J Neurol (1992) 239:31-35
Journal of
Neurology © Springer-Verlag 1992
Intrathecal versus systemic corticosteroids in the treatment of multiple sclerosis: results of a pilot study Reinhard Heun*, Ulrich Siiwka, Heinrich Riittinger, and Klaus Schimrigk Abteilung ftir Neurologie der Universitfitsklinik, W-6650 Homburg/Saar, Federal Republic of Germany
Received November 30, 1990 / Received in revised form March 21, 1991 / Accepted March 28, 1991
Summary. Fifty patients with multiple sclerosis were treated either by corticosteroids given systemically or by intrathecal injection of a steroid crystal suspension. Before and 3 weeks after the beginning of the treatment we examined the patients according to the Expanded Disability Status Scale (EDSS). Four patients had to be excluded from evaluation. In 23 patients the examination revealed at least a small improvement in their disability status. There were 7 intrathecally and 5 systemically treated patients whose disability was significantly reduced. One patient under intrathecal treatment showed a minor deterioration in disability. There was no clear difference in the frequency of improved symptoms or in EDSS scores between the two therapies. Key words: Multiple sclerosis - Corticosteroids - Intrathecal treatment
Introduction The treatment of acute relapses and acute progression of symptoms in multiple sclerosis (MS) by oral and intravenous corticosteroids is well established. One possible alternative to such systemic treatment is the intrathecal injection of steroids. The first report of a patient treated intrathecally with steroids came from Kamen and Erdman [21]. Further reports of larger samples were also promising [2, 3, 6, 7, 11, 12, 27, 34, 43, 47]. The rationale for this mode of treatment was the achievement of high intrathecal drug levels and the reduction of systemic side-effects [21]. A reduction of spasticity and an improvement of walking ability and bladder function were claimed [7, 8, 11]. With the increase in the use of the intrathecal method many reports of side-effects have been published. These include transient meningeal irritations, bladder paralyses, paraesthesias of legs [1, 8], and more serious permanent effects such as adhesive arachnoiditis [13, 30], aseptic men* Present address and address for offprint requests: Psychiatrische Universitgtsklinik, Untere Zahlbacher Strasse 8, W-6500 Mainz, Federal Republic of Germany
ingitis [13, 30], bacterial meningitis [10, 44], sclerosing pachymeningitis [1, 5] and a conus medullaris syndrome [9] (for review of these and patients with other neurological disorders, see [4, 20, 29]). In 1981 Bernat [4] stated that there was no evidence that intrathecal therapy offered any advantage over a higher steroid dosage given systemically, and that there was no steroid preparation available which was specially designed for this purpose. An ideal preparation for that purpose should contain no glycols, no alcohols, no phenols, no bacteriostatic agents, and should be a crystalline steroid salt dissolved at the bedside in sterile saline or lactated Ringer solution and should be injected immediately. As the negative experiences were based mostly on the intrathecal application of methytprednisolone acetate (Depo-Medrol), and as the side-effects could possibly be attributed to the solvents or the bacteriostatic additives in the preparation, but not to the steroid itself [1, 4, 23], in the late 1970s and early 1980s German clinicians began to use triamcinolone crystal suspensions for intrathecal administration [23, 31, 38]. The authors reported only low risks and minor side-effects. Up to now, most publications on intrathecal steroid therapy have been case reports or retrospective reports of uncontrolled treatments of larger samples. There has been only one small trial including a systemically treated control sample of 10 patients, which did not show any advantage of either therapy [281. The results of an interesting prospective double-blind study [16, 39-41] with patients suffering spinal symptoms have not yet been fully published. We have been using the intrathecal application of triamcinolone for MS since the early 1980s [19]. Our clinical impression was that this route was in many cases superior to the systemic, and showed less systemic side-effects. Even in patients where the clinical evaluation revealed cerebral manifestations of the disease and where systemic steroids did not lead to any clinical improvement, good and some times remarkable effects of intrathecal therapy could be seen. As there was no clear proof of efficacy, no benefitrisk evaluation and no clear indication of this (at least in
32 0,5
s o m e cases) p r o m i s i n g t h e r a p y , we started a pilot study with 50 p a t i e n t s , 25 of t h e m t r e a t e d b y systemic a n d 25 b y i n t r a t h e c a l a d m i n i s t r a t i o n of steroids.
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Patients and methods
Fifty consecutively admitted inpatients with a definite diagnosis of MS according to the criteria of Poser et al. [33] were included in the study. They were informed about the study and consented to take part. All patients had had recent deterioration in symptoms with acute relapses or ongoing chronic progression. For randomization the first 5 patients were treated systemically and the next 10 intrathecally, then changing the route for every 10 successive patients. Group i consisted of 25 patients who received three intrathecal injections of 40 mg triamcinolone acetonide crystal suspension on days 1, 8 and 15 after admission. Group 2, 25 patients, received systemic corticosteroids according to our usual scheme: methylprednisolone 100 mg i.v. from day i to day 5, 80 mg i.v. from day 6 to 10, 60 mg i.v. from day 11 to 15, 40mg p.o. from day 16 to 20, 20rag p.o. from day 21 to 25, 20mg p.o. every 2nd day for 10 more days after day 25. On the day of admission (day 0) and 21 days later the patients were examined neurologically and their status was evaluated according to the Expanded Disability Status Scale (EDSS [25]), the Ambulation Index (AI [15]) and the Incapacity Scale (IS [24]). Somatosensory and visual evoked potentials were also measured, and published earlier [17]. All patients had one diagnostic lumbar puncture before the beginning of the treatment. The data of 4 patients had to be excluded from evaluation. One patient with multiple epileptic fits in her history had a severe fit 5
Ell
-1.5
cO
-2.0 -2.5 0
tions). EDSS, Expanded Disability Status Score; MS, multiple sclerosis Treatment
Intrathecal Systemic triammethylcinolone prednisolone
Sex (male/female)
9/13
Age (years)
37.0 (12.2) 42.1 (14.2) P = 0 . 1 6
Duration of MS Course of MS before the deterioration which led to admission: - fully remittent - remittent with residues - chronic progressive with relapses - purely chronic progressive
6.8
7.8
4
6
8
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EDSS before systemic treatment
Fig. la, b. Change in Expanded Disability Status Score (EDSS) followed by intrathecal (a) or systemic (b) therapy. A decrease in EDSS is equivalent to clinical improvement and vice versa. If there is more than one point at one place, the others are clustered nearby
U-test
9/15
(7.7)
2
EDSS before intrathecal treatment
b
Table 1. Description of the patient sample, means (standard devia-
0
(6.0) P = 0 . 3 8
7 5
3 6
4
2
6
13
EDSS at day 0 EDSS at day 21
4.2 (1.8) 3.7 (1.9)
5.0 (2.0)
Ambulation index: - at day 0 - at day 21
2.6 (2.5) 2.2 (2.0)
4.3 (2.4) 3.9 (2.4)
P = 0.015
Incapacity scale: - score at day 0 - score at day 21
6.5 (7.4) 5.2 (5.8)
11.7 (8.0) 11.1 (8.1)
P = 0.012
P = 0.017
5.0 (2.o)
days after intrathecal injection. One patient was primarily treated intrathecally, because she suffered from diabetes mellitus and needed 80 IU insulin/day. (She had a clear improvement of her gait, her score in the EDSS improved from 7.5 to 6.5, her insulin dose remained unchanged.) Two other patients had severe headaches after the first lumbar puncture and refused the next injections. The description of the patients is given in Table 1. Both therapy groups - 22 patients treated intrathecally and 24 patients treated systemically - were comparable in age, sex and duration of the disease. There was no significant difference in the distribution of different courses of the disease between the groups (chi-square test, P >>0.05), but the disability scores at the beginning of the treatment showed relevant differences as a result of our random selection (Table 1).
Results
A p a r t f r o m 2 of the p a t i e n t s who h a d to b e excluded f r o m e v a l u a t i o n , 7 of the o t h e r 46 p a t i e n t s h a d m i n o r h e a d a c h e s . I n 3 p a t i e n t s who were t r e a t e d i n t r a t h e c a l l y a n d h a d h e a d a c h e s after the first l u m b a r p u n c t u r e these were less p r o n o u n c e d after the s e c o n d or third l u m b a r p u n c t u r e . O t h e r r e l e v a n t side-effect did n o t a p p e a r in either group.
33 Table 2. Number of changes in neurological functions according to
EDSS in both therapeutic groups Functional system
Treatment
Outcome
Pyramidal
Intrathecal Systemic
8 7
10 16
4 1
Cerebellar
Intrathecal Systemic
6 10
14 10
2 4
Brain stem
Intrathecal Systemic
5 6
14 14
3 4
Sensory
Intrathecal Systemic
8 8
10 12
4 4
ImStable proved
Deteriorated
The EDSS scores at the beginning of therapy and the changes in EDSS scores after treatment are shown in Fig. 1. In our sample there was no correlation between the degree of disability at the beginning and the degree of improvement: the rank correlation coefficient according to Kendall (see [42]) for the relation of the EDSS scores before the beginning of treatment and the reduction of EDSS scores by clinical improvement was tau = - 0 . 1 7 2 7 and P ( t a u ) = 0.074. This insignificant tendency for a weak correlation might only influence the therapeutic comparison to a minor degree. Only 1 patient, who was treated intrathecally, suffered a deterioration in her disability status. On day 17 after admission she had severe painful paraesthesia in her right arm that disappeared during the next 2 weeks without any additional treatment. The mean EDSS score in group 1 improved from 4.2 to 3.7 and in group 2 improved from 5.4 to 5.0. The changes in both groups were significant (Wilcoxon test [42]P_< 0.01). Thirteen of the 22 intrathecally treated and 10 of the 24 systemically treated patients showed an improvement in their expanded disability status scores of at least 0.5 steps; an improvement of at least 1.0 on the EDSS was found in 7 intrathecally and in 5 systemically treated patients. The frequency of improvement was not significantly different between the therapeutic regimes (chi-squared test, P >>0.05). Having seen that there was no clear advantage for one route of application as judged from the EDSS, AI or IS, which globally describe disability, we looked at special symptoms which might have benefitted from one or the other treatment. Table 2 shows the changes in the functional systems of the EDSS comparing intrathecally and systemically treated patients. There are no clear differences between the two groups concerning the changes in the pyramidal, cerebellar, sensory and brain-stem functions (chi-squared test, P > 0.05). Other functional systems could not be compared as the frequency of involvement was too low to allow therapeutic comparisons. We further investigated the effects of each therapy on the outcome of special subgroups, e.g. patients with significant clinical improvement (change in EDSS -> 1.0
[26]), patients with different courses of MS, patients with spinal symptoms, spasticity and patients who were treated very early after the beginning of new symptoms (data not shown), but the groups were rather small and we could not find any significant differences. Such subgroup analyses will be of interest in the following study with a larger sample of patients.
Discussion
In our study, as in that of Mazzarello et al. [28], it was not possible to find either of the two strategies to be superior. As the groups of this study were quite small and thus the beta-error [42] high, we could not have expected to obtain decisive results at this time, but we were able to show that there are effects of intrathecal treatment and that they are comparable and not inferior to the effects of systemic steroid treatment. A methodological problem of our study was that at the beginning of treatment both therapy groups showed some differences in clinical features which might have influenced the results to a minor degree. This could have happened as we had randomized strictly according to the sequence of admission but not to any special variable such as age, sex, course or duration of the disease, etc. The intention was to exclude any influence of the (unblinded) investigators on the therapeutic decisions, which seemed to us more important than the risk that both groups could by chance be different in special features. The observation period might have been so short as to have excluded effects with a longer latency; however, all patients were examined under identical clinical conditions, precisely 21 days after the beginning of treatment. Some authors have described special indications for intrathecal application of steroids, e.g. acute exacerbations [45], acute transverse myelitis [18] or spinal symptomatology [22]. We did not select patients with any special symptomatology for our study, as we believe that the clinical as well as the pathophysiological and pharmacological data [14, 27, 32, 37, 46, 48] are inadequate to provide any indication for the intrathecal treatment with triamcinolone. As expected our data did not show any pronounced effect of either of the two therapies on any special functional system. The symptoms of patients with good results were not very different from those found in patients with less or no clinical improvement. One might speculate that patients with acute relapses and with less marked symptoms might have been over-represented in this group and, through the normal recovery from acute relapses, this group showed more and better improvement. However, it is remarkable that there were 3 patients with chronic progression who clearly improved after intrathecal administration of steroids, but none after systemic treatment. This might have occurred by chance, but surely will be of major interest if it can be replicated. A recent study on the treatment of spinal symptoms in patients with chronic progressive MS conducted by Rohrbach and colleagues in Wt~rzburg has not yet been published. Preliminary reports were given at neurologi-
34 cal conferences [16, 39-41]. They found an advantage of the intrathecal therapy over systemic treatment. The different results can be explained by the differences in the study designs. As mentioned above (and in contrast to R o h r b a c h and colleagues) our clinical observations were not restricted to patients with prevailing spinal symptoms and chronic progression, regardless of the difficulty of defining spinal versus other symptomatology in patients. These restrictions on the patient sample, the double doses (80 mg triamcinolone), the higher frequencies of treatment (intervals between lumbar punctures 3 - 4 days), the longer observation period, and the use of the spinal score in Wfirzburg might have led to the finding of positive effects which could not be seen in a mixed sample or in the smaller subgroup of patients with spinal symptoms in H o m b u r g using the EDSS. On the other hand, it could be speculated that the systemic therapy with the unusual drug triamcinolone at the dose which was used as an equivalent to the intrathecal dose had for some reason no or only minor effects on disability. This could have caused a superiority of intrathecal therapy which might otherwise be inferior to systemic treatment with other m o r e frequently used steroids, such as methylprednisolone. Continuing our study will allow us to decide whether the restriction to spinal symptomatology and chronic progression in Wfirzburg was useful. In accordance with Neu and colleagues [31, 32, 38], Kappos et al. [23], and R o h r b a c h et al. [39-41] who also used triamcinolone crystal suspensions, we could not find any severe side-effects. The patient who was excluded after her epileptic fit had that fit 5 days after intrathecal treatment. She had had several seizures during the years before therapy and had another 3 months after that treatment. In her M R I scan there was a subcortical lesion which was about 3.5 cm in diameter, and in the E E G there were left temporal focal signs. Thus, we think that this seizure could not be attributed to the therapy. H e a d a c h e s even in the patients who refused a second lumbar puncture never lasted m o r e than 2 days and only rarely had to be treated with acetylsalicylic acid. We did not especially monitor their duration or the intensity, but our impression was that the headaches in the intrathecally treated group were not m o r e pronounced than in the systemically treated patients who had one lumbar puncture before the beginning of the therapy. It could be claimed that our sample size is too small to reveal significant side-effects. This is very probable, as we have not seen such severe cases in our outpatient clinic after following up m o r e than 200 other patients treated intrathecally. In agreement with Wilkinson [48] we think that the intrathecal treatment could still be useful even if in some patients side-effects occur. This would be the case if the benefit for even a few patients (which m a n y authors have claimed for intrathecal methylprednisolone [2, 3, 6, 7, 11, 12, 27, 28, 34-36, 43, 47] and others for triamcinolone [22, 31, 38] and which we have seen in our clinic at least in some cases) were large enough to result in a good benefit-risk ratio. Despite the small sample size, our pilot study is still one of the largest prospective studies on intrathecal
steroid administration in MS that included a systemically treated control group. Further evaluation of intrathecal steroid treatment is warranted and is in progress.
References 1. Abel R Jr, Nelson DA, Bernat JL (1977) Complications from methylprednisolone acetate (Depo-Medrol). Del Med J 49: 331-343 2. Baker AG (1967) Intrathecal methylprednisolone for multiple sclerosis: evaluation by a standard neurological rating. Ann Allergy 25 : 665-672 3. Beck RH (1967) Polarizing solution and intrathecal methylprednisolone acetate in multiple sclerosis: follow-up study. J Am Osteopath Assoc 66: 664-666 4, Bernat JL (1981) Intraspinal steroid therapy. Neurology 31: 168-171 5. Bernat JL, Sadowsky CH, Vincent FM, Nordgren RE, Margolis G (1976) Sclerosing spinal pachymeningitis. J Neurol Neurosurg Psychiatry 39:1124-1128 6. Boines GJ (1963) Predictable remissions in multiple sclerosis. Del Med J 35 : 200-202 7. Boines GJ (1969) The management of the multiple sclerosis patient. Behav Neuropsychiatry 1 : 29-32 8. Buskirk C van, Poffenbarger AL, Capriles LF, Idea BV (1964) Treatment of multiple sclerosis with intrathecal steroids. Neurology 14 : 595-597 9. Cohen FL (1979) Conus medullaris syndrome following multiple intrathecal corticosteroid injections. Arch Neurol 36:228-230 10. Dougherty JH, Fraser RAR (1978) Complications following intraspinal injections of steroids. J Neurosurg 48:1023-1025 11. Goepel W, Bertram W (1971) Erfahrungen mit der intrathekalen Glukokortikoidtherapie bei entzt~ndlichen neurologischen Erkrankungen (Bericht tiber 35 FSlle). Z )krztl Fortbild (Jena) 65 : 99-103 12. Goldstein NP, McKenzie BF, McGuckin WF (1962) Changes in cerebrospinal fluid of patients with multiple sclerosis after treatment with intrathecal methylprednisolone acetate: a preliminary report. Proc Mayo Clin 37: 657-668 13. Goldstein NP, McKenzie BF, McGuckin WF, Mattox VR (1970) Experimental intrathecal administration of methylprednisolone acetate in multiple sclerosis. Trans Am Neurol Assoc 95 : 243-244 14. Haack D, Weik U, Thal H-U, Rauhut, Clar H, Umlauf B (1984) Vergleichende Untersuchungen fiber die Konzentrationen synthetischer Kortikosteroide im Plasma, Liquor cerebrospinalis und im Hirngewebe. Prakt Noffallmed 2 : 39-46 15. Hauser SL, Dawson DM, Lehrich JR, Beal MF, Sherwin VK, Propper RD, Mills JA, Weiner ML (1983) Intensive immunosuppression in progressive multiple sclerosis. N Engl J Med 308 : 173-180 16. Hennes A, Rohrbach E, Kappos L, Staedt D, Kaiser D, Dommasch D, Mertens HG, Haack D (1989) Intrathekale vs orale Corticosteroid-Therapie spinaler Symptome bei Multipler Sklerose - eine Doppelblindstudie. Schweiz Arch Neurol Psychiatr 140 : 183-184 17. Heun R, Eraser W, Schimrigk K (1989) Evozierte Potentiale unter intrathekaler und systemischer Kortikosteroid-Therapie bei Multipler Sklerose. EEG-EMG 20 : 88-91 18. Hielscher H (1981) Akute Schfibe der multiplen Sklerose. Med Welt 32 : 185-188 19. Holzer G (1983) Zytologische Befunde unter intrathekaler Kortisontherapie bei MS. Psycho 9 : 400-401 20. Hopf HC, Besser R (1983) Neurologische Komplikationen nach intrathekater Applikation yon Medikamenten. Verh Dtsch Ges Neurol 2 : 146-157 21. Kamen GF, Erdman GL (1953) Subdural administration of hydrocortisone in multiple sclerosis: effect of ACTH. J Am Geriatr Soc 1 : 794-804
35 22. Kappos L, Mertens H-G (1987) Neurologische Erkrankungen. In: Kaiser H (ed) Cortisonderivate in Klinik und Praxis, 8th edn. Thieme, Stuttgart, pp 164-178 23. Kappos L, Krauseneck P, Dommasch D, Damm W, Bogdahn U, Mertens H-G (1985) Vertrfiglichkeit von TriamcinolonAcetonid-Kristallsuspension und Antibiotika bei intrathekaler Applikation. Verh Dtsch Oes Neurol 3 : 505-508 24. Kurtzke JF (198l) A proposal for a uniform minimal record of disability in multiple sclerosis. Acta Neurol Scand 64 : 110-129 25. Kurtzke JF (1983) Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology 33 : 1444-1452 26. Kurtzke JF (1984) Disability rating scales in multiple sclerosis. Ann NY Acad Sci 436 : 347-360 27. Massaro A R (1978) Modifications of the cerebrospinal fluid IgG concentrations in patients with multiple sclerosis treated with intrathecal steroids. J Neurol 219 : 221-226 28. Mazzarello P, Poloni M, Piccolo G, Cosi V, Pinelli P (1983) Intrathecal methylprednisolone acetate in multiple sclerosis treatment. Acta Neurol Belg 83 : 190-196 29. Nelson DA (1988) Dangers from methylprednisolone acetate therapy by intraspinal injection. Arch Neurol 45 : 804-806 30. Nelson DA, Vates TS, Thomas RB (1973) Complications from intrathecal steroid therapy in patients with multiple sclerosis. Acta Neurol Scand 49 : 176-188 31. Neu I (1982) Intrathekale Gabe eines Depot-Kortikosteroids. Mttnch Med Wochenschr 124 : 67-68 32. Neu I, Reusche E, Rodiek S (1978) Endogener Cortisolspiegel nach intrathekaler Gabe von Triamcinolon-acetonid bei neurologischen Erkrankungen. Dtsch Med Wochenschr 103: 1368-1370 33. Poser CM, Paty DW, Scheinberg L, McDonald WI, Davis FA, Ebers GC, Johnson KP, Sibley WA, Silberberg DH, Tourtellotte WW (1983) New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann Neurol 13:227-231 34. Ringer W A (1968) The treatment of multiple sclerosis with intrathecally administered methylprednisolone acetate. J Indiana State Med Assoc 61 : 1213-1215 35. Rivera VM (1981) Intraspinal steroid therapy. Neurology 31: 1060-1061 36. Rivera VM (1989) Safety of intrathecal steroids in multiple sclerosis. Arch Neurol 46 : 718-719
37. Rocchelli B, Poloni M, Mazzarello P, Piccolo G, Delodovici M, Pinelli P (1982) Intrathecal methylprednisolone acetate in multiple sclerosis treatment: effect on the blood-CSF barrier and on the intrathecal IgG production. Ital J Neurol Sci 2: 119-126 38. Rodiek SO, Neu I (1979) Klinische Erfahrungen mit intrathekaler Gabe von Triamcinolon-Acetonid bei neurologischen Erkrankungen. Therapiewoche 29:1123-1126 39. Rohrbach E, Kappos L, Stgdt D, Hennes A, Kaiser D, Schmidt S, Dommasch D (1987) Intrathekale vs. orale Kortikosteroidtherapie von spinalen Symptomen bei multipler Sklerose (eine kontrollierte Doppelblindstudie). Verh Dtsch Ges Neurol 4: 410-411 40. Rohrbach E, Kappos L, St~idt D, Hennes A, Kaiser D, Schmitt D, Haack D, Mertens HG (1988) Effects, side-effecs and pharmacokinetics of intrathecal vs. oral corticosteroids in spinal symptoms of multiple sclerosis: results of a double-blind controlled trial. J Neurol 235 [Suppl] : 40-41 41. Rohrbach E, Kappos L, St~idt D, Kaiser D, Hennes A, Dommasch D, Mertens HG (1988) Intrathecal versus oral corticosteroid therapy of spinal symptoms in multiple sclerosis: a doubleblind controlled trial. Neurology 38 [Suppl 1] : 256 42. Sachs L (1984) Angewandte Statistik, 6th edn. Springer, Berlin Heidelberg NewYork 43. Schmidt E (1967) Erfahrungen mit der intrathecalen Corticosteroidbehandlung der Polysklerose und anderer neurologischer Erkrankungen. Psychiatr Neurol Med Psychol 19: 152156 44. Schock G, Wieczorek V (1974) Meningitis nach intrathekaler Applikation von Kortikosteroiden. Psychiatr Neurol Med Psychol 26 : 477-479 45. Sehgal AD, Gardner WJ (1963) Place of intrathecal methylprednisolone acetate in neurological disorders. Trans Am Neurol Assoc 88 : 275-276 46. Sehgal AD, Tweed DC, Gardner WJ, Foote MK (1963) Laboratory studies after intrathecal corticosteroids. Arch Neurol 9 : 74-78 47. Vito SJ de, Mannarelli A A (1966) Polarizing solutions and intrathecal methylprednisolone acetate in therapy of multiple sclerosis: preliminary study. J Am Osteopath Assoc 65:713-722 48. Wilkinson H (1989) Dangers from methylprednisolone acetate therapy by intraspinal injection. Arch Neurol 46 : 721-722
Journal of
Neurology © Springer-Verlag 1992
Intrathecal versus systemic corticosteroids in the treatment of multiple sclerosis: results of a pilot study Reinhard Heun*, Ulrich Siiwka, Heinrich Riittinger, and Klaus Schimrigk Abteilung ftir Neurologie der Universitfitsklinik, W-6650 Homburg/Saar, Federal Republic of Germany
Received November 30, 1990 / Received in revised form March 21, 1991 / Accepted March 28, 1991
Summary. Fifty patients with multiple sclerosis were treated either by corticosteroids given systemically or by intrathecal injection of a steroid crystal suspension. Before and 3 weeks after the beginning of the treatment we examined the patients according to the Expanded Disability Status Scale (EDSS). Four patients had to be excluded from evaluation. In 23 patients the examination revealed at least a small improvement in their disability status. There were 7 intrathecally and 5 systemically treated patients whose disability was significantly reduced. One patient under intrathecal treatment showed a minor deterioration in disability. There was no clear difference in the frequency of improved symptoms or in EDSS scores between the two therapies. Key words: Multiple sclerosis - Corticosteroids - Intrathecal treatment
Introduction The treatment of acute relapses and acute progression of symptoms in multiple sclerosis (MS) by oral and intravenous corticosteroids is well established. One possible alternative to such systemic treatment is the intrathecal injection of steroids. The first report of a patient treated intrathecally with steroids came from Kamen and Erdman [21]. Further reports of larger samples were also promising [2, 3, 6, 7, 11, 12, 27, 34, 43, 47]. The rationale for this mode of treatment was the achievement of high intrathecal drug levels and the reduction of systemic side-effects [21]. A reduction of spasticity and an improvement of walking ability and bladder function were claimed [7, 8, 11]. With the increase in the use of the intrathecal method many reports of side-effects have been published. These include transient meningeal irritations, bladder paralyses, paraesthesias of legs [1, 8], and more serious permanent effects such as adhesive arachnoiditis [13, 30], aseptic men* Present address and address for offprint requests: Psychiatrische Universitgtsklinik, Untere Zahlbacher Strasse 8, W-6500 Mainz, Federal Republic of Germany
ingitis [13, 30], bacterial meningitis [10, 44], sclerosing pachymeningitis [1, 5] and a conus medullaris syndrome [9] (for review of these and patients with other neurological disorders, see [4, 20, 29]). In 1981 Bernat [4] stated that there was no evidence that intrathecal therapy offered any advantage over a higher steroid dosage given systemically, and that there was no steroid preparation available which was specially designed for this purpose. An ideal preparation for that purpose should contain no glycols, no alcohols, no phenols, no bacteriostatic agents, and should be a crystalline steroid salt dissolved at the bedside in sterile saline or lactated Ringer solution and should be injected immediately. As the negative experiences were based mostly on the intrathecal application of methytprednisolone acetate (Depo-Medrol), and as the side-effects could possibly be attributed to the solvents or the bacteriostatic additives in the preparation, but not to the steroid itself [1, 4, 23], in the late 1970s and early 1980s German clinicians began to use triamcinolone crystal suspensions for intrathecal administration [23, 31, 38]. The authors reported only low risks and minor side-effects. Up to now, most publications on intrathecal steroid therapy have been case reports or retrospective reports of uncontrolled treatments of larger samples. There has been only one small trial including a systemically treated control sample of 10 patients, which did not show any advantage of either therapy [281. The results of an interesting prospective double-blind study [16, 39-41] with patients suffering spinal symptoms have not yet been fully published. We have been using the intrathecal application of triamcinolone for MS since the early 1980s [19]. Our clinical impression was that this route was in many cases superior to the systemic, and showed less systemic side-effects. Even in patients where the clinical evaluation revealed cerebral manifestations of the disease and where systemic steroids did not lead to any clinical improvement, good and some times remarkable effects of intrathecal therapy could be seen. As there was no clear proof of efficacy, no benefitrisk evaluation and no clear indication of this (at least in
32 0,5
s o m e cases) p r o m i s i n g t h e r a p y , we started a pilot study with 50 p a t i e n t s , 25 of t h e m t r e a t e d b y systemic a n d 25 b y i n t r a t h e c a l a d m i n i s t r a t i o n of steroids.
8
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/00
£3 -0.5
0 0 0 0
-1.0
88
0
0
UJ
Patients and methods
Fifty consecutively admitted inpatients with a definite diagnosis of MS according to the criteria of Poser et al. [33] were included in the study. They were informed about the study and consented to take part. All patients had had recent deterioration in symptoms with acute relapses or ongoing chronic progression. For randomization the first 5 patients were treated systemically and the next 10 intrathecally, then changing the route for every 10 successive patients. Group i consisted of 25 patients who received three intrathecal injections of 40 mg triamcinolone acetonide crystal suspension on days 1, 8 and 15 after admission. Group 2, 25 patients, received systemic corticosteroids according to our usual scheme: methylprednisolone 100 mg i.v. from day i to day 5, 80 mg i.v. from day 6 to 10, 60 mg i.v. from day 11 to 15, 40mg p.o. from day 16 to 20, 20rag p.o. from day 21 to 25, 20mg p.o. every 2nd day for 10 more days after day 25. On the day of admission (day 0) and 21 days later the patients were examined neurologically and their status was evaluated according to the Expanded Disability Status Scale (EDSS [25]), the Ambulation Index (AI [15]) and the Incapacity Scale (IS [24]). Somatosensory and visual evoked potentials were also measured, and published earlier [17]. All patients had one diagnostic lumbar puncture before the beginning of the treatment. The data of 4 patients had to be excluded from evaluation. One patient with multiple epileptic fits in her history had a severe fit 5
Ell
-1.5
cO
-2.0 -2.5 0
tions). EDSS, Expanded Disability Status Score; MS, multiple sclerosis Treatment
Intrathecal Systemic triammethylcinolone prednisolone
Sex (male/female)
9/13
Age (years)
37.0 (12.2) 42.1 (14.2) P = 0 . 1 6
Duration of MS Course of MS before the deterioration which led to admission: - fully remittent - remittent with residues - chronic progressive with relapses - purely chronic progressive
6.8
7.8
4
6
8
0.5
98
0
0
CO
§oo
-0.5 UJ
.E -1.0
0 0
0
13) C
-1.5
o
0
-2.0
o
-2.5
0
2
4
6
8
EDSS before systemic treatment
Fig. la, b. Change in Expanded Disability Status Score (EDSS) followed by intrathecal (a) or systemic (b) therapy. A decrease in EDSS is equivalent to clinical improvement and vice versa. If there is more than one point at one place, the others are clustered nearby
U-test
9/15
(7.7)
2
EDSS before intrathecal treatment
b
Table 1. Description of the patient sample, means (standard devia-
0
(6.0) P = 0 . 3 8
7 5
3 6
4
2
6
13
EDSS at day 0 EDSS at day 21
4.2 (1.8) 3.7 (1.9)
5.0 (2.0)
Ambulation index: - at day 0 - at day 21
2.6 (2.5) 2.2 (2.0)
4.3 (2.4) 3.9 (2.4)
P = 0.015
Incapacity scale: - score at day 0 - score at day 21
6.5 (7.4) 5.2 (5.8)
11.7 (8.0) 11.1 (8.1)
P = 0.012
P = 0.017
5.0 (2.o)
days after intrathecal injection. One patient was primarily treated intrathecally, because she suffered from diabetes mellitus and needed 80 IU insulin/day. (She had a clear improvement of her gait, her score in the EDSS improved from 7.5 to 6.5, her insulin dose remained unchanged.) Two other patients had severe headaches after the first lumbar puncture and refused the next injections. The description of the patients is given in Table 1. Both therapy groups - 22 patients treated intrathecally and 24 patients treated systemically - were comparable in age, sex and duration of the disease. There was no significant difference in the distribution of different courses of the disease between the groups (chi-square test, P >>0.05), but the disability scores at the beginning of the treatment showed relevant differences as a result of our random selection (Table 1).
Results
A p a r t f r o m 2 of the p a t i e n t s who h a d to b e excluded f r o m e v a l u a t i o n , 7 of the o t h e r 46 p a t i e n t s h a d m i n o r h e a d a c h e s . I n 3 p a t i e n t s who were t r e a t e d i n t r a t h e c a l l y a n d h a d h e a d a c h e s after the first l u m b a r p u n c t u r e these were less p r o n o u n c e d after the s e c o n d or third l u m b a r p u n c t u r e . O t h e r r e l e v a n t side-effect did n o t a p p e a r in either group.
33 Table 2. Number of changes in neurological functions according to
EDSS in both therapeutic groups Functional system
Treatment
Outcome
Pyramidal
Intrathecal Systemic
8 7
10 16
4 1
Cerebellar
Intrathecal Systemic
6 10
14 10
2 4
Brain stem
Intrathecal Systemic
5 6
14 14
3 4
Sensory
Intrathecal Systemic
8 8
10 12
4 4
ImStable proved
Deteriorated
The EDSS scores at the beginning of therapy and the changes in EDSS scores after treatment are shown in Fig. 1. In our sample there was no correlation between the degree of disability at the beginning and the degree of improvement: the rank correlation coefficient according to Kendall (see [42]) for the relation of the EDSS scores before the beginning of treatment and the reduction of EDSS scores by clinical improvement was tau = - 0 . 1 7 2 7 and P ( t a u ) = 0.074. This insignificant tendency for a weak correlation might only influence the therapeutic comparison to a minor degree. Only 1 patient, who was treated intrathecally, suffered a deterioration in her disability status. On day 17 after admission she had severe painful paraesthesia in her right arm that disappeared during the next 2 weeks without any additional treatment. The mean EDSS score in group 1 improved from 4.2 to 3.7 and in group 2 improved from 5.4 to 5.0. The changes in both groups were significant (Wilcoxon test [42]P_< 0.01). Thirteen of the 22 intrathecally treated and 10 of the 24 systemically treated patients showed an improvement in their expanded disability status scores of at least 0.5 steps; an improvement of at least 1.0 on the EDSS was found in 7 intrathecally and in 5 systemically treated patients. The frequency of improvement was not significantly different between the therapeutic regimes (chi-squared test, P >>0.05). Having seen that there was no clear advantage for one route of application as judged from the EDSS, AI or IS, which globally describe disability, we looked at special symptoms which might have benefitted from one or the other treatment. Table 2 shows the changes in the functional systems of the EDSS comparing intrathecally and systemically treated patients. There are no clear differences between the two groups concerning the changes in the pyramidal, cerebellar, sensory and brain-stem functions (chi-squared test, P > 0.05). Other functional systems could not be compared as the frequency of involvement was too low to allow therapeutic comparisons. We further investigated the effects of each therapy on the outcome of special subgroups, e.g. patients with significant clinical improvement (change in EDSS -> 1.0
[26]), patients with different courses of MS, patients with spinal symptoms, spasticity and patients who were treated very early after the beginning of new symptoms (data not shown), but the groups were rather small and we could not find any significant differences. Such subgroup analyses will be of interest in the following study with a larger sample of patients.
Discussion
In our study, as in that of Mazzarello et al. [28], it was not possible to find either of the two strategies to be superior. As the groups of this study were quite small and thus the beta-error [42] high, we could not have expected to obtain decisive results at this time, but we were able to show that there are effects of intrathecal treatment and that they are comparable and not inferior to the effects of systemic steroid treatment. A methodological problem of our study was that at the beginning of treatment both therapy groups showed some differences in clinical features which might have influenced the results to a minor degree. This could have happened as we had randomized strictly according to the sequence of admission but not to any special variable such as age, sex, course or duration of the disease, etc. The intention was to exclude any influence of the (unblinded) investigators on the therapeutic decisions, which seemed to us more important than the risk that both groups could by chance be different in special features. The observation period might have been so short as to have excluded effects with a longer latency; however, all patients were examined under identical clinical conditions, precisely 21 days after the beginning of treatment. Some authors have described special indications for intrathecal application of steroids, e.g. acute exacerbations [45], acute transverse myelitis [18] or spinal symptomatology [22]. We did not select patients with any special symptomatology for our study, as we believe that the clinical as well as the pathophysiological and pharmacological data [14, 27, 32, 37, 46, 48] are inadequate to provide any indication for the intrathecal treatment with triamcinolone. As expected our data did not show any pronounced effect of either of the two therapies on any special functional system. The symptoms of patients with good results were not very different from those found in patients with less or no clinical improvement. One might speculate that patients with acute relapses and with less marked symptoms might have been over-represented in this group and, through the normal recovery from acute relapses, this group showed more and better improvement. However, it is remarkable that there were 3 patients with chronic progression who clearly improved after intrathecal administration of steroids, but none after systemic treatment. This might have occurred by chance, but surely will be of major interest if it can be replicated. A recent study on the treatment of spinal symptoms in patients with chronic progressive MS conducted by Rohrbach and colleagues in Wt~rzburg has not yet been published. Preliminary reports were given at neurologi-
34 cal conferences [16, 39-41]. They found an advantage of the intrathecal therapy over systemic treatment. The different results can be explained by the differences in the study designs. As mentioned above (and in contrast to R o h r b a c h and colleagues) our clinical observations were not restricted to patients with prevailing spinal symptoms and chronic progression, regardless of the difficulty of defining spinal versus other symptomatology in patients. These restrictions on the patient sample, the double doses (80 mg triamcinolone), the higher frequencies of treatment (intervals between lumbar punctures 3 - 4 days), the longer observation period, and the use of the spinal score in Wfirzburg might have led to the finding of positive effects which could not be seen in a mixed sample or in the smaller subgroup of patients with spinal symptoms in H o m b u r g using the EDSS. On the other hand, it could be speculated that the systemic therapy with the unusual drug triamcinolone at the dose which was used as an equivalent to the intrathecal dose had for some reason no or only minor effects on disability. This could have caused a superiority of intrathecal therapy which might otherwise be inferior to systemic treatment with other m o r e frequently used steroids, such as methylprednisolone. Continuing our study will allow us to decide whether the restriction to spinal symptomatology and chronic progression in Wfirzburg was useful. In accordance with Neu and colleagues [31, 32, 38], Kappos et al. [23], and R o h r b a c h et al. [39-41] who also used triamcinolone crystal suspensions, we could not find any severe side-effects. The patient who was excluded after her epileptic fit had that fit 5 days after intrathecal treatment. She had had several seizures during the years before therapy and had another 3 months after that treatment. In her M R I scan there was a subcortical lesion which was about 3.5 cm in diameter, and in the E E G there were left temporal focal signs. Thus, we think that this seizure could not be attributed to the therapy. H e a d a c h e s even in the patients who refused a second lumbar puncture never lasted m o r e than 2 days and only rarely had to be treated with acetylsalicylic acid. We did not especially monitor their duration or the intensity, but our impression was that the headaches in the intrathecally treated group were not m o r e pronounced than in the systemically treated patients who had one lumbar puncture before the beginning of the therapy. It could be claimed that our sample size is too small to reveal significant side-effects. This is very probable, as we have not seen such severe cases in our outpatient clinic after following up m o r e than 200 other patients treated intrathecally. In agreement with Wilkinson [48] we think that the intrathecal treatment could still be useful even if in some patients side-effects occur. This would be the case if the benefit for even a few patients (which m a n y authors have claimed for intrathecal methylprednisolone [2, 3, 6, 7, 11, 12, 27, 28, 34-36, 43, 47] and others for triamcinolone [22, 31, 38] and which we have seen in our clinic at least in some cases) were large enough to result in a good benefit-risk ratio. Despite the small sample size, our pilot study is still one of the largest prospective studies on intrathecal
steroid administration in MS that included a systemically treated control group. Further evaluation of intrathecal steroid treatment is warranted and is in progress.
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