Journal of Clinical Apheresis 30:43–45 (2015)
Case Report Immunoadsorption Therapy for Neuromyelitis Optica Spectrum Disorders Long After the Acute Phase Masatake Kobayashi,1 Kazunori Nanri,2* Takeshi Taguchi,2 Tomoko Ishiko,2 Masaharu Yoshida,3 Noriko Yoshikawa,3 Kentaro Sugisaki,3 and Nobuyuki Tanaka2 1
Department of Cardiology, Tokyo Medical University, Hachioji Medical Center, Tokyo, Japan Department of Neurology, Tokyo Medical University, Hachioji Medical Center, Tokyo, Japan 3 Department of Nephrology, Tokyo Medical University, Hachioji Medical Center, Tokyo, Japan 2
Neuromyelitis optica (NMO) is a severe inflammatory demyelinating disease with exacerbations involving recurrent or bilateral optic neuritis and longitudinally extensive transverse myelitis. Pulse steroid therapy is recommended as the initial, acute-phase treatment for NMO. If ineffective, treatment with plasma exchange (PE) should commence. However, no evidence exists to support the effectiveness of PE long after the acute phase. Immunoadsorption therapy (IA) eliminates pathogenic antibodies while sparing other plasma proteins. With IA, side effects of PE resulting from protein substitution can be avoided. However, whether IA is effective for NMO remains unclear. We describe a patient with anti-aquaporin-4-positive myelitis who responded to IA using a tryptophan polyvinyl alcohol gel column that was begun 52 days after disease onset following the acute phase. Even long after the acute phase when symptoms appear to be stable, IA may be effective and should not be C 2014 Wiley Periodicals, Inc. excluded as a treatment choice. J. Clin. Apheresis 30:43–45, 2015. V Key words: neuromyelitis optica; plasmapheresis; steroid therapy
Neuromyelitis optica (NMO) is a severe inflammatory demyelinating disease with exacerbations involving recurrent or bilateral optic neuritis and longitudinally extensive transverse myelitis (LETM). Owing to overlapping symptomatology, NMO can be difficult to distinguish from multiple sclerosis (MS), and NMO was originally considered by some to be a form of MS. Identification of antibodies against the aquaporin-4 (AQP4) water channel protein (anti-AQP4) has changed the concept of NMO, and positivity for anti-AQP4 is recognized to be important for the diagnosis of NMO. Apart from NMO, some patients with recurrent optic neuritis or recurrent LETM alone are also often positive for anti-AQP4, and a diagnosis of NMO spectrum disorder (NMOSD) is given to such patients. NMOSD comprises conditions that include both AQP4-IgG seropositivity and one of the index events of the disease (recurrent or bilateral optic neuritis and LETM) . Pulse steroid therapy is recommended as the initial, acute-phase treatment for NMO and NMOSD. If this is ineffective, treatment with plasma exchange (PE) is recommended, and starting PE early has been reported to improve the prognosis . However, no evidence C 2014 Wiley Periodicals, Inc. V
exists to support the effectiveness of PE long after the acute phase of NMO or NMOSD. Although, simple PE is recommended to treat NMO or NMOSD , immunoadsorption therapy (IA) provides a more selective approach and the potential for technical innovations in therapeutic apheresis techniques, allowing the elimination of pathogenic antibodies while sparing other plasma proteins. With IA, side effects of PE resulting from protein substitution can be avoided. However, no evidence exists regarding whether IA therapy is effective for NMO or NMOSD. We describe a male patient with severe myelitis who was positive for anti-AQP4 and who dramatically responded to IA that was begun on Day 52 after onset following the acute phase of the disease. This case provides valuable information on the treatment of NMO and NMOSD.
*Correspondence to: Kazunori Nanri, Department of Neurology, Tokyo Medical University, Hachioji Medical Center, 1163 Tatemachi, Hachioji, Tokyo 193-0998, Japan. E-mail: [email protected]
Received 28 June 2013; Accepted 21 March 2014 Published online 6 May 2014 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/jca.21324
Kobayashi et al.
The patient was a 42-year-old man with a history of alopecia areata in 2007 and a positive anti-SS-B level of 12.2 U/mL in February 2009. Left extremity weakness and right hemisensory deficits developed in late June 2009, and he visited our hospital on June 29. At this time, magnetic resonance imaging (MRI) revealed T2 hyperintense lesions within the spinal cord extending from C1 to C3. Results of manual muscle testing (MMT) were as follows: left upper extremity, Grade 3–4 (3: muscle strength is reduced such that the joint can be moved only against gravity, 4: muscle contraction can still move the joint against resistance); left lower extremity, Grade 4–5 (5: muscle contracts normally against full resistance). Anti-SS-A was positive (162 U/mL), and other autoantibodies, including anti-SS-B, were negative. Cerebrospinal fluid examination showed an increase in cells (8/mL) and the protein level (55 mg/dL). Brain MRI was normal. Because of positive anti-SS-A and previously positive anti-SS-B findings, we suspected autoimmune-related myelitis and started pulse steroid therapy on hospital Day 1 and then began oral steroid therapy with prednisolone 60 mg/day. Improvement in symptoms was not seen, and consequently, a second course of pulse steroid therapy was initiated on hospital Day 8. Despite two courses of pulse steroid therapy, the patient’s neurologic status continued to worsen; the muscles of his left upper and lower extremities weakened over time, with worsening to MMT Grade 2 (2: muscle can move only if the resistance of gravity is removed) on Day 24 after onset. The area of high signal intensity on T2-weighted MRI extended vertically. Based on the positive anti-AQP4 result, we changed the diagnosis to NMOSD on Day 23. On Day 25 after onset, we started IA after obtaining informed consent, but we were forced to cancel this first attempt after one procedure due to a pulmonary embolism resulting from a thrombus attached to the tip of the intravenous catheter. Thereafter, muscle strength of both the left upper and lower extremities remained at MMT Grade 2. We restarted IA on Day 52 after onset. IA was performed using a tryptophan-linked polyvinyl alcohol adsorber TR-350 (Asahi Kasei Medical Co., Tokyo, Japan) after membrane plasma separation with a polyethylene plasma separator OP-05W (Asahi Kasei Medical Co.) under 100 mL/min blood flow. The adsorber, plasma separator, and tubing system were for single use only. Combined anticoagulation with unfractionated heparin was used for all treatments. The treated plasma volume was 2,000-mL plasma for all treatments. IA was performed three times per week, and a total of 12 procedures were performed. Journal of Clinical Apheresis DOI 10.1002/jca
After restarting IA, muscle strength on the left side gradually improved. After nine procedures of adsorption, muscle strength of both the left upper and lower extremities improved to MMT Grade 5, and the patient was ambulatory and was discharged from the hospital. Afterward, he made good progress without recurrence of symptoms, and as of April 2013, he has been treated as an outpatient with use of prednisolone 9 mg/ day and cyclosporin 350 mg/day. High signal intensity on T2-weighted MRI has almost disappeared. DISCUSSION
In our case, plasmapheresis could not be performed in the acute phase. For this reason, left hemiplegia did not improve after 4 weeks, and the neurological deficits appeared to be stable. However, the patient responded to IA that was resumed on Day 52 after onset, and muscle strength returned to almost normal. For steroid-resistant MS relapses, PE has been established as a treatment option recommended by guidelines. However, Heigl et al. treated a total of 60 MS patients including one NMO patient with a steroidrefractory relapse with IA. Among the main symptoms, optic neuritis (26) and spastic paresis (26) predominated. The response rate was 88%, which was noninferior to previous results with PE. PE is a nonselective extracorporeal process of plasma removal with volume replacement. In contrast, IA is a selective technique for the removal of autoantibodies and immune complexes with fewer associated adverse effects . Heigl et al. concluded that IA for the treatment of steroidrefractory MS relapses is safe and effective . PE is an efficient add-on therapy for steroidresistant NMO, and plasmapheresis in NMO is often done using PE . Double-membrane filtration plasmapheresis has also been reported to be effective [7,8]. Few reports have been published about IA. However, we selected IA therapy for our NMO patient, because as mentioned above, Heigl et al. reported that IA was safe and effective for optic neuritis-predominant steroid-resistant MS relapses including one NMO patient, and IA has previously been reported to be effective in one Japanese case . In our patient, IA resulted in a complete response even though it was started late. Early initiation of PE has been reported to improve the prognosis of NMO. Keegan et al. noted that early initiation of therapy is associated with greater improvement; however, patients treated more than 60 days after disease onset often experience a favorable response and should not be excluded from treatment . In our patient, IA therapy was started 52 days after onset, when neurological deficits appeared to be stable after the acute phase. However, IA was dramatically effective. With MS, Heigl et al. reported that the time interval between the start of the relapse until initiation of
IA Therapy for NMOSD Long After the Acute Phase
IA therapy was an average of 58 days, and IA was effective in 88% of the patients. Surprisingly, the longest intervals with successful treatment were 100, 120, or 180 days . Accordingly, in inflammatory demyelinating diseases of the central nervous system, such as MS and NMO, the effective period for treatment with plasmapheresis may be much longer than previously thought. CONCLUSIONS
We described a male patient with severe myelitis who was positive for anti-AQP4 and who dramatically responded to IA that was begun long after the acute phase of the disease. Even when the diagnosis of NMO is delayed and neurological damage appears to be stable, plasmapheresis may improve the patient’s quality of life. Regarding plasmapheresis, the advantages of IA include the absence of a need for a replacement solution and few complications. IA may be promising as a treatment of choice for NMO and should be investigated in a larger number of patients. REFERENCES 1. Lana-Peixoto MA, Callegaro D. The expanded spectrum of neuromyelitis optica: evidences for a new definition. Arq Neuropsiquiatr 2012;70:807–813.
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Journal of Clinical Apheresis DOI 10.1002/jca