Journal of the Neurological Sciences 211 (2003) 81 - 84 Efficacy and safety of repeated intrathecal triamcinolone acetonide application in progressive multiple sclerosis patients Volker Hoffmann, Sebastian Schimrigk, Saida Islamova, Kerstin Hellwig, Carsten Lukas, Nils Brune, Dieter Po¨hlau, Horst Przuntek, Thomas Mu¨ller* Department of Neurology, St. Josef-Hospital, Ruhr-University of Bochum, Gudrunstrasse 56, 44791 Bochum, Germany Received 19 July 2002; received in revised form 12 February 2003; accepted 13 February 2003 Available immunomodulatory and conventional steroid treatment options for patients with progressive multiple sclerosis (MS) only provide limited symptomatic benefit. We performed an open trial on the short-term and long-term efficacy and safety of repeated intrathecalapplication of the sustained release steroid triamcinolone acetonide (TCA) in 36 progressive MS patients. Six TCA administrations,performed every third day, reduced the EDSS score (initial: 5.6 F 0.93 [mean F S.D.]; end: 4.9 F 1.0; p < 0.001) and increased the walkingdistance (WD) (initial: 294 F 314 m; end: 604 F 540 m; p < 0.001). Twenty MS patients continued intrathecal TCA treatment with one TCAinjection performed with a variable frequency ranging from 6 to 12 weeks. Both EDSS and walking distance remained stable in these patientsuntil the end of the follow-up investigation period. No serious side effects occurred. We conclude that repeated intrathecal TCA injectionprovides substantial benefit for progressive MS patients with predominantly spinal symptoms.
D 2003 Elsevier Science B.V. All rights reserved.
Keywords: Progressive multiple sclerosis; Efficacy; Triamcinolone acetonide; Intrathecal the sustained release compound triamcinolone acetonide(TCA) However, a distinct superior clinical benefit To date, clinical trials on patients with progressive of intraspinal TCA administration did not occur in an open multiple sclerosis (MS) showed no clear evidence of an study, which compared the efficacy of intravenous meth- effective symptomatic treatment, which stabilized or ylprednisolone administration with repeated intrathecal reversed disability, particularly once the disease enters TCA injections, performed maximally three times within the progressive stage. Immunomodulatory compounds effi- 3 weeks An increasing number of reports of serious caciously reduce the rate of MS relapses, but do not side effects, i.e. adhesive arachnoiditis or sterile meningi- convincingly, positively alter or even improve patients tis, nearly caused a cessation of further trials on the with progressive MS Numerous papers exist on the efficacy of intraspinal steroid application in MS. Putative pros and cons and/or on the efficacy of intrathecal admin- hypothetical causes were the risks of lumbar puncture itself istration of different dosages of various conventional and/or the applied steroid, mostly methylprednisolone sustained release steroid compounds, i.e. methylpredniso- acetate, and its preservatives The revival of intrathecal lone acetate, in the MS literature. Beneficial, though steroid treatment started with the positive outcome of a controversially discussed, effects appeared in progressive trial on intractable postherpetic neuralgia, in which 89 MS patients with predominantly spinal symptomatology patients received up to a maximum of four intraspinal according to case reports, open trials and one double-blind, methylprednisolone applications within 4 weeks without controlled study with some steroid preparations, including The objective of this open, prospective study in pro- gressive MS patients was to show the short- and long-termefficacy and the tolerability of repeated intrathecal TCA * Corresponding author. Tel./fax: +49-234-509-2426.
E-mail address: (T. Mu¨ller).
0022-510X/03/$ - see front matter D 2003 Elsevier Science B.V. All rights reserved.
doi:10.1016/S0022-510X(03)00060-1 V. Hoffmann et al. / Journal of the Neurological Sciences 211 (2003) 81-84 (EDSSTCA course) with simultaneous estimation of walkingdistance (WD) We offered patients who showed an improvement of their EDSS score of at least one point or adistinct increase of their WD after their first six TCA We enrolled 36 MS patients (subtypes: 22 secondary- applications further treatment on a regular basis with one progressive; 14 primary-progressive; female: 24; male 12; TCA application of individually varying frequency of every into this study We only included participants 6 - 12 weeks based on the treating physician's clinical with an EDSS score of V 7.5. Subjects did not receive impression and the patient's judgement. We also simulta- steroids and were on a stable immunomodulatory drug neously scored these patients with the EDSS (EDSSfollow-up) treatment for at least 4 weeks before study entry. They and measured the WD (WDfollow-up) before each TCA had to experience distinct MS symptom progression, which corresponded to at least one point on the EDSS scale, in thelast 2 years before study entry, but had to be stable for at least 4 weeks before inclusion. The trial design did notallow for participants with a history of seizures, subdural Each subject gave informed written consent. The local hematoma and/or severe post-lumbar puncture syndrome.
ethics committee approved this study.
We used an atraumatic (SprotteR) needle for intrathecal Data showed a normal distribution according to the treatment in order to reduce the risk for onset of post-lumbar Kolmogorow - Smirnow test. As a result, we only per- puncture syndrome We took 5 - 7 ml of cerebrospinal formed parametric tests. We used ANCOVA with fluid (CSF) for cell count and protein analysis for safety repeated measure design for comparison of EDSS scores reasons. Then we dissolved 40 mg ( = 1 ml) TCA in 9 ml of and walking distance before and after the course of six sterile saline solution (0.9%) under sterile conditions and TCA injections. We set age, MS subtypes and duration slowly injected this mixture over a period of approximately 5 of disease as covariates. An additional ANCOVA anal- min. Then patients had to stay in the supine position for at ysis was performed in the follow-up patient group. We set the number of TCA applications, the follow-uptreatment duration in months, age, and duration of MS and MS subtypes as covariates. We employed theTukeys Honest Significance Difference Test for post We performed EDSS scoring before the first injection (EDSSinitial) and on the day after the last TCA application 3.1. Efficacy of the initial six TCA injections EDSS scores significantly (ANCOVA F(df 1, 35) = 63.55, p = 2.23e À 09) decreased WD significantly (ANCOVA F(df 1, 35) = 32.32, p = 2.02e À 06) increased Neither the EDSS score nor the WD worsened in Sixteen patients (subtypes: 10 secondary-progressive; 6 primary-progressive) stopped further TCA treatment, five of them (subtypes: 2 secondary-progressive; 3 primary- progressive) had no benefit concerning their EDSS score and their WD, one further primary-progressive MS patient only experienced an EDSS improvement from 6.5 to 6.0.
The remaining 10 MS patients did not want to participate for various reasons and were lost for standardized follow- up evaluations. Nevertheless, statistical analysis in these Values represent mean F standard deviation, minimum - maximum, age and 16 patients revealed a significant reduction of the EDSS duration of disease is given in years, walking distance (WD) is given in score (ANCOVA F(df 1, 15) = 18.36, p = 0.00065) and a meters, n = number of subjects, TCA = triamcinolone acetonide, TCAcourse = values after six TCA injections within 3 weeks, TCA follow- significant WD increase (ANCOVA F(df 1, 15) = 12.94, up = values of further TCA treatment as described in the methods section.
V. Hoffmann et al. / Journal of the Neurological Sciences 211 (2003) 81-84 Twenty patients (subtypes: 12 secondary-progressive; 8 toms, and we cannot draw any conclusions on the impact primary-progressive) wished to receive further TCA appli- of TCA treatment on progression of MS. Therefore, there cations due to their positive response and therefore entered is an urgent need for further confirmatory trials to addi- tionally address all these issues. However, concerninglong-term steroid therapy and progression of MS, we stress that there are positive outcomes of trials withintravenous methylprednisolone administration in various The duration of follow-up treatment was 13.1 F 6.22, application rates and dosages on long-term disease pro- 3 - 23 [mean F S.D., range] months with 6.35 F 3.91, gression and/or on brain atrophy in secondary-progressive 2 - 15 TCA injections. The post hoc analysis shows and, respectively, relapsing - remitting MS patients that the significant EDSS reduction occurred after the In contrast to studies on intravenous oral steroid treatment, initial six TCA applications and then remained stable we did not observe the typical side effects of systemic high- (ANCOVA F(df 2, 38) =18.31, p = 2.7e À 06, post hoc analy- dosage steroid administration. Onset of side effects of sis: EDSSinitial versus EDSSTCA course: p = 0.00012; lumbar puncture were negligible since we used an atraumatic EDSSinitial versus EDSSfollow-up: p = 0.0009; EDSSTCA course In conclusion, our data demonstrate the efficacy and Correspondingly, the same outcome was evident con- safety of repeated intrathecal TCA application on the cerning the estimation of WD despite a further insignificant symptoms in progressive MS patients, which markedly increase (ANCOVA F(df 2, 38) = 16.07, p = 8.76e À 06; post improved. We point out that only MS specialists with hoc analysis: WDinitial versus WDTCA course: p = 0.0002; broad experience of intraspinal TCA application should WDinitial versus WDfollow-up: p = 0.0001; WDTCA course ver- perform this kind of therapy after careful information and risk-benefit evaluation in cooperation with the There was no significant impact of covariates in the patient. Further trials on the efficacy and safety of statistical analysis (data not shown).
intrathecal TCA treatment and comparisons to systemichigh-dosage steroid treatment are urgently needed in We performed a total of 340 lumbar punctures in this trial. We occasionally observed a transitory increase ofCSF protein above 500 mg/l (total: 14). A temporary rise of CSF cells occurred (total: 17), but this did not induceclinical symptoms in any case. The maximum cell count [1] Goodin DS, Frohman EM, Garmany Jr GP, Halper J, Likosky WH, was 38/Al. Five patients developed headache after lumbar Lublin FD, et al. Disease modifying therapies in multiple sclerosis:report of the Therapeutics and Technology Assessment Subcommittee puncture (total: 13), but they did not stop further TCA of the American Academy of Neurology and the MS Council for treatment. We once observed onset of transitory tinnitus Clinical Practice Guidelines. Neurology 2002;58(2):169 - 78.
in combination with temporary pain in the lower extrem- [2] Rohrbach E, Kappos L, Sta¨dt D, Kaiser D, Hennes A, Dommasch D, ities in one patient. Deep vein thrombosis, ovarian et al. Intrathecal versus oral corticosteroid therapy of spinal symptoms cancer, and traumatic bone fracture occurred in the in multiple sclerosis: a double-blind controlled trial. Neurology 1988;38(Suppl 1):256.
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[4] Nelson DA, Landau WM. Intraspinal steroids: history, efficacy, acci- dentality, and controversy with review of United States Food andDrug Administration reports. J Neurol Neurosurg Psychiatry 2001;70(4):433 - 43.
Our results demonstrate the efficacy and safety of [5] Kotani N, Kushikata T, Hashimoto H, Kimura F, Muraoka M, Yodono repeated intraspinal TCA application in progressive MS M, et al. Intrathecal methylprednisolone for intractable postherpetic patients with spinal symptoms. Our application rate with neuralgia. N Engl J Med 2000;343(21):1514 - 9.
six TCA injections within 3 weeks was distinctly higher [6] Poser CM, Paty DW, Scheinberg L, McDonald WI, Davis FA, Ebers GC, et al. New diagnostic criteria for multiple sclerosis: guidelines for compared with earlier trials Our analysis also research protocols. Ann Neurol 1983;13(3):227 - 31.
strongly indicates that most primary- and secondary-pro- [7] Braune HJ, Huffmann GA. A prospective double-blind clinical trial, gressive, even very advanced, MS patients improve from comparing the sharp Quincke needle (22G) with an ''atraumatic'' this therapeutic approach with six TCA injections. How- needle (22G) in the induction of post-lumbar puncture headache. Acta ever, our study design and performance does not allow [8] Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an any conclusion concerning the duration of the achieved expanded disability status scale (EDSS). Neurology 1983;33(11): benefit. Our long-term results did not show a further statistically significant additional benefit on MS symp- [9] Neu I, Reusche E, Rodiek S. Endogenous cortisol levels after intra- V. Hoffmann et al. / Journal of the Neurological Sciences 211 (2003) 81-84 thecal injection of triamicinolone acetonide in patients with neuro- nisolone in secondary-progressive multiple sclerosis. Neurology logical disease. Dtsch Med Wochenschr 1978;103(35):1368 - 70 [au- [11] Zivadinov R, Rudick RA, De Masi R, Nasuelli D, Ukmar M, Pozzi- [10] Goodkin DE, Kinkel RP, Weinstock-Guttman B, VanderBrug-Meden- Mucelli RS, et al. Effects of IV methylprednisolone on brain atrophy dorp S, Secic M, Gogol D, et al. A phase II study of i.v. methylpred- in relapsing - remitting MS. Neurology 2001;57(7):1239 - 47.


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