Serial Gadolintum-enhanced Magnetic
`Resonance Imaging Scans in Patients with
`Early, Relapsing-Remitting Multiple
`Sclerosis: Implications for Clinical Trials
`and Natural History
`
`Jonathan O. Harris, MD,* Joseph A. Frank, MD,?§ Nicholas Patronas, MD," Dale EF. McFarlin, MD,*
`and Henry F. McFarland, MD”
`
`
`Six patients wich early, mild, relapsing-remitting multiple sclerosis were studied with monthly gadclinium-enhanced
`magnetic resonance imaging scans for 8 to 11 months. Numerous enhancing lesions were observed irrespective of
`clinical activity. Four of the G patients had one or more enhancing lesions present on each examination. The other 2
`patients had enhancing lesions noted in 7 and 9 of 11 months. In contrast, only two clinical exacerbations were
`observed during the study period. Neither the exacerbations nor other changes in symptoms or signs correlated with
`occurrence of the enhancing lesions. Enhancement generally persisted for less than 1 month. The opening of the
`blood-brain barrier as reflected by gadolinium enhancement on magnetic resonance imaging may represent ongoing
`disease activity in patients with mild, relapsing-remicting multiple sclerosis who are clinically stable. The frequency
`of these lesions appears te be sufficient to use as an outcome measurein clinical trials testing clinical efficacy in patients
`with early, relapsing-remitting multiple sclerosis.
`
`Harris JO, Frank JA, Patronas N, McFarlin DE, McFarland HF.Serial gadolinium-enhanced magnetic resonance
`imaging scans in patients with early relapsing-remitting multiple sclerosis: implications for
`clinical trials and natural history. Ann Neurol 1991;29:548-555
`
`
`In spite of extensive investigations, mulaple sclerosis
`(MS) remains a disease of uncertain cause and without
`an effective treatment. An immunopathological pro-
`cess is generally postulated to contribute to the patho-
`genesis, and various forms of immunosuppressive ther-
`apy have been attempted. Unfortunately, therapeutic
`trials in patients with MS are accompanied by many
`difficulties, including unpredictable changes in disabil-
`ity. Additionally, measurements of efficacy are limited
`to assessing disability that may not adequately reflect
`disease activicry. Therapeutic crials have usually in-
`volved patients with chronic, progressive disease and
`with moderate co severe disability, Ie has been argued
`that
`the course in the chronic, progressive phase of
`the disease is more predictable and che relationship
`between the risk and che benefic of treatment more
`acceptable.
`Increasingly, however,
`investigators are
`coming to the conclusion that treatment of the disease
`in the earlier stages may be necessary to have signifi-
`cant impact on its course.
`
`From che “Neuroimmunology Branch, and the TDiagnostic Radiol-
`ogy Deparimenc, National Institutes of Health, Bethesda, MD, and
`the Departments of $Radiology and §lnternal Medicine, George-
`town University Medical Center, Washington, DC.
`
`Recent studies in patients with MS, with magnetic
`resonance imaging (MRI), suggest the presence of dis-
`ease activity as measured by newabnormalities on T2-
`weighted images or by gadolintum-enhancing lesions in
`patients who are clinically stable [1-7]. This provides
`further
`rationale for
`treating patients with early,
`relapsing-remitting disease. The major obstacle has
`been the lack of reliable means of assessing efficacy,
`particularly at this stage of the disease.
`A study of
`serial gadopentetate dimeglumine
`(GdDTPA)-enhanced MRI was initiated to determine
`if the technique can be used to establish an outcome
`measurement in the treatment of patients with early,
`relapsing-remitting disease. These studies were also
`undertaken co further define the natural history of the
`disease in this early phase. To date, 6 patients with
`early, relapsing-remicting disease have been studied ar
`monthly intervals for 8 to 11 months, These patients
`had only mild disabilicy and were generally clinically
`stable during the period of the study. Substantial num-
`
`Received Sep 13, 1990, and in revised form Nov 15. Accepted for
`publication Nov 19, 1990.
`Address correspondence to Dr McFarland, Neurcimmunology
`Branch, National Instituces of Health, Building 10, Room $B16,
`Bethesda, MD 20892.
`
`548 Copyright © 1991 by the American Neurological Association
`
`Page 1 of 8
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`LtEl
`
` FOZB-L1403
`
`ereies)
`
`Biogen Exhibit 2221
`Mylanv. Biogen
`IPR 2018-01403
`
`Page 1 of 8
`
`Biogen Exhibit 2221
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`IPR 2018-01403
`
`

`

`Table 1. Clinical Characteristics of Patients at Onset ofStudy
`
`Age (vr)
`
`Sex
`
`Duration
`of MS
`(mo)
`
`Month
`after Last
`Exacerbation
`
`EDSS
`at First
`Month
`
`EDSS
`at Last
`Month
`
`WBC
`(CSF)
`
`IgG
`Index
`
`Presence of
`OCB
`
`Patient No.
`-
`0.65
`0
`1.5
`1.5
`3
`5
`F
`43
`1
`+
`1.70
`0
`1.5
`L5
`5
`10
`F
`29
`2
`+
`1.06
`1
`2.0
`2.0
`8
`32
`F
`40
`3
`2
`8
`M
`35
`4
`+
`0.69
`4
`1.5
`1.5
`+
`2.30
`25
`1.5
`15
`4
`13
`F
`26
`5
`+
`1.93
`2
`2.5
`35
`4
`35
`F
`39
`6
`
`mS) 18
`4.3
`17.2
`cae
`34
`Mean
`
`M5 = multiple sclerosis; EDSS = Expanded Disability Starus Score; WBC = whire blocd cell counr; CSF = cerebrospinal fluid; OCB =
`dligocional bands.
`
`bers of enhancing lesions have been observed in these
`patients, indicating that disease activity is occurring in
`the early phases of the disease even during clinically
`stable periods. These findings have implications for
`both the pathogenesis and experimental treatment of
`patients with MS.
`
`Methods
`Patient Selection
`Six patiencs with MS, referred by local physicians to be con-
`sidered for ongoing clinical studies, were sclected for chis
`Intramural Research Board—approved protocol. Individuals
`were chosen who filled the criteria of clinically definite MS
`as defined by Poser and colleagues [8], were judged to have
`mild, early, relapsing-remicting diseases (i.c., an Expanded
`Disability Staras Score [EDSS] of3.5 or less) [9], and would
`be able co complete monthly MRI scans. Informed consent
`was obtained from each patient before starting the study.
`
`Patient Evalwation
`Patients were admitted to the Clinical Center, National [nsti-
`cutes of Health (Bethesda, MD), for complete physical and
`neurological examination, lumbar punccure, and the initial
`MRI scan. Subsequently, patients were examined and imaged
`monthly (every 4 weeks) at the same ume of day. The exarn-
`ining physician (H. M.} was blinded to the resulcs of all MRI
`scans. An exacerbation was defined by using a modification
`of the criteria of Schumacher and co-workers [10] and con-
`sisted of a new symptom or worsening of previous symptoms
`associated with significant changes in signs and lasting more
`than 24 hours, Histories of increased symptoms that repre-
`sented either mild changes in preexisting symptoms or were
`hot associated with new or changed signs were judged insuf-
`ficient to classify as an exacerbation. During the study, some
`patients were also noted to have changed or new neurological
`signs; these were usually mild, not associated wich new symp-
`toms, and classified as changed signs, nor exacerbations.
`
`MRI Seans
`Imaging was performed monthly for 8 to 11 months in 6
`patients. Reproducible head positioning from month to
`month was assured by placing one viramin E capsule in the
`external car canal and taping a second ae the lareral canthus
`
`Page 2 of 8
`
`of the eye. The canthal meatal line between these capsules
`delineated che plane of each scan. MRI scans were per-
`formed on a General Electric Signa 1.5 T (General Electric,
`Milwaukee, WI) by using a’T2-weighted spin echo pulse se-
`quence with an echo time (TE) of 80 msec, a repetition time
`(TR) of 2,000 msec, 2 excitations, a 128 x 256 acquisition
`matrix, and S-mm contiguous interleaved slices. T1-weighted
`spin echo (TR GOO/TE 20) images of che brain were per-
`formed before and after GUDTPA (Magnevist 0.1 mmole/
`ke, Berlex Laboracories, Cedar Knolls, NJ} was administered
`using 2 excitations, a 192 X 256 acquisition matrix, and
`S-mm contiguous interleaved slices. All studies were per-
`formed with a fleld of view of 24 cm.
`
`lmage Evaluation
`Tl-weighted images after contrast were visually compared
`with Tl-weighted images before contrast. Most enhancing
`lesions are easily recognized as areas of increased signal inten-
`sity in the white matter. Questionable small areas of enhance-
`Ment near the cortical surface were excluded from the analy-
`sis. Moreover, possible small arcas of enhancement in the
`white matter were not included unless a corresponding area
`of abnormality was identified on the T2-weighted images.
`New enhancing lesions were defined as lesions that were
`not presenc on the T]-weighted enhanced MRI performed 1
`month previously.
`
`Results
`Clinical Characteristics of Patients
`The 6 patients examined in this study had early, mild
`MSofthe relapsing-remitting form. ‘Their clinical char-
`acteristics at the onset of this scudy are shown in Table
`1. The mean duration of disease, dated from the first
`clinical sign or syrmptom, was 17.2 months; and the
`mean level of disability, measured by using the EDSS,
`was 1.9. One of the 6 patients (Patient 6} was recov-
`eting from a period of worsening before entry into this
`study. All of the patients had experienced an exacer-
`bation within 8 months before encry. Cerebrospinal
`fluid findings consistent with the diagnosis of MS (an
`elevated immunoglobulin IgG index and oligoclonal
`bands) were found in al] but 1 patient.
`
`Harris et al; Serial Enhanced MRI in MS
`
`549
`
`Page 2 of 8
`
`

`

`Table 2. Clinteal Convse of Patients
`GdDTPA+
`Lesions
`T?2 Lesions
`Change in
`Change
`Exacerbations
`in Signs
`Symptoms
`Fatigue
`on Initial
`Per Scan
`Scans (n}
`(pn)
`ny
`fn)
`(ny?
`Scan {n}
`(mean, n)
`
`
`Patient No.
`3.6
`41
`5
`6
`1
`0
`8
`i
`7
`22
`4
`0
`0
`0
`iL
`2
`1.6
`46
`2
`2
`2
`0
`HH
`3
`3.0
`64
`1
`2
`ab
`1
`8
`4
`2.6
`75
`G
`3b
`ab
`l
`11
`5
`6.2
`74
`4
`4
`1
`0
`11
`6
`
`
`
`
`
`60 2 8 i?Toral iG
`
`‘Number ofoccasions.
`One occasion was associated with an exacerbation.
`
`The patients were clinically evaluated monthlyat the
`time of MRI examination for a total of 60 occasions.
`Table 2? summarizes che clinical course of patients dur-
`ing the study. There was no permanent worsening in
`the patients’ level of disabilicy. Two patients had clini-
`cal exacerbations during the study. The exacerbation
`in 1 patient (Patient 5) occurred during the third
`month in the study and was characterized by decreased
`sensation in the lower extremities. This resulted in an
`0.5 increase in EDSS that persisted for 1 month. One
`exacerbation occurred in 1 patient (Patient 4}. It oc-
`curred in the seventh month and was characterized by
`decreased temperature sensation in the right foor that
`resulted in a 0.5 increase in the EDSS, which returned
`to baseline the nexe month. A third patient (Patient
`G) entered the study with an EDSS score of 3.5 and
`subsequently improved to a score of 2.3, predomi-
`nantly due to improvement of strength in the lower
`extremities. The EDSS score did aor change in the
`remaining 3 patients.
`
`MRI Findings
`The initial MRI scans of the G patients were consistent
`with early, mild MS. T2-weighted images showed dis-
`crete lesions that were generally periventricular. This
`pattern did not change significandy by the end of the
`study period. After administration of GdDTPA, an-
`merous enhancing lesions (2 = 29) were noted on
`Tl-weighted studies. All of these enhancing lesions ex-
`hibited corresponding areas of increased signal inten-
`sity on T2-weighted images. Representative images for
`1 patient done at the beginning and end of the study
`are shown in Figure 1.
`
`LONGITUDINAL sTupIES. The frequent occurrence of
`enhancing lesions was confirmed by analysis of the se-
`rial studies. New enhancing lesions (n = 113) occurred
`in all patients during the course of the scudy. The num-
`ber and time course of enhancing lesions in individual
`
`550 Annals of Neurology Vol 29 No S May LOO!
`
`Page 3 of 8
`
`patients are shown in Figure 2. Each patient appeared
`unique with respect to che number of newlesions and
`differences from month te month. The maximum num-
`ber of enhancing lesions varied among the patients,
`with some patients having as many as 10 lesions at one
`time, whereas other patients, such as Patienc 2, never
`had more than two lesions. In each patient, the number
`of lesions varied from month to month, however, a
`striking observation was that one or more enhancing
`lesions were visible in most patients on all occasions.
`The average numberof enhancing lesions seen on MRI
`scans is noted in Table 2.
`
`CLINICAL CORRELATIONS. There was almost total lack
`of clinical correlation with numbers or locations of the
`enhancing lesions. Patients who had exacerbations or
`had changed signs or syrnptoms insufficient to be classi-
`fied 2s an exacerbation did not have enhancing lesions
`that could explain those findings.
`Ir is possible that
`some of the clinical changes were related to active le-
`sions in the spinal cord, which was not studied. Exacer-
`bations and changed signs or symptoms are noted on
`individual graphs (see Fig 2). In addition to thelack of
`correlation with specific signs and symptoms, there was
`also no correlation between the frequency oflesions
`and general clinical changes,
`including subjective as-
`pects of fatigue (see Table 2), Patiencs with a higher
`mean number of lesions per scan, however, tended to
`complain more frequently of symptoms (7 = 0.47).
`
`EVOLUTION OF ENHANCING LESIONS. Most new enhanc-
`ing fesions did not enhance on the next scan 1 month
`facer. Excluding lesions enhancing on the first and last
`scan, for which the total duration of enhancementcan-
`not be calculated, 94 new enhancing lesions were ob-
`served. Sixty-nine of these did not enhance 4 weeks
`later. Twenty lesions continued to enhance for greater
`than 4 weeks bur less than 8 weeks. Three lesions
`persisted longer than 8 weeks but less chan 12 weeks,
`
`Page 3 of 8
`
`

`

`
`
`Cc
`D
`
`Fig 1. Representative magnetic resonance tyages from 1 pa-
`tent (Patient G) at the beginning (A. B) and end of ourstudy
`(C, Dy, Panels A and C are T2-weighted images. Panels Band
`D ave Tl -welghted images after administration of gacapentetate
`dimeslumine (GdDTPA}. Enbancing lesions appear as regrony of
`
`tnereased signal intensity (white) on Tl -weighted images after
`administration ofGADTPA,. Note the size andrelative brightness
`(igual intensity) af the T2 lesions that correipand to the en-
`bancing lesions,
`
`Page 4 of 8
`
`Harris et al: Serial Enhanced MRI in MS
`
`551
`
`Page 4 of 8
`
`

`

`
`
`
`
`o ZO
`
`o=<<
`
`==i
`
`ua
`
`t
`
`PATIENT 2
`
`MONTHS
`
`PATIENT 4
`
`v7)
`
`= Swu
`
`d
`ol
`
`G Z
`
`zQ=<i=i s
`
`o
`
`B
`
`w= 9u
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`—_
`
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`
`o=<<
`
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`
`at)
`Fe
`
`MONTHS
`
`PATIENT 6
`
`S
`
`Ss
`
`§s
`
`D
`
`4p)
`2
`oise]Lil
`al
`
`PATIENT 1
`
`S
`
`LESIONS
`#ENHANCING
`LESIONS
`#ENHANCING
`LESIONS
`#ENHANCING
`
`oO
`
`MONTHS
`
`MONTHS
`
`EF
`
`Fig 2, Graphs A-F showpatterns of enbancement in individ-
`wal patients (Patients 1-6, respectively), The solid upper trace
`shows the total number ofenbancing lestonsfrom each month. The
`lower, dasbed line reveals the total numberof netenhancing le-
`sions each month, An "XX" marks the time of exacerbation, An
`“§”sienifes yuild signs or symptoms thet did not meet the criteria
`joran exacerbation (see Methods}.
`
`552 Annals of Neurology Vol 20 No 3 May 199L
`
`Page 5 of 8
`
`Page 5 of 8
`
`

`

`Table 3. Lesion Development over Time As Shown by T2-weighted MRI Scans
`Month
`
`
`
`
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`
`Lesion No.
`
`i
`2
`3
`4
`5
`6
`?
`8
`9
`10
`11
`12
`13
`14
`15
`16
`i?
`18
`19
`
`7
`22
`23
`24
`25
`26
`27
`
`Open circles represent increased signal intensiry on T2-weighted images at the site of enhancing lesions. Pitted circles document the month or
`months when enhancemenc was seen. A question mark denotes a possible T2 abnormality chat could not definitively be separated from
`background “noise.” Elipsis (.
`. ) indicates no T2 abnormalicry was seen. Lesions 15, 17, and 19 are examples of lesions occurring in previously
`normal white matter, whereas lesions 13, 20, and 26 are enhancing lesions in ofd plaques. Very small areas with increased signal intensity on
`Ta-weighted scans were often aored co predare enhancing lesions by | to 2 months. Lesions 18 and 21 are examples of this phenomenon.
`MRJ = magnetic resonance imaging.
`
`and two additional lesions persisted for longer than 12
`weeks but less than 16 weeks. Nolesions consistently
`enhanced for more than 16 weeks. Four of the five
`lesions that persisted longer than 8 weeks occurred
`in the patient (Patient 6} who also had the most new
`enhancing lesions. This raises che possibility chat en-
`hancing lesions of longer duration may occur in pa-
`tients with more severe disease activity.
`
`PERSISTENCE OF T2 ABNORMALITIES. Enhancing lesions
`occurred in two contexrs. The frst was a new enhanc-
`ing lesion in an area that appeared to have normal sig-
`nai intensity on prior MRI scans. The second context
`was at the site of abnormal signal intensicy that had
`been present from the stare of the study and most likely
`represented enhancement at the border of an older
`plaque, Enhancing lesions in the first context usually
`evolved into persistent T2-weighted abnormalities. tn
`the second context, older lesions generally appeared
`to enlarge. Only rarely did enhancing lesions resolve
`without subsequent abnormalities. A detailed chronol-
`
`Page 6 of 8
`
`ogy of enhancing lesions in Patient 5 is shown in Table
`3. Twenty-seven lesions enhanced in this patient, and
`two lesions {lesions 12 and 23) subsequently reen-
`hanced after a 1 or 2-month period without enhance-
`ment. The final scan showed that definite T2-weighted
`abnormalities persisced in 25 of che lesions. The sites
`of the remaining two enhancing lesions (lesions 17 and
`19) could be identified, but these could not be defi-
`nitely separated from background “noise.”
`The surface area of lesions at the beginning and end
`of this study were quantitated on T2-weighted images
`in 3 patients to determineif this method could be used
`to measure change in amount of diseased tissue over
`time (data not shown). This approach was nor satis-
`factory because of the frequenc occurrence of enhanc-
`ing lesions that were visualized as large abnormalities
`in T2-weighted sequences but
`thac resolved into
`smaller T2-nonenhancing lesions in later images. Con-
`sequently, the inclusion of these regions in the analysis
`Bave actifactually large increases or decreases in dis-
`eased tissue, depending on whether the enhancing le-
`sion was present on che initial or final scan.
`
`Liarris er al: Serial Enhanced MRI
`
`in MS
`
`553
`
`Page 6 of 8
`
`

`

`Discussion
`Six patients with early MS of the relapsing-remitting
`form were studied in detail. These patients were young
`and withoutsignificant disabiliry. They correspond to
`the type of patient with MS who would be ideal to
`treat, to prevent progression of their disease. Despite
`their relatively stable clinical course, frequent open-
`ing of the blood-brain barrier, as documented by
`GdDTPA-enhanced MRI scanning, was seen in all pa-
`sents. Enhancing lesions occurred in the absence of
`clinical changes, and when new signs and symptoms
`did occur, there was no correlation with the numbers
`or location of enhancing lesions on brain MRI scan.
`The spinal cord was nor imaged.
`These findings have three major implications for the
`pathogenesis and natural history of MS. First, frequent
`opening of the blood-brain barrier appears to be a com-
`mon feature in brains of patients with early, relapsing-
`remitting MS. As shown previously [7], enhancement
`lasted for less than 1 month in most lesions, and most
`new enhancing lesions persisted as permanent abnor-
`malities on T2-weighted images at the end of che study.
`Second, persistent disease activity may occur in pa-
`tients with relapsing-remitting MS who are clinically
`stable. The concept of a “relapsing-remitting” form of
`MSis based on clinical expression of neurological signs
`and symptoms over time. Conceptually, MS has been
`thought to be “active” when the patient is in a clinical
`relapse, and “stable” or “inactive” beeween relapses.
`From pathology studies, however, it has been long ap-
`preciaced thac licdle correlacion exists between clinical
`manifestations of MS and the extent of MS plaque
`formation in the brain {11}. Additionally, earlier im-
`aging studies using computed tomography and MRJ
`have documented lesions developing without clinical
`expression [1—7, 12-14]. Our resules confirm and ex-
`tend these findings. One interpretation of these results
`is that disease activiry in MS coincides with the pres-
`ence of new enhancing brain lesions in patients, irre-
`spective of new signs or symptoms. Because lesions
`persist after enhancement, it would be accurate to be-
`lieve chat enhancement on MRI scans may often better
`reflect actual disease activity than reliance on only clini-
`cal signs and symptoms. If this is correct, the G patients
`in this study had continuous disease activity. It is cau-
`tioned that the sample size is small andit is not possible
`to estimate how frequene this level of disease activity
`would be in a larger population of patients with similar
`clinical characteristics.
`Thied, opening of the blood-brain barrier seems to
`be related to new lesion development and enlargemenx
`of preexisting lesions. As shown in Table 3, almest
`ali enhancing lesions are followed by permanent T2
`abnorrnalities. These findings indicate that GdDTPA
`enhancement has a close temporal relationship with the
`fixed T2 abnormalities prominent in patiencs with MS.
`
`554 Annals of Neurology Vol 29 No 5) May 1991
`
`Page 7 of 8
`
`Consequently, it seems likely chat the opening of the
`blood-brain barrier represents an early, if sot the ini-
`tial, event in lesion development. The relationship be-
`nveen opening of the blood-brain barrier and the neu-
`ropathology of plaque
`formation is not known.
`Preliminary correlation of GdDTPA enhancement
`with pathology in our laboratory indicates that a hyper-
`acute inflammatory reaction is occurring at the site of
`enhancement [15].
`Ic is noc clear if other separate
`pathological processes are required for demyelination
`or if a treatment that could alter the opening of the
`blood-brain barrier would prevent permanent T2 ab-
`normalities from developing,
`This study does not address the relationship between
`disease activity, as reflected by MRI scans, and evencual
`disability.
`Ic can be postulated that enhancing lesions
`contribute to the pathological changes characteristic in
`patients with MS. Consequently, patients with frequent
`enhancing lesions would have an increased risk of sub-
`stantial disability. An accurate assessment of the rela-
`tionship berween enhancing MRI lesions anddisability,
`however, will depend on the longterm follow-up of
`patients such as those described in this report. The
`absence of enhancing lesions in the brain does not nec-
`essarily assure less disabiliry because lesions can also
`eccur in the spinal cord, often resulting in pronounced
`disabiliry. Because the spinal cord was not imaged in
`the present study, the relationship between signs and
`symptoms and disease activity in the spinal cord could
`not be ascertained. The importance of spinal cord le-
`sions is suggested by the 2 patients noted as having
`clinical exacerbations during this study. Neither had
`new enhancing lesions in the brain to explain the symp-
`toms, and the findings were most likely due to spinal
`cord lesions.
`In addition to che pathogenesis and natural history
`of MS, our results have implications for clinical trials
`in patienes wich mild MS. Currently, clinical measures
`of outcome such as reported symptoms, repeated phys-
`ical examinations, disability seales, or a change in the
`number of clinical relapses with treatment are used to
`assess therapy. If substantial subclinical disease activity
`is occurring, as suggested by the current findings as
`well as by previous reports [1—-7, 12-14],thenclinical
`parameters may not be reliable measures of suppres-
`sion of disease activicy in this phase of the illness,
`Clearly, in this study, clinical parameters did not accu-
`rately reflece changes documented by MRI scans.
`Enhancing lesions
`appear
`to occur
`frequently
`enough to be used as an outcome parameter in thera-
`peutic trials.
`In contrast to new or enlarging lesions
`seen on T2-weighted scans,
`lesions thac enhance are
`easily detected and measured on Tl-weighted images
`after GdDTPA administration.
`In view of their fre-
`quencyand ease of detection, suppression of enhanc-
`ing lesions could be used as the principal outcomevari-
`
`Page 7 of 8
`
`

`

`able in relatively short, pilot weatment trials. Short
`tnals are important to contain costs as weil as co limit
`the exposure of patients to potentially toxic rrearments.
`Based on our results, the design of a phase IT creat-
`ment
`trial can be derived. Monthly enhanced MRI
`scanning from 4 to 6 months seemssufficient to estab-
`lish the pretrearment baseline frequency of enhance-
`ment. This would be followed by a treatmenc period
`lasting from 6 to 8 months, again wich monthly MRI
`scans, Elimination or pronounced reduction of enhanc-
`ing lesions with creatment would be used to teste chera-
`peutic efficacy.
`The results described in the present study may be,
`in part, unique for patienrs with early, mild, relapsing-
`remitting MS. The frequencyof enhancing lesions may
`vary substantially in patients with other disease charac-
`teristics. It has been recenrly reported that che number
`of enhancing lesions varies significantly in patients with
`progressive disease beginning with a relapsing-remit-
`ting course versus those patients with disease begin-
`ning with a progressive course; enhancing lesions were
`more frequent in the former patients [16].
`The assessment of amount of diseased tissue, as re-
`flected by the numberoflesions or the area or volume
`of increased signal intensity on T2-weighted scans at
`the beginning and end of the study, also appears co be
`a possible outcome measure, useful
`in clinical crials.
`Counting the numberof individuallesions is inaccurate
`because many became confluent and, withour precise
`three-dimensional representations of lesions, they can-
`not be easily enumerated. Ourinitial effort to assess
`area or volumeofdiseasedtissue was also discouraging,
`The frequent occurrence of enhancing lesions made
`calculating the surface arca of lesions on T2-weighted
`images difficult and prone to overestimating true lesion
`burden. The continuing technological advances being
`made in computer analysis of MRI scans may eventu-
`ally alleviate this difficulty.
`Our findings suggest that MS is a progressive discase
`even during the early stazes when it appears clinically
`stable. MRI provides a sensitive method for detecting
`patients with MS, with MRI evidence ofactive disease.
`We hope MRI can be combined with experimental
`therapies to identify quickly and more safely those
`therapies chat may be effective in patients who will
`most likely benefit from treatment, chat is, those pa-
`tients with mild, relapsing-remitting disease.
`
`We thank Ms Susan Inscue and Ms Jeannere Black for their excel-
`lene technical magnetic resonance imaging skills throughout this
`
`study. We also chank Ms Heidi Maloni for her excellent assistance
`with patenc care and planning throughoutthis study. This work was
`performed in the In Vivo Nuclear Magnetic Resonance Research
`Center of the National Insticures of Hlealeh, Bethesda, MD.
`
`3.
`
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`in MS
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`$55
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