Abstract
Background: IV methylprednisolone (IVMP) has been used to treat relapses in patients with relapsing-remitting (RR) MS, but its effect on disease progression is not known. Furthermore, there are no data on the impact of IVMP on T1 black holes or whole-brain atrophy. Objective: To determine the effect of IVMP on MRI measures of the destructive pathology in patients with RR-MS and secondarily to determine the effect of IVMP on disability progression in patients with RR-MS. Methods: The authors conducted a randomized, controlled, single-blind, phase II clinical trial of IVMP in patients with RR-MS. Eighty-eight patients with RR-MS with baseline Expanded Disability Status Scale (EDSS) scores of ≤5.5 were randomly assigned to regular pulses of IVMP (1 g/day for 5 days with an oral prednisone taper) or IVMP at the same dose schedule only for relapses (IVMP for relapses) and followed without other disease-modifying drug therapy for 5 years. Pulsed IVMP was given every 4 months for 3 years and then every 6 months for the subsequent 2 years. Patients had quantitative cranial MRI scans at study entry and after 5 years and standardized clinical assessments every 4 to 6 months. Results: Eighty-one of 88 patients completed the trial as planned, and treatment was well tolerated. Baseline demographic, clinical, and MRI measures were well matched in the two study arms. Patients on the pulsed IVMP arm received more MP than patients on the control arm of the study (p < 0.0001). Mean change in T1 black hole volume favored pulsed IVMP therapy (+1.3 vs +5.2 mL; p < 0.0001), as did mean change in brain parenchymal volume (+2.6 vs −74.5 mL; p = 0.003). There was no significant difference between treatment arms in the change in T2 volume or annual relapse rate during the study. However, there was significantly more EDSS score worsening in the control group, receiving IVMP only for relapses. There was a 32.2% reduction (p ≤ 0.0001) in the probability of sustained EDSS score worsening in the pulsed MP arm compared with the relapse treatment arm. At the end of the study, EDSS was better in the pulsed MP group (1.7 vs 3.4; p < 0.0001). Prolonged treatment with pulsed IVMP was safe and well tolerated; only two patients dropped out for toxic side effects over 5 years. Conclusions: In patients with RR-MS, treatment with pulses of IVMP slows development of T1 black holes, prevents or delays whole-brain atrophy, and prevents or delays disability progression. A phase III study of IVMP pulses is warranted.
During the past two decades, use of IV methylprednisolone (IVMP) for MS relapses has gained increasing acceptance.1-4⇓⇓⇓ There is general consensus that IVMP hastens recovery from MS relapses. For this reason, it is considered the standard treatment for relapses of MS.
There is some suggestion that MP treatment may change the natural history of relapsing-remitting (RR) MS. The results of the Optic Neuritis Treatment Trial (ONTT)5-7⇓⇓ suggested that IVMP delays the development of clinically definite MS following optic neuritis. The ONTT generated considerable controversy in the neurologic community because the results were not anticipated in advance of the study. Also, it was unclear whether the ONTT results could be generalized to clinically isolated syndromes other than optic neuritis or to RR-MS. To date, there have been no double-blind, placebo-controlled clinical trials that have clarified the efficacy of IVMP as a disease-modifying therapy in RR-MS.
The only study to determine whether pulses of IVMP changed the natural history of MS was performed in patients with progressive MS.8 It was a double-blind, dose-comparison phase II study of bimonthly IVMP pulses in patients with secondary progressive (SP) MS. Whereas there was no significant treatment-related difference in the primary outcome (the proportion of patients with sustained Expanded Disability Status Scale [EDSS] score worsening), a beneficial effect was detected with the high-dose regimen as measured by the preplanned secondary analysis, a comparison of time to onset of sustained progression of disability. The authors concluded that the results were adequately encouraging to warrant a phase III trial of corticosteroids in SP-MS.
Several studies indicated that IVMP produced a rapid reduction in gadolinium enhancement.9-13⇓⇓⇓⇓ A serial study using gadolinium-enhanced MRI scans after IVMP treatment for acute relapses demonstrated that lesions frequently appeared within 1 month despite continued clinical improvement.14 In another study, it was shown that the effect of IVMP on gadolinium enhancement persisted for an average of 9.7 weeks.15 Two recent studies16,17⇓ reported that the effect of pulsed IVMP on gadolinium enhancement and inflammation was dose dependent and lasted for up to 6 months.
The long-term quantitative effect of IVMP on conventional and unconventional MRI parameters is unknown. Results of several cross-sectional and longitudinal studies18,19⇓ have shown weak or no correlation between T2 lesion load and clinical disability, in part because of the nonspecific nature of T2 lesions and lack of correlation with specific histopathologic abnormalities.20,21⇓ More recently, MRI measures of brain atrophy22-26⇓⇓⇓⇓ and T1 black holes27,28⇓ have been used as surrogate markers in monitoring destructive pathologic processes that most likely relate to MS disease progression. There are no published data about the effect of MP pulses on the accumulation of T2 and T1 lesion volumes or on the changes of brain parenchymal volumes.
Several longitudinal studies on brain atrophy in patients with MS22-26⇓⇓⇓⇓ established that the loss of brain parenchyma is principally a disease-dependent phenomenon. The pathologic processes responsible for atrophy are uncertain, but a combination of demyelination and axonal loss could be hypothesized. There may also be a contribution from reduced axonal diameter and tissue contraction from astrogliosis. To understand the nature of corticosteroid-induced brain atrophy in other non-CNS diseases, it has been suggested that the action of steroids could be twofold: steroid-induced protein catabolism and reduction of water due to the decreased vascular permeability. In the first case, the effects could be systemic and induced by long-term treatment, whereas in the second, there could be cerebral dehydration with short-term treatment or rapid dose-regimen changes. The latter hypothesis has been confirmed by several experimental studies that examined electrolyte balance and changes of osmolarity in humans.29,30⇓
There are no data related to the relationship between long-term corticosteroid treatment and brain atrophy in patients with MS. Patients with the most active disease have higher rates of brain atrophy. As the same patients receive more frequent treatment with corticosteroids, the relative contributions of MS disease activity and possible steroid-induced brain atrophy have not been determined. Clarifying this issue is of great importance for two main reasons: 1) if the chronic use of corticosteroids is neurotoxic, it may contribute to progressive brain atrophy in patients with clinically active MS; and 2) if corticosteroids accelerate brain atrophy, alternative therapy for relapses would be highly desirable.
We conducted a randomized, controlled, single-blind, phase II clinical trial of IVMP to determine the effect of IVMP on MRI lesions and brain atrophy. The effect of pulsed IVMP therapy on conventional and unconventional MRI quantitative markers of the destructive pathology (T2 and T1 lesion volume and brain parenchymal volume changes) was compared with the results obtained in control patients who received IVMP only at the time of clinical relapses. A secondary objective of the study was to assess whether pulsed IVMP therapy modified the clinical course of RR-MS.
Materials and methods.
Patients.
Participation in the study was considered in 126 consecutive unselected patients affected by clinically definite MS according to the diagnostic criteria proposed by Poser et al.,31 who were seen in routine follow-up at the Center for the Diagnosis and Therapy of MS operating in the Department of Clinical Medicine and Neurology of the University of Trieste (Italy). Inclusion criteria were as follows: clinically definite MS, RR disease course, aged 18 to 60 years, disease duration of 1 to 10 years, EDSS score of ≤5.5,32 and written informed consent from all the patients. Exclusion criteria were concurrent exacerbation or progression of the disease and steroid treatment in the 3 months preceding the study entry, immunomodulating and immunosuppressive treatment in the 2 years preceding study entry, preexisting concomitant disorders and conditions that can cause brain atrophy (e.g., neurodegenerative disorder, cerebrovascular disease, positive history of alcohol abuse), and positive history for recurrent infections or psychiatric disorders that could worsen with corticosteroid treatment. RR disease was defined as the presence of unequivocal relapses with full or partial recovery but without definite disease progression during the periods between relapses. From 126 consecutive unselected patients screened for the study, 90 patients satisfied entry criteria. These patients had an initial neurologic, EKG, chest radiograph, and complete routine laboratory examination. Female patients had pregnancy tests, as appropriate. Two patients were excluded owing to abnormal laboratory test results. The remaining 88 patients (60 women and 28 men) were enrolled in the study (figure 1).
Figure 1. Trial profile. IVMP = IV methylprednisolone.
Intervention.
The patients were randomly assigned to receive either regular pulses of IVMP (1 g/day for 5 days with an oral prednisone taper) and the same treatment for relapses as required (pulsed IVMP) or IVMP at the same dose schedule only for relapses (IVMP for relapses). Pulsed IVMP was given every 4 months for 3 years and then every 6 months for the subsequent 2 years. Forty-three cases were assigned to the pulsed IVMP arm, and 45 cases were assigned to the IVMP for relapse arm. Each IV pulse was followed by prednisone administered orally starting on day 6 and concluding on day 9. The tapering dose of prednisone was initiated at 50 mg for 2 days followed by 25 mg for 2 days. Ranitidine 300 mg was given each evening.
Randomization method.
Conduct of the study.
The study design was planned as a randomized, controlled, single-blind, phase II clinical trial of IVMP in which the baseline MRI results were to be compared with those at the end of the study. Conventional and unconventional short- and long-term quantitative MRI measures have a high sensitivity in detecting pathologic activity in RR-MS over time.20,22,25,28⇓⇓⇓ Randomization was accomplished using simple block randomization in groups of four. Treatment assignment was randomly generated by the unblinded study statistician who had no contact with study subjects. Clinical data were collected every 4 months over the first 3 years and every 6 months in the following 2 years. At each scheduled visit, an EDSS score was determined by the same examiner, the patients provided a history of side effects, and laboratory testing was conducted. Additional visits were conducted in the event of a relapse, disease progression, or when requested by the patient. During the study, symptomatic therapy not interfering with IVMP was permitted. Patients and clinical examiners were not blinded to the treatment assignment during the study, but radiologists conducting image analysis were blinded to treatment assignment. Bone density studies were not done on the entire patient population at baseline. However, bone density measures were done on many patients during the study but without standardized study protocol.
In advance of the study, the following were defined as reasons for removing a patient from the protocol: 1) a personal decision on the part of the patient not to complete the first 3 years of the study, 2) toxic side effects to such an extent that it was inadvisable to continue steroid treatment, 3) the onset of diseases related to corticosteroid treatment or not related to corticosteroid treatment but such as to make it dangerous, 4) the onset of disorders or conditions other than MS that can cause brain atrophy, 5) protocol deviations related to the planned interval between pulses of IVMP, 6) the use of immunomodulating or immunosuppressive disease-modifying treatment, and 7) abnormal laboratory test results on three successive determinations.
Four patients in the pulsed IVMP arm and three patients in IVMP for relapse arm met one of these criteria and were subsequently excluded from the analysis.
Outcome measures.
MRI.
The primary end point of the study was the treatment effect on quantitative MRI parameters (T2 and T1 lesion volume and brain parenchymal volume changes).
Image acquisition.
Brain MRI was performed at baseline and at the end of the study on a Philips Gyroscan S 15 ACS II 1.5 T unit (Philips International, Eindhoven, the Netherlands). Axial images of the brain were obtained with 5-mm slice thickness using proton density (PD)/T2-weighted spin echo (repetition time [TR] 2,709 ms/echo time [TE] 20 to 80 ms) and unenhanced T1-weighted conventional spin echo (TR 600/TE 27) sequences. A matrix of 179 × 256 pixels was used for a total of 24 sections. Field of view was 220 mm. Patients were positioned in the magnet according to European Community guidelines.33 The MRI examinations were performed on the same MRI unit at baseline and at the end of the study. At the end of the 5-year follow-up, the final MRI scan was done a minimum of 60 days after the last steroid treatment to avoid any transient effects of steroids on MRI results. The median intervals between the final steroid treatment and the final MRI scan were 69 (Q1-66, Q3-78) days in the pulsed IVMP arm and 135 (Q1-123, Q3-160) days in the IVMP for relapse arm (p < 0.001).
Image analysis.
Two investigators, blinded to the patients’ clinical characteristics and clinical status, performed the image analysis at baseline and at the end of the study on a Sun Ultra 5 Promo workstation (Sun Microsystems, Mountain View, CA). MRI data were transferred directly to the computer system of the medical imaging processing group by a home-developed network transferring system. Lesion volume was calculated using highly reproducible semiautomatic local thresholding technique for lesion segmentation.34,35⇓ The lesions were first outlined on PD-weighted hard copies on each axial slice (T2-weighted scans were always used to increase confidence in lesion detection). The measurements of lesion area were then performed on computer-displayed images by the same observers, keeping the marked hard copies as a reference. Reproducibility was calculated as a coefficient of variation (CV; 100% × SD/mean) between the repeated measurements by two investigators blinded to patient details and diagnosis. To determine the reproducibility of the method, we repeated five measurements on the same image sets of 10 patients with MS. The mean CV for T2 lesion volume was 3.1% (range 2.1 to 4.5%) for interobserver reproducibility and 2.7% (range 1.8 to 4.5%) for intraobserver reproducibility. A conservative approach for the calculations of lesions in T1-weighted images was used. A hypointense lesion was defined as any region visible on the T1-weighted sequence with a low signal (short TR, short TE) intensity between those of the CSF and gray matter and corresponding to a region of high signal intensity on the T2-weighted sequence (long TR, long TE). The mean CV for T1 lesion volume was 4.5% (range 2.4 to 6.7%) for interobserver reproducibility and 3.9% (range 1.9 to 6.5%) for intraobserver reproducibility. Lesions were delineated as regions of interest, and the volume was simply calculated for each sequence by multiplying the total region-of-interest area by the slice thickness. The results are expressed in milliliters.
The evaluation of brain atrophy was performed on T1-weighted conventional spin echo sequences measuring the brain parenchymal volume. An interactive home-developed program that incorporates the semiautomatic and automatic segmentation processes was employed for the measurements. First, the external edge of whole-brain parenchyma was determined by semiautomatic iterative morphologic scalping of the external brain surface. Then, an automatic segmentation of the CSF spaces and brain parenchyma was performed using a knowledge-based automatic segmentation algorithm for histogram thresholding analysis. This segmentation process creates automatically CSF- and brain parenchyma-only images and calculates the volumes of brain parenchyma and CSF. To determine the reproducibility of the method, 10 patients with MS and 10 sex- and age-matched healthy volunteers had two separate MRI scans within 1 week. The mean CV for brain parenchyma volumes in this group was 0.39% (range 0.09 to 0.56%) for interobserver reproducibility and 0.37% (range 0.09 to 0.52%) for intraobserver reproducibility. This level of reproducibility was in agreement with those in recently published studies using different segmentation measurement techniques where inter- and intraobserver variability was typically estimated between 0.19 and 1%.24-26⇓⇓
Disability progression.
A secondary end point of the study was the disability progression, which was defined as sustained EDSS score worsening. We required at least a 1.0-point worsening from baseline for patients who entered at or below an EDSS score of 5.0 or a 0.5-point worsening from baseline for patients who entered at an EDSS score of 5.5. Worsening was required to persist for at least two consecutive 4-month visits during the first 3 years of the study or at least two consecutive 6-month visits during the fourth and fifth years of the study. We determined both the proportion of patients in each arm who met these criteria and the time to the beginning of sustained disability progression. We also determined the absolute EDSS score changes between baseline and final visit (year 5) in the two arms of the study.
Relapse-related variables.
Relapses were defined as the appearance or reappearance of one or more symptoms, attributable to MS, accompanied by objective deterioration on neurologic examination, lasting at least 24 hours, in the absence of fever, and preceded by neurologic stability for at least 30 days and in the absence of steroid withdrawal within 60 days of the new event. We determined the annualized relapse rate, the time to first relapse, and the proportion of patients who had clinical relapses.
Statistical analysis.
Statistical analysis was performed by using the Statistical Package for the Social Sciences (SPSS, version 10.0, Chicago, IL). Only patients with complete follow-up data (fully evaluable cases) were analyzed. For comparisons between the groups, the χ2 test, the Mann–Whitney U test, and the Wilcoxon rank sum test were used, as appropriate. Within-patient change from baseline MRI measures was tested using paired t-test. The relationship between MRI and clinical variables at baseline and at the end of the study was investigated by Spearman rank correlation coefficients corrected for multiple comparisons. Multiple stepwise linear regression analysis (forward selection model) was used to evaluate the relationship between percentage change in MRI variables and baseline or on-study characteristics. Various models were created to identify potential predictors of brain atrophy over the study. The minimum significance level for entry and for staying in the equation was 0.05. Time to onset of sustained EDSS progression and probability of remaining progression-free were analyzed using the Kaplan–Meier method with significance determined by a log rank test. All p values were based on two-tailed tests.
Results.
Patients.
Baseline characteristics were comparable in the two treatment arms (table 1). Patients were approximately 32 years of age and had a mean disease duration of 5.6 to 5.8 years. Median EDSS score was 2.0 in both treatment arms, and MRI parameters were well matched. Baseline mean brain parenchymal volume was 1,255 mL in the pulsed MP arm and 1,264 mL in the relapse treatment arm.
Characteristics of patients with relapsing–remitting MS at baseline
Eighty-one patients (92%) completed the 5-year study protocol as planned, including 39 (92.8%) in the pulsed MP group and 42 (93.3%) in the relapse treatment control group. Seven patients dropped out of the study: four (9.3%) in the pulsed MP group and three (6.7%) in the control group. In the pulsed MP group, the treatment was discontinued for adverse events and laboratory abnormalities (two patients) and for deviation from the protocol and patient decision (two patients), whereas in the control group, one patient discontinued the treatment for progression of the disease and two patients for deviation from the protocol and patient decision.
Patients in the pulsed IVMP arm received an average of 67.6 g (SD 12.2 g) of MP and patients in the IVMP for relapse arm received 20.3 g (SD 20 g) (p < 0.0001).
MRI variables.
MRI characteristics at the end of the study showed significant differences in favor of the pulsed MP arm (table 2). Both treatment arms showed a significant increase in T2 volume between baseline and year 5, and there were no significant differences in T2 lesion volume between the two treatment arms at the 5-year follow-up. Mean change in T2 lesion volume was +11.6 mL (95% CI +8.2 to +15.9; 122.9%) for the pulsed MP group and +17.5 mL (95% CI +12.6 to +23.6; 169.9%) for the control group (p = NS).
Characteristics of patients with relapsing–remitting MS at end of study
However, there were significant end-of-study differences in T1 lesion volume and brain parenchymal volume. Both groups demonstrated significant increases in T1 lesion volumes over the study, but this was significantly less in the pulsed MP group. The mean change in T1 lesion volume was +1.3 mL (95% CI +0.92 to +1.78; 92.8%) in the pulsed MP group and +5.2 mL (95% CI +3.7 to +7; 335%) in the control group (p < 0.0001). At baseline, T1 lesion volumes represented a mean of 14.6% of T2 lesion volumes in the pulsed MP group and 14.9% in the control group, whereas at the end of the study, T1 lesion volumes were 12.6% of T2 lesion volumes in the pulsed MP arm and 24.1% for the relapse MP arm (p < 0.0001).
Patients in the pulsed MP arm did not develop brain atrophy during the study. Absolute change in brain parenchymal volume from baseline was +2.6 mL (95% CI +1.8 to +3.6; +0.2%) in the pulsed IVMP arm and −74.5 mL (95% CI −53.7 to −100.6; −5.9%) in the relapse treatment arm (p = 0.003).
There were no significant correlations between baseline MRI and clinical variables in either group. At baseline, T2 and T1 lesion volumes correlated with brain parenchymal volumes with similar magnitude (r = 0.37 to 0.43; p = 0.01 to 0.004). Correlations between MRI change and clinical changes according to the treatment arm are shown in table 3. There was a significant but weak correlation between T2 and T1 lesion volume changes over 5 years in the pulsed MP group and a stronger correlation in the relapse treatment group. A correlation between T2 lesion volume changes and brain parenchymal volume changes was present only in the relapse treatment group, indicating that the decrease of brain parenchymal volume and the increase of T2 lesion volume occurred separately in the pulsed MP group. There was also a somewhat stronger correlation between change in T1 lesion volume and change in brain parenchymal volume in the relapse treatment group compared with the pulsed MP group. At the end of the follow-up, we demonstrated an inverse relationship between total dose of MP and brain parenchymal volume change and between EDSS score change and brain parenchymal volume change.
Correlations between changes in MRI and clinical characteristics according to treatment arm
Multiple regression models were used to evaluate the relationship between the baseline clinical characteristics and percentage change in MRI parameters over 5 years. In the pulsed MP group, none of the baseline clinical or MRI parameters was significantly correlated with the subsequent 5-year change in brain parenchymal volume. In the relapse treatment group, baseline T1 lesion volume was correlated with subsequent 5-year change in brain parenchymal volume (r = −0.62, p < 0.0001). Multiple regression models were also used to evaluate the relationship between clinical and MRI changes in the two groups and the percentage change in brain parenchymal volume over the 5 years of the study. In the pulsed MP group, T1 lesion change was correlated with brain parenchymal volume change (r = −0.48, p = 0.003). In the relapse treatment group, T2 and T1 lesion volume changes were related to brain parenchymal volume change (r = −0.88, p < 0.0001; and r = −0.92, p < 0.0001).
Clinical efficacy variables.
Clinical characteristics of the study participants were different in favor of pulsed IVMP at the end of the study (see table 2). There were no significant differences between the two groups in the number of patients who concluded the study, the number of relapses during the study, the annualized relapse rate over the study, or the time to first relapse. Thirty-one patients in the pulsed MP group (79.5%) and 39 patients in the relapse treatment control group (92.6%) experienced clinical relapses during the study (p = 0.009). The number of steroid interventions in the relapse-only group was higher than in the pulsed MP group (4.1 vs 1.8; p = 0.001). At the end of the study, however, the pulsed MP group had lower EDSS compared with the relapse treatment group (1.7 vs 3.4; p < 0.0001). Time to sustained EDSS progression was longer in the pulsed IVMP arm (p < 0.0001) (figure 2). There was a 32.2% reduction (p < 0.0001) in the probability of sustained EDSS worsening in the pulsed MP arm compared with the relapse treatment arm (see figure 2). The beneficial effect of pulsed IVMP became evident after 8 months of treatment and was evident through month 42 (see figure 2). Eight patients developed confirmed SP-MS during the study: one (2.6%) in the pulsed MP group and seven (16.3%) among the control subjects (p ≤ 0.0001).
Figure 2. Time survival curve to the onset of sustained Expanded Disability Status Scale score worsening. Log rank test p < 0.001. MP = methylprednisolone. + = pulse MP group; □ = control group.
Safety and tolerability.
Only two patients in the pulsed IVMP arm dropped out of the study for serious adverse events. In one patient, IVMP was discontinued after the fourth pulse when the patient developed acute glomerulonephritis. The second patient was removed from the study after the fifth IVMP pulse for severe osteoporosis. Almost all the patients had “metallic taste” sensation during MP treatment. In both groups, minor short-term adverse events (insomnia, pyrosis, anxiety–nervousness, constipation, acneiform rash, and polyphagia) were frequent and well tolerated and did not require treatment. Long-term adverse events were uncommon but included osteoporosis (2), arterial hypertension (1), and recurrent herpetic infections (1). They did not require discontinuation of the planned therapy and were treated with appropriate symptomatic therapy.
Discussion.
One of the important early aims of this study was to determine whether corticosteroids induced brain atrophy. As a CNS disease, however, MS is not the ideal model for studying this possible effect. However, longitudinal studies in patients with MS have demonstrated progressive brain atrophy in patients with RR-MS, which presumably results from the early pathologic processes in MS brain.36 Furthermore, some studies22-26⇓⇓⇓⇓ have established that the annual progression of brain atrophy is similar among specific MS types and that it can be reduced by disease-modifying therapy.37 Therefore, the effect of corticosteroids on brain atrophy in MS was postulated to be determined by the net effect of treatment on the pathologic processes together with the direct effect of corticosteroid treatment on parenchymal volumes. To determine the net effects of pulsed MP therapy on MRI markers, we compared the baseline data in the pulsed MP and control groups with those obtained after 5-year follow-up.
Although well matched at baseline, both groups had significantly increased T2 and T1 lesion volumes evident on the year 5 MRI scans. However, the increase was more pronounced for the control group, especially for T1 lesion volumes (p ≤ 0.0001). Whereas there was not a significant difference between the T2 lesion volumes in the two groups, there was a trend suggesting increased T2 lesion accumulation in the control group. These findings are consistent with the correlation analyses, which demonstrated similar correlation coefficients between the two groups at baseline but stronger correlations in the control group at the end of the study, indicating that the changes of lesion volumes went on simultaneously in this group of patients. On the contrary, in the pulsed MP group, we showed almost the same correlation coefficients between T2 and T1 lesion volume changes both at the baseline and at the end of the study and a lower mean percentage change in T2 compared with T1 lesion volume over 5 years (122.8 versus 92.8%), suggesting that pulsed MP therapy has a favorable effect on the accumulation of T1 lesions (“black holes”). As regards the change in T2 and T1 lesion volumes during the study, the only published data comparable with our 5-year results are T2 lesion area changes from the Betaseron RR-MS trial,38 which demonstrated an increase in 99% of placebo-treated and in 11.3% of interferon-α1b-treated patients over 5 years.
Patients in the control arm developed significant brain atrophy evident on the year 5 MRI scans. Mean percentage change of brain parenchymal volume was −5.9% in 5 years, which is consistent with the annual rate of brain atrophy reported in longitudinal natural history studies.22-26⇓⇓⇓⇓ Moreover, at the end of the study, the control group showed significant differences in brain parenchymal volumes compared with the pulsed MP group. The analyses indicated that decreasing brain parenchymal volume and increasing T2 and T1 lesion volumes were correlated in the control arm. On the contrary, those in the pulsed IVMP arm did not develop brain atrophy during the study. This finding suggests a “protective” effect of pulsed MP on the development of brain atrophy. The results of this study indicate that the development of brain atrophy in patients with MS with high clinical and MRI disease activity is disease related and that the net effect of pulsed MP is protective rather than neurotoxic. A protective effect of pulsed MP therapy is also supported by the correlation analysis, which revealed an inverse relationship between the brain parenchymal volume changes and the total dose of IVMP (r = 0.35, p = 0.02). This indicated that patients who received higher total doses of IVMP showed the lowest changes of brain parenchymal volume during the study.
Our decision to administer pulsed IVMP therapy every 4 months in the first 3 years of the study and biannually in the following 2 years was based on the results of various MRI studies15-17⇓⇓ demonstrating that IVMP may have dose-dependent benefits for as long as 6 months. The data suggest that IVMP affects early events in lesion formation or lesion propagation in addition to more transient beneficial effects on established areas of inflammation and demyelination. Studies utilizing magnetization transfer and diffusion-weighted imaging suggest that newly enhancing lesions arise in areas with abnormal tissue characteristics occurring in the months before the occurrence of a detectable enhancing lesion.39-41⇓⇓ Therefore, pulsed IVMP could favorably affect events responsible for early microscopic pre-enhancing lesion formation in the normal-appearing white matter. If this hypothesis is true, pulsed IVMP administration might exert a “surveillance” effect, inhibiting formation of microscopic foci of demyelination and enlargement of preexisting microscopic lesions into macroscopic ones.
Our study indicates that pulsed IVMP has a beneficial effect on whole-brain parenchyma, preventing progressive brain atrophy. Several authors37,42,43⇓⇓ suggested that gadolinium-enhancing inflammatory lesions initiate the process that ultimately leads to cerebral atrophy, whereas others26 concluded that the enhanced T1 lesions were not a significant factor in the pathogenesis of whole-brain atrophy in RR-MS. It is probable that frequent pulses of IVMP, which result in early dramatic reduction of gadolinium-enhancing lesions, indirectly exert a “protective” effect on the development of brain atrophy. However, our findings demonstrated that the pulsed IVMP therapy failed to stop the accumulation of burden of disease (T2 lesion volume) in the pulsed MP group. This observation is not explained, but the finding of decreased T1/T2 ratios in the pulsed steroid group suggests that T2 accumulation had a differential consequence on brain tissue integrity in the two study arms.
We did not find a significant difference between the two groups in the mean number of relapses, mean annual relapse rate during the study, or time to the first relapse, proportion of patients in each group who had clinical relapses, and number of steroid interventions in the relapse treatment control group. In contrast, disability assessed by EDSS score over 5 years improved slightly in the pulsed MP group but deteriorated significantly in the control group. Time to sustained progression in EDSS score was significantly lengthened in the pulsed MP group (see figure 2). The beneficial effect of pulsed IVMP became evident after 8 months of treatment and was evident through month 42. Probably, the failure to find a treatment effect after 42 months in both treatment groups was conditioned by the different time schedule of the visits in the first 3 years of treatment (every 4 months) and in the subsequent 2 years (every 6 months). The correlation analysis revealed an inverse relationship between the brain parenchymal volume changes and the EDSS score changes (r = 0.35, p = 0.02) in the pulsed MP group, indicating that patients who remained stable in their brain parenchymal volumes also did not progress in the EDSS. At the end of the study, the EDSS changes correlated with the T1 and T2 lesion volume and brain parenchymal volume changes in the control group (r = 0.42, p = 0.013; r = 0.40, p = 0.017; and r = -0.38, p = 0.025).
The mechanisms responsible for parenchymal atrophy in MS are uncertain, but the most accepted opinion is that the causative mechanism is a combination of demyelination and axonal loss.44,45⇓ Different pathologic and MRI studies27,28⇓ demonstrated recently that the T1-hypointense lesions represent areas of more severe axonal damage. Therefore, the pathologic substrate of the progressive development of brain atrophy and the accumulation of black holes seem to be predominantly axonal damage that leads irreversibly to neuronal dropout. Our findings showed that the beneficial effect of pulsed IVMP therapy was more evident on these two MRI measures. One could hypothesize that corticosteroid-induced remyelination46-48⇓⇓ prevents early axonal loss and subsequently the accumulation of black holes and progression of brain atrophy. Recently, a strong correlation between the increase in T1-hypointense lesion load, the decrease of brain parenchymal volume, and the increase in disability was reported.22-28⇓⇓⇓⇓⇓⇓
In our study, the control arm worsened substantially over 5 years in both clinical and MRI parameters. Possibly, the substantial stability of the disability status in the pulsed IVMP arm could be explained by a beneficial effect of pulsed IVMP on the MRI measures (T1 lesion volume and brain parenchymal volume) related to axonal loss. Our study did not demonstrate that pulsed IVMP therapy was effective on measures of disease activity (annual relapse rate and T2 lesion volume). The pathologic processes responsible for accumulation of disability progression and inflammatory activity in the earliest phase of the disease could be somehow influenced by pulsed IVMP therapy.
The current study established that the prolonged use of pulsed IVMP was safe and well tolerated, as only two patients dropped out for toxic side effects over 5 years. Our on-study evaluation of short-term side effects demonstrated that almost every pulsed treatment was accompanied by minor adverse events, which did not requested any specific symptomatic treatment.
Over 5 years, adverse effects with repeated pulses occurred in only four cases. It has been reported8 that over 2 years, only one patient in the IVMP group dropped out of the study. In our study, only two cases developed osteoporosis after the fourth year of treatment, but they decided to carry on the study with the addition of symptomatic therapy. However, during the study, there was no systematic effort to determine whether patients developed osteoporosis, so the true incidence of osteoporosis may be substantially higher than that reported.
Placebo-controlled, double-blind, randomized trials are needed to more definitively establish the role of pulsed IVMP in RR-MS as a disease-modifying therapy, either alone or in combination with the standard disease-modifying drugs interferon-β and glatiramer acetate.
- Received October 31, 2000.
- Accepted May 15, 2001.
References
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