journal ofNeurology, Neurosurgery, and Psychiatry 1997;62:285—287
`
`285
`
`
`
`SHORT REPORT
`
`
`Gadolinium enhanced MRI predicts clinical and
`MRI disease activity in relapsing-remitting
`multiple sclerosis
`
`T Koudriavtseva, A J Thompson, M Fiorelli, C Gasperini, S Bastianello, A Bozzao,
`A Paolillo, A Pisani, S Galgani, C Pozzilli
`
`Abstract
`The aim of the study was to evaluate the
`predictive power of baseline gadolinium
`(Gd) enhanced MRI in relation to subse-
`quent clinical and MRI activity.
`Sixty eight patients with clinically defi-
`nite relapsing-remitting multiple sclero-
`sis had a baseline Gd enhanced MRI and
`were
`followed up clinically and by
`monthly Gd enhanced MRI
`for
`six
`months.
`The occurrence of relapses during the
`follow up period was predicted by the
`presence of at least one enhancing lesion
`on the baseline MRI
`(P < 0-05). The
`number and volume of enhancing lesions
`at baseline were significantly associated
`with both enhancing lesions observed
`during the follow up period (P < 0-0001)
`and the accumulation of abnormality on
`T2 weighted images (P < 0-0001). More-
`over,
`the presence of three or more
`enhancing lesions at baseline scan was
`consistently associated with the develop-
`ment of permanent abnormalities on T2
`weighted images six months later.
`The study suggests that the number and
`volume of Gd enhancing lesions at a sin-
`gle examination are strong short term
`predictors of subsequent clinical and MRI
`activity.
`
`Cf Neural Neurosurg Psychiatry 1997;62:285—287)
`
`relapsing-remitting multiple
`Keywords:
`enhanced MRI; predictivity
`
`sclerosis;
`
`There is a general agreement that an abnormal
`MRI in patients presenting with a clinically
`isolated syndrome suggestive of multiple scle-
`rosis is predictive of the development of clini—
`cally definite multiple sclerosis.” The value of
`MRI in predicting disease progression is less
`clear in clinically definite multiple sclerosis. A
`serial MRI study over a two to three year
`period in nine patients with relapsing-remit-
`ting multiple sclerosis suggested that lesion
`enhancement may be related to subsequent
`clinical worsening.7 Another study showed
`that the number of enhancing lesions during
`the six month serial MRI study was weakly
`
`predictive of disability at five years in sec-
`ondary progressive multiple sclerosis.8 By con—
`trast other authors reported that the change in
`number of new lesions on T2 weighted images
`or number of enhancing lesions on T1
`weighted images did not predict the changes in
`disability two weeks later?
`The aim of this study was to identify
`whether baseline gadolinium (Gd) enhanced
`MRI predicts six month clinical and MRI
`activity
`in
`relapsing—remitting multiple
`sclerosis.
`
`Materials and methods
`As part of an open cross over recombinant
`human interferon [3-13 study, 68 patients with
`relapsing—remitting multiple
`sclerosis were
`studied clinically and with monthly enhanced
`MRI over a six month observation period
`before the treatment phase.10 Neurological
`examination was also performed at the time of
`clinical exacerbations. In case of relapse the
`patients were treated with intravenous methyl-
`prednisolone (1 g daily for six days).
`Brain MRI was performed on a Toshiba 50
`S superconductive 05 unit using a T2
`weighted spin echo pulse sequence with echo
`times (TE) of 30 and 90 ms, a repetition time
`(TR) of 2500 ms, two excitations, 256 X 160
`matrix, and 5 mm slices with a 1 mm gap
`between sections in a field of view of 25 cm.
`T1 weighted spin echo (TR 400/TE 18)
`images were obtained 15 minutes after injec-
`tion of Gd—DTPA at 0-1 mmol/kg.
`The presence and number of enhancing
`lesions on T1 weighted postcontrast images
`were identified directly from the computer
`screen with a multislice view. The volume of
`enhancing lesions was estimated with a semi-
`automated local
`thresholding technique by
`analysing each slice in turn (Sun Microsystem,
`Mountain View, CA, USA).“
`T2 weighted images were analysed at the
`baseline and the seventh scan with a semiauto-
`mated thresholding technique.” The number
`of new lesions and the change in total lesion
`volume from baseline to the seventh scan were
`compared.
`
`DATA ANALYSIS
`
`The presence of at least one enhancing lesion
`(enhancing scan), the number and volume of
`
`Deparunent of
`Neurological Sciences,
`University of Rome
`“La Sapienza”, Italy
`T Koudriavtseva
`M Fiorelli
`C Gasperini
`S Bastianello
`A Bonao
`A Paolillo
`A Pisani
`C Pozzilli
`
`Institute ofNeurology,
`Queen Square,
`London, UK
`A J Thompson
`Deparunent of
`Neurology, S Camillo
`Hospital, Rome, Italy
`S Galgani
`Correspondence to:
`Dr Tatiana Koudriavtseva,
`Dipartimento di Scienze,
`Neurologiche, I Clinics
`Neurologica, Universita “La
`Sapienza’ di Roma, Viale
`dell’UniverSita 30, 00185
`Roma, Italy.
`Received 18 July 1 996
`and in revised form
`11 November 1996
`Accepted 20 November 1996
`
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`286
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`Koudria'vtse-ua, Thompson, Fiorelli, Gasperini, Bastianello, Bozzao, et al
`
`total enhancing lesions and total lesion volume
`on T2 weighted images on the baseline scan
`were considered as the baseline MRI parame-
`ters.
`
`The occurrence of relapses over the six
`month follow up period was defined as the
`indicator of clinical activity.
`Activity on MRI included the mean number
`and volume of monthly enhancing lesions
`(total and new) over the follow up, the num-
`ber of new lesions, and the change in total
`lesion volume on T2 weighted images from
`baseline to seventh scan.
`The relations between all baseline MRI
`parameters
`considered as being potential
`determinants and indicators of disease activity
`were evaluated by linear regression analysis
`and logistic regression analysis. Unpaired t
`tests and 12 tests were also used.
`
`Results
`BASELINE CLINICAL/MRI FEATURES
`We studied 68 patients with relapsing-remitting
`multiple sclerosis (21 men and 47 women).
`Mean (SD) age was 30-5 (7-3) years, disease
`duration was 5-0 (2-9) years, and expanded dis-
`ability status scale (EDSS)
`score was 2-15
`(0-9). The number of relapses in the previous
`12 months was 1-5 (0-8) and the time between
`the last relapse and study entry was 5-1 (3-2)
`months.
`The mean (SD) number and volume of
`enhancing lesions on baseline scan were 1-8
`(3-6) (range 0 to 23, median 1) and 231 (403)
`mm3 (range 0 to 2335, median 75) respectively.
`The mean total lesion volume on T2 weighted
`
`
`
`
`
`Table 1 Association of baseline MRI parameters with indicators ofMRI disease activity
`during a six month follow up
`Indicators ofMRI activity
`Predictive baseline
`
` MRI parameters duringfollow up [3 (SEM) P value
`No of enhancing lesions
`Mean No of monthly
`enhancing lesions
`Mean No of monthly
`new enhancing lesions
`No ofnew lesions on T2
`Mean volume of monthly
`enhancing lesions (mm’)
`Change in total lesion
`volume on T2 (mm’)
`Change in total lesion
`volume on T2 (mm’)
`
`Volume of enhancing
`lesions (mm’)
`
`Total lesion volume on
`T2 (mm’)
`
`B = linear regression coefficient.
`
`1-02 (0-08)
`0-92 (0-07)
`058 (0-17)
`
`1-09 (0-17)
`213 (1-05)
`
`< 0-0001
`< 0-0001
`< 0-0001
`
`< 00001
`< 005
`
`0-12 (0-04)
`
`< 0-001
`
`images was 13 201 (11 548) mm3 (range 1135 to
`48 890, median 8975). An enhancing baseline
`scan was seen in 35 (51%) of the 68 patients.
`The number of relapses in the year before study
`did not predict the presence of enhancement on
`the baseline scan, whereas the time between the
`last relapse and baseline scan did so (P = 0-02,
`unpaired t test).
`
`CLINICAL AND MRI FINDINGS OVER THE SIX
`MONTH PERIOD
`
`Thirty six patients (53%) had a total of 58
`clinical exacerbations, 43 of which required
`treatment with corticosteroids.
`Enhancing lesions were detected on 238
`(58%) of 407 scans. The mean (SD) number
`of monthly total and new Gd enhancing
`lesions per patient were 3-0 (4-3) (range 0 to
`23-5, median 1-5) and 2-6 (3-8) (range 0 to
`21-7, median 1-3) respectively, and the vol-
`ume of total enhancing lesions was 471 (693)
`mm3 (range 0 to 3708, median 193). The
`presence of at least one enhancing scan over
`the six month period was noted in 33 of the 35
`patients (94%) with enhancing baseline scan
`and in 28 of 33 patients (85%) with unen—
`hancing baseline scan.
`
`RELATIONS BETWEEN BASELINE MRI
`CHARACTERISTICS AND INDICATORS OF DISEASE
`ACTIVITY
`
`Twenty three of the 35 patients (66%) with an
`enhancing baseline scan and 13 of the 33
`patients (39%) with a non-enhancing scan had
`a relapse. At
`logistic regression analysis, a
`baseline enhancing scan significantly predicted
`the occurrence of relapses (odds ratio 32,
`95% confidence interval 1-2—8-9, P < 0-05).
`At
`linear regression analysis the number of
`enhancing lesions on the baseline scan was
`predictive of the number of monthly total and
`new enhancing lesions (P < 0-0001) whereas
`enhancing volume predicted the volume of
`monthly total enhancing lesions (P < 0-0001;
`table 1). Similar results were found when the
`first scans after each methylprednisolone treat-
`ment were excluded (43 of 407 scans; data not
`shown).
`The number of enhancing lesions on the
`baseline scan also predicted the number of
`new lesions on T2 weighted images from base—
`line to seventh scan (P < 0-0001). Finally, the
`total lesion volume on T2 weighted images
`and the volume of enhancing lesions on the
`baseline scan predicted the change in total
`lesion
`volume
`on T2 weighted images
`(P < 0001 and P < 0-05 respectively; table 1).
`The patients with three or more Gd
`enhancing lesions on baseline scan had a sig—
`nificantly higher rate (100% probability) of
`occurrence of new lesions and of an increase in
`total lesion volume on T2 weighted images at
`follow up compared with those with two, one,
`or no enhancing lesions (P = 0-03 and P =
`0-01, 12 test respectively). However, the proba—
`bility of having a clinical relapse in the patients
`with three or more enhancing lesions on the
`baseline scan was not significantly different
`from that of the others (P = 0-4,
`952
`test;
`table 2).
`
`Table 2 Relation between Gd enhancing lesion: on baseline MRI and disease activity
`over a six month period
`No of Gd enhancing lesions on baseline MR1
` 0 1 2 3 z 4
`
`
`
`
`No of patients
`33
`ll
`10
`5
`9
`No of patients with increased
`total lesion volume on T2
`No of patients with
`new lesions on T2
`No of patients with relapses
`No of new enhancing
`lesions/month/patient:
`9-]
`5-1
`1-9
`1-9
`1
`Mean
`6-3
`6-8
`1-8
`1-3
`0-5
`Median
`
`
`
`
`
`0—7-3 0—5-3 02—37 0578-3Range 3721-7
`Values in parentheses are %.
`
`22 (68)
`
`20 (61)
`13 (39)
`
`7 (64)
`
`10 (91)
`7 (64)
`
`6 (60)
`
`8 (80)
`7 (70)
`
`5 (100)
`
`9 (100)
`
`5 (100)
`3 (60)
`
`9 (100)
`6 (67)
`
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`Gadolinium enhanced MRI predicts clinical and MRI disease activity in relapsing-remitting multiple sclerosis
`
`287
`
`Discussion
`The type of clinical course or the phase of dis-
`ease are poor predictors of subsequent wors-
`ening in multiple sclerosis and there is some
`evidence that MRI may be superior in this
`respect.7 3 ‘2 '3
`This study demonstrates that the presence
`of a single enhancing scan is predictive of sub—
`sequent
`relapse. Because patients with an
`enhancing scan will develop more enhancing
`lesions during follow up, it is likely that one of
`these lesions could be located in a clinically
`relevant brain area.
`We found that the number of enhancing
`lesions on the baseline scan predicts the mean
`number of total and new enhancing lesions
`during the follow up period. Miller et al have
`similarly reported that a single enhancing MRI
`can be quite strongly predictive of the amount
`of enhancing activity in the next
`three
`months.” Furthermore,
`the number of new
`lesions and the increase in total lesion volume
`on T2 weighted images from baseline to sev-
`enth scan were predicted by the number and
`volume of enhancing lesions
`at baseline
`respectively. These data strongly suggest that
`the more active the disease, the greater the
`accumulation of permanent
`abnormalities
`even over a brief follow up period. This is not
`surprising since longitudinal MRI studies have
`previously shown that most enhancing lesions
`are followed by permanent T2 abnormalities.”
`The change in total lesion volume on T2
`weighted images is also predicted by the total
`lesion volume on the baseline scan. This find—
`ing complements previous MRI studies, which
`demonstrated that in patients with a clinically
`isolated syndrome suggestive of multiple scle-
`rosis the lesion load at presentation correlates
`with increase in lesion load at five year follow
`up? 6
`Our study supports the role of Gd enhanced
`brain MRI as a possible surrogate marker for
`exploratory or preliminary phase II trials. In
`this respect, the term “surrogate” seems to be
`appropriate as
`it
`indicates
`a non—clinical
`assessment which may predict short
`term
`disease
`activity. Furthermore,
`the highly
`predictive value of three or more enhancing
`
`lesions on baseline scan for subsequent MRI
`activity emphasises the importance of includ-
`ing MRI in relatively short term trials.
`
`We thank Professor Cesare Fieschi, Professor Luigi Bozzao, Dr
`Giuseppe Piazza
`(Depamnent of Neurology, S Camillo
`Hospital, Rome), Dr Massimo Filippi
`(Department of
`Neurology,
`Scientific
`Institute Ospedale San Raffaele,
`University of Milan, Milan, Italy), and Dr Mark A Horsfield
`(Division of Medical Physics, University of Leicester) for help—
`ful suggestions; Dr Roberto Camerini, Dr Carla Buttinelli, and
`Dr Enrico Nlillefiorini for their assistance and eflort; and Ares
`Serono for financial support.
`
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