Clinical Neurology and Neurosurgery 125 (2014) 217–221
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Japanese cases of neuromyelitis optica spectrum disorder associated with myasthenia gravis and a review of the literature Ryotaro Ikeguchi a,∗ , Yuko Shimizu a , Shigeaki Suzuki b , Satoru Shimizu c , Chiaki Kabasawa a , Shiori Hashimoto a , Masayuki Masuda d , Yuriko Nagane e , Kimiaki Utsugisawa e , Yasushi Suzuki f , Toshiyuki Takahashi g , Hiroya Utsumi h , Kazuo Fujihara g , Norihiro Suzuki b , Shinichiro Uchiyama a a
Department of Neurology, Tokyo Women’s Medical University School of Medicine, Tokyo, Japan Department of Neurology, Keio University School of Medicine, Tokyo, Japan c Medical Research Institute, Tokyo Women’s Medical University, Tokyo, Japan d Department of Neurology, Tokyo Medical University, Tokyo, Japan e Department of Neurology, Hanamaki General Hospital, Iwate, Japan f Department of Neurology, National Hospital Organization Sendai Medical Center, Sendai, Japan g Department of Neurology, Tohoku University Graduate School of Medicine, Sendai, Japan h Department of Neurology, Kamata General Hospital, Tokyo, Japan b
a r t i c l e
i n f o
Article history: Received 15 September 2013 Received in revised form 7 May 2014 Accepted 19 July 2014 Available online 20 August 2014 Keywords: Acetylcholine receptor antibody Myasthenia gravis Neuromyelitis optica Regulatory T cell Thymectomy
a b s t r a c t Background: The incidence of concurrent myasthenia gravis (MG) and neuromyelitis optica spectrum disorder (NMOSD) is higher than what chance predicts, yet it remains unclear why MG and NMOSD appear concurrently. Objective: The purpose of the present study was to examine the clinical features of the concurrence of these diseases. Methods: Clinical details were analyzed retrospectively. Results: Three (0.5%) out of 631 MG patients had confirmed (n = 2) or suspected (n = 1) NMOSD. Two of these patients were women. All showed early-onset MG (EOMG) that preceded NMOSD and were positive for acetylcholine receptor antibody (AChR-Ab). Two patients were tested for aquaporin 4 antibody (AQP4Ab) and were positive. Two patients were treated with a thymectomy that preceded NMOSD. Two patients had decreased frequency of regulatory T (Treg) cells. We identified in the literature 46 patients with both MG and NMOSD. Our results of female predominance, EOMG, MG preceding NMOSD, and positive AChR-Ab are consistent with previous descriptions. Conclusions: This is the first report to examine the frequency of NMOSD in Japanese patients with MG. The reduction and/or dysfunction of Treg cells may be one cause of NMOSD development in MG. © 2014 Elsevier B.V. All rights reserved.
1. Introduction Neuromyelitis optica (NMO) is an inflammatory autoimmune disease characterized by monophasic or relapsing attacks of optic neuritis (ON) and myelitis. In many NMO patients, aquaporin 4 antibody (AQP4-Ab) and NMO-IgG are present in the serum and CSF. Wingerchuk et al. [1] proposed that neuromyelitis optica spectrum disorder (NMOSD), which is limited to ON or longitudinally
∗ Corresponding author at: Department of Neurology, Tokyo Women’s Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan. Tel.: +81 3 3353 8111; fax: +81 3 5269 7324. E-mail addresses:
[email protected],
[email protected] (R. Ikeguchi). http://dx.doi.org/10.1016/j.clineuro.2014.07.036 0303-8467/© 2014 Elsevier B.V. All rights reserved.
extensive myelitis with titers for AQP4-Ab/NMO-IgG, has common pathological condition of NMO. NMO patients often have concurrent autoimmune disease, such as Sjögren syndrome and systemic lupus erythematosus (SLE), and the concurrence of NMOSD and myasthenia gravis (MG) has been reported recently [2–19]. It remains unclear, however, why MG and NMOSD appear concurrently. In the present report, we attempt to identify the causes of concurrent MG and NMOSD by examining our cases and cases previously reported in the literature. 2. Materials and methods Clinical details were analyzed retrospectively. The NMO/NMOSD diagnosis was made according to the diagnostic
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Table 1 Present and previous cases of concurrent MG and NMOSD MG: myasthenia gravis, NMO: neuromyelitis optica, NMOSD: neuromyelitis optica spectrum disorder, NA: not available, AChR: acetylcholine receptor, AQP4: aquaporin 4, *The onset of NMOSD preceding thymectomy in only one case [17]. Author/year
Diagnostic NMO or NMOSD
AChR-Ab
AQP4-Ab
Thymectomy
Thymic histology
O’Riordan et al. (1996) [2] Isbister et al. (2003) [3] Antoine et al. (2004) [4] Furukawa et al. (2006) [5] Gotkine et al. (2006) [6] Kister et al. (2006) [7]
Number of cases 1 1 1 2 1 4
NMO NMOSD suspected NMO 2 NMO NMOSD 4 NMO
1 positive 1 positive 1 positive 2 positive 1 positive 4 positive
NA 1 1 1 1 4
NA 1 Hyperplasia 1 thymoma 1 hyperplasia NA 3 hyperplasia 1 NA
Ikeda et al. (2007) [8] Bichuetti et al. (2008) [10] Kay et al. (2008) [11] Uzawa et al. (2009) [12]
1 1 1 2
NMO NMO NMO 2 NMO
Negative NA 1 positive 2 positive
Not done Not done Not done 2 negative 1 positive 2 positive 1 negative 1 not done Not done Not done 1 positive 2 positive
1 1 0 2
1 hyperplasia NA
Kohsaka et al. 2009 [13] Etemadifar et al. (2011) [14] Jarius et al. (2012) [15]
1 1 10
NMOSD NMO 6 NMO, 4 NMOSD
1 positive 1 positive 9 positive 1 not done
1 positive 1 positive 10 positive
1 0 6
Hironishi et al. (2012) [16] Leite et al. (2012) [17]
1 16
NMOSD suspected 9 NMO, 7 NMOSD
1 positive 16 positive
1 negative 16 positive
1 11*
1 1 3
NMO NMOSD 2 NMOSD, 1 NMOSD suspected
1 positive 1 positive 3 positive
1 1 2
49
30 NMO, 16 NMOSD, 3 NMOSD suspected
46 positive
1 positive 1 positive 2 positive 1 not done 38 positive
Ogaki et al. (2012) [18] Tsujii et al. (2012) [19] Present cases Total
criteria revised in 2006 and in agreement with the NMOSD criteria described by Wingerchuk et al. [1]. We examined records of MG patients treated at 6 neurological centers in Japan. We evaluated the frequency of CD4+ CD25+ CD127low/− regulatory T (Treg) cells among peripheral CD4+ T cells. In addition, we examined cases reported in the literature between January 1990 and December 2012 in which MG and NMO/NMOSD were diagnosed in the same patient (Table 1). These cases were identified with a PubMed search using the terms “neuromyelitis optica,” “myelitis,” “optic neuritis,” “multiple sclerosis,” and “myasthenia gravis.” Clinical information was obtained after the patients had given their informed consent, and the study was approved by the Institutional Review Board of each hospital. 3. Statistical analysis Statistical analysis was performed using the JMP 10 statistical software package (SAS institute). Comparisons between groups were performed with Student’s t-test. Statistical significance was determined by p values < 0.05. 4. Case report 4.1. Case 1 A Japanese woman developed dysarthria and weakness of the extremities at age 25. The diagnosis of generalized MG was confirmed by elevated AChR-Ab titer and a positive edrophonium test. She underwent thymectomy at age 29, and thymic histology was normal. After thymectomy, her symptoms gradually improved; thus, prednisolone treatment was stopped. At 49 years of age, she was admitted to our hospital with a gait disturbance. A neurological exam revealed paresis in both legs, decreased sensation below the T5 level. Laboratory tests for anti-nuclear antibody (ANA), anti-SS-A, B antibodies, and anti-DNA antibody were negative. The proportion of Treg cells among peripheral CD4+ T cells was decreased (7.3%; normal range 10.0 ± 1.5%). The CSF contained 7
35
1 hyperplasia 1 NA 1 hyperplasia 3 hyperplasia 2 normal 1 thymitis 1 hyperplasia 8 hyperplasia 3 normal NA 1 hyperplasia 1 thymoma 1 normal 21 hyperplasia, 2 thymoma 1 Thymitis, 6 normal
leukocytes/l and 38 mg/dl of protein. Spinal MRI revealed a longitudinal signal with an increased T2 intensity below C5 (more than 3 vertebral segments) (Fig. 1). Brain MRI was normal. A diagnosis of NMOSD was made, based on the positive serum AQP4-Ab findings. High-dose intravenous methylprednisolone pulse (HIMP) was initiated, and her neurological symptoms gradually improved. After 2 years, she was able to walk unassisted under maintenance therapy with prednisolone. 4.2. Case 2 A Japanese woman developed diplopia and ptosis at age 47. A MG diagnosis was confirmed by elevated AChR-Ab titer and a positive edrophonium test, and she was started on prednisolone. She developed extremity weakness at age 61 under prednisolone treatment. Chest CT did not show any thymic abnormality. At 70 years of age, she experienced acute vision loss in the left eye. She was diagnosed with ON and was treated with HIMP. Although her visual acuity improved, her disability persisted. Two years later, she was admitted to our hospital due to a relapse of ON in her right eye; she was under prednisolone treatment at that time. Neurological examination revealed right eye blindness. Laboratory tests for ANA and anti-DNA antibody were negative. Spinal MRI results were normal, brain MRI revealed ON for the right eye. She was treated with HIMP, but showed little improvement. Therefore, prednisolone treatment was continued. Nine years after developing ON in the right eye, she showed positive results for serum AQP4-Ab and was diagnosed with NMOSD. Follow-up examination conducted when she was 79 showed decreased proportion of Treg cells among peripheral CD4+ T cells (6.0%). 4.3. Case 3 A Japanese man developed diplopia, ptosis, and dysarthria at age 41. A diagnosis of generalized MG was confirmed by elevated AChRAb titer and a positive edrophonium test. Chest CT showed thymic abnormality, and he underwent thymectomy. Thymic histology
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positive response to steroid treatment, and his underlying autoimmune disease (MG) indicate NMOSD. 5. Results 5.1. Our cases From the 3 patients described in our reports (Table 2), 2 were women. In each patient, MG preceded NMOSD, and the mean age at onset was 37.7 for MG and 57.3 for NMOSD. All 3 patients were AChR-Ab positive, and serum AQP4-Ab was positive in 2 cases (no measurement in case 3). Two patients were previously treated with thymectomy. The mean latency from thymectomy to NMOSD onset was 16 years. Thymic histology revealed normal findings in case 1 and invasive thymoma in case 3. Compared to healthy controls, 2 patients (cases 1 and 2) had decreased proportion of Treg cells; Treg cell proportion was not examined in case 3. Further, we compared the proportion of Treg cells in cases 1 and 2 with that in cases of MG without NMOSD (n = 11). Although there was no significant difference, the mean proportion of Treg cells in cases 1 and 2 (6.6 ± 0.9%; range, 6.0–7.3%, n = 2) was lower than that in cases of MG without NMOSD (8.2 ± 2.7%; range, 3.8–13.1%, n = 11). 5.2. Cases in previous reports We identified, from previous reports, 46 patients with MG and NMO/NMOSD (Table 1) [2–19]. The demographic, clinical, and serological findings are presented in Table 2. Of the 46 patients identified in the literature, 43 (93.4%) were women. The mean age of MG onset was 26.9 years, and MG preceded NMOSD in most cases (41/45, 91.1%). The mean age of NMOSD onset was 40.5 years. AChR-Ab was detected in 43 of the 44 cases (97.7%), and serum AQP4-Ab was detected in 36 of the 40 cases (90.0%). For the 40 patients in which MG preceded NMOSD, 32 (80%) were treated with thymectomy. The mean latency from thymectomy to NMOSD development was 11.7 years. Thymic histology, which was available in 28 patients, revealed thymic hyperplasia in 21 patients (75%) and thymoma in 1 patient (4%).
Fig. 1. MRI of the spinal cord. (a) Case 1: sagittal T2-weighted image demonstrates a longitudinally hyperintense lesion below the C5 level and a swollen spinal cord. (b) and (c) Case 1: axial T2-weighted image demonstrates a centrally located hyperintense lesion in the spinal cord. (d) Case 3: sagittal T2-weighted image demonstrates a longitudinally hyperintense lesion from C4 to T9 and a swollen spinal cord. (e) and (f) Case 3: axial T2-weighted image demonstrates a centrally located hyperintense lesion in the spinal cord.
indicated invasive thymoma. Therefore, he underwent radiation therapy. At 53 years of age, during his hospitalization due to pneumonia, he developed gait disturbance and was not receiving any immunosuppressive therapy including steroid therapy. A neurological exam revealed paresis in both legs and decreased sensation below the T5 level. Laboratory tests for ANA, anti-DNA antibody, and lupus coagulant were negative. The CSF contained 3 leukocytes/l and 89 mg/dl of protein. Spinal MRI revealed a swollen spinal cord longitudinally and increased T2-signal intensity between C4–T9 levels (Fig. 1). Brain MRI was normal. He was diagnosed with transverse myelitis and was started prednisolone. After 3 weeks, the abnormal spinal cord MRI findings disappeared. Although his symptoms improved, the paresis in both legs persisted. This patient was transferred to another hospital for rehabilitation, and was not evaluated with a follow-up examination. AQP4-Ab measurements were unavailable for this patient. Nevertheless, we think that the long spinal cord lesion, his
5.3. Comparison between thymectomized and non-thymectomized cases We examined the age at NMOSD onset and latency from MG onset to NMOSD onset in thymectomized and non-thymectomized groups (Table 3). The age at onset for NMOSD and MG were both lower in thymectomized patients than in non-thymectomized patients (Table 3), but these differences were statistically insignificant. 6. Discussion Both MG and NMOSD are rare diseases. The prevalence of MG in Japan is 11.8:100,000 [20] and the prevalence of NMO in Denmark is 4.4:100,000 [21]. Therefore, one would expect one case with both diseases per 190 million people. According to previous reports and our own findings, it seems that the frequency of concurrent MG and NMOSD is higher than what would be predicted by chance. 6.1. Our cases and cases in previous reports We identified a total 49 patients with MG and NMOSD. Our results showing female predominance, EOMG, MG preceding NMOSD, and positive AChR-Ab are consistent with previous descriptions (Table 2). In our cases, the mean age of onset for MG and NMOSD was higher than those described in previous
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Table 2 Comparison of present and previous cases MG: myasthenia gravis, NMO: neuromyelitis optica, NMOSD: neuromyelitis optica spectrum disorder, AChR: acetylcholine receptor, Ab: antibody, AQP4: aquaporin 4. Present cases (n = 3)
Previous cases (n = 46)
Total
Sex (male:female) Race
1:2 Asian 3 (100%) (n = 3)
Mean age at MG onset (year) MG clinical type (generalized: ocular) Early onset MG (EOMG) Rate of MG preceding NMOSD AChR–Ab positive Mean age at NMOSD onset (year) Mean age at NMOSD onset in MG preceding NMOSD (year) NMO:NMOSD:NMOSD suspected AQP4-Ab positive Rate of thymectomy Rate of thymectomy preceding NMOSD Thymic histology
37.7 (25–47) (n = 3) 3: 0 (n = 3) 3 (100%) (n = 3) 3 (100%) (n = 3) 3 (100%) (n = 3) 57.3 (49–70) (n = 3) 57.3 (49–70) (n = 3)
3:43 Caucasian: Asian: Others = 55%:29%:17% (n = 42) 26.9 (10–51) (n = 44) 27: 6 (n = 33) 43 (97.7%) (n = 44) 41 (91.1%) (n = 45) 43 (97.7%) (n = 44) 40.5 (19–67) (n = 46) 41.5 (19–67) (n = 41)
4: 45 Caucasian: Asian: Others = 51%:33%:15% (n = 45) 27.6 (10–51) (n = 47) 30:6 (n = 36) 46 (97.9%) (n = 47) 44 (91.7%) (n = 48) 46 (97.9%) (n = 47) 41.6 (19–70) (n = 49) 42.6 (19–70) (n = 44)
Mean latency MG onset to NMOSD onset in MG preceding NMOSD (year) Mean latency MG onset to thymectomy in MG preceding NMOSD (year) Mean latency thymectomy to NMOSD in thymectomy preceding NMOSD (year)
19.7 (12–24) (n = 3)
30:14:2 36 (90.0%) (n = 40) 33 (73.3%) (n = 45) 32 (80.0%) (n = 40) Hyperplasia:thymoma:thymitis: normal = 21(75%):1(4%):1(4%):5(18%) (n = 28) 15.5 (