In multiple sclerosis (MS), the clinical course and degree of disability resulting
from autoimmune inflammation of the central nervous system and from axonal damage
vary[1], often beginning in the initial phases[2]. Certain patients reach greater degrees of disability within a short period of time.
This severe progressive form is referred to as malignant multiple sclerosis (MMS)
when an Expanded Disability Status Scale (EDSS) score of 6 is reached within five
years of disease onset[3],[4]. Early recognition of potentially severe cases based on prognostic factors is crucial
when making therapeutic decisions to reduce the risk of disability and impaired quality
of life. This study analyzed a cohort of Brazilian patients to identify cases of MMS
and potential prognostic factors indicating more severe progression.
METHODS
This observational study included a retrospective analysis of demographic data and
clinical data collected from medical records of 293 MS patients according to McDonald
et al criteria[5]. The patients had been regularly followed up at the Hospital Federal da Lagoa in Rio de Janeiro, Brazil. Based on the time to reach EDSS 6, patients were classified
as MMS up to five years, or non-malignant-MS (NMMS) after five years. The internal review board of the Gafrée and Guinle Teaching Hospital
approved the protocol.
Frequencies, percentages, means and standard deviations were calculated for demographic
and clinical variables. To analyze progression, Kaplan-Meier curves were constructed
based on the time to reach EDSS 3 and 6 and were analyzed by the log-rank test. To
compare malignant and non-malignant forms, odds ratios and 95% confidence intervals
were calculated. The Student’s t-test was used to analyze the time between the first
attacks. Statistical significance was defined as p < 0.05.
RESULTS
Twenty-five patients had MMS (8,53%). Most were women (52%) and of African descent
(52%), 64% of patients were 30 years old or younger at the disease onset. Relapsing
remitting MS (RRMS) was more common than the primary-progressive form (PPMS) in NMMS
(93.7% versus 68%; p < 0.001), whereas PPMS was more prevalent in MMS (32% versus
5.2%; p < 0.001). There was a non-significant difference between the groups in the
mean time from first symptom until diagnosis (4.2 versus 6.0 years).The median time
from first symptom until diagnosis was four years for non-malignant form (0.1 to 29
years) and two years for MMS (0.5 to 25 years). Mean time until treatment with disease-modifying
drugs was significantly shorter in MMS (4.0 versus 7.7 years; p = 0.025).
[Table] shows the comparison of the demographic characteristics and clinical progression
between groups. Significant differences were found for sex, ethnicity, recovery after
the first attack, number of relapses during the first year, and time between the first
two attacks.
Table
Comparison of demographic and clinical characteristics between patients with malignant
(MMS) and non-malignant multiple sclerosis (NMMS).
|
Characteristics
|
MMS (25)
|
NMMS (268)
|
OR (95%CI)
|
p-value
|
|
|
|
|
n (%)
|
n (%)
|
|
Gender
|
|
Male
|
12 (48.0)
|
59 (22.1)
|
3.27
|
0.007
|
|
Female
|
13 (52.0)
|
209 (77.9)
|
(1.42–7.54)
|
|
Ethnicity
|
|
Non-white
|
13(52.0)
|
78 (29.1)
|
2.80
|
0.020
|
|
White
|
11(44.0)
|
185 (69.0)
|
(1.2–6.5)
|
|
Recovery from the first attack
|
|
No
|
9 (37.5)
|
11 (5.0)
|
11.5
|
< 0.001
|
|
Yes
|
15 (62.5)
|
211 (95.0)
|
(4.1–32.1)
|
|
Number of relapses during 1st year
|
|
2 or more relapses
|
10 (40.0)
|
39 (14.6)
|
4,6
|
0.002
|
|
1 relapse
|
11 (44.0)
|
198 (73.9)
|
(1.8–11.6)
|
|
Time interval between 1st and 2nd attacks
|
18 (81.8)
|
140 (55.8)
|
3.6
|
0.013
|
|
≤ 2 years
|
4 (18.2)
|
111 (44.2)
|
(1.2–10.8)
|
|
>2 years
|
17 (6.4)
|
3 (12.0)
|
|
The differences in n correspond to the absence of information.
Regarding the clinical progression, the risk for progression was 10-fold greater for
patients with MMS (OR = 14.5; 95%CI: 4.4–48.1); 35.5% of MMS patients had reached
secondary progression versus 3.6% in NMMS (p < 0.001). In MMS, 87% of patients reached
EDSS 3 within three years and 44% reached EDSS 6 directly, 44% of patients MMS reached
EDSS 6 before 40 years of age versus 7% of NMMS patients (p < 0.001). (This data is
not shown in the [Table]).
The time to reach disability markers was significantly shorter in patients with RRMS
classified as MMS compared to those classified as NMMS (EDSS 3: 12 versus 192 months,
p < 0.001) (EDSS 6: 36 versus 324 months; p < 0.001). The [Figure] represents time curves to reach EDSS 3 and 6.
Figure Kaplan Meier curves of time in months to reach EDSS 3 and 6 for RRMS malignant and
no malignant.EDSS: Expanded Disability Status Scale; RRMS: Relapsing remitting MS.
DISCUSSION
The nomenclature and criteria define the more severe progressive forms of MS, although
the degree of disability and time to reach disability constitute the principal parameters.
In addition to MMS, the term aggressive MS has also been used. The different criteria adopted always include the early disability
provoked by frequent attacks and/or progression, and intense inflammatory activity
detected by magnetic resonance imaging[6]. The term fulminant MS, although adopted previously, is currently associated with Marburg’s variant in which
progression is monophasic with inexorable deterioration and rapid death[7].
Malignant/aggressive forms occur in 4-14% of cases[3],[4]; and this Brazilian cohort, in which 8.5% of patients developed severe disability
within five years, confirmed these data. This percentage includes both RRMS and PPMS;
however, if only the former were considered, this rate would fall to 5.8%. In the
few studies conducted on malignant/aggressive forms, most patients had RRMS[3],[4]. Of the MMS cases in the present study, over half had RRMS.
Including PPMS patients may create a bias, since their progression rate is faster,
with these patients reaching EDSS 6 within five years. Gholipour et al. included PPMS
patients and reported a frequency of MMS of 78.57%[3], while Menon et al. reported 25.57% of PPMS cases in a group of MMS patients[4].
Despite the severity, RRMS patients respond to treatment with immunomodulators and
immunosuppressant and immunoablative therapy if inflammatory activity is present[6]. Only RRMS patients are included in the progression curves presented here, and the
median times until reaching the markers of moderate and severe disability were one
and three years respectively, revealing a short period in which there is a viable
therapeutic window. Although no consensus exists on the time and degree of disability
required to classify MS as severe, EDSS 6 is used as a cut-off point for the implementation
of aggressive treatment[4].
In studies on the natural history of MS, clinical factors have been linked to a more
severe prognosis[3],[4],[8],[9],[10]. Many of these factors were observed in the patients classified as MMS in this study.
There were significantly more patients of African descent, patients in whom motor
symptoms were the first manifestation, a shorter time interval between initial attacks,
more patients with a residual deficit from the first attack, more patients with more
than one attack in the first year, and more cases of progression right from the onset.
Conversely, MMS has been described as being more common in men[3],[4], while in this study more women had MMS. A larger sample population may have achieved
different results.
In conclusion, according to the generally accepted concept of MMS, < 10% of patients
in this Brazilian cohort reached severe disability within five years. Identifying
demographic and clinical prognostic factors may make early treatment with more effective
drugs more feasible.
