Cyclosporin A in treatment of refractory patients with chronic inflammatory demyelinating polyradiculoneuropathy

Journal of the Neurological Sciences 224 (2004) 29 – 35 www.elsevier.com/locate/jns

Cyclosporin A in treatment of refractory patients with chronic inflammatory demyelinating polyradiculoneuropathy Masayuki Matsuda *, Kenichi Hoshi, Takahisa Gono, Hiroshi Morita, Shu-ichi Ikeda The Third Department of Medicine, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano 390-8621, Japan Received 21 January 2004; received in revised form 20 May 2004; accepted 24 May 2004 Available online 17 July 2004

Abstract To investigate the therapeutic efficacy of cyclosporin A (CyA) in the treatment of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), a microemulsion form of this drug (NeoralR) was orally given to seven patients with the disease who were unresponsive or resistant to conventional therapies. The daily dose of CyA was carefully controlled in order to keep the plasma trough concentration between 100 and 150 ng/ml. Within 1 month of initiation of CyA, all patients subjectively showed improvement of clinical symptoms, while both modified Rankin and INCAT disability scores were significantly decreased ( p < 0.05) and grip strength was significantly increased ( p < 0.05) 3 months after initiation compared with before. Total protein in the cerebrospinal fluid was significantly decreased 3 and 6 months after starting CyA ( p < 0.05). Although the maximal motor nerve conduction velocity showed a significant improvement in the median nerve 1 to 1.5 years after commencement of CyA ( p < 0.05), there were no significant changes in any other neurophysiological parameters. One patient with anti-sulphoglucuronyl paragloboside IgM antibodies gradually became resistant to CyA, but the rest have since been in good neurological condition without complications ascribable to this drug. These results suggest that oral CyA may be effective even for refractory cases with CIDP. CyA should be actively considered as a therapeutic option when patients with CIDP are resistant to conventional treatment. D 2004 Elsevier B.V. All rights reserved. Keywords: Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP); Cyclosporin A; High-dose intravenous immunoglobulin; Corticosteroid; Nerve conduction velocity

1. Introduction Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an immune-mediated disease characterized clinically by progressive or relapsing muscle weakness and/ or sensory disturbance with neurophysiological abnormalities indicative of slowing or block of peripheral nerve conduction, and pathologically by demyelination on nerve biopsy [1,2]. This disease is considered to be a treatable cause of prolonged neurological disability, and immunomodulatory therapies, including high-dose intravenous immunoglobulin (IVIG), corticosteroid and plasmapheresis, have been established as an effective treatment on the basis of randomized trials [3]. Among them IVIG has been most

* Corresponding author. Tel.: +81-263-37-2673; fax: +81-263-373427. E-mail address: [email protected] (M. Matsuda). 0022-510X/$ - see front matter D 2004 Elsevier B.V. All rights reserved. doi:10.1016/j.jns.2004.05.014

frequently employed in the treatment of CIDP because of procedural ease and safety; this is true also in Japan since the approval of IVIG in 2000 by the Ministry of Public Health, Labor and Welfare, and it has shown good therapeutic effects. In some patients, however, the established treatments are ineffective or unusable because of adverse effects. Even though IVIG and/or plasmapheresis are effective, they sometimes have to be repeated frequently despite their high cost in order to maintain neurological remission. In such patients it remains unclear which treatment should be selected as the next therapeutic option. In this study we prospectively investigated the clinical benefits and complications of oral cyclosporin A (CyA) in seven patients with CIDP who failed to achieve a successful and/or prolonged response to the conventional treatments mentioned above. Although several recent reports have already demonstrated the therapeutic efficacy of CyA in CIDP [4 – 6], we employed a microemulsion form of this drug, which is relatively new compared with the oil-based formulation,

IVIG

PSL

33 28 21 20 18 10 9 + +

+ + + + + + + + + + + + + + + +

DM

+

+ + + + + DM, GCb DMb

8 4 5 8 9 3 3 probable probable probable definite probable definite definite

According to the criteria of American Academy of Neurology AIDS Task Force. b These complications developed as adverse effects of PSL. CyA: cyclosporin A, SGPG: sulphoglucuronyl paragloboside, PSL: prednisolone, IVIG: high-dose intravenous immunoglobulin, AZT: azathioprine, CY: cyclophosphamide, DM: diabetes mellitus, GC: glaucoma, ND: not done.

To check renal and liver dysfunction prior to commencement of CyA, each patient received routine laboratory examinations, including hematology, blood chemistry, creatinine clearance and urinalysis. No abnormal findings could be found in any patients, including those with associated diabetes mellitus. CyA microemulsion (NeoralR; Novartis, Basel, Switzerland) was given orally to the patients every 12

a

2.2. Administration of CyA and monitoring

Table 1 Clinical profiles of the patients

We studied seven patients with CIDP who had been admitted to our hospital between April 2000 and June 2003 (six men and one woman; age range, 22 to 53 years; mean, 38.9 F 19.2 years). They were diagnosed as having probable or definite CIDP following the criteria of the American Academy of Neurology AIDS Task Force [7]. Patient profiles are summarized in Table 1. Mean disease duration before starting CyA was 5.7 F 3.5 years, and all patients showed a chronic progressive course. Anti-ganglioside and anti-sulphoglucuronyl paragloboside (SGPG) IgM antibodies in serum were determined by enzyme-linked immunosorbent assay (ELISA) in all patients; the former were negative in all cases while the latter showed a positive result only in case 4. In this patient, however, IgM paraproteinemia could not be confirmed on immunofixation. There were no preceding complications other than diabetes mellitus in cases 1, 2 and 6, and glaucoma in case 1. In cases 1 and 2 overt diabetes mellitus was ascribable to oral prednisolone which had been administered for treatment of CIDP. In all patients various immunomodulatory treatments had been performed before starting CyA: IVIG in all cases, oral prednisolone in six, immunoadsorption in five, azathioprine and cyclophosphamide pulse therapy in two each, and plasma exchange in one. In case 1 immunoadsorption and oral prednisolone were effective for muscle weakness in the extremities, but this symptom worsened soon after tapering oral prednisolone, which was done because of associated diabetes mellitus and bilateral glaucoma. This patient was resistant to both IVIG and cyclophosphamide pulse therapy. In cases 2 to 4 IVIG was effective for neurological symptoms, especially muscle weakness in the extremities, but frequent administration was necessary at an extremely high cost in order to maintain the remission. Cases 5 to 7 were unresponsive to any treatment performed, including oral prednisolone, IVIG and immunoadsorption, and muscle weakness and sensory disturbance gradually deteriorated in parallel with an increase in total protein in the cerebrospinal fluid (CSF).

ND ND ND demyelination ND demyelination demyelination

2.1. Patients

M M F M M M M

2. Patients and methods

30 44 22 39 47 53 37

and showed its effectiveness more precisely by clinical and neurophysiological evaluations.

1 2 3 4 5 6 7

Diagnosis Disease Anti-ganglioside Anti-SGPG Complications Treatment performed before starting CyA Duration of Treatment Complications of CIDPa duration antibody in sera IgM antibody on starting CyA therapy performed ascribable to PSL IVIG AZT CY Immuno- Plasma on starting in sera CyA (months) with CyA CyA therapy pulse adsorption exchange CyA (years)

M. Matsuda et al. / Journal of the Neurological Sciences 224 (2004) 29–35

Case Onset Sex Nerve number age biopsy (years)

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M. Matsuda et al. / Journal of the Neurological Sciences 224 (2004) 29–35

h with their informed consent. The daily dose of CyA was started at 5 mg/kg/day, and was carefully controlled in order to keep the plasma trough concentration between 100 and 150 ng/ml. When the trough concentration either exceeded 200 ng/ml or was between 150 and 200 ng/ml on two successive occasions, the daily dose was reduced 50 mg at a time. To detect development of hypertension and abnormalities in laboratory data, particularly renal dysfunction, as early as possible, hematology and blood chemistry as well as the blood pressure were examined every week during admission and every month at the outpatient clinic. If the serum creatinine levels doubled despite dose adjustment, CyA was discontinued. 2.3. Clinical and laboratory assessment of therapeutic outcomes Therapeutic effects were objectively evaluated with the following markers: INCAT disability score [8], modified Rankin score [9], grip strength, total protein in CSF and neurophysiological parameters. The former two were evaluated every month for the initial 3 months and later at 3monthly intervals. Grip strength was measured three times each in both hands, and was expressed as the average of these values at 3-monthly intervals. Total protein in CSF was determined 3 and 6 months after commencement of CyA and later at 6-monthly intervals. Adverse effects of CyA and complications were also recorded. To neurophysiologically assess motor function, the maximal motor nerve conduction velocity (MCV) was measured in both the median and tibial nerves. An active surface electrode was placed on the muscle belly and a reference electrode on the distal tendon to record the compound muscle action potential (CMAP) of the abductor pollicis brevis muscle (APB) and abductor hallucis longus muscle (AHL). The median nerve was stimulated at the wrist (7.0 cm proximal to the active recording electrode over the APB) and elbow, with supramaximal electrical shock in order to evoke the distal and proximal CMAP (the maximal Mresponse), respectively. The size and terminal latency of CMAP of the APB, latency-time difference between F- and M-waves, and conduction velocity and frequency of F-wave were measured at the same time. Also in the tibial nerve these parameters were recorded at the AHL in the same manner with stimulation at the ankle (internal malleolus, 10.0 cm proximal to the active recording electrode over the AHL) and knee (popliteal fossa). The maximal sensory nerve conduction velocity (SCV) of both the median and tibial nerves was measured using the direct method, because sensory nerve action potentials in the patients were too small to record with surface electrodes in the usual antidromic manner. The stimulating surface ring electrodes were placed on the second finger and the third toe, and pairs of needle recording electrodes were insulated at the wrist, elbow, internal malleolus, and popliteal fossa. In this manner we could achieve precise measurements of the SCV of

31

both distal areas (finger –wrist and toe – ankle) and proximal areas (wrist –elbow and ankle –knee). These neurophysiological studies were performed before, and 6 months and 1 to 1.5 years after commencement of CyA. 2.4. Statistics To determine statistically significant differences between before and after starting CyA, Wilcoxon’s signed rank test was employed for modified Rankin and INCAT disability scores, grip strength, total protein in CSF and neurophysiological parameters. The results represent the mean F stanstandard deviation where applicable, and a p-level less than 0.05 was considered to be statistically significant. Commercially available statistics software was used for data analysis (StatView for Macintosh, Abacus Concepts, Berkeley, CA, USA).

3. Results The observation period after starting CyA was 19.9 F 8.7 months with a range of 9 to 33 months (Table 1). To keep the plasma trough concentration of CyA between 100 and 150 ng/ml, all patients required a daily dose of 3 – 5 mg/kg. All of them subjectively showed improvement of muscle weakness and/or sensory disturbance 2 to 4 weeks after starting CyA. Cases 1 and 5 in particular came to be able to walk by themselves 2 months after commencement of CyA, although a wheelchair had been necessary for daily life before starting this drug. Case 3 was able to return to work as a housewife, and delivered a baby during treatment with CyA. CyA was not tapered in the observation period even after a patient reached a clinically stable state. In parallel with the improvement in clinical symptoms and daily life activities, both modified Rankin and INCAT disability scores were significantly decreased ( p < 0.05) and grip strength was significantly increased ( p < 0.05) 3 months after commencement of CyA compared with before (Fig. 1A – C). No other treatment was given in combination with CyA except in cases 1 and 4 (Table 1). Since in case 1 deterioration of muscle weakness reappeared in the extremities after cessation of oral prednisolone, this drug was restarted and kept at a dose of 5 mg/day after gradual tapering with co-administration of CyA. In case 4 additional administration of CyA lengthened the intervals between IVIG for the initial 1 year, but thereafter IVIG again became frequently necessary in order to avoid neurological deterioration. Oral CyA was discontinued 1 year 8 months after commencement, and the patient has since been treated with IVIG and other experimental protocols. A significant decrease in total protein in CSF was seen 3 and 6 months after starting CyA compared with before ( p < 0.05, Fig. 1D). In cases 5 to 7 total protein in CSF was assessed before and only 3 months after starting CyA, but cases 1 and 2 have persistently shown low levels of this

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M. Matsuda et al. / Journal of the Neurological Sciences 224 (2004) 29–35

4. Discussion 4.1. Efficacy of CyA in refractory CIDP

Fig. 1. Temporal profiles of INCAT (A) and modified Rankin (B) scores, grip strength (C) and total protein in the cerebrospinal fluid (CSF) (D). Both INCAT and modified Rankin disability scores were significantly decreased ( p < 0.05), and grip strength was significantly increased ( p < 0.05) 3 months after starting cyclosporin A (CyA) compared with before. In case 5 grip strength was not assessed. A significant decrease was seen in total protein in CSF 3 and 6 months after commencement of CyA ( p < 0.05). In cases 3 and 5 total protein in CSF was assessed before and only 3 months after starting CyA because of pregnancy and interruption of the follow-up in the outpatient clinic, respectively. Closed circle: case 1, open circle: case 2, closed square: case 3, open square: case 4, closed triangle: case 5, open triangle: case 6, cross: case 7.

marker for 2 years. In case 4 total protein in CSF was again elevated 1 year after commencement of CyA in parallel with an increase in the frequency of IVIG. Results of neurophysiological examinations are summarized in Table 2. In the median nerve a significant improvement was seen in MCV ( p < 0.05) 1 to 1.5 years after commencement of CyA, while in the tibial nerve there were no significant differences in any of neurophysiological parameters between before and after starting CyA. There were no data indicating worsening of peripheral nerve function during this treatment. No increase was seen in either the blood pressure or serum levels of creatinine, and none of the patients had any other complications ascribable to CyA treatment (Table 1).

In this study all of the seven patients with refractory CIDP clinically showed an apparent improvement in neurological symptoms along with a decrease in total protein in CSF within 3 months of starting oral CyA, although significant changes could be detected in few neurophysiological parameters. Improvement in daily life activities was objectively expressed as a decrease in modified Rankin and INCAT disability scores as well as an increase in grip strength. On the basis of these clinical data the therapeutic effect of CyA was considered to reach a peak 3 to 6 months after commencement of the drug. In the case with antiSGPG IgM antibody, CyA was discontinued because of a gradual decrease in efficacy with frequent requirement of IVIG, but the other six patients have since been successfully treated with this drug with or without a small dose of prednisolone. No serious complications ascribable to CyA were seen throughout the observation period, and these clinical findings suggest that in regard of both effectiveness and safety this drug can be used in refractory patients with CIDP. Several recent reports have demonstrated the therapeutic efficacy of oral CyA in refractory cases of CIDP as in our patients [4 –6]. Although Barnett et al. [4] found CyA to be clinically effective also in neurophysiological examinations, significant changes were seen in few such parameters in our study possibly because of irreversible and/or severe impairment of peripheral nerves. With respect to the therapeutic effects of CyA, however, the absence of significant deterioration in these parameters was thought to be rather important because all of the patients in our study had shown a clinically and neurophysiologically chronic progressive course before commencement of this drug. In our study total protein in CSF significantly declined in parallel with improvement in clinical symptoms and decrease in disability scores. Since increased total protein in CSF in general reflects active inflammation in the proximal portion of peripheral nerves, this marker might be more reliable and sensitive than neurophysiological parameters for objectively evaluating disease activity of CIDP and the therapeutic effects of CyA. 4.2. Clinical advantages of CyA In the treatment of refractory patients with CIDP, immunosuppressive agents have often been tried as the next therapeutic option [3]. We employed oral CyA in this study because of three clinical advantages. The first is that CyA can selectively suppress T-cell functions. This drug acts as a calcineurin inhibitor, and reversibly and strongly suppresses cytokine production mainly from helper T cells [10]. Because autoreactive T cells are considered to be central to the pathogenesis of CIDP [11], CyA can probably avoid both

M. Matsuda et al. / Journal of the Neurological Sciences 224 (2004) 29–35

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Table 2 Change in somatic nerve function after commencement of CyA treatment Tibial nerve

Before 6 1 to Normal months 1.5 value years

Median nerve

Before 6 1 to months 1.5 years

MCV

39.8 7.4

MCV

42.1 7.7

Mean S.D. p-value (before vs. 6 months or 1 to 1.5 years) p-value (6 months vs. 1 to 1.5 years) Terminal Mean latency S.D. p-value (before vs. 6 months or 1 to 1.5 years) p-value (6 months vs. 1 to 1.5 years) Size of distal Mean CMAP S.D. (stimulation: p-value (before vs. internal 6 months or 1 to malleolus) 1.5 years) p-value (6 months vs. 1 to 1.5 years) Size of proximal Mean CMAP S.D. (stimulation: p-value (before vs. popliteal fossa) 6 months or 1 to 1.5 years) p-value (6 months vs. 1 to 1.5 years) CMAP size ratio Mean (proximal CMAP/ S.D. distal CMAP) p-value (before vs. 6 months or 1 to 1.5 years) p-value (6 months vs. 1 to 1.5 years) Latency-time Mean difference S.D. between p-value (before vs. F- and 6 months or 1 to M-waves 1.5 years) p-value (6 months vs. 1 to 1.5 years) F-wave Mean conduction S.D. velocity p-value (before vs. 6 months or 1 to 1.5 years) p-value (6 months vs. 1 to 1.5 years) Frequency of Mean F-waves S.D. p-value (before vs. 6 months or 1 to 1.5 years) p-value (6 months vs. 1 to 1.5 years)

41.8 4.6 0.99

38.8 7.3 0.36

0.99 5.3 2.1

4.2 0.5 0.47

5.1 1.1 0.47

0.65 37.4 26.2

44.2 32.5 0.27

41.7 30.8 0.47

0.11 29.1 23.5

34.1 24.3 0.47

30.6 24.5 0.99

0.99 74.8 14.6

77.8 14.9 0.72

72.0 5.3 0.59

0.59 61.0 16.6

56.9 14.3 0.27

68.6 15.3 0.59

0.65 36.2 13.1

37.8 10.7 0.72

32.0 8.5 0.18

0.99 75.0 25.5

90.0 20.0 0.18

96.7 5.8 0.18

NE

>45 m/s

Mean S.D. p-value (before vs. 6 months or 1 to 1.5 years) p-value (6 months vs. 1 to 1.5 years) < 5.0 ms Terminal Mean latency S.D. p-value (before vs. 6 months or 1 to 1.5 years) p-value (6 months vs. 1 to 1.5 years) mVms Size of distal Mean CMAP S.D. (stimulation: p-value (before vs. wrist) 6 months or 1 to 1.5 years) p-value (6 months vs. 1 to 1.5 years) mVms Size of proximal Mean CMAP S.D. (stimulation: p-value (before vs. elbow) 6 months or 1 to 1.5 years) p-value (6 months vs. 1 to 1.5 years) % CMAP size ratio Mean (proximal S.D. CMAP/distal p-value (before vs. CMAP) 6 months or 1 to 1.5 years) p-value (6 months vs. 1 to 1.5 years) < 50 ms Latency-time Mean difference S.D. Between F- and p-value (before vs. M-waves 6 months or 1 to 1.5 years) p-value (6 months vs. 1 to 1.5 years) >50 m/s F-wave Mean conduction S.D. velocity p-value (before vs. 6 months or 1 to 1.5 years) p-value (6 months vs. 1 to 1.5 years) 100% Frequency of Mean F-waves S.D. p-value (before vs. 6 months or 1 to 1.5 years) p-value (6 months vs. 1 to 1.5 years)

44.5 7.9 0.09

Normal value

47.7 >55 m/s 5.6 0.03

0.07 4.0 0.9

3.9 0.8 0.44

3.6 0.4 0.68

< 3.8 ms

0.46 29.0 24.7

37.9 28.4 0.12

33.0 mVms 15.8 0.46

0.08 23 24.7

30.2 28.1 0.48

27.3 mVms 19.7 0.35

0.35 72.1 25.7

71.6 23.0 0.89

75.7 % 25.7 0.25

0.69 34.9 7.8

30.9 7.9 0.14

33.8 2.9 0.99

< 25 ms

0.65 37.2 16.8

31.0 28.0 0.75

43.0 5.3 0.99

< 60 m/s

0.65 63.9 31.5

46.9 42.1 0.17

90.0 >75% 8.7 0.42

0.65 (continued on next page)

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M. Matsuda et al. / Journal of the Neurological Sciences 224 (2004) 29–35

Table 2 (continued ) Tibial nerve

SCV distal part (3rd toe – ankle)

SCV proximal part (ankle – knee)

Before 6 1 to Normal months 1.5 value years Mean 40.2 S.D. 10.7 p-value (before vs. 6 months or 1 to 1.5 years) p-value (6 months vs. 1 to 1.5 years) Mean 46.2 S.D. 8.1 p-value (before vs. 6 months or 1 to 1.5 years) p-value (6 months vs. 1 to 1.5 years)

30.5 21.6 0.47

39.8 7.9 0.86

>40 m/s

Median nerve SCV distal part (2nd finger – wrist)

0.11 37.3 26.0 0.47

48.7 10.3 0.11

>51 m/s

0.29

SCV proximal part (wrist – elbow)

Before 6 1 to months 1.5 years Mean 44.4 S.D. 8.8 p-value (before vs. 6 months or 1 to 1.5 years) p-value (6 months vs. 1 to 1.5 years) Mean 51.2 S.D. 11.1 p-value (before vs. 6 months or 1 to 1.5 years) p-value (6 months vs. 1 to 1.5 years)

41.1 20.6 0.40

Normal value

48.7 >55 m/s 2.2 0.89

0.89 43.0 20.3 0.26

55.5 >61 m/s 3.9 0.53

0.14

NE: not evaluated because of small number of samples.

the progression and relapse of disease with little influence on other immunological systems. In this study no patients showed any infectious episodes ascribable to administration of this drug. The second advantage is that CyA is superior to other immunosuppressive agents with regard to adverse effects. Cyclophosphamide and azathioprine have sometimes been employed in the treatment of CIDP, but it is well known that these drugs show toxicity for reproductive function and have highly carcinogenic activity. These harmful effects are particularly important in young patients [12,13], as in cases 1 and 3 in this study, and case 3 was able to deliver a healthy baby under CyA therapy alone. With CyA nephrotoxicity and hypertension are considered to be the most serious adverse effects, but these can be easily avoided by keeping the trough concentration at low levels [4]. The other advantage of CyA is the relatively early appearance of therapeutic effects. In collagen diseases in which CyA is sometimes employed for treatment, therapeutic effects from this drug have been reported to appear within 1 month [14 –16], whereas other immunosuppressive agents usually require at least 2 to 3 months. In this study a subjectively apparent improvement in neurological symptoms was also seen in all patients within 1 month after starting CyA. Such a quick appearance of therapeutic effects is a key factor in preventing rapid progression of disability and complications, including infection and pressure sores, particularly in patients with severe involvement of the extremities as in cases 1 and 5 in this study. 4.3. Therapeutic dose of CyA An oil-based formulation of CyA was employed in the previous reports [4– 6] while a microemulsion was used in our study. Compared with the earlier oil-based formulation, the clinical benefits of microemulsion arise from greater and more consistent absorption of CyA, improved dose-linearity,

and reduced inter- and intra-patient variability [17,18], which result in increased efficacy of the drug. In the largest study among the previous reports, that by Barnett et al. [4], 19 patients with refractory CIDP were divided into two groups, and both were treated with CyA at a dose of 8 to 11 and 3 to 7 mg/kg/day, respectively. Although there were no significant differences in the effectiveness of CyA between the two groups, renal dysfunction and hypertension were more frequently seen in the former. In the present study all the patients have been successfully treated with CyA at a dose of 3 to 5 mg/kg/day with plasma trough concentrations of 50 to 150 ng/ml irrespective of the severity of clinical symptoms and neurophysiological abnormalities. Considering that our patients showed no serious complications ascribable to CyA, an adequate dose of this drug in CIDP might be 5 mg/kg/day at most, and monitoring of the plasma trough concentration is always necessary with regard to both therapeutic and adverse effects. To clarify how long CyA should be given to patients at this dose after achieving clinically good control, a long-term follow-up study is necessary.

5. Conclusions Oral CyA should be actively considered as a therapeutic option in refractory patients with CIDP. Considering the extremely high cost of IVIG, procedural risk, and the difficulty of plasmapheresis, oral CyA may be useful even when these treatments are effective but frequently necessary in order to avoid clinical relapse and/or progression.

Acknowledgements The authors are grateful to Drs. N. Yuki and K. Susuki, Department of Neurology, Dokkyo University School of

M. Matsuda et al. / Journal of the Neurological Sciences 224 (2004) 29–35

Medicine, for determination of anti-ganglioside and antiSGPG IgM antibodies by ELISA. This work was supported by a grant from Neuroimmunological Disease Research Committee of the Intractable Disease Division, the Ministry of Public Health, Labor and Welfare, Japan.

[9]

[10]

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