://tan.sagepub.com
TAN0010.1177/1756285616646332Therapeutic Advances in Neurological DisordersS Faissner, J Nikolayczik
Therapeutic Advances in Neurological Disorders
Immunoadsorption in patients with neuromyelitis optica spectrum disorder Simon Faissner, Johanna Nikolayczik, Andrew Chan, Ralf Gold, Min-Suk Yoon and Aiden Haghikia
Original Research
Ther Adv Neurol Disord 2016, Vol. 9(4) 281–286 DOI: 10.1177/ 1756285616646332 © The Author(s), 2016. Reprints and permissions: http://www.sagepub.co.uk/ journalsPermissions.nav
Abstract Introduction: Neuromyelitis optica spectrum disorder (NMOSD) is a neuroinflammatory disorder of the central nervous system, distinct from multiple sclerosis by affecting predominantly the optic nerve and the spinal cord, and mediated by antibodies directed against aquaporin 4 (AQP4-ab) as a possible pathomechanistic hallmark of NMOSD. Therapeutic options include immunosuppression with steroids or B-cell-depleting agents as baseline therapies, as well as plasma exchange (PLEX) and/or immunoadsorption (IA) during relapses. Until now, data concerning the efficacy of IA alone are scarce. Methods: Visual evoked potentials (VEPs), visual acuity and changes of symptoms at relapse leading to admission in NMOSD patients (n = 10) treated with IA in a single-centre setting were evaluated retrospectively. Results: All patients profited from the procedure and showed an amelioration of admission symptoms. Three patients improved in visual acuity, another three patients remained stable, whereas five patients showed an improvement in VEPs. Discussion: In this small cohort, IA constitutes a valid therapeutic option for patients with NMOSD as an equivalent to PLEX. Analysis in larger cohorts is warranted.
Keywords: aquaporin 4 antibodies, immunosuppressive treatment, multiple sclerosis-related disease, plasmapheresis
Introduction Neuromyelitis optica (NMO) is an inflammatory disease of the central nervous system affecting mainly the optic nerve and the spinal cord with a longitudinal transversal myelitis. Originally NMO was considered as a subtype of multiple sclerosis (MS). In 2004, however, the identification of an antibody against the astrocytic aquaporin-4 water channel protein (AQP4-ab) led to a paradigm change of the disease [Lennon et al. 2005]. Today, NMO spectrum disorder (NMOSD) is used as a unifying term according to the revised guidelines from 2015 [Wingerchuk et al. 2015]. Here, NMOSDs with or without detection of AQP4-ab are differentiated. In the case of AQP4-ab negativity, two core clinical characteristics have to be fulfilled such as optic neuritis, acute myelitis, area postrema syndrome or acute brainstem syndrome. Additionally, magnetic resonance imaging (MRI) requirements have to be
fulfilled (i.e. spinal MRI with lesions of ⩾3 vertebral bodies, acute optic neuritis, and acute brainstem lesions) [Wingerchuk et al. 2015]. Treatment options include immunosuppression with steroids as well as B-cell-depleting therapies as baseline treatment [Trebst et al. 2014; Kleiter et al. 2015]. Additionally, procedures such as plasma exchange (PLEX) or immunoadsorption (IA) can be performed to remove pathogenic AQP4-ab and proinflammatory cytokines during relapses. Data regarding the efficacy of IA alone in NMO is scarce. Performing IA alone leads only to a distraction of pathologic antibodies sparing other plasma proteins [Kobayashi et al. 2014], and thus, may avoid potential allergic side effects resulting from albumin substitution, and unselective elimination of other plasma proteins in patients treated with PLEX. Additionally, IA is less challenging for the circulation and there is no risk related to the transmission of human material
Correspondence to: Simon Faissner, MD Aiden Haghikia, MD Department of Neurology, St. Josef-Hospital, RuhrUniversity, Gudrunstr. 56, D-44791 Bochum, Germany [email protected] [email protected] Johanna Nikolayczik Andrew Chan, MD Ralf Gold, MD Min-Suk Yoon, MD Department of Neurology, St. Josef-Hospital, Ruhr-University, Bochum, Germany
http://tan.sagepub.com 281
Therapeutic Advances in Neurological Disorders 9(4) compared with PLEX. IA is also advantageous for patients who do not want to receive human material for religious reasons. Yet IA is a medical procedure which is not licensed in some countries such as the United States. Here, we present a retrospective case series of 10 patients with likely NMOSD treated with IA in a German university centre setting. Methods Extensive clinical and paraclinical data from patients with definite or likely NMOSD filed during hospital treatment were assessed for the retrospective evaluation of IA efficacy. Diagnosis was based on the revised Wingerchuk criteria for NMOSD from 2015 [Wingerchuk et al. 2015]. Testing for AQP4-abs was performed with the indirect immunofluorescent test, performed in the laboratory (EUROIMMUN, Lübeck, Germany). In six patients AQP4-abs were negative but symptoms and radiological findings were suggestive of NMOSD. We included patients who had received IA in the period between January 2011 and November 2014. Patients were 34.6 years old (range 22–49), 6/10 patients were female and the median Expanded Disability Status Scale (EDSS) score was 4.75 (range 2.5– 9). All patients were treated at a single centre and were devoid of acute infections (clinically, white blood cell counts and C-reactive protein). IA was performed after written informed consent of all patients and after placement of a Shaldon´s catheter in the left or right jugular vein. Each exchange session had a mean duration of 2 hours. Patients had 5.2 (range 3–7) cycles of IA. IA treatment was performed using the tryptophan-linked polyvinyl alcohol adsorber TR-350(L) after membrane plasma separation with the polyethylene plasma separator OP-05W (Asahi Kasei Medical Tokyo, Japan) in combination with the Octo Nova technology SW 4.30.5 (DIAMED Medizintechnik, Cologne, Germany). Plasma volume was between 2–2.5 l per session. IA was antibody specific but not AQP4-abs specific. The patients were evaluated clinically and with visual evoked potentials (VEPs) before and after the IA. VEPs were generated using the Keypoint software (Medtronic, Meerbusch, Germany). Follow-up VEPs were performed 0.75 days post IA in the mean (±1.75 days SD). In two patients the follow-up VEP was performed one day before the end of the procedure. Visual acuity was evaluated bedside with an eye chart placed approximately 35 cm in front of the eyes of the patient.
Retrospective evaluation of the patients was permitted by Ruhr University ethics committee (No 15-5268). Results and long-term treatment In eight patients VEPs before and after IA were available. Three patients had improved P-100 latencies of VEPs after IA on the left eye, and two on the right eye (Figure 1). Three patients had longer P-100 latencies on the left eye, and four on the right eye. In two patients a stimulus response was only detected after IA on the left side, and in one patient on the right side. For seven patients, visual acuity was documented and showed amelioration after IA in four of the patients and stable visual acuity in three patients (Figure 1). There was no worsening in visual acuity in any of the patients. Correlation of VEPs with visual acuity was not significant but showed a trend towards better visual acuity (Figure 2). Concerning the initial symptoms which led to admission, all patients showed a benefit with an amelioration of clinical deficits after IA (Table 1). Follow-up treatment was initiated with rituximab (n = 3), tocilizumab (n = 3), fingolimod (n = 1), mitoxantrone (n = 1) and interferon-β1a intramuscularly 1 × 30 µg (n = 1); for one patient no follow-up data were available. Discussion In our current case series, we report on 10 patients diagnosed with NMOSD or clinical and radiological findings suggestive of NMOSD treated with IA alone, which to our knowledge is the first of its kind. While the proportion of patients who had stable or improved latencies of VEPs was similar, most of the patients profited concerning visual acuity. This seemingly controversial finding may be due to the observation that visual acuity improves prior to electrophysiological alterations. The limitations of the study are clearly the low number of patients. However, for rare diseases there is often no class I evidence available. An additional weakness of the current study is that not all patients clearly fulfilled the 2015 revised Wingerchuk criteria for NMOSD but were classified as syndromes likely to be NMOSD. Additionally, as this is a retrospective analysis, there was unfortunately not more information available concerning improvement from treatment than documented in Table 1.
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Figure 1. Latencies of VEPs on the left (A) and right (B) side and visual acuity (left, C; right D). On the left n = 3 patients profited from IA, whereas in 2 patients a stimulus response was only detected after IA. 3 patients showed worsened latencies. On the right n = 2 patients had better VEPs, in 1 patient a stimulus response was only detected after IA, whereas 4 had worsened latencies. Visual acuity was either better (n = 3, left eye; n = 4 right eye) or stable (n = 4 left eye; n = 3 right eye). §, If no stimulus response was detectable VEPs were set to 250 ms. IA, immunoadsorption; VEPs, visual evoked potentials.
Figure 2. Correlation of VEPs (ms) and visual acuity (%) before (A) and after (B) IA is shown (data of left and right eye are shown together). There is a trend towards better visual acuity. §, VEPs without stimulus response were set to 250 ms (A, four data points; B, one data point). IA, immunoadsorption; VEPs, visual evoked potentials.
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Multiple infratentorial T2 lesions, no Gd enhancing lesion
No current MRI
Right thalamus 5 mm lesion (Gd not applied)
No current MRI
No lesions
3 T2 hyperintense lesions, left supratentorial, no Gd enhancement No current MRI
T2 hyperintense lesions pons and mesencephalon, no Gd enhancement
T2 hyperintense lesions (no Gd enhancement)
Right cerebellum, cerebellar peduncle
Brain
No signs of optic neuritis in MRI
No current MRI
No signs of optic neuritis in MRI
Prominent optic nerve with signal alteration No current MRI
No current MRI
No signs of optic neuritis in MRI
No signs of optic neuritis in MRI
No signs of optic neuritis in MRI
No signs of optic neuritis in MRI
Optic nerve
Region of inflammation
Multiple T2 hyperintense lesions in the thoracic spinal cord. C5–6 Gd enhancement
No current MRI
Gd + lesion C5/6, multiple T2 hyperintense lesions cervical myelon T2 hyperintense lesion C2 without Gd enhancement C1–3 T2 hyperintense lesions, no Gd enhancement, T1–8 hyperintense lesions, no Gd enhancement No lesions
T2 hyperintense lesions from Dens to C7 with Gd enhancement C2-4 Gd enhancement. T2 hyperintense lesions from T5–11, no Gd enhancement Gd enhancing lesion C2
T 2/3, 5–9 hyperintense lesions
Spinal cord
Yes
Positive
No
Yes
Positive
Negative
No
Yes
Positive
Negative
No
No
Negative
Negative
No
Yes
Positive
Negative
Yes
Fulfilled Wingerchuk 2015 criteria
Negative
AQP4-ab status
Unsteady gait
VA left 0.05
Blurred vision on the right, VA 0.8
VA left side only shadowy recognition of fingers Right sided spastic tetraparesis
Hemihypaesthesia right side, VA right
Hypaesthesia, ataxia
Left sided spastic tetraparesis, upper extremities can be moved against gravity
Left sided spastic tetraparesis, unsteady gait
VA affected
Main Symptom before IA
Better
Better
Better
Better
Better, persons can be recognized↑
Hemihypaesthesia absent
Both better
Better, upper extremities proximal can be moved against resistance
Amelioration of tetraparesis
Better
Changes of initial symptoms after IA
VEP, left 112.5 ms, right 105 ms VA left 70.0, VA right 32.0 VEP, left no SR, right no SR VA left 4.0, VA right 85.0
VEP, left 141.3 ms, right 148.0 ms
VA left 75.0 VA right 50.0
VA left 100.0, VA right 0
VEP, left no SR, right no SR VA left 10.0, VA right 5.0
Before
VEP, left 108 ms↓, right 110 ms VA left 75.0↑, VA right 75.0↑ VEP, left 174.3↑, right 178.8↑ VA left 50.0↑, VA right 85.0
VEP, left 163.8 ms, right 157.5 ms
VA left 85.0↑ VA right 85.0↑
VA left 100.0, VA right 20.0↑
VEP, left 180.0 ms, right no SR VA left 10.0, VA right 50.0↑
After
Changes of VEP and VA, if affected
Rebif 22
Aza, GLAT, Mitoxantrone, Rituximab
Avonex, GLAT
Avonex, Interferon alpha, Rebif 22, Rebif 44, GLAT
Rebif 44, GLAT
Rebif 22
Aza, GLAT, NAT
Previous treatments
Rituximab
Tocilizumab
Avonex
Tocilizumab
Fingolimod
Unknown
Mitoxantrone
Rituximab
Tocilizumab
Rituximab
Treatment following IA
Aza, Azathioprine; EDSS, Expanded Disability Status Scale; Gd, gadolinium; GLAT, Glatiramer acetate; IA, immunoadsorption; MRI, magnetic resonance imaging; NAT, Natalizumab; SR, stimulus response; VA, visual acuity; VEP, visual evoked potential. Improvements of VEP P100 latencies (ms) and VA are shown in bold letters.
Age
Patient
Table 1. Clinical data of patients.
Therapeutic Advances in Neurological Disorders 9(4)
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S Faissner, J Nikolayczik et al. Some patients were on drugs following IA which are not recommended for the treatment of NMO such as in patient number 6 (fingolimod). Fingolimod can lead to the development of extensive brain lesions in NMOSD [Min et al. 2012]. Patient number eight was treated with Avonex (Biogen, USA) following IA. In a retrospective analysis from Thailand, in patients with NMO or NMOSD, the EDSS worsened in 53.3% of the cases under interferon beta [Jarernsook et al. 2013], which is therefore not recommended in NMOSD. The reason for the controversial finding that some patients were on MS medications was that they were in the first place categorized as having MS, and in the course the diagnosis was changed to NMOSD. As this was a retrospective analysis, outcome parameters could not be addressed concerning the clinical symptoms, thus VEP and visual acuity seemed the most objective measures that were performed on a routine basis. The EDSS was not used to evaluate the clinical course after IA, as the target symptom was more precise to evaluate the clinical improvement. Levy and colleagues proposed a new severity scale for NMO at the Annual American Neurology meeting in 2015, which may potentially replace the EDSS in a prospective cohort [Levy et al. 2015]. PLEX has been shown previously to be effective in NMOSD [Miyamoto and Kusunoki, 2009; Munemoto et al. 2011]. Recently, it could be shown in one patient with NMOSD positive for AQP4-ab who suffered from acute transverse myelitis that IA is also effective in long term means in NMOSD [Kobayashi et al. 2014]. In an evaluation of 871 attacks by the Neuromyelitis Optica Study group isolated myelitis responded better to the combination of PLEX with IA than to high dose steroids as first treatment course [Kleiter et al. 2015]. Although severe side effects in IA have been less frequently reported than in PLEX there are reliable data available on clinical efficacy such as steroid refractory MS relapses comparing these two procedures. IA leads to immediate antibody elimination, pulsed induction of antibody redistribution, and immunomodulation [Klingel et al. 2013]. IA has been successfully used in other neurological autoimmune diseases, such as corticosteroid nonresponsive MS relapses for decades. In total, 68 MS patients have been published until now of whom >65% had a beneficial clinical response to treatment. In relapses mainly comprising optic neuritis, the response rates were even higher (>75%)
[Klingel et al. 2013]. In natalizumab-associated progressive multifocal leucoencephalopathy a combination of a single cycle of PLEX with two cycles of IA is highly effective in reliably eliminating natalizumab. Furthermore, IA has been used for the treatment of limbic encephalitis and led to a clinical response in about 70% of the patients in a retrospective analysis of 30 patients, irrespective of whether PLEX or IA have been used [Ehrlich et al. 2013]. Summarizing, our study provides evidence for the efficacy of IA as a valid treatment option for NMOSD in the acute phase of disease. Our data provide the basis for further studies regarding the efficacy of IA versus PLEX in larger patient cohorts and to better understand its mechanism of action in the context of NMOSD. Acknowledgements The authors thank DIAMED Medizintechnik (Cologne, Germany) for initial financial support for tryptophan-linked polyvinyl alcohol adsorber TR-350(L). Funding The author(s) received no financial support for the research, authorship, and/or publication of this article. Conflict of interest statement The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: The authors declare the following potential conflicts of interest, none of which are related to the content of the manuscript. Simon Faissner received travel grants from Biogen Idec and Genzyme. Andrew Chan received personal compensation as a speaker or consultant for Bayer Schering, Biogen Idec, Merck Serono, Sanofi-Aventis and Teva Neuroscience. He also received research support from the German Ministry for Education and Research (BMBF, German Competence Network Multiple Sclerosis (KKNMS), CONTROL MS, 01GI0914), Bayer Schering, Biogen Idec, Merck Serono and Novartis. Ralf Gold serves on scientific advisory boards for Teva Pharmaceutical Industries Ltd., Biogen Idec, Bayer Schering Pharma, and Novartis; has received speaker honoraria from Biogen Idec, Teva Pharmaceutical Industries Ltd., Bayer Schering Pharma, and Novartis; serves as editor for Therapeutic Advances in Neurological Diseases, is on the editorial boards of Experimental
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Therapeutic Advances in Neurological Disorders 9(4) Neurology and the Journal of Neuroimmunology; and receives research support from Teva Pharmaceutical Industries Ltd., Biogen Idec, Bayer Schering Pharma, Genzyme, Merck Serono, and Novartis. Min-Suk Yoon received speaker´s honoraria from CSL Behring. Aiden Haghikia received travel grants from Bayer Healthcare and Genzyme.
spectrum disorders long after the acute phase. J Clin Apher 30: 43–45.
References
Min, J., Kim, B. and Lee, K. (2012) Development of extensive brain lesions following fingolimod (FTY720) treatment in a patient with neuromyelitis optica spectrum disorder. Mult Scler 18: 113–115.
Ehrlich, S., Fassbender, C., Blaes, C., Finke, C., Günther, A., Harms, L. et al. (2013) Therapeutische Apherese bei autoimmuner Enzephalitis: eine bundesweite Datenerhebung. Nervenarzt 84: 498–507. Jarernsook, B., Siritho, S. and Prayoonwiwat, N. (2013) Efficacy and safety of beta-interferon in Thai patients with demyelinating diseases. Mult Scler 19: 585–592. Kleiter, I., Gahlen, A., Borisow, N., Fischer, K., Wernecke, K., Wegner, B. et al. (2015) Neuromyelitis optica: Evaluation of 871 attacks and 1,153 treatment courses. Ann Neurol DOI: 10.1002/ana.24554. [Epub ahead of print]. Klingel, R., Heibges, A. and Fassbender, C. (2013) Neurologic diseases of the central nervous system with pathophysiologically relevant autoantibodiesperspectives for immunoadsorption. Atheroscler Suppl 14: 161–165. Visit SAGE journals online http://tan.sagepub.com
SAGE journals
Kobayashi, M., Nanri, K., Taguchi, T., Ishiko, T., Yoshida, M., Yoshikawa, N. et al. (2014) Immunoadsorption therapy for neuromyelitis optica
Lennon, V., Kryzer, T., Pittock, S., Verkman, A. and Hinson, S. (2005) IgG marker of optic-spinal multiple sclerosis binds to the aquaporin-4 water channel. J Exp Med 202: 473–477. Levy, M., Mealy, M., Jarius, S., Paul, F., Aktas, O., Broadley, S. et al. (2015) New Acute Severity Scale for Neuromyelitis Optica Relapses. Presented at the AAN Annual Meeting, 22 April 2015, Washington.
Miyamoto, K. and Kusunoki, S. (2009) Intermittent plasmapheresis prevents recurrence in neuromyelitis optica. Ther Apher Dial 13: 505–508. Munemoto, M., Otaki, Y., Kasama, S., Nanami, M., Tokuyama, M., Yahiro, M. et al. (2011) Therapeutic efficacy of double filtration plasmapheresis in patients with anti-aquaporin-4 antibody-positive multiple sclerosis. J Clin Neurosci 18: 478–480. Trebst, C., Jarius, S., Berthele, A., Paul, F., Schippling, S., Wildemann, B. et al. (2014) Neuromyelitis Optica Study Group (NEMOS). Update on the diagnosis and treatment of neuromyelitis optica: recommendations of the Neuromyelitis Optica Study Group (NEMOS). J Neurol 261: 1–16. Wingerchuk, D., Banwell, B., Bennett, J., Cabre, P., Carroll, W., Chitnis, T. et al. (2015) International consensus diagnostic criteria for neuromyelitis optica spectrum disorders. Neurology 85: 177–189.
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