Objectives To clarify the clinical features of combined central and peripheral demyelination (CCPD) via a nationwide survey.
Methods The following characteristics were used to define CCPD: T2 high-signal intensity lesions in the brain, optic nerves or spinal cord on MRI, or abnormalities on visual-evoked potentials; conduction delay, conduction block, temporal dispersion or F-wave abnormalities suggesting demyelinating neuropathy based on nerve conduction studies; exclusion of secondary demyelination. We conducted a nationwide survey in 2012, sending questionnaires to 1332 adult and paediatric neurology institutions in Japan.
Results We collated 40 CCPD cases, including 29 women. Age at onset was 31.7±14.1 years (mean±SD). Sensory disturbance (94.9%), motor weakness (92.5%) and gait disturbance (79.5%) were common. Although cerebrospinal fluid protein levels were increased in 82.5%, oligoclonal IgG bands and elevated IgG indices were detected in 7.4% and 18.5% of cases, respectively. Fifteen of 21 patients (71.4%) had abnormal visual-evoked potentials. Antineurofascin 155 antibodies were positive in 5/11 (45.5%). Corticosteroids, intravenous immunoglobulins and plasmapheresis resulted in an 83.3%, 66.7% and 87.5% improvement, respectively, whereas interferon-β was effective in only 10% of cases. CCPD cases with simultaneous onset of central nervous system (CNS) and peripheral nervous system (PNS) involvement exhibited greater disability, but less recurrence and more frequent extensive cerebral and spinal cord MRI lesions compared to those with temporarily separated onset, whereas optic nerve involvement was more common in the latter.
Conclusions CCPD shows different characteristics from classical demyelinating diseases, and distinctive features exist between cases with simultaneous and temporarily separated onset of CNS and PNS involvement.
- MULTIPLE SCLEROSIS
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Inflammatory demyelinating diseases are immune-mediated inflammatory disorders of the nervous system, which are divided into two categories: those affecting the central nervous system (CNS), such as acute disseminated encephalomyelitis and multiple sclerosis (MS) and those affecting the peripheral nervous system (PNS), including Guillain-Barré syndrome and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP).
Demyelinating diseases usually affect either the CNS or PNS, possibly because the relevant autoimmune cells recognise only CNS or PNS antigens. However, it has occasionally been reported that patients with demyelination in the CNS or PNS also exhibit demyelination in the other nervous system. It was reported that 13 of 150 patients with MS had symptoms related to peripheral neuropathy and 4 had demyelinating polyneuropathy.1 In addition, 5 of 100 patients with CIDP had symptomatic CNS involvement.2 Demyelinating conditions affecting both the CNS and PNS are described using various diagnostic names, such as combined central and peripheral demyelination (CCPD), CIDP with CNS involvement and CIDP with multifocal CNS demyelination.3 Although case reports or a small series of studies of such cases have been repeatedly found in the literature,4–17 whether such conditions represent a distinct disease entity remains to be determined. Since large-scale epidemiological studies on this condition have never before been performed, we conducted a nationwide survey in Japan to uncover the demographic features of CCPD.
In this survey, CCPD was defined as fulfilling the following criteria:
CNS involvement criterion: T2 high-signal intensity lesions in the brain, optic nerves or spinal cord on MRI, or abnormalities on visual-evoked potentials (VEPs).
PNS involvement criterion: conduction delay, conduction block, temporal dispersion or F-wave abnormalities, suggesting peripheral demyelinating neuropathy according to nerve conduction studies (NCS). In the present study, it was mandatory that among median, ulnar and tibial nerves, at least two nerves had the aforementioned abnormal findings suggestive of demyelination.
Exclusion criterion: secondary demyelinating diseases or changes, such as infectious diseases (eg, human T lymphocyte trophic virus type 1-associated myelopathy, syphilis, neuroborreliosis, HIV infection or progressive multifocal leucoencephalopathy), pre-existing inflammatory diseases (eg, sarcoidosis, Behçet's disease, Sjögren's syndrome, vasculitis or other collagen diseases), mitochondrial disease, metabolic/toxic diseases (eg, vitamin deficiency, amyloidosis, chronic alcoholism, diabetes mellitus or subacute myelo-opticoneuropathy due to clioquinol intoxication, cervical spondylotic myelopathy, syringomyelia, spinocerebellar degeneration, multiple myeloma, other tumours, inherited diseases (eg, leucodystrophies), cerebrovascular disease and non-specific lesions on T2-weighted MRI (eg, leucoaraiosis). In our previous study on CCPD,18 all seven CCPD cases fulfilled the EFNS/PNS criteria for CIDP and six cases met the McDonald criteria (2011) for MS.19 ,20 Therefore, we did not exclude patients who eventually met either MS or CIDP criteria for the present survey.
Patients with CCPD who visited adult or paediatric neurologists between 2007 and 2011, and met the aforementioned diagnostic criteria were surveyed in 2012. The survey was conducted in two steps. First, a primary questionnaire sheet was sent to 1332 institutions in Japan, which included educational facilities accredited by the Japanese Society of Neurology, neurology departments with two or more board-certified neurologists, neurology departments in hospitals with more than 500 beds, paediatric departments in hospitals with any board-certified paediatric neurologist and departments of paediatrics in medical schools. A response was received from 671 institutions (50.3%), of which 41 institutions reported 57 cases. In the second step, a survey using a detailed questionnaire sheet about each patient was sent to the institutions that reported the CCPD cases. This questionnaire requested the age at onset, sex, history of preceding diseases, habitation area, mode of onset, clinical signs and symptoms, Hughes functional scale scores (grade 0: normal; grade 1: minimal symptoms and signs, able to run; grade 2: able to walk 5 m independently; grade 3: able to walk 5 m with the use of aids; grade 4: chairuser or bedbound; grade 5: requires assisted ventilation; grade 6: dead)21 at the peak and in remission, laboratory findings, MRI findings of the brain and spinal cord, VEP and NCS findings, differential diagnosis, clinical course, treatment and outcomes. In this second survey, 54 of 57 cases (94.7%) were collated from 38 institutions (92.7%).
Among 54 cases collated, 14 cases were excluded for the following reasons: four cases did not meet CNS involvement criteria; four cases did not meet PNS involvement criteri/a; two cases lacked basic clinical data; two cases were experienced outside the term of this survey; and two cases were strongly suspected of having other diseases (cerebral vascular disease in one and leucodystrophy in another). In the present survey, CNS and PNS symptoms developed less than 2 months apart were regarded as simultaneous or sequential onset of both CNS and PNS involvement. The mode of onset was defined as acute (reaching a maximum intensity within 1 week), subacute (reaching a maximum intensity after 1 week to 1 month) or chronic (reaching a maximum intensity after 1 month).
Continuous variables were summarised by descriptive statistics, and categorical variables were summarised using counts of patients and percentages. For comparisons between two groups, qualitative variables were analysed using Fisher's exact test. Continuous variables that followed a parametric distribution were analysed with Student's t tests, whereas non-parametric variables were analysed with the Mann-Whitney U test.
The demographic features of 40 patients with CCPD are summarised in table 1. The mean age at onset was 31.7±14.1 years (range: 8–59 years), with disease duration of 137.9±124.8 months. The male to female ratio was 1:2.6 (11/29). The mode of onset was acute in 19.4%, subacute in 45.2% and chronic in 35.5%. Clinical courses were monophasic in 10 (26.3%), relapsing remitting in 20 (52.6%) and chronic progressive in 8 (21.1%) cases. Four patients had antecedent infections, of which three had respiratory infections and one had an alimentary infection. Only one patient developed CCPD after a vaccination (details of the vaccination are unknown). In the present survey, 67.5% (27/40) of the patients with CCPD met the McDonald criteria20 for MS, while 87.5% (35/40) fulfilled the EFNS/PNS definite criteria for CIDP.19
Neurological symptoms and signs
The initial symptoms related to CNS involvement, such as visual disturbance, hemiplegia and hemibody sensory disturbance, were observed in 15 cases (39.5%), those related to PNS involvement, such as weakness and sensory disturbance of four extremities, in 15 cases (39.5%), and those related to both CNS and PNS involvement (simultaneous or sequential occurrence) in 8 cases (21%). The most common symptom/sign during the entire course was sensory disturbance (94.9%), the second most common symptom/sign was motor weakness (92.5%) and the third was gait disturbance (79.5%). Visual disturbance was observed in nearly half of the patients, with approximately 50% exhibiting bilateral involvement. Overall, cranial nerves were affected in 30/40 (75%) cases and optic nerves were the most commonly affected (19/30, 63.3%; see online supplementary table). Hyporeflexia and hyper-reflexia were seen in 65% and 22.5%, respectively, while four patients had both, depending on what was examined. Pathological reflexes were found in 45% and sphincter disturbance was present in 47.4%. About one-fourth of the patients showed muscle atrophy and cerebellar ataxia. Mental disturbance, seizure and respiratory disturbance were only occasionally observed.
Laboratory findings of peripheral blood and cerebrospinal fluid
Increased C reactive protein levels were found in only 10.5% of the cases and none of the patients had abnormal glycated haemoglobin levels (table 2). Few patients had common autoantibodies. Antiaquaporin 4 (AQP4) antibodies were not detected in any of the patients, whereas antineurofascin155 antibodies were found in 5/11 (45.5%). Epstein-Barr virus, herpes simplex virus, varicella zoster virus and mycoplasma were negative in all examined cases. Cerebrospinal fluid (CSF) protein levels were increased in 82.5% of the cases, while pleocytosis was present in 27.5%, indicating albuminocytological dissociation in 57.5%. The CSF oligoclonal IgG band positivity rate was only 7.4% and an elevated IgG index was found in 18.5% of the cases.
Neuroimaging, VEP and NCS findings
Following MRI examination, cerebral, cerebellar, brainstem and optic nerve lesions were detected in 75%, 15%, 32.5% and 17.5%, respectively (table 3). Among cases with cerebral lesions, 36.7% had nine or more lesions. Large lesions (>3 cm in diameter) were observed in 25% and gadolinium (Gd)-enhanced lesions were found in only 17.5%. Spinal cord lesions were found in 30/40 (75%) and the lesions in 11 cases were Gd-enhanced. Longitudinally extensive spinal cord lesions (LESCLs), extending three or more vertebral segments, were present in 3/40 (7.5%). VEPs were abnormal in 15/21 patients (71.4%) and bilaterally observed in 53.3% of these. Based on neurological, MRI and VEP findings, the involvement of multiple affected CNS sites (either two or three sites among the brain, optic nerves and spinal cord) was found in 70% of patients with CCPD, while isolated involvement of the brain, optic nerve lesions or spinal cord was present in 10%, 2.5% and 17.5%, respectively. Devic type (optic-spinal) involvement was observed in only 5%. In motor NCS, decreased motor nerve conduction velocity and prolonged F-wave latency were the most common findings, and were observed in 77.5% and 70% of patients with CCPD, respectively (table 4). Abnormal compound muscle action potential amplitude, prolonged distal latency and decreased F-wave occurrence were detected in approximately half of the patients. Conduction block and temporal dispersion were detected in 27.5% and 40%, respectively. In sensory NCS, decreased or absent sensory nerve action potential was recognised in as much as 87.5%, while decreased sensory nerve conduction velocity was present in 42.5%.
Treatment and prognosis
Patients with CCPD were most commonly treated with either intravenous or oral corticosteroids, followed by intravenous immunoglobulins, resulting in 83.3%, 75% and 66.7% improvement, respectively (table 5). Plasmapheresis was performed in only eight patients, of whom seven (87.5%) improved. By contrast, interferon-β (IFN-β) was effective in only one patient and the disease was actually exacerbated in three patients. At the illness peak, 16/40 (40%) patients with CCPD had severe disability, with a Hughes functional scale score of 4 or more, and three required artificial ventilation (figure 1). However, after treatment, 26 of 40 (65%) patients had no or only mild disabilities (≤1 Hughes functional scale score).
Comparison of clinical features between patients with CCPD with simultaneous or temporarily separated onset of CNS and PNS involvement
We classified the collated patients into two subgroups according to the pattern of onset: simultaneous or sequential involvement of both CNS and PNS at onset (simultaneous onset group), or temporarily separated onset of CNS and PNS involvement (temporarily separated onset group). Follow-up period and disease duration were significantly shorter in the simultaneous onset group than in the temporarily separated onset group (44.6±45.0 months vs 112.0±97.7 months, p=0.0316 and 56.9±58.2 vs 169.3±128.5 months, p=0.0055, respectively; table 6). In the temporarily separated onset group, patients who had already been diagnosed as MS when PNS demyelination developed were seen in 9/15 (60%), while those who had already been diagnosed as CIDP when CNS demyelination developed were seen in 7/15 (46.7%) cases. The Hughes functional scale scores at the peak of illness were significantly greater in the simultaneous onset group than the temporarily separated onset group (2.73±1.14 vs 3.75±1.39, p=0.0457). The monophasic course was more frequently observed in the simultaneous onset group than the temporarily separated onset group (75% vs 10.3%, p=0.0008), whereas the relapsing–remitting course was more common in the temporarily separated onset group than the simultaneous onset group (65.5% vs 12.5%, p=0.0140). Visual disturbance and sensory disturbance were more commonly present in the temporarily separated onset group than the simultaneous onset group (63.3% vs 0%, p=0.0015 and 100% vs 71.4%, p=0.0315, respectively), while respiratory disturbance occurred more often in the simultaneous onset group than in the temporarily separated onset group (37.5% vs 0%, p=0.0066). On MRI, cerebral lesions >3 cm and LESCLs were more frequently found in the simultaneous onset group than in the temporarily separated onset group (62.5% vs 16.7%, p=0 0.0186, and 37.5% vs 0%, p=0.0066, respectively). For the CNS affected sites, there were significantly more patients with PNS involvement and isolated brain involvement in the simultaneous onset group than in the temporarily separated onset group (37.5% vs 3.3%, p=0.0237). By contrast, no patients in the simultaneous onset group had PNS involvement and isolated spinal cord involvement, while six patients in the temporarily separated group showed PNS and isolated spinal cord involvement. Abnormal VEPs tended to be more frequently detected in the temporarily separated onset group than in the simultaneous onset group (82.4% vs 25%, p=0.0526). The Hughes functional scale scores were significantly lower following immunotherapies compared with pretreatment scores in the temporarily separated onset group and the simultaneous onset group (2.73±1.14 to 1.43±1.28, p=0.0002, and 3.75±1.39 to 1.50±1.60, p=0.0203, respectively). However, the improvement in these scores was more remarkable in the simultaneous onset group than in the temporarily separated onset group (2.25±1.16 vs 1.30±0.99, p=0.0427; figure 2). Even when we excluded the patient with a history of vaccination, we obtained essentially the same results, although the difference in the Hughes grade scores at the peak, and the score changes after treatment between the temporarily separated onset group and the simultaneous onset group, were no longer statistically significant because of the smaller sample size (data not shown).
CCPD is an extremely rare and devastating disease. We identified 40 patients throughout Japan during the study period. The numbers of registered MS and patients with CIDP in Japan in 2011 were 16 140 and 2986, respectively.22 Even taking into consideration the response rates (50.3% in the first survey and 94.7% in the second), patients with CCPD were a very minor population (84 at most) among those with idiopathic demyelinating disorders (likely less than 0.52% of MS and 2.8% of patients with CIDP in Japan). The present nationwide survey is valuable for determining the characteristic features of CCPD. However, the study had some limitations. Many neurologists answered the questionnaires before the CCPD diagnostic criteria were established. In addition, because there are no specific biomarkers for either MS or CIDP, we could not differentiate these conditions from CCPD; instead, the number of patients who eventually met either the established MS or CIDP criteria was indicated. Nevertheless, the present study analysing the largest number of patients with CCPD defined by the same criteria is significant.
According to results from this study, CCPD was found in a preponderance of females and young adults. However, the age of onset ranged from 8 to 59 years, suggesting CCPD occurrence in a wide age range, except for elderly people. Thus, the ages of onset for CCPD overlap with those for MS and CIDP. Subacute or chronic onset was observed more often than acute onset, while a relapsing remitting or chronic progressive course was more common than a monophasic course. This suggested that a persisting inflammation affecting both the CNS and PNS was the main form of the disease. Indeed, most patients with CCPD reported in the literature to date show a relapsing remitting or chronic progressive course.4–6 ,8–11 ,13–16 Initial symptoms that related to either CNS or PNS involvement were equally observed. CCPD had very high frequencies of motor weakness (>90%), as well as sensory disturbance with various distributions. Cranial nerve involvement that included optic nerves was also commonly seen in CCPD (75%).
The presence of widespread peripheral demyelination, as revealed by NCS and high frequency of albuminocytological dissociation, is compatible with CIDP. The abundant discrete CNS lesions which include the optic nerves and spinal cord on MRI are consistent with MS. However, several features distinct from MS were observed in the present study, including a low frequency of CSF IgG abnormalities and poor response to IFN-β. Zéphir et al16 also reported an absence of CSF oligoclonal IgG bands in five cases with CCPD. Collectively, these findings suggest that at least some mechanisms are distinct from MS function in CCPD.
Most patients with CCPD responded well to immunotherapies, regardless of acute or chronic onset, suggesting a contributory immune/inflammatory mechanism. Although we found only one paper reporting on the efficacy of the combined use of intravenous immunoglobulin and plasma exchange in a case of CCPD,12 the present study disclosed for the first time a high efficacy for plasma exchange in CCPD, which may suggest humoral immunity involvement. A female preponderance in CCPD is also consistent with the nature of autoimmune diseases, although common systemic autoantibodies and antiganglioside antibodies were infrequent, as in previous reports.8–12 ,16 ,23 The unresponsiveness or even disease exacerbation following IFN-β therapy found in our study was consistent with previous reports of CIDP development after IFN-β introduction in patients with MS.24 ,25 Such a phenomenon may also support an autoantibody-mediated mechanism because type I IFNs potently stimulate the production of all subclasses of IgG antibodies.26 These findings suggest the involvement of specific autoantibodies reactive to antigens that are commonly present in CNS and PNS tissues in CCPD. Additional large-scale studies will be needed to clarify the relevant antigens in this condition.
There were several distinctive features between cases of simultaneous and temporarily separated onset of CCPD. A relapsing remitting course was observed more often in the latter than in the former, whereas a monophasic course was observed more often in the simultaneous onset. This difference may be because of the classification criteria as well as the shorter observation period of the simultaneous onset group. However, Adamovic et al17 reported that among 13 paediatric patients with acute simultaneous inflammatory demyelination of both the CNS and PNS, recurrence was seen only in 2 (15.4%) cases. Accordingly, as in our series, the simultaneous onset cases were followed-up nearly 4 years on average. Therefore, simultaneous onset CCPD may be less likely to recur. In addition, the difference in clinical and laboratory manifestations cannot be explained solely by the difference in observation times. For example, visual disturbance and VEP abnormalities were observed more frequently in the temporarily separated onset group than in the simultaneous onset group, in which none of the cases showed apparent visual impairment. By contrast, frequencies of other cranial nerve involvements did not differ between the simultaneous onset and temporarily separated onset groups. Thus, frequent optic nerve involvement appears to be one characteristic feature of CCPD with temporarily separated onset. This suggestion is consistent with previous case reports examining relapsing CIDP with optic nerve lesions,27–29 as well as the relatively high frequency of VEP abnormalities in relapsing or progressive patients with CIDP (8/17, 47%).23 Therefore, this may be a useful laboratory test for suspected CCPD cases, especially those with relapsing CIDP as a presenting feature. By contrast, the simultaneous onset group had a significantly higher frequency of patients with PNS involvement and isolated brain involvement than the temporarily separated onset group, and no patients in the simultaneous onset group had PNS involvement and isolated spinal cord involvement, whereas 20% of the temporarily separated group patients did. Collectively, such differences in the CNS sites of involvement further indicate that distinct mechanisms are operating in these two subgroups.
It is interesting to note that LESCLs were exclusively found in the simultaneous onset group and extensive cerebral lesions were also more common in the simultaneous onset group than in the temporarily separated onset group. Since no AQP4 antibodies were detected in any CCPD cases examined, LESCLs are likely produced by a mechanism distinct from that in neuromyelitis optica (NMO). Indeed, Devic type (optic–spinal) involvement was seen only in the temporarily separated group but not in the simultaneous onset group, further suggesting that LESCLs in the simultaneous onset group are produced by mechanisms distinct from those in NMO. Although the mechanisms for such extensive lesions remain unknown, it is important to raise CCPD as a differential diagnosis for LESCLs and extensive brain lesions.
In the present series, compared with the temporarily separate onset cases, the simultaneous onset cases exhibited more severe disabilities at the peak of illness, such as higher frequencies of respiratory disturbance and greater Hughes functional scale scores, which were likely a reflection of the high frequency of extensive brain and spinal cord MRI lesions. These findings were consistent with those of Adamovic et al,17 who showed that among 13 paediatric patients with acute simultaneous inflammatory demyelination of the CNS and PNS, 6 were bedbound or wheelchair users and one remained on mechanical ventilation at discharge. In our series, however, the simultaneous onset group showed improvements similar to or better than the temporarily separated onset group after immunotherapy, suggesting a high efficacy of immunotherapy for simultaneous onset CCPD, despite severe manifestations. Further studies and characterisation of simultaneous onset and temporarily separated onset CCPD cases may support the existence of two CCPD subtypes and help to shed light on the distinct mechanisms between the two subtypes.
In conclusion, CCPD exhibits distinctive features from those of the classical demyelinating diseases and, therefore, may be a distinct disease, but it is not a simple coexistence of MS and CIDP. Simultaneous onset CCPD is characterised by severe disability with a relatively high frequency of respiratory disturbance, as well as extensive brain and spinal cord lesions observed in MRI scans. By contrast, temporarily separated onset CCPD features a high frequency of optic nerve involvement. Although CCPD is extremely rare, awareness of this condition is important because responses to disease-modifying drugs, such as IFN-β, for patients with CCPD are different from those in patients with MS, and appropriate immunotherapies may well produce satisfactory outcomes with minimal disabilities.
The contributors who had patients with CCPD and answered our survey were as follows (in alphabetical order): K Aoki (Toyama Prefectural Central Hospital, Toyama); H Arahata (National Hospital Organization Omuta National Hospital, Fukuoka); K Deguchi (Kagawa University Faculty of Medicine, Kagawa); T Fujimoto (Sasebo City General Hospital, Nagasaki); M Fukuda (Marianna University School of Medicine Yokohama Seibu Hospital, Kanagawa); M Hirano (Sakai Hospital, Osaka); S Hisahara (Sapporo Medical University School of Medicine, Hokkaido); H Ishiguro (Japanese Red Cross Akita Hospital, Akita); M Ito (Nagoya University Graduate School of Medicine, Aichi); K Ito (Hekinan Municipal Hospital, Aichi); Y Izuno (Kumamoto Naika Hospital, Kumamoto); Y Kikkawa (Japanese Red Cross Narita Hospital, Chiba); A Kimura (Gifu University Graduate School of Medicine, Gifu); M Matsui (Kanazawa Medical University, Ishikawa); N Matsui (The University of Tokushima Graduate School, Tokushima); M Matsuo (Saga University, Faculty of Medicine, Saga); K Matsuura (Suzuka Kaisei Hospital, Mie); H Mikami (Teikyo University Chiba Medical Center, Chiba); K Miyamoto (Kinki University School of Medicine, Osaka); M Mori (Chiba University Graduate School of Medicine, Chiba); T Mutoh (Fujita Health University, School of Medicine, Aichi); T Narita-Masuda (Nagasaki University, Nagasaki); Y Niimi (Fujita Health University, School of Medicine, Aichi); C Nohara (Ebara Hospital, Tokyo); H Nozaki (Kawasaki Municipal Hospital, Kanagawa); S Ono (Teikyo University Chiba Medical Center, Chiba); Y Sakiyama (Jichi Medical University, Saitama Medical Center, Saitama); M Satake (Hamanomachi Hospital, Fukuoka); K Simoya (Fukuoka Yutaka Central Hospital, Fukuoka); H Shiraishi (Nagasaki University, Nagasaki); T Suenaga (Tenri Hospital, Nara); S Suwazono (National Hospital Organization Okinawa National Hospital, Okinawa); K Suzuki (The Jikei University Katsushika Medical Center, Tokyo); Y Suzuki (Yaizu City Hospital, Shizuoka); A Takei (Hokuyukai Neurology Hospital, Hokkaido); H Toji (Hiroshima City Hiroshima Citizens Hospital, Hiroshima); S Watanabe (Hyogo College of Medicine, Hyogo); T Yamada (Saiseikai Fukuoka General Hospital, Fukuoka); T Yamamoto (Hirosaki University School of Medicine, Aomori); T Yamawaki (Hiroshima City Hiroshima Citizens Hospital, Hiroshima).
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Contributors HO, DM, TY and JK conceived the study, supervised the analyses and wrote the paper. RY, NK, TM, MH and HM participated in procedure development and collated the data.
Funding This study was supported in part by a Health and Labour Sciences Research Grant on Intractable Diseases (H24-Nanchitou (Nan)-Ippan-055) from the Ministry of Health, Labour, and Welfare, Japan.
Competing interests RY and TM have received research support from Bayer Schering Pharma, Biogen Idec, Novartis Pharma and Mitsubishi Tanabe Pharma. JK is a consultant for Biogen Idec Japan and Medical Review. He has received honoraria from Bayer Healthcare, Mitsubishi Tanabe Pharma, Nobelpharma, Otsuka Pharmaceutical and Medical Review. He is funded by a research grant for Nervous and Mental Disorders from the Ministry of Health, Labour and Welfare, Japan and grants from the Japan Science and Technology Agency and the Ministry of Education, Culture, Sports, Science and Technology, Japan.
Patient consent Obtained.
Ethics approval The study was approved by the Kyushu University Hospital ethical standards committee.
Provenance and peer review Not commissioned; externally peer reviewed.