Serial Gadolinium—enhanced Magnetic
`Resonance Imaging Scans in Patients with
`Early, Relapsing—Remitting Multiple
`Sclerosis: Implications for Clinical Trials
`and Natural History
`
`Jonathan 0. Harris, MD,’ Joseph A. Frank, MD,i§ Nicholas Patton-as, MDfii Dale E. McFarlin, MDf
`and Henry F. McFarland, MD'
`
`
`Six patients with early, mild, relapsing-remitting multiple sclerosis were studied with monthly gadolinium—enhanced
`magnetic resonance imaging scans for 8 to 11 months. Numerous enhancing lesions were observed irrespective of
`clinical activity. Four of the 6 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 correiated 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, relapsingremitting multiple sclerosis who are clinically stable. The frequency
`of these lesions appears to be sufficient to use as an outcome measure in clinical trials testing clinical efficacy in patients
`with early, relapsing-remitting multiple sclerosis.
`
`l-IarrisJO, FrankJA. Patronas N. McFarlin D13, McFarland HF. Serial gadoliniumrenhanced magnetic resonance
`imaging scans in patients with early relapsing-remitting multiple sclerosis: implications for
`clinical trials and natural history. Ann Neurol 1991;29:548—355
`
`
`In spite of extensive investigations, multiple sclerosis
`(MS) remains a disease of uncertain cause and without
`an effective treatment. An immunopathological pro-
`cess is generally posrulated to contribute to the patho-
`genesis, and various forms of immunosupptessive 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 reflecr
`disease activity. Therapeutic trials have usually in—
`volved patients with chronic, progressive disease and
`with moderate to severe disability. It has been argued
`that
`the course in the chronic, progressive phase of
`the disease is more predictable and the relationship
`between the risk and the benefit 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.
`
`Recent studies in patients with MS, with magnetic
`resonance imaging (MRI), suggest the presence of dis—
`ease activity as measured by new abnormalities on T2-
`weighted images or by gadolinium—enhancing losions 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 to further define the natural history of the
`disease in this early phase. To date, 6 patients with
`early, relapsing-renutting disease have been studied at
`monthly intervals for 8 to 11 months. These patients
`had only mild disability and were generally clinically
`stable during the period of the study. Substantial num-
`
`From the 'Nettroimmunology Branch, and the TDiagnostic Radiol-
`ogy Department. National Institutes of Health. Bethesda, MD, and
`the Departments of iRarlioiogy and §lnternal Medicine, George-
`town University Medical Center. Washington, DC.
`
`Received Sep 1?). i990. and in revised form Nov 15. Accepted For
`publication Nov 19, E990.
`Address correspondence to Dr McFarland. Neutoimrnunology
`Branch. National Institutes of Health. Building [0. Room 5316,
`Bethesda. MD 20892.
`
`548 Copyright (Ii) l991 by the American Neurological Association
`
`Page 1 of 8
`
`stew (are clog
`
`
`
`
` M.—III-Imhbtesi.
`
`Biogen Exhibit 2221
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`IPR 2018-01403
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`Page 1 of 8
`
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`

`

`Tabfe I . Clinical Characteristics of Patients at Onset Qmedy
`
`Age (yr)
`
`Sex
`
`Duration
`of MS
`(mo)
`
`Month
`after Last
`Exacerbation
`
`EDSS
`at Firs:
`Month
`
`EDSS
`at Last
`Month
`
`WBC
`(VCSF)
`
`lgG
`Index
`
`Presence of
`OCB
`
`Patient No.
`—
`0.65
`0
`1.5
`1.5
`3
`5
`F
`45
`1
`+
`1.?0
`0
`1.5
`1.5
`5
`10
`F
`29
`2
`+
`1.06
`1
`2.0
`2.0
`8
`32
`F
`40
`3
`2
`8
`M
`25
`4
`+
`0.69
`4
`1.5
`1.5
`+
`2.50
`25
`1.5
`1.5
`4
`13
`F
`26
`5
`+
`1.93
`2
`2.5
`5.5
`4
`35
`F
`59
`6
`
`1.9 1.8
`.
`.
`4.5
`l?.2
`.
`34
`Mean
`
`MS '—-w multiple sclerosis; EDSS = Expanded Disability Status Score; WBC = white blood cell count; CSF = cerebrospinai fluid; OCB :
`oligocional 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 patients with MS, referred by local physicians to be con-
`sidered for ongoing clinical studies, were selected for this
`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—remitting diseases (i.e., an Expanded
`Disability Status Score [EDSS] of 3.5 or less) [9}, and would
`be able to compiete monthly MRI scans. Informed consent
`was obtained from each patient before starting the Study.
`
`Pcm‘em finalization
`Patients were admitted to the Clinical Center. National Insti-
`tutes of Heaith (Bethesda, MD), for complete physical and
`neurological examination, lumbar puncture, and the initiai
`MRI scan. Subsequently, patients were examined and imaged
`monthly (every 11 weeks) at the same time of day. The exam~
`ining physician (H. M.) was blinded to the results 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 lasdng more
`than 24 hours. Histories of increased symptoms that repre-
`sented either mild changes in preexisting symptoms or were
`not associated with new or changed signs were iudged insuf—
`ficient to ciassify as an exacerbation. During the study. some
`patients were also noted to have changed or new neuroiogicai
`signs; these were usually mild, not associated with new symp-
`toms, and classified as changed signs, not exacerbations.
`
`MRI Scam
`Imaging was performed monthly for 8 to 11 months in 6
`patients. Reproducible head positioning from month to
`month was assured by placing one vitamin E capsule in the
`external ear canal and taping a second at the lateral canthus
`
`Page 2 0f 8
`
`of the eye. The canthai meatal line between these capsules
`delineated the plane of each scan. MRI scans were per-
`formed on a General Electric Signa 1.5 T (General Electric,
`Milwaukee, WI) by using a TZ-weighted spin echo pulse se-
`quence with an echo time (TB) of 80 msec, a repetition time
`(TR) of 2,000 msec, 2 excitations, a 128 X 256 acquisition
`matrix, and 5-mm contiguous interieaved slices. Tl-weighted
`spin echo (TR GOO/TE 20) images of the brain were per-
`formed before and after GdDTPA (Magnevist 0.1 mmole.’
`kg, Berlex laboratories, Cedar Knoiis, NJ} was administered
`using 2 excitations, a 192 X 256 acquisition matrix, and
`5-mtn contiguous interleaved slices. All Studies were per-
`formed with a field of View of 24 cm.
`
`Image finalization
`'I‘l-weighted images after contrast were visually compared
`with Tl-mreighted images before contrast. Most enhancing
`lesions are easily recognized as areas of increased signal intenh
`sity in the white matter. Questionable small areas ofenhanco
`ment near the cortical surface were excluded from the analy-
`sis. Moreover, possible smail areas of enhancement in the
`white matter were not included uniess a corresponding area
`of abnormality was identified on the ”IQ-weighted images.
`New enhancing iesions were defined as lesions that were
`nor present on the T1 —weighted enhanced MR1 performed 1
`month previously.
`
`Results
`
`Clinical Characteristics of Patient:
`The 6 patients examined in this study had eariy, miid
`MS of the relapsing-remitting form. Their clinical char-
`aCteriStics at the onset of this study are shown in Table
`1. The mean duration of disease, dated from the firsr
`ciinical sign or symptom, was 1?.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-
`ering from a period of worsening before entry into this
`study. All of the patients had experienced an exacer-
`bation within 8 months before entry. Cerebrospinal
`fluid findings consistent with the diagnosis of MS (an
`eievated immunoglobulin IgG index and oiigoclonal
`bands) were found in ail but 1 patient.
`
`Harris et al: Serial Enhanced MRI in MS
`
`549
`
`Page 2 of 8
`
`

`

`”ladle 2. Climbs! Carma ofPafr'errt;
`GdDTI’A-i—
`Lesions
`T2 Lesions
`Change in
`Change
`Exacerbations
`in Signs
`Symptoms
`Fatigue
`on Initiai
`Per Scan
`Scans (11}
`(n)
`(11)“
`(of
`tn)‘l
`Scan in)
`(mean, n!
`
`
`Patient No.
`3.6
`41
`5
`6
`1
`0
`8
`i
`0.?
`22
`4
`0
`0
`0
`ll
`2
`1.6
`46
`2
`2
`2
`0
`I
`l
`3
`3.0
`(vi
`1
`2b
`2b
`1
`8
`4
`2.6
`75
`0
`3b
`2b
`1
`11
`3
`6.2
`.711
`4
`ti
`1
`0
`11
`6
`
`
`
`
`
`60 2 8 E"Total i6
`
`‘Numbcr of occasions.
`hOne occasion was associated with an exacerbation.
`
`The patients were clinically evaluated monthly at the
`time of MRI examination for a total of 60 occasions.
`
`Table 2 summarizes the clinicai course of patients dur-
`ing the study. There was no permanent worsening in
`the patients' level of disability. 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 B‘DSS that persisted for 1 month. One
`exacerbation occurred in 1 patient (Patient 4}. It oc-
`curred in the seventh month and was characrerized by
`decreased temperature sensation in the right foot that
`resulted in a 0.5 increase in the EDSS, which returned
`to baseline the next month. A third patient (Patient
`6) entered the scudy with an EDSS score of 3.3 and
`subsequently improved to a score of 2.5, predomi—
`nantiy due to improvement of strength in the lower
`extremities. The EDSS score did not change in the
`remaining 3 patients.
`
`MRI Findings
`The initial MR! scans of the 6 patients were consistent
`with early, mild MS. T2-weighted images showed dis—
`crete lesions that were generally periventricular. This
`pattern did not change significantly by the end of the
`study period. After adminisrration of GdDTPA, nu-
`merous enhancing lesions (:1 = 29) were noted on
`T1-weighted studies. All of these enhancing lesions ex-
`hihited 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 ].
`
`LONGWUDINAI. sruoms. The frequent occurrence of
`enhancing iesions was confirmed by analysis of the se-
`rial Studies. New enhancing lesions (n = 115) occurred
`in all patients during the course of the study. The num-
`her and time course of enhancing lesions in individual
`
`550 Annals of Neurology Vol 29 No 5 May E99}.
`
`Page 3 0f 8
`
`patients are shown in Figure 2. Each patient appeared
`unique With respect to the number of new Eesions and
`differences from month to 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 Patient 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 number of enhancing lesions seen on MRI
`scans is neted in Table 2.
`
`CLINICAL CORRELnTIONS. There was almost total lack
`of clinical correlation with numbers or iocations of the
`
`enhancing lesions. Patients who had exacerbations or
`had changed signs or symptoms insufficient to be classi-
`fied as an exacerbation did not have enhancing lesions
`that could explain those findings. It
`is possible that
`some of the clinical changes were related to acrive le—
`sions in the spinal cord, which was nor studied. Exacer—
`bations and changed signs or symptoms are nored on
`individual graphs (see Fig 2). in addition to the lack of
`correlation with specific signs and symptoms, there was
`also no correlation between the frequency of lesions
`and general clinical changes,
`including subiective as-
`pects of fatigue (see Table 2). Patients with a higher
`mean number of lesions per scan, however, tended to
`complain more frequently of symptoms {r2 = 0.47).
`
`EVOLUTION or ENHANCING LESIONS. Mosr new enhanc-
`ing iesions did tint enhance on the next scan 1 month
`later. Excluding lesions enhancing on the firsr and last
`scan, for which the torai duration of enhancement can-
`
`not be calculated, 94 new enhancing iesions were ob—
`served. Sixty-nine of these did net enhance 4 weeks
`Eater. Twenty lesions continued to enhance for greater
`than 4 weeks but less than 8 weeks. Three lesions
`persisted longer than 8 weeks but less than 12 weeks,
`
`Page 3 of 8
`
`

`

` C
`
`D
`
`Fig I. Represerzmu'zre magucn'c resonance image: from 1 pa-
`rim! (Patient 6} at {be beginniug (A. B) and cm! of amulmfi-
`(C, D}. Panels A am! C are T2vu'efigbted imagej. Pariefj B and
`D are T'I—wrigbted z'magas afler admimflmrim {Jgadnfmuemle
`dz'lmglzmzirze fGa’DTPA}. Rabarrring [axiom appear as region! (J
`
`I'rzrrmred signal imemiry nubile) rm 341409;}:th image: afier
`aliitiniflmfiau afGrIDTP/L Nate the Jize and rehab” 6rr'gr5meu
`{Ifgrmf {Warm-5}} {If (be T2 [tsiam‘ h’mt mn‘afpand m [be en-
`[gaming {ejfamu
`
`Page 4 0f 8
`
`Harris er a1: Serial Enhanced MRI in MS
`
`iii
`
`Page 4 of 8
`
`

`

`PATIENT 1
`
`S
`
`PATIENT 2
`
`
`
`“-2
`O
`E
`L14
`._1
`
`0
`z
`‘2’
`:2
`I
`E
`11:
`
`MONTHS
`B
`
`
`m
`2
`Q
`(.0
`L11
`
`J
`g
`a
`2
`g
`z
`Lu
`3:
`
`A
`
`m
`2
`9
`m
`Lu
`
`J
`<5
`E
`0
`2
`§
`2
`m
`a;
`
`C.
`
`tn
`2
`g
`“3
`3
`{.5
`g
`O
`z
`4
`g
`Lu
`4*
`
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`
`PATIENT 4
`
`m
`g
`a
`u:
`_:
`
`{5
`z
`:3
`z
`4
`=2:
`LU
`it
`
`D
`
`
`
`3
`o
`"c5
`E
`
`g
`..
`3
`1E
`1‘.
`5
`3|:
`
`MONTHS
`
`F
`
`MONTHS
`
`Fig 2. Graphs A—F .rbow patterns of erzbanremm: in indirid-
`1m! pariah“ (Patient; 1—6.
`:vspectir'elj-J‘. Tbs Jar/id zrppw' mm:
`shale-1t If}? mm! number ofenhancing 1:51}erfrom ear]: mam/J. T/Je
`Jamar. drzibed [inc Term]: Ilse rota! numém' of new enhancing 11>-
`.riom em}: womb. Ar: “X" mark; the time of marerbatian. A}:
`"S" Jfiqritfiex mild Sign: ar symptom“ that did not meal Ilse rrileria
`fin- an) matey-write» (sec Malawi}.
`
`552 Annals of Neurology V0! 29 No S May 199].
`
`Page 5 0f 8
`
`Page 5 of 8
`
`

`

`Table 3. Letitia Development W-‘b‘f Time A; 55mm k; 'I‘2-wet‘glired MRI 5mm
`Month
`
`LCsionNo.
`
`i
`2
`3
`4
`5
`6
`7
`8
`9
`10
`11
`12
`15
`14
`15
`16
`E?
`
`E8
`1‘)
`
`l
`
`C
`O
`o
`o
`0
`O
`O
`
`3‘
`O
`
`?
`O
`o
`
`O
`
`2
`
`O
`O
`I
`0
`O
`0
`0
`O
`.3
`?
`C}
`
`O
`
`3
`
`O
`O
`O
`O
`O
`O
`O
`0
`O
`O
`O
`O
`?
`..
`?
`
`4
`
`O
`O
`O
`O
`O
`O
`O
`O
`O
`O
`O
`O
`O
`O
`?
`
`0
`
`0
`>
`
`O
`
`O
`
`
`
`OOOIO0000000000000000
`
`
`
`wooo;ooo;o~oooooooooogooooow
`
`O
`fl
`O
`22
`?
`?
`..
`23
`?
`O
`?
`O
`24
`O
`O
`5
`O
`25
`?
`O
`c
`O
`26
`
`27
`O
`,
`2
`o
`
`:3
`
`-.l
`
`\C
`
`,_.C
`
`H .._.
`
`
`
`oowooooo;oooooooooooogooooow
`
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`
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`
`ooooooooworoooooooooogooooo
`
`Open circles represent increased signal intensity on Til-weighted images :11 the site of enhancing lesions. Filled circles document the month or
`months when enhancement was seen. A question marl-t denotes a possible T2 abnormality that could not definitively be Separated From
`background "noise.” Elipsis (.
`.
`.) indicates on T2 abnormality was seen. Lesions 15, 1?, and 19 are examples of lesions occurring in previously
`normal white matter. whereas lesions 15, 20, and 26 are enhancing lesions in old plaques. Very small iu‘ens with increased signal intensity on
`TZ-wcightcd scans were oFten noted to predate enhancing lesions by l to 2 months. Lesions 18 and 21 are examples of this phenomenon.
`MRI = magnetic resonance imaging.
`
`and two additional lesions persisted for longer than 12
`weeks but less than 16 weeks. No lesions 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 the possibility that enn
`hancing lesions of longer duration may occur in pa-
`tients with more severe disease activity.
`
`PERSISTENCE OF '1‘2 ABNonsmtn'ms. Enhancing lesions
`occurred in two contexrs. The lit-St was s new enhanc—
`
`ing lesion in an area that appeared to have normal sig—
`nal intensity on prior MRI scans. The second context
`was at the site of abnormal signal intensity that had
`been present from the Start of the Study and 1110.9: likely
`represented enhancement at the border of an older
`plaque. Enhancing lesions in the first context usually
`evolved into persistent TZ—weighted abnormalities. in
`the second context, older lesions generally appeared
`to enlarge. Only rarely did enhancing lesions resolve
`without subsequent abnormalities. A detailed chronol-
`
`Page 6 0f 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-weightecl
`abnormalities persisred in 25 of the 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 determine if this method could be used
`to measure change in amount of diseased tissue over
`time (data not shown). This approach was not satis-
`facrory because of the frequent occurrence of enhanc-
`ing lesions that were visualized as large abnormalities
`in "IQ—weighted sequences but
`that
`resolved into
`smaller T2-nonenhancing lesions in later images. Con—
`sequently, the inclusion of these regions in the analysis
`gave artifactually large increases or decreases in dis-
`eased tissue, depending on whether the enhancing le—
`sion was present on the initial or final scan.
`
`Harris et 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 without significant disability. 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 MR1 scanning, was seen in all pa—
`tients. 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 not 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 m05t
`new enhancing lesions persisted as permanent abnor-
`malities on T2—weighted images at the end of the 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
`MS is based on clinical expression of neurological signs
`and symptoms over time. Conceptualiy, MS has been
`thought to be “active" when the patient is in a clinical
`relapse, and "stable” or “inaCtive” between relapses.
`From pathology studies, however, it has been long apw
`predated that little correlation 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 MRI
`have documented lesions developing without clinical
`expression l: 1—.7, 12—14]. Our results confirm and ex-
`tend these findings. One interpretation of these results
`is that disease activity 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 that enhancement on MRI scans may often better
`reflecr acrual disease activity than reliance on only clini-
`cal signs and symptoms. If this is correct, the 6 patients
`in this study had continuous disease acrivity. It is can-
`tioned that the sample size is small and it is net possible
`to estimate how frequent this level of disease aCtivity
`would be in a larger population of patients with similar
`clinical characteristics.
`
`Third, Opening of the blood-brain barrier seems to
`be related to new lesion development and enlargement
`of preexisting lesions. As shown in Table 3, almost
`all enhancing lesions are followed by permanent T2
`abnormalities. These findings indicate that GdDTPA
`enhancement has a close temporal relationship with the
`fixed T2 abnormalities prominent in patients with MS.
`
`554 Annals of Neurology Vol 29 No S May 1991
`
`Page 7 0f 8
`
`Consequently, it seems likely that the opening of the
`blood-brain barrier represents an early, if not the ini-
`tial, event in lesion develoPment. The relationship be—
`tween 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].
`It
`is not 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 nor address the relationship between
`disease acrivity, as reflected by MRI scans, and eventual
`disability. {t can be posrulated 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 between enhancing MRI lesions and disability,
`however, will depend on the long-term follow—up of
`patients such as those described in this report. The
`absence of enhancing lesions in the brain does nor nec-
`essarily assure less disability because lesions can also
`occur in the spinal cord, often resulting in pronounced
`disability. 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 suggesred by the 2 patients nored 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 the pathogenesis and natural history
`of MS, our results have implications for clinical trials
`in patients with mild MS. Currently, clinical measures
`of outcome such as reported symptoms, repeated phys-
`ical examinations, disability scales, 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}, then clinical
`parameters may net be reliable measures of suppres-
`sion of disease activity in this phase of the illness.
`Clearly, in this study, clinical parameters did no: accu-
`rately refiecr changes documented by MR! 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 that enhance are
`easily detected and measured on T1-weighted images
`after GdDTPA administration.
`In view of their fre-
`
`quency and ease of detection, suppression of enhanc-
`ing lesions could be used as the principal outcome vari-
`
`Page 7 of 8
`
`

`

`treatment trials. Short
`able in relatively short, pilot
`trials are important to contain costs as well as to limit
`the exposure of patients to pocentially toxic treatments.
`Based on our results, the design of a phase [I treat-
`ment
`trial can be derived. Monthly enhanced MRI
`scanning from 4 to 6 months seems sufficient to esrab-
`lish the pretreatment baseline frequency of enhance-
`ment. This would be followed by a treatment period
`lasting from 6 to 8 months, again with monthly MRI
`scans. Elimination or pronounced reducrion of enhanc-
`ing lesions with treatment would be used to test thera-
`peutit efficacy.
`The results described in the present Study may be,
`in part, unique for patients with early, mild, relapsing—
`rcmitting MS. The frequency of enhancing lesions may
`vary subsmntially in patients with other disease charac—
`teristics. It has been recently reported that the 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 number of lesions or the area or volume
`of increased signal intensity on TIE-weighted scans at
`the beginning and end of the Study, also appears to be
`a possible outcome measure, useful
`in clinical
`trials.
`Counting the number of individual lesions is inaccurate
`because many became confluent and, without precise
`three-dimensional representations of lesions, they can-
`not be easily enumerated. Our initial effort to assess
`area or volume ofdiseased tissue was also discouraging.
`The frequent occurrence of enhancing lesions made
`calculating the surface area of lesions on T2—weighted
`images difficult and prone to overesrimating true lesion
`burden. The continuing technological advances being
`made in computer analysis of MRI scans may eventu~
`ally alleviate this difficulty.
`Our findings sage-st that MS is a progressive disease
`even during the early stages when it appears clinically
`Stable. MRI provides a sensitive method for detecting
`patients with MS, with MRI evidence of active disease.
`We hope MRI can be combined with experimental
`therapies to identify quickly and more safely those
`therapies that may be effecrive in patients who will
`most likely benefit from treatment, that is, those pa-
`tients with mild, relapsing-remitting disease.
`
`We thank Ms Susan Inscue and Ms Jeannette Black for their excel-
`lent technical magnetic resonance imaging skills throughout this
`
`study. We also thank Ms Heidi Maloni for her excellent assiscance
`with patient care and planning throughout this study. This work was
`performed in the In Vivo Nuclear Magnetic Resonance Research
`Center of the National Institutes of Health, Bethesda, MD.
`
`a]
`
`3.
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