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`Pulsed Intravenous Methylprednisolone
`Therapy in Progressive Multiple Sclerosis:
`Need for a Controlled Trial
`
`ore than half of patients with relapsing-
`
`M remittingmultiplesclerosis(MS)developapro-
`
`gressiveillness in about 10 to 15 years (second-
`ary progressive MS), and 10% to 15% ofall patients with
`MS enterthe progressive stage from onset (primary pro-
`gressive MS). After a patient reaches level 4 on the Ex-
`pandedDisability Status Scale,' the rate of progression be-
`comes identical in primary and secondary progressivecases.
`This suggests a common mechanism for progression, which
`may be related to axonal abnormalities. For progressive
`forms of MS,unless they are associated with rapid pro-
`gression and evidence of inflammation, there is no ac-
`cepted treatment. In our experience, a subset of patients
`with progressive MS showsan objective and measurable
`response to intravenous methylprednisolone sodium suc-
`cinate (IVMP)treatment. The aim ofthis letter is to report
`the effects of pulsed IVMPtherapygivenfor years in a sub-
`set of patients with progressive MS.
`Using the central records system of the Mayo Clinic
`(Rochester, Minn), we reviewed the medical records ofall
`patients (490) who received IVMP treatment as outpa-
`tients for MS between 1990 and2002.Inclusion in our study
`required (1) primary or secondary progressive MS;(2) no
`acute exacerbation for 1 year; (3) no injectable or oral im-
`munomodulators for 1 year; (4) pulsed IVMPat a dose of
`1g/moor3 doses of1 g/d every 3 months;(5) pulsed IVMP
`therapy for at least 1 year; (6) documented semiannualfol-
`low-up examinations; and (7) documented worsening of
`neurologic examination findings in the year preceding
`therapy. Results ofall patients meeting these criteria are
`reported. Data including demographic (sex, age at onset,
`and ageat first pulsed IVMP treatment) andclinical char-
`acteristics (neurologic examination findings and mag-
`netic resonance imaging data when available) were ob-
`tained. The Mayo Clinic institutional review board (No.
`1599-02) approvedthe study. Standard neurologic exami-
`nations were performedfor eachpatient, and data from stan-
`dard questionnaires (regarding fatigue, bowel and blad-
`der functions, and mobility) were used. A 1-point change
`in each componentof the neurologic record and Func-
`tional System Scale' was used to determine worsening or
`improvement. Changeshad to be confirmed bythe re-
`sults ofat least 2 examinations done 6 months apart. Scores
`that were not consistently worsening or improving by 1
`point were considered unchanged. Our data (Table) are
`categorized as improved, worse, or unchanged. At every
`visit, data were obtained by a blinded examiner. The
`Table shows thetreatmenteffectat the last neurologic ex-
`amination.
`Ten patients metthe inclusion criteria (Table). The
`mean+SD age at MS onset was 42.0+13.5 years. The
`mean+SDage at pulsed [VMPtreatmentinitiation was
`
`47.0+14.2 years. The mean+SD length of pulsed IVMP
`use was 3.8+2.6 years. The male-female ratio was 3:2. In
`5 patients, other treatments (oral prednisolone, inter-
`feron alfa, cyclophosphamide, andinterferon beta)failed
`to slow the rate of progression. Of the 10 patients, 9 did
`not develop acute exacerbation during the course ofIVMP
`treatment. At 1 year following pulsed IVMPtreatments,
`fatigue improved in 6 patients and worsened in 2. Spas-
`ticity improvedin 9 (90%) of 10 patients; motorstrength
`improved in 8 (80%) of 10. Motor improvement was con-
`fined to pyramidalfunctions. Ataxia worsenedin 6 (60%)
`of 10 patients and improvedin none. Boweland bladder
`problems worsened in 6 (60%) of 10. One patient devel-
`oped a newclinical attack ofMSassociated with gadolin-
`ium enhancement and was switched to interferon beta
`therapy. Another patient requested to switch to inter-
`feron therapy because of adverse effects related to mood
`andsleep hygiene.All patients were monitoredfor the de-
`velopment of osteoporosis. Patients were encouraged to
`take multivitamin and calcium supplements.
`Theresults of this small study suggestthat there may
`be a treatmenteffect of pulsed [VMPin a subsetof pa-
`tients with progressive MS. The generally accepted view
`is that steroids do nothave long-term effects on the pro-
`gression of MS. However, in the Optic Neuritis Treat-
`mentTrial,’ the developmentof clinical MS was delayed
`by the use of intravenoussteroids. This was unexpected
`and suggests potential neuroprotective or extended im-
`munomodulatory effects of 'VMP. More recently, a cross-
`overtrial of 35 Italian patients with a “primarily chronic
`progressive form of multiple sclerosis”*?'*” who werere-
`ceiving IVMP showed improvementlasting up to 90 days
`after treatment. In anothertrial, 18 of 32 patients with
`chronic progressive MS showed a measurable improve-
`mentin ExpandedDisability Status Scale scores by a mean
`of 0.56 at 12 months of follow-up after IVMP treat-
`ment.‘ In a novel study, parameters related to the pro-
`gression of MS were followed for 5 years in 88 patients
`receiving pulsed IVMP either independentofrelapses or
`for relapses only.’ The study was unblinded anddid not
`have a placebo arm. Pulsed [VMP therapydelayed thefor-
`mation of T1 black holes, which are considered compat-
`ible with areas of axonalloss. The treatment also slowed
`the progression of disability and had a protective effect
`on atrophy.
`A mechanism independent of demyelination may be
`responsible for progressive MS. The magnetic resonance
`imaging marker that correlates best with disability is the
`T1-hypointense lesion load. We proposethat pulsed IVMP
`therapy may have axonalprotective effects. This may be
`related to enhanced remyelination and consequential axo-
`nal protection.° Direct neuroprotective effects of cortico-
`steroids have been observed in animal experiments and
`are partially explained by their trophic and proliferative _
`effects on astrocytes. Steroids also suppress nitric oxide
`levels and attenuate the aberrant expression ofcertain pro-
`teins that are indicators of abnormal synaptogenesis, de-
`nervation, and muscle atrophy.
`
`_
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`ARCH NEUROL/VOL61, JULY 2004
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`“Improvement orworsening was defined
`function at the initiation of IVMP treatmentto that at
`
`iewesaborpaesteeeeMinn)neurologicexaminationresultscomparing
`chronicprogressiveformofmultiplesclerosis. EurNeurol, 1995;35;193-198,
`The fact that certain neurologicfunctionsim-
`4 Bergamaschi R, VersinoM, Raiola E,Citterio A, Cosi V. High-dose methyl-
`proved in our study (spasticity and motor weakness),
`prednisoloneinfusionsin
`g
`1 chronic progressive multiplesele-
`
`whereas othersdid not (ataxia and bladder dysfunc-
`3. twednoyRudickRA,De MasiR,etal. EffectsofIV methylprednisolone
`rosis
`patients:oneyearfollow-up.ActaNeurol (Napoli). 1993;15;33-43.
`tion), argues againstaplacebo effect of IVMP. We con-
`on brain atrophyin relapsing-remitting MS. Neurology. 2001,57:1239-1247,
`cludethata large, long-term, placebo-controlled, double-
`6, PavelkoKD, vanEngelen BG,Rodriguez M. Accelerationintherate ofCNS
`blinded phase 3 study of pulsed IVMPtherapyin
`ooo in lysolecithin-induceddemyelination.JNeurosci. 1998;18:
`
`498-2505.
`progressive MSis warranted.
`
`Istvan Pirko,MD
`Moses Rodriguez, MD
`
`This study wassupported by grants RO1-NS24180, RO1-
`NS32129, ROI-NS38468 from the National Institutes of
`Health, Bethesda, Md.
`Correspondence:Dr Rodriguez,Department of Neu-
`rology,MayoaeRochester,MN55905
`(rodriguez.mBea
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`Comparison of Magnetic Resonance
`Imaging Abnormalitiesin Japanese
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