One hundred six research subjects were enrolled in the original study. Nineteen subjects discontinued the protocol for various reasons; this report provides information on the remaining 87 subjects. These 87 research subjects were observed for a mean of 6.6 years (range: 3.6-7.8 years). Eight of 15 subjects who initially entered with a diagnosis of CIS transitioned to MS during the course of the study; 7 to RRMS, and 1 to SPMS. The remaining 7 CIS patients remained stable and were still classified as CIS at the final visit. In the 7 cases transitioning to RRMS, conversion was based on a second relapse. Seven of the 36 patients initially categorized as RRMS transitioned to SPMS.
Baseline characteristics for the research subjects are listed in , grouped according to disease classification at the final visit. There were no significant differences between BPF, GMF, or WMF in HCs compared with CIS patients who did not convert to MS during the study (all p-values > 0.79). Brain parenchymal fraction was significantly lower in RRMS patients compared with HCs (p<0.01), and significantly lower in SPMS patients compared with RRMS patients (p <0.0001). Similarly, GMF and WMF were significantly lower in MS patients compared with HCs (all p-values <0.01), and lower in SPMS compared with RRMS (p<0.001). shows the percent difference at baseline between HCs and the patients groups at baseline. Patients with RRMS had average BPF values 2.2% lower than HCs; SPMS had average baseline values 6.8% lower than HCs.
Percent Difference From Healthy Controls At Start Of Study
Subsequent analyses excluded the 7 CIS cases who did not convert to MS during the study, and focused on 63 MS patients and the HCs. At baseline, GMF and WMF were both moderately correlated to EDSS, MSFC, and all 3 components of the MSFC. Baseline correlations with disability were generally stronger for WM atrophy than GM atrophy for each disability measure except for the PASAT. The strongest disability correlate of WMF was 9HT (r = 0.63, p < 0.0001) and for GMF it was the overall MSFC (r=0.49, p<0.0001).
Baseline BPF, GMF and WMF for the MS patients correlated with EDSS status at the last visit. Twenty of 63 patients (32%) had EDSS scores ≥ 6.0 at the last visit. Compared with the less disabled group, the group with EDSS ≥ 6.0 had lower baseline GM fraction (0.521 +/- 0.029 vs 0.537 +/- 0.022, p<0.05), and WM fraction (0.281 +/- 0.014 vs 0.300 +/- 0.018, p<0.01). Baseline BPF, GMF and WMF were correlated with last visit EDSS status as illustrated in . For each of the 3 atrophy measures, there was significantly increased likelihood of being in the EDSS ≥ 6.0 category at the follow up visit in the quartile with the highest amount of atrophy at baseline compared to the quartile with the lowest amount. Patients in the worst quartile of baseline atrophy scores had ≥ 50% likelihood of being in the EDSS ≥ 6.0 group at the final visit; patients in the best quartile of baseline atrophy scores had ≤ 13% risk of being in the EDSS ≥ group at the final visit.
Percent EDSS ≥ 6.0 At Last Visit According To Atrophy At Baseline Visit
Disability progression defined using MSFC occurred more frequently than disability progression defined using EDSS. Forty-six percent of the MS patients had disability progression measured by MSFC, compared with 33% measured by EDSS. Characteristics of patients with disability progression defined using MSFC are shown in . Patients with disability progression were older, had longer disease duration, were more likely to be classified as SPMS at baseline, had higher baseline EDSS, more EDSS change, worse baseline atrophy, and higher annual rates of GMF decline during the study. shows the rate of GMF and WMF decline for patients with MSFC-defined disability progression compared with MSFC-stable patients, shown as fold-increases compared with concurrently studied HCs. White matter fraction decline was similar in the two groups (2.8-fold increase in patients with MSFC-progression vs 3.9-fold increase in MSFC-stable patients). In contrast, the GMF decline was 14.2-fold higher in patients with MSFC -progression compared with 6.3-fold increase in MSFC-stable patients.
Characteristics of Study Subjects by MSFC Progression Status
Fold Increase In Atrophy Rates Compared With Healthy Controls By Disability Progression1
Accelerated GM atrophy was observed in both RRMS and SPMS patients with MSFC-defined disability progression. Annual GM fraction decline for RRMS and SPMS with MSFC -progression was -0.311% and -0.423%, respectively. Annual GM fraction decline for RRMS and SPMS who were MSFC-stable was -0.174% and -0.183%, respectively. This finding indicates that the relationship between MSFC disability progression and GM fraction decline was constant across disease categories, and not driven by the higher proportion of SPMS patients with MSFC disability progression.
In contrast, there were no differences in GM fraction or WM fraction change in patients with EDSS disability progression compared with EDSS-stable patients. Characteristics of patients with EDSS disability progression are shown in . They were less likely to be classified as SPMS at the baseline, indicating that the EDSS scale identifies more patients with disability progression at earlier stages of the disease than at later stages. This suggests that the scale becomes less sensitive in SPMS patients. Otherwise, the characteristics of patients with EDSS disability progression were similar to EDSS-stable patients. In particular, there were no differences in BPF, GM fraction, or WM fraction at baseline, or in atrophy progression during the study.
Characteristics of Study Subjects by EDSS Progression Status
The data in and demonstrate that MSFC progression correlated with whole brain and gray matter atrophy, while EDSS progression did not. This finding emphasized the fact that different patients were classified as having progressed on disability by use of the two measures, as shown in . Only 62% of the patients were classified the same by both MSFC- and EDSS-based definitions of disability progression, while 38% were classified as disability progression by one but not the other measure. Twenty-five percent worsened on MSFC but not EDSS, and 13% worsened on EDSS but not MSFC. Twenty-one percent worsened on both MSFC and EDSS, and 41% were stable on both measures.
Relationship Between MSFC and EDSS Progression
Characteristics of patients classified as discordant for MSFC and EDSS progression are compared in . Compared with subjects who progressed only by EDSS criteria, patients who progressed only by MSFC criteria had longer disease duration, were more likely to be SPMS patients, had higher baseline EDSS, and worse baseline atrophy scores. These results indicate that disability defined by EDSS but not confirmed by MSFC occurs largely in patients at low levels of the EDSS scale, and in patients with low levels of brain atrophy and low rates of brain atrophy progression. Subjects who progressed only by MSFC criteria had higher EDSS scores, higher levels of brain atrophy, and greater brain atrophy progression. Taken together, these results suggest that EDSS misclassifies MS disability progression in patients at the low end of the EDSS scale. In those cases, function is stable as measured by MSFC, and brain atrophy rates are low. The data further suggests that EDSS is an insensitive measure of disability progression in more severely affected patients. In those cases, EDSS is stable, but patients worsen as measured by MSFC and have high rates of brain atrophy. The combination of these two problems probably accounts for lack of correlation between EDSS progression and rates of brain atrophy, and suggests that MSFC progression has more biological meaning than EDSS progression.
Characteristics of Patients By MSFC and EDSS Progression