Using Gadolinium—enhanced Magnetic
`Resonance imaging Lesions to Monitor
`Disease Activity in Multiple Sclerosis
`
`Henry F. McFarland, MD,‘ Joseph A. Frank, MD; Paui S. Albert, PhD,i Mary E. Smith, MD,“
`Roland Martin, MD," Jonathan 0. Harris, MD,’ Nicholas Patronas, MD,:§
`Heidi Maloni, RN,‘ and Dale E. McFarlin, MD‘
`
`
`The highly variable clinical course and the lack of a direct measurement of disease activity have made evaluation of
`experimental therapies in multiple sclerosis (MS) difficult. Recent studies indicate that clinically silent lesions can be
`demonstrated by magnetic resonance imaging (MRI) in patients with mild relapsing-remitting MS. Thus, MRI may
`provide a means for monitoring therapeutic trials in the early phase of MS. We studied 12 patients longitudinally for
`12 to 21 months with monthly gadolinium (GED-enhanced Mills. The data have been used to identify the most effective
`design of a clinical trial using Gd-enhanced lesions as the outcome measure. Frequent (>i/mo) Gd-enhancing lesions
`were observed in 9 of the 12 patients, indicating that the disease is active even during the early phase of the illness.
`The frequency of the lesions was not constant; there was marked fluctuation in lesion number from month to month.
`However, the magnitude of the peak number of lesions and the frequency of the peaks varied among patients. Because
`of this variability, the most effective use of Gd—enhancing lesions as an outcome measure in a clinical trial was a
`crossover design with study arms of sufficient duration to allow accurate estimation of lesion frequency. Monitoring
`(id-enhancing lesions may be an effective tool to assist in the assessment of experimental therapies in early MS.
`McFarland HF, Frank JA, Albert PS, Smith ME, Martin R. Harris ]0, Patronas N, Maloni H,
`McFarlin DE. Using gadoliniumenhanced magnetic resonance imaging lesions to monitor
`disease activity in multiple sclerosis. Ann Neurol 1992;32:758—766
`mm
`
`The clinical variability in multiple sclerosis (MS) has
`cur in the cerebrum in clinically stable patients {9, 10].
`made design and assessment of clinical
`trials difficult
`In addition, use of gadolinium (Gd) with Tl-weighted
`[1}. Although there is increasing interest in treating
`imaging can identify areas of breakdown in the blood-
`patients before significant disabiiity occurs, the inability
`brain barrier. These areas of enhancement seem to rep—
`to predict the future course of the disease has made
`resent the initial stage of lesion development [12—15]
`assessment of the risk—benefit relationship difficult.
`and are probably associated with active inflammation
`Some patients will continue to have mild disease
`[14, 16}. Recent studies, including an initial report on
`throughout
`the course of the illness. Treatment of
`6 of the patients from our present study, indicate that
`these patients early in the course of the disease with
`frequent, new Cid-enhancing lesions occur in patients
`potentially toxic treatments may pose greater risk than
`without corresponding clinical changes [l7«-l9}. These
`the disease. Further complicating clinical trials has been
`findings indicate that MRI parameters and, in particu-
`the difficulty in measuring disease activity, which is
`lar, Gel—enhancing lesions, should be helpful in moni-
`usually asseSSed indirectly by measuring disability.
`toring disease activity in patients with MS and may
`Magnetic resonance imaging (MRI) is well established
`provide a suitable tool for assessing the effectiveness
`as the optimal imaging technique for the diagnosis of
`of clinical trials, particularly in patients with early, mild,
`MS [2—8}. and the presence of disease activity in the
`relapsing-remitting MS [1, 20].
`absence of clinical changes has been confirmed by re—
`Our previous investigation of patients with MS using
`cent MRI studies [9, 10]. Areas of increased signal
`(Ed-enhanced MRI suggested that the occurrence of
`on T2-weighted images, which reflect demyelination,
`enhancing lesions was not constant over time. Because
`inflammation. or edema [11}, have been shown to oc-
`the pattern of lesion occurrence affects the usefulness
`
`
`From the ’Neuroimmunology Branch anti the TBiornetry Branch,
`National Institute of Neurological Disease and Stroke, and the iDi-
`agnostic Radiology Department. Clinical Center, National institutes
`of Health. Bethesda. MD; and the §Depattrnent of Radiology.
`Georgetown University Medical Center. Washington. DC.
`
`Received Jan 8. 1992, and in revised form Apr 20 and ion 24.
`Accepted for publicationjun 28. 1992.
`Address correspondence to Dr McFarland. National institutes of
`Health, Building 10, Room 51516, Bethesda. MD 20892.
`
`758
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`Page 1 0f 10
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`Taéle I . Clinical Parameters of Patients Sit/died lay Serial Gadolr'niuwit-enhanced MRI
`
`Average No.
`(Ed-enhancing
`Lesions
`EDSS
`Years
`Age
`from
`Months
`—-—-———-—-—
`————-——-
`
`Patient
`(yr)
`Diagnosis
`Course
`Studied
`Start
`End
`Exacerbations
`Total
`New
`
`1
`2
`3
`4
`5
`6
`'I
`8
`9
`10
`11
`12
`
`44
`29
`41
`28
`28
`41
`38
`31
`38
`28
`43
`60
`
`2
`2
`5
`3
`2.5
`3.5
`16
`10
`2.5
`6
`9
`17
`
`EUR
`EUR
`RIR
`R/R
`R/R
`RJ'R
`RlR-CP
`R/R
`RJ'R
`R/R
`EUR
`CP
`
`19
`i9
`20
`19
`21
`20
`14
`1-4
`15
`12
`14
`12
`
`1.3
`2.0
`1.5
`1.5
`1.5
`3.5
`5.5
`1.5
`2.0
`6.5
`2.0
`6.0
`
`1.5
`2.0
`LS
`2.0
`1.5
`2.5
`6.0
`1.5
`2.5
`6.5
`2.0
`6.5
`
`0
`l
`1
`#1
`l
`1
`0
`2
`3
`1
`1
`0
`
`3.4
`0.5
`1.6
`5.0
`5.3
`5.6
`1.8
`5.6
`0.9
`8.0
`3.2
`0.1
`
`2.2
`0.2
`1.1
`31.1
`2.4
`3.3
`1.1
`3.5
`0.7
`5.9
`2.1
`0.1
`
`RJ'R = relapsing—remitting: C? : chronic-progressive.
`
`consistent with previous reports {15, 18]. Twenty-
`eight percent of the lesions were seen on 2 concurrent
`examinations, whereas 5% persisted for 3 months.
`None of the lesions persisred for more than 4 months.
`In general, lesions persisting for 2 months or longer
`were observed in patients with a large number of new
`enhancing lesions (Patients 5, 6, 8, and 10). Reen-
`hancement of lesions that were enhanced previously
`was observed in 5 patients. It is likely that reenhance—
`ment will be observed more frequently as patients are
`followed longer.
`The mean number of Cid-enhancing lesions per
`month varied among the 12 patients. Although 3 of
`the patients with relapsing-remitting disease (Patients
`2, 5, and 9) and both of the patients with chronic-
`ptogtessive disease (Patients 7 and 12) had an average
`of 2 or fewer new lesions per month, 4 of the patients
`with relapsing-tenutting disease (Patients 4, 6, 8, and
`10) had an average of 3 or more new lesions per
`month.
`
`Pattern of Lesion Occurrence
`As indicated, inspecrion of the frequencies of new enw
`hancing lesions indicated that the lesions were not oc-
`curring at a constant rate but tended to occur in bursts
`of increased lesion frequency. Figure 1 illustrates the
`fluctuating number of Cid-enhancing lesions in Patient
`4. By inspection, the pattern of lesion frequency in this
`patient had a cyclical trend. A suggestion of a similar
`cyclical pattern in lesion frequency was also observed
`in the ether patients. Consequently, the likelihood that
`the pattern of lesion occurrence was not random was
`assessed using Poisson regression models as described
`in Materials and Methods. In 6 of the 10 patients with
`relapsing-remitting MS, the total and new lesion data
`
`760 Annals of Neurology Vol 32 No 6 December 1992
`
`Page 3 0f 10
`
`fit a model employing a sinusoidal mean significantly
`better than a model using a constant mean (p < 0.01)
`(Fig 2). This finding indicates that the mean of the
`lesion frequency was net constant and that the lesions
`were not occurring with random frequency. Although
`not reaching statisrical significance, a sinusoidal trend
`in lesion frequency was also observed in 3 of the re-
`maining 4 patients (p < 0.06, 0.12, 0.121. The Poisson
`regression model with sinusoidal trends was used only
`as a means to describe the fluctuating nature of lesion
`frequency over short durations and to test for non-
`constancy in lesion frequency. The model was not in-
`tended as a definitive descriptiOn of lesion occurrence.
`Using the fitted curves, the period between the peaks
`in lesion frequency varied considerably and ranged
`from 2.1.
`to 12 months. The mean period between
`peaks in the patients showing a significant fit to a sinu—
`soidal curve was 6.2 and 5.9 months for all 10 patients.
`
`Correlation; Between Clinical Changer and
`Gal-enhancing Leriom
`the frequency of enhancing
`As reported previously,
`lesions seen on MRI did nor necessarily parallel clinical
`changes. Most notable was Patient 12, who despite
`continued clinical progression had only I enhancing
`lesion during 10 months of study. Because the clinical
`course demonstrated by Patient 12 may represent a
`unique form of MS (i.e., primary chronic-progressive
`MS) [18, 28, 29], the findings from this patient were
`excluded from the subsequent analysis.
`A dissociation between clinical change and enhanc-
`ing lesions in the cerebrum Was observed in the 11
`remaining patients. All had new enhancing lesions,
`often numerous,
`that occurred without new symp-
`toms or abnormalities on neurological examination.
`
`Page 3 of 10
`
`

`

`
`
`12
`
`10
`
`mm
`
`
`
`NumberofEnhancingLesions
`
`Patient 4
`
`4—1:-
`
`--o-- Toial Lesions
`-----o----
`New Lesions
`
`
`gunman-mu-
`
`
`
`
`Fig I . (A) Fluctuations in number of total and new Gd—
`mbana'ug [ariam in Patient 4'. (B) T] weighed pwrgaa'oiirz-
`farm MRI of Pan's”: 4 at mom}; I4. Four nprexenmn'w jliré:
`
`are 55mm: demonstrah'ng ”Marple enhancing Iaiam. (C) Tl-
`weighted pastgadolim'um MRI an! month 15. Fam' reprexentatiw
`dim Jbvwz'ng fla’uctibn in number afenbarzcing lasions.
`
`McFarland er 31: MRI Lesions in MS 761
`
`Page 4 of 10
`
`Page 4 of 10
`
`

`

`_—___—_m.._fi__—__—_.n_——«_me—o—-—————~——-—
`
`Patient 3
`
`Patient 4
`
`1!
`
`anuoncy - 2.1 mo.
`p I 0.01
`
`l
`H
`I
`I:
`L
`I
`I
`I
`o
`n
`I
`
`
`
`nasaswuuaumn
`Month
`
`Patient 6
`
`Patient 3
`
`Frequency - n5 mo.
`
`FrequIncy - 3.2 mo.
`p 1 0.01
`
`l'
`If
`Iw
`L
`I
`7
`a
`nI
`
`I
`H
`I
`I
`L
`I
`
`t
`o
`n
`
`Fuqulncy - 12.0 mo.
`9 I 0.01
`
`10
`
`I
`
`a
`
`‘
`
`2 n
`
`a
`
`12
`
`10
`
`8
`
`6
`
`4
`
`a n
`
`I!
`R
`I
`Ir
`L
`I
`I
`I
`o
`n
`I
`
`'
`H
`:
`L
`:
`I
`o
`3
`
`r
`N
`I
`w
`L
`I
`
`t
`a
`n
`a
`
`
`
`
`I
`Month
`
`Patient 10
`
`Patient 11
`
`uzaaawtzuwneon
`Mania
`
`Frequency - 4.2 mo.
`p < 0.01
`
`D
`
`2
`
`In
`
`Iv
`
`I
`
`10
`
`12
`
`1‘
`
`1!
`
`$8
`
`29
`
`2!
`
`
`
`Fig 2. Tbs objerwd number of new [axiom and thefflqzlemy of
`Atrium derirredfmm the belt fining Poisson regrem'an model with
`Jinmaidal friends. (A) p < 0.01. (B) p > 0.01.
`
`For example, Patient 1, who had a mean of 2.2 new
`Gd-enhancing lesions per month, was clinically stable
`throughout the 19-month study period. Each of the
`remaining 10 patients had one or more exacerbations
`(see Table 1). The clinical
`findings associated with
`these exacerbations could not be explained by the loca-
`tion of the new enhancing lesions in the cerebrum and,
`in most instances, were consistent with involvement of
`the spinal cord or the brainstem.
`
`762 Annals of Neurology Vol 32 No 6 December 1992
`
`Page 5 0f 10
`
`Page 5 of 10
`
`

`

`"WW
`
`Patient 1
`
`Patient 2
`
`Froqulncy - 4.9 m.
`
`vac—Iol'(-Ih o
`
`a
`
`a
`
`a
`
`1:
`m
`Month
`
`so
`
`2:
`
`12
`Fuqunncy - 6.3 mo.
`
`10
`
`o
`
`I‘
`
`2 D
`
`D
`
`i
`
`
`22
`
`’
`20
`
`'—'
`2
`
`i
`
`I
`
`I
`
`13
`1O
`Mnnlh
`
`14
`
`I.
`
`15
`
`can—nel-to:5
`
`Patient 5
`
`PatientQ
`
`.- H
`
`
`
`
`
`
`u0
`
`(I
`
`Frequlney - 8.8 mo. 1
`
` Ian—alr-£I2Q
`
`memy I (0 mo.
`
`N
`
`Ian—Ill'(I:‘
`
`0
`
`2
`
`I
`
`O
`
`l
`
`1C
`
`10
`
`18
`
`20
`
`22
`
`G
`
`2
`
`4
`
`8
`
`l
`
`‘2
`K)
`Month
`
`14
`
`1B
`
`1!
`
`2O
`
`22
`
`12
`10
`Mofllh
`
`
`Fig 2 (continued)
`
`Trig! Design Using Gd—mbemzhg Lesions as an
`Outcome Msuture
`
`Although it is reasonable to consider using Gel-enhanc—
`ing lesions as an outcome measurement in therapeutic
`trials, the fluctuations in lesion frequency nored herein
`indicate that there are patential difficulties with this
`approach. To explore the usefulness of the approach,
`we assessed the longitudinal MRI data obtained in this
`study using a statisdcal technique termed bootstrap anal-
`ysis, which involves repeated random resampling of the
`data. Using this technique, we calculated the required
`sample sizes for 2 trial designs: a parallel groups design
`and a crossover design. First, the sample sizes required
`to detecr a 50% reduction in lesion frequency in a
`therapeuric trial using a parallel groups design was cal-
`culated (Table 2). The number of new lesions, in con—
`trast to the number of renal lesions, was chosen as the
`most appropriate measure because an effecrive treat~
`ment would be more likely to stop new lesion develop-
`ment than to shorten the duration of lesions. The sam-
`
`ple size estimates for a parallel groups design were very
`high and decreased only slightly when the number of
`MRIs for each individual was increased. The large sam—
`
`Page 6 0f 10
`
`Tab}? 2. Emmet!!! Stamp}: S129.; Reqyfrm'j’br a Clinical Trial
`in MS Uting a Parallel Group: Benign and New
`Gal-enhancing Lesions (2: tbs Owrome Measure
`
`
`
` per Subject Sample Size“ No. MRls
`
`No. Monthly MRIs
`
`1
`165
`530
`2
`114
`342
`3
`Nil
`408
`4
`94
`470
`S
`90
`540
`6
`90
`630
`
`lSample size required {at each of the two groups (a treatment and a
`placebo group) to detect a 50% reduction in lesions/month with a
`power of 0.8 and an alpha = 0.05 (two-tail test).
`
`ple sizes were due largely to the variability among pa-
`tients.
`
`Because of the large sample sizes required for a par—
`allel groups design, a crossover study design was next
`considered. The bootstrap analysis was used to com—
`pute the sample sizes required to deteCt a 50% reduc-
`tion in the number of enhancing lesions due to treat-
`
`McFarland et al: MR1 Lesions in MS
`
`763
`
`Page 6 of 10
`
`

`

`
`
`DESIGNS FOR CROSS-OVER STUDY
`
`Baseline
`Finding
`
`l
`
`Treatment
`
`Treatment
`
`Crossover
`Washout
`
`Treatment
`
`
`
`Randomization
`Tre 1
`nt
`Baseline
`a me
`
`Finding
`Selection
`
`
`a)
`
`bl
`
`cl
`
`Fig 3. Croster-er derignr raring Cid-enhanced MRI lesion: at the
`priman- outcome- retried/e.
`
`ment For 3 crossover design variations (Fig 3; Table 3).
`The first 2 crossover designs are similar because hOth
`compare the frequency of lesions in the treatment ver-
`sus the nontreatment arm. In the open crossover de-
`sign (see Fig 3A), the sample sizes are based on the
`assumption that patients with relapsing-remitting dis-
`ease would be entered into the trial regardless of lesion
`frequency. This design could be easily modified, how-
`ever, to selecr for treatment only patients with a prede-
`termined lesion frequency.
`Disadvantages of the open crossover design include
`lack of randomization, difficulty in assessing the MRIs
`in a blinded manner, and a potential bias in the treat-
`ment effecr because treatment always follows the non—
`treatment arm.
`In the second crossover design (see
`Fig BB), patients would be randomized at entry into
`treatment and placebo groups with subsequent cross-
`over. This approach eliminates the disadvantages noted
`with the open crossover design. To avoid a carryover
`effect of the experimental treatment, a Burnonth wash-
`
`out period was included in the design. Because an ad-
`ditional MRJ would be needed after the washout pe-
`riod to identify new lesions, the number of MRIs was
`greater than in the open crossover design.
`The third crossover design (see Fig 3C) allows for
`the selection of patients with a particular esion fre-
`quency before randomization. This trial design incor-
`porates elements of both paraliel groups and crossover
`designs because the outcome analysis would compare
`the change in lesion frequency in the treatment group
`with that of the placebo grOup. Consequently, the sam-
`ple size would be greater than twice that for the open
`crossover design (see Table 5} but less than that re-
`quired for the parallel groups design. Because the fluc-
`tuations in lesion frequency were usually 3 to 7 months
`in duration, an initial assessment period of less than 4
`months was unlikely to provide an accurate estimate
`of the lesion frequency. Thus, sample sizes for shorter
`periods were nor calculated.
`
`Discussion
`
`Although there has been increasing interest in using
`MRI as an outcome measure in assessing efficacy of
`experimental treatments in patients with MS, the ap-
`prOpriate design of trials incorporating MRE measure-
`ments of disease activity has only begun to be con»
`sidered [1, 20]. Various MRI parameters,
`including
`new lesions as demonstrated on T2—weighted images,
`changes in the amount (area or volume) of diseased
`tissue identified by increased '12 signal or lesions that
`enhance following administration of Gd could be used
`as an outcome measure. Because breakdown in the
`blood—brain barrier as reflected by Gd enhancement
`has been shown to usually represent the initial stage in
`lesion development {15] and because Gad-enhancing
`lesions are easily identified, deenhancing lesions rep
`resent a reasonable choice for monitoring disease activ-
`ity. Before any MRI parameters can be used to moni-
`tor MS, however, the natural history of that parameter
`must be established in patients without treatment. The
`
`Tailale 3. animated Sample Size: Requiredfor a Clinical Trial Using
`Crossover Designs and New (Yd-enhancing Lelia»; a: the Outcome Manure
`
`Design A
`
`Design B
`
`Design C
`
`No. MRIS
`per Patient
`
`per Study Arm
`Sample Size“
`No. MRIs
`Sample Size
`No. Millsb
`Sample Size‘
`No. Mills
`1
`55
`165
`50
`200
`2
`27
`135
`34
`204
`.
`.
`.
`.
`.
`5
`22
`154
`28
`224
`425
`47
`4
`18
`162
`20
`200
`495
`45
`5
`17
`187
`17
`204
`
`
`12 156 12 168 316 403
`
`
`
`
`
`.
`
`'Patienrs not preselected fer lesion frequency.
`l’An additional MRI is required at the beginning of each arm to identify new lesions.
`‘Parients with 2 or more new enhancing lesionsfmonth. Sample size and number of MRls does not include patients screened and excluded.
`
`764 Annals of Neurology Vol 32 No 6 December 1992
`
`Page 7 0f 10
`
`Page 7 of 10
`
`

`

`longitudinal Study of Gd-enhanced MR1 le
`present
`sions was undertaken to define the natural history of
`these abnonnalities, particularly during the early,
`te—
`lapsing-remitting phase and, based on this longitu-
`dinal data,
`to esrablish how (Ed-enhancing lesions
`could be best used as an effecu've outcome measure in
`clinical treatment trials.
`
`The findings described herein confirm previous MRI
`Studies {9, 10}, which demonstrated that MS can be a
`progressive disease even during the early, relapsing-
`remitting phase and that focal disruptions in the blood-
`brain barrier are readily observed during periods of
`clinical remission {17—19}. importantly, the longitudi-
`nal Study of the patients in this Study showed that the
`frequency of Gd—enhancing lesions is not constant. In
`all patients, the number of Cid-enhancing lesions fluc-
`tuated; in some patients a striking variation in lesion
`frequency was noted to occur, with a suggestion of
`regularity. The lesion frequency did not appear to oc--
`cur randomly because a better fit of the data was dem-
`onstrated employing a Statistical model using a sinusoi-
`dal mean funcn'on than with one using a conStant mean
`funcrion. We believe it is unlikely that the fluctuations
`in lesion frequency in individual patients will continue
`to occur with a constant periodicity and do not suggest
`that
`the Poisson regression model with sinusoidal
`trends provides a definitive description of lesion occur—
`rence over the duration of disease. With extended fol-
`
`the pattern of lesion frequency in individual
`low-up,
`patients may change and butscs of lesions may occur
`either more or less frequently. However, the cyclical
`trend in lesion frequency represents an important con—
`sideration in the design of clinical trials using Gd-en-
`hancing lesions as an outcome measure. Short periods
`of Study could easily fail to identify the true mean in
`lesion frequency and could lead to incorrect conclu-
`sions. Although additional longitudinal patient data are
`needed, the present findings indicate that study periods
`of 6 months or ionger are probably needed to obtain
`a reasonable measure of the frequency of lesions.
`We examined 2 general approaches for the design
`of a clinical trial using Gd—enhanced lesions as the out-
`come measure and calculated the sample sizes and
`number of MRls required for the various designs. The
`firsr approach examined,
`the parallel groups design,
`would require prohibitively large sample sizes and
`MRI resources. Only a small reduction in the sample
`size occurred when the number of MRls per patient
`was increased, reflecting the large variability among pa-
`tients. Similar sample sizes were recently reported by
`ether investigators using data obtained from I? pa-
`tients with either relapsing—remitting or secondary pro-
`gressive MS followed for 6 months with monthly MRls
`{20]. On the basis of the frequency of Gel-enhancing
`lesions, 150 patients would be required for a 6-month
`parallel study.
`
`Page 8 0f 10
`
`To minimize the effect of variability among patients,
`we next examined the use of 5 variations of a crossover
`design. The first employed an initial series of MRls to
`establish the baseline frequency of enhancing lesions
`in each patient, followed by crossover to a treatment
`group. Nor unexpectedly, the required sample sizes
`for this crossover design were substantially smaller
`than for the parallel groups design, and the required
`sample sizes declined as the number of MRls in-
`creased. The reduction in sample size seen when the
`number of monthly MRls increased from 5 to 6 in
`each arm of the Study reflecrecl the frequency of the
`bursts of lesions, which was, on average, approximately
`6 months.
`
`Disadvantages of the open crossover design include
`lack of randomization and difficulty in assessing the
`MRls in a blinded fashion. A solution would be to
`
`randomize patients at entry and to incorporate a wash-
`out period at the titne of crossover to avoid a treatment
`carryover effect. The duration of the washout period
`could be varied depending on the nature of the treat—
`ment. The randomized crossover design would require
`sample sizes similar to those for the open crossover
`design. Generally, sample sizes are insensitive to small
`changes in the washout period. When the carryover
`effecr of a treatment cannor be assessed,
`the Open
`crossover design would be preferable to design 2.
`A concern regarding the randomized crosmver de~
`sign is that patients with low frequencies of enhancing
`lesions (e.g., Patient 2, who had fewer than 1 new
`lesion per month) would be included; in fact, the sam-
`ple sizes are calculated on that basis. The relationship
`between lesion frequency and eventual disability is un-
`known. However, a recent Study demonstrated that
`patients with benign MS have fewer enhancing lesions
`than most patients with relapsing-remitting MS {50].
`Until
`the relationship between lesion frequency and
`eventual disability is better understood, it would seem
`best to select patients with frequent lesions for thera—
`peutic trials, particularly if the treatment has porential
`risks. A third possibility (see Fig 3C) represents a
`blending of crossover and parallel groups design. This
`design uses an initial evaluation phase to determine
`lesion frequency and a subsequent randomization to
`treatment and placebo groups. Unfortunately, a sample
`size of 31 patients and more than 400 MRls would
`be required to conduct this trial. Although this design
`would seem optimal for treatments Other than those
`with only minimal risk,
`the required MR1 resources
`are prohibitive unless MRI units dedicated to MS re-
`search are available or the design is used in multicen—
`ter studies. Consequently, the open crossover design,
`which allows selection of patients with sufficient lesion
`frequencies, followed by an open crosswet to treat-
`ment represents the second choice for testing treat-
`ments with potential risks.
`
`McFarland et al: MRI Lesions in MS
`
`765
`
`Page 8 of 10
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`The findings in this and other studies indicate that
`MRI can provide a means For assessing one aspect
`of disease activity in patients with early. relapsing
`remitting MS. The results also indicate that monitoring
`lesions by MRI can be an effective outcome measure
`in clinical trials in MS. Evaluation of other MR1 param—
`eters. such as the change in the volume of white matter
`lesions with increased signal intensity on T2-weighted
`MRI, also may be helpful in monitoring outcome of
`therapy. The relationship between frequency of MRI
`lesions as well as other MR1 measurements of diseue
`and clinical disability awaits longer follow-up of pa-
`tients such as those in this study. Consequently, we
`do not prOpose that MRI parameters become the sole
`outcome measures in examining therapeutic effects.
`We do prepose that MRI asse55rnent represents a
`means for accurately selecting potentially effective
`treatments that can then be evaluated in more costly
`phase-Ill clinical trials. This approach will allow the
`diminishing resources available for clinical studies to
`be used with the greatesr efficiency.
`
`This work was performed in part at the in Vivo Nuclear Magnetic
`Resonance Research Center of the National Institutes of Health.
`Bethesda. MD.
`
`We thank Ms Susan lnscoe and Ms jeanette Black for their excellent
`technical magnetic resonance imaging skills throughout this study.
`We titanic Mrs Irene Naveau For her excellent nursing support during
`the study. We thank the patients {or their cooperation in this study.
`
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