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Comparison of triple dose vs standard dose gadolinium-DTPA for detection of MRI enhancing lesions in patients with primary progressive multiple sclerosis
.A REPETITIVE DNA SEOl’ENCE 5’ T() THE Hl!MAN PROTEIN GENE MAY BE LINKED TO MULTIPLE DANISH PATIENTS
MYELIN BASIC SCLEROSIS IN
ASSESSMENT TREATMENT
OF THE EFFICACY OF COPOLYMER-l OF MS BY QUANI=ITA’IJVE MRI
IN THE
JA, RI Grossman, JK Udupa, S Samarasekera, Y M&i. H Hait. M Grossman, CS Constantinescu, DL Kolson, F Gonzalez-Scarano, DH Silberberg, KP Johnson. Cleveland Clinic, Cleveland, OH, Univ. of Penn., Philadelphia, PA; Univ. of Maryland, Baltimore, MD; Teva/Lemmon, Kulpsville, PA; USA The recently completed Phase III trial of Copolymer-l (Cop-l. waxone@) demonstrated it to be well-tolerated and to reduce relapse rate and development of disability in ambulatory patients with relapsingremitting MS. The present studies were undertake to assess the utility of MRI as a surrogate measure of MS disease activity and severity in a clinical trial. 27 patients enrolled in the Cop-l trial at the Univ. of Penn. underwent serial MRI studies at Months 0, 1.3.6, 12,18,20,22, and 24. Axial fast spin echo images approximating proton density (PD) and T2weighted (TZ-WI) images (3 mm contiguous slices, TR 2500 msec. TE 1890 msec) and axial Tl-WI (3 mm contiguous slices, TR 600 msec, TE 27 msec) before and after gadolinium (0.1 mmolkg) were acquired at 1.5 Tesla. Volumetric analyses were performed using 3DVIEWNIX, a fullyautomated image analysis program that segments images by manipulation of fuzzy-connected components (pixels) based on their signal intensity. 3DVIEWNIX requires 30 sec. of operator time per case and is highly reproducible, with maximum intra- and inter-rater variability in lesion volume determination of less than 1.5% spanning the range of total T2lesion burden. As expected, total cerebral lesion volume (increased signal on PD/T2-WI) varied substantially between patients. Surprisingly, selected individual patients exhibited as great as 5-fold changes during the study. Disease activity, measured as the number of enhancing foci, varied between studies from 0 to 9. Determination of the volumes of gadolinium enhancement is in progress. Suggestive trends favoring Cop-l were seen in changes in total TZ-lesion volume over time and gadolinium enhancement. However, these studies did not have sufficient statistical power to demonstrate a clear-cut treatment effect. Quantitative MRI has become a frequently-used supplementary measure in experimental therapeutic studies in MS. However, variability in total ‘I%lesion volume complicates its use as a treatment endpoint.
The myelm basic protein MBP gene 1s a can&date locus for disease suscepttbility tn multlple sclerosis (MS). In the present study a part of the tetranucleotide (TGCA), repeat polymorphism 5’ to the MBP gene situated between 5’1 I16 and 5’19 I7 bp was examined in 90 Danish MS patients and 106 controls. Lymphocyte DNA was isolated and used m PCR a\+ay. The PCR fragments were separated by electro-phoresis. Hereby we found three different band patterns, I.e. a homozygote with a 450 bp fragment, a homozygote with a fragment of 350 bp and a heterozygote with both bands present. The 450 bp fragment occurred significantly more often among MS pntlents than in the control group tp
gene the 5’ interfound
NO INCREASE OF SERUM AUTOANTIBODIES AFI-ER SHORT-TERM THERAPY WI-I-H IFN-BETA IN RELAPSINGREMITTING MULTIPLE SCLEROSIS
COMPARISON
OF TRIPLE
DOSE VS STANDARD
DETECTION OF MRI ENHANCING PROGRESSIVE MULTIPLE SCLEROSIS.
LESIONS
u, M Filippi, *A Campi. B Colombo. Depts of Neurology and *Neuroradiology. LJniversrt& di Milano (Italy).
(prr-trortmcnt prnod), hx patwnts werv randomly assqnrd to two trP&nrnt groups, whrh rrs rl wcrk for 6 months. The followmg serum autwmtihodies were mwsur4 *ftw 3 and 6 months of the prr-treatmmt period, and after 3 and 6 months of IFh-hrtd thrmpy: .mtinuilear (ANA), an&thyroid, antiirardiolipti (aCLA, holh CPL and MPL). Onr patient dmpprd out during the first month of thwapy. 2nd
ANA
I
ANA
1 X1
lb/64
1 x0
7/(*1(1113Ya)
Ant,-Lhvr.
(2.3
2/M
(2‘9%)
LLA
MPL
l-l/68
(20
&LA
GPL
Z/M
(2.Y%)
l’atwnt+
who
wcrc
5%)
h%)
positive
Pretreat
20/6x
l2Y4%l
11/67
llb.4%1
Y/&
(13.2%)’
h/b7
2/w
(2.9%)
l/*7(1.5%)
5/w
(7 4%)
n/67(11
3/N)
(4.4%)
3/67
for ANA
at 1:4ll wcw
pi”%)
/ ,_ lY/671284%i W/67
t
(14.9%;
O/h7 YX) (4.5%)
also tested
W/h7 3/67
(2?.Y%l
*C Per&a, *G Scotti, N Canal. IRCCS Ospedale San Raffale,
This study was performed to evaluate whether a triple dose. (TD) of gadolinium-DTPA (Gd-DTPA) increases the sensitivity of brain magnetic resonance imaging (MRI) for detecting enhancing lesions in patients with primary progressive muhiple sclerosis (PPMS). T 1 -weighted brain MRI scans were obtained for 10 patients with PPMS in 2 sessions. In the first session, one scan was obtained 5 to 7 minutes after the injection of 0.1 mmol/kg GdDTPA (standard dose, SD). In the second session. 6 to 24 hours later, one scan before and two scans 5 to 7 minutes and one hour after the injection of 0.3 mmol/kg Gd-DTPA (TD) were obtained. Four enhancing lesions were detected in 2 patients with the SD of Gd-DTPA. The numbers of enhancing lesions increased to 13 and the numbers of patients with such lesions to 5 with the TD and to 14 and 6 in the one-hour delayed scans. The mean enhancing area/patient was 6.8 mm2 (range=O-25.6 mm2) in the SD yans. 28.6 mm2 (rangeO-136.4 mm2) in the TD scans and 38.4 mm (range=4-175.1 mm*) in the one-hour delayed scans. The mean contrast-noise ratio for enhancing lesions detected with the TD of Gd-DTPA was higher than for lesions detected with the
Methods: WV mrdsun%d thr> titc‘rs of tifc,nmt autoantlhodics m ti group of multrpL< s~loros~> (MS) Pdtirnts h.forr and during tiatmcnt with human n~
Results:
DOSE GADOLINILIM-DTF’A FOR IN PATIENTS WITH PRIMARY
I
(4.5%)
for antI-DNA
SD
of
Gd-DTPA
(p
and
the one-hour
delayed
scan
(p=O.o4).
These data indicate that with a triple dose of Gd-DTPA many more enhancing lesions can be detected in patients with PPMS. This is important both for planning clinical trials and for detecting in-viva such patients.
-31.
the
presence
of
inflammation
in
the
lesions
of
MYELIN BASIC SCLEROSIS IN
ASSESSMENT TREATMENT
OF THE EFFICACY OF COPOLYMER-l OF MS BY QUANI=ITA’IJVE MRI
IN THE
JA, RI Grossman, JK Udupa, S Samarasekera, Y M&i. H Hait. M Grossman, CS Constantinescu, DL Kolson, F Gonzalez-Scarano, DH Silberberg, KP Johnson. Cleveland Clinic, Cleveland, OH, Univ. of Penn., Philadelphia, PA; Univ. of Maryland, Baltimore, MD; Teva/Lemmon, Kulpsville, PA; USA The recently completed Phase III trial of Copolymer-l (Cop-l. waxone@) demonstrated it to be well-tolerated and to reduce relapse rate and development of disability in ambulatory patients with relapsingremitting MS. The present studies were undertake to assess the utility of MRI as a surrogate measure of MS disease activity and severity in a clinical trial. 27 patients enrolled in the Cop-l trial at the Univ. of Penn. underwent serial MRI studies at Months 0, 1.3.6, 12,18,20,22, and 24. Axial fast spin echo images approximating proton density (PD) and T2weighted (TZ-WI) images (3 mm contiguous slices, TR 2500 msec. TE 1890 msec) and axial Tl-WI (3 mm contiguous slices, TR 600 msec, TE 27 msec) before and after gadolinium (0.1 mmolkg) were acquired at 1.5 Tesla. Volumetric analyses were performed using 3DVIEWNIX, a fullyautomated image analysis program that segments images by manipulation of fuzzy-connected components (pixels) based on their signal intensity. 3DVIEWNIX requires 30 sec. of operator time per case and is highly reproducible, with maximum intra- and inter-rater variability in lesion volume determination of less than 1.5% spanning the range of total T2lesion burden. As expected, total cerebral lesion volume (increased signal on PD/T2-WI) varied substantially between patients. Surprisingly, selected individual patients exhibited as great as 5-fold changes during the study. Disease activity, measured as the number of enhancing foci, varied between studies from 0 to 9. Determination of the volumes of gadolinium enhancement is in progress. Suggestive trends favoring Cop-l were seen in changes in total TZ-lesion volume over time and gadolinium enhancement. However, these studies did not have sufficient statistical power to demonstrate a clear-cut treatment effect. Quantitative MRI has become a frequently-used supplementary measure in experimental therapeutic studies in MS. However, variability in total ‘I%lesion volume complicates its use as a treatment endpoint.
The myelm basic protein MBP gene 1s a can&date locus for disease suscepttbility tn multlple sclerosis (MS). In the present study a part of the tetranucleotide (TGCA), repeat polymorphism 5’ to the MBP gene situated between 5’1 I16 and 5’19 I7 bp was examined in 90 Danish MS patients and 106 controls. Lymphocyte DNA was isolated and used m PCR a\+ay. The PCR fragments were separated by electro-phoresis. Hereby we found three different band patterns, I.e. a homozygote with a 450 bp fragment, a homozygote with a fragment of 350 bp and a heterozygote with both bands present. The 450 bp fragment occurred significantly more often among MS pntlents than in the control group tp
gene the 5’ interfound
NO INCREASE OF SERUM AUTOANTIBODIES AFI-ER SHORT-TERM THERAPY WI-I-H IFN-BETA IN RELAPSINGREMITTING MULTIPLE SCLEROSIS
COMPARISON
OF TRIPLE
DOSE VS STANDARD
DETECTION OF MRI ENHANCING PROGRESSIVE MULTIPLE SCLEROSIS.
LESIONS
u, M Filippi, *A Campi. B Colombo. Depts of Neurology and *Neuroradiology. LJniversrt& di Milano (Italy).
(prr-trortmcnt prnod), hx patwnts werv randomly assqnrd to two trP&nrnt groups, whrh rr
ANA
I
ANA
1 X1
lb/64
1 x0
7/(*1(1113Ya)
Ant,-Lhvr.
(2.3
2/M
(2‘9%)
LLA
MPL
l-l/68
(20
&LA
GPL
Z/M
(2.Y%)
l’atwnt+
who
wcrc
5%)
h%)
positive
Pretreat
20/6x
l2Y4%l
11/67
llb.4%1
Y/&
(13.2%)’
h/b7
2/w
(2.9%)
l/*7(1.5%)
5/w
(7 4%)
n/67(11
3/N)
(4.4%)
3/67
for ANA
at 1:4ll wcw
pi”%)
/ ,_ lY/671284%i W/67
t
(14.9%;
O/h7 YX) (4.5%)
also tested
W/h7 3/67
(2?.Y%l
*C Per&a, *G Scotti, N Canal. IRCCS Ospedale San Raffale,
This study was performed to evaluate whether a triple dose. (TD) of gadolinium-DTPA (Gd-DTPA) increases the sensitivity of brain magnetic resonance imaging (MRI) for detecting enhancing lesions in patients with primary progressive muhiple sclerosis (PPMS). T 1 -weighted brain MRI scans were obtained for 10 patients with PPMS in 2 sessions. In the first session, one scan was obtained 5 to 7 minutes after the injection of 0.1 mmol/kg GdDTPA (standard dose, SD). In the second session. 6 to 24 hours later, one scan before and two scans 5 to 7 minutes and one hour after the injection of 0.3 mmol/kg Gd-DTPA (TD) were obtained. Four enhancing lesions were detected in 2 patients with the SD of Gd-DTPA. The numbers of enhancing lesions increased to 13 and the numbers of patients with such lesions to 5 with the TD and to 14 and 6 in the one-hour delayed scans. The mean enhancing area/patient was 6.8 mm2 (range=O-25.6 mm2) in the SD yans. 28.6 mm2 (rangeO-136.4 mm2) in the TD scans and 38.4 mm (range=4-175.1 mm*) in the one-hour delayed scans. The mean contrast-noise ratio for enhancing lesions detected with the TD of Gd-DTPA was higher than for lesions detected with the
Methods: WV mrdsun%d thr> titc‘rs of tifc,nmt autoantlhodics m ti group of multrpL< s~loros~> (MS) Pdtirnts h.forr and during tiatmcnt with human n~
Results:
DOSE GADOLINILIM-DTF’A FOR IN PATIENTS WITH PRIMARY
I
(4.5%)
for antI-DNA
SD
of
Gd-DTPA
(p
and
the one-hour
delayed
scan
(p=O.o4).
These data indicate that with a triple dose of Gd-DTPA many more enhancing lesions can be detected in patients with PPMS. This is important both for planning clinical trials and for detecting in-viva such patients.
-31.
the
presence
of
inflammation
in
the
lesions
of