INTRODUCTION

Approximately 2.8 million people worldwide are affected by multiple sclerosis (MS), a chronic inflammatory and neurodegenerative disease of the brain and spinal cord, that typically causes severe physical disability and has a higher prevalence in women ¹. MS generates a great personal and socioeconomic burden; the average age of onset of the disease is 30 years and after approximately 25 years of diagnosis, most patients will need help to walk ². The presentation of this disease is diverse and may include sensory and vision problems, motor deficits, fatigue, pain, and cognitive deficits. The variation in clinical manifestations correlates with the occurrence and expansion of lesion sites in the central nervous system ^{( 3}. Lesions are caused by infiltration of immune cells across the blood-brain barrier which promotes inflammation, myelin loss, gliosis and neuroaxonal degeneration ⁴.

The clinical manifestations are the result of motor disturbances of the sensory, visual, and autonomic systems ⁵. The most representative clinical features of the disease are optic neuritis, myelitis, brain stem/brain symptoms, cerebellum, and paroxysmal events ⁶. The McDonald criteria are the most widely used diagnostic criteria; they consider the clinical characteristics of the disease, the lesions and diagnostic aids that demonstrate the diffusion of the lesions in the area (different regions) and in time (evolution of the disease); as well as the intrathecal presence of immunoglobulins (Ig) ⁷.

The Expanded Disability Status Scale (EDSS) is the most widely used scale for monitoring the disease, and has the advantage of being able to be used during routine neurological examinations ⁸. Disability in MS patients is assessed by the EDSS on a range of 0 to 10, where 0 indicates no disability and 10 indicates death from MS ⁹. The scale allows the monitoring of disability progression, defined in clinical trials as the increase of the EDSS value by at least 0.5 points, remaining constant for at least six months, in the absence of flare-ups ¹⁰. The problems caused by the disease are associated with cognitive and physical alterations that can lead the patient to a deterioration in quality of life ¹¹. The factors that influence the progression of disability are all the characteristics that inform about the evolution of the disease and that can guide how it will evolve over time ¹².

Disability is one of the most important aspects to evaluate regarding MS, for this reason, most studies relate prognostic factors to the EDSS score ¹³. Some good and bad prognostic factors for the progression of disability in MS have been described in the literature, which have helped to identify the risk in patients ². However, the factors described so far have only been useful up to a given level of disability, but a statistical model that integrates sociodemographic, clinical, and radiological variables and explains the time of disability progression in MS in Colombia has not been obtained. Therefore, the aim of this study was to determine the sociodemographic, clinical, and radiological factors associated with disability progression in MS patients.

MATERIALS AND METHODS

RESULTS

Sociodemographic, clinical, and radiological characterization

A total of 216 patients were included in the study (Figure 1). We present the distribution of patients who had progression of disability (PD) and those who did not have progression of disability (NP). Twenty-five percent of participants showed an increase in the EDSS score, which was defined as the increase of at least 0.5 points sustained for at least six months between assessments. The median age at the beginning of follow-up was 47 years (IQR: 38-56) for the PD group, and 41 years (IQR: 31-53) for the NP group. Furthermore, 56.6% of those in the PD group and 71.2% of those in the NP group were diagnosed before the age of 40 years. Most participants were women; 65.1% in the PD group and 80.9% in the NP group. The relapsing-remitting phenotype (RR) was the most frequent among participants, with 52.8% in the PD group and 17.8% in the NP group. On the other hand, 30% of participants from the PD group were found to have the primary progressive phenotype (PP), meanwhile, the secondary progressive phenotype (SP) was found in 17% of the participants.

Figure 1 Flowchart of the inclusion of patients with multiple sclerosis for disability progression analysis. 

The median time from the onset of symptoms to diagnosis was the same for participants from both groups; the median number of years to diagnosis was higher in the PD group at 8.16 years (IQR: 3.75-12.58). Cardiovascular drugs (antihypertensives and antiarrhythmics) were used in 24.5% of the participants who had PD. The consumption of antidepressants was higher in those with PD (37.7%), whereas 13.2% of participants from the PD group had mental illness and 16.9% had other neurological diseases. Regarding complications, 64.1% of those in the PD group had cerebellar type complications, 15.1% had bladder and bowel complications and 52.8% had vision problems. Sensory onset symptoms were found in 36.2% of those in the NP group, while 30.2% had cerebellar disease onset symptoms. Among those in the PD group, 82.7% had spinal cord lesions identified by MRI and 40.4% had active lesions (Table 1).

Table 1 Characteristics of patients with multiple sclerosis according to progression of disability. 

Variable	Progression to disability (PD)		Non-progression to disability (NP)		p-value b	p-value c
	n=53	%	n=163	%
Age a	47	38−56	41	31−53	0.010	0.010
Sex
Men	19	35.9	31	19.0	0.010	0.010
Women	34	64.1	132	81.0
Age at diagnostic
<40	30	56.6	116	71.2	0.070	0.010
>40	23	43.4	47	28.8
RR phenotype
Yes	28	52.8	29	17.8	0.010	0.010
No	25	47.2	134	82.2
PP phenotype
Yes	16	30.2	15	9.2	0.010	0.010
No	37	69.8	148	90.8
SP phenotype
Yes	9	17.0	14	8.6	0.140	0.160
No	44	83.0	149	91.4
Time of symptoms to diagnosis (months) a	12	8−48	12	6−36	0.930	0.890
Years since diagnosis a	8,16	3.75−12.58	6,1	6−36	0.010	0.010
Cardiovascular medications
Yes	13	24.5	21	12.9	0.070	0.080
No	40	75.5	142	87.1
Antidepressants
Yes	20	37.7	31	19.0	0.050	0.060
No	33	62.3	132	81.0
Mental disorders
Yes	7	13.2	12	7.4	0.100	0.190
No	46	86.8	151	92.6
Neurological Diseases
Yes	9	17.0	12	7.4	0.030	0.040
No	44	83.0	151	92.6
Cerebellar complications
Yes	34	64.2	60	36.8	0.010	0.010
No	19	35.8	103	63.2
Vision problems
Yes	28	52.8	72	44.2	0.340	0.160
No	25	47.2	91	55.8
Bowel and bladder complications
Yes	8	15.1	19	11.7	0.670	0.540
No	45	84.9	144	88.3
Sensitivity symptoms
Yes	11	20.7	59	36.2	0.030	0.080
No	42	79.3	104	63.8
Brainstem symptoms
Yes	2	3.8	1	0.6	0.040	0.010
No	51	96.2	162	99.4
Cerebellar symptoms
Yes	16	30.2	29	17.8	0.020	0.030
No	37	69.8	134	82.2
Spinal cord injuries
Yes	43	82.7	45	27.9	0.120	0.160
No	9	17.3	116	72.1
Active injuries
Yes	21	40.4	44	27.3	0.010	0.030
No	31	59.6	117	72.7

^a Median and interquartile range; ^b Chi-square test or Mann Whitney U test; ^c Log-Rank test.

RR: relapsing remitting. PP: primary progressive.

Overall survival

The overall median survival time was 78 months with an interquartile range of 70-83 months (Figure 2). The cumulative follow-up time was 70-60.5 months. More events were reported during months 22 and 36, with four in each month. The period with the most patient losses was month 32, with seven losses.

Overall survival curve for disability progression of the 216 patients who were included in the study, showing the time to disability progression exposing failures (progression). n: number 

DISCUSSION

We found that male patients had a 2.5 faster progression than female patients. This result is supported by studies showing that women are less likely to progress to disability or do so more slowly, although the disease is more frequent in women ¹⁷. Ribbons et al. analyzed data from 15,826 MS patients from 25 countries comparing EDSS scores by sex, and male MS patients showed a faster EDSS progression ¹⁸.

On the other hand, MRI is considered a useful tool for the identification of demyelinating areas, lesions, and blood-brain barrier rupture ¹⁹. We found that the patients with active lesions on MRI showed faster progression. Studies have reported that the importance of finding active lesions lies in the opportunity to predict the clinical deterioration of the patient and therefore the loss of brain volume; consequences in the patient will depend on the site of the lesion ²⁰. Harrison et al. reported that, using magnetic resonance imaging, cortical lesion burden, including the number and volume of lesions, was closely related to physical disability and cognitive dysfunction ²¹. On 2018, a study by Eshaghi et al., that included 1417 subjects (253 with clinically isolated syndrome, 708 with relapsing-remitting multiple sclerosis, 128 with secondary progressive multiple sclerosis, 125 with primary progressive multiple sclerosis and 203 healthy control subjects); reported that, the first regions to atrophy in patients with clinically isolated syndrome and RR multiple sclerosis were the posterior cingulate cortex and precuneus, followed by the medial cingulate cortex, brainstem and thalamus. A similar atrophy sequence was detected in PP multiple sclerosis with involvement of the thalamus, cuneus, precuneus and pallidum, followed by the brainstem and posterior cingulate cortex. The cerebellum, caudate and putamen showed early atrophy in RR phenotype cases and late atrophy in PP phenotype cases ²².

Our results show that 64.1% of the patients who progressed to disability had cerebellar lesions. Such complications have been related to increased scores on the disability scale and have even played an important role in the progression from isolated clinical syndrome to MS ²³. In MS patients, demyelination of the gray matter of the cerebellum, more than any other brain region, is five times greater than the demyelination of the white matter ²⁴. This may be a consequence of overlying meningeal inflammation in the deep folia, which harbors a static inflammatory milieu (such as cytokines and immunoglobulins) ²⁵. Therefore, overlying inflammation in the cerebellum may amplify other pathological mechanisms such as retrograde neurodegeneration secondary to white matter lesions ^{24 , 25}. Early cerebellar presentation is associated with unfavorable outcomes, whereas early brainstem presentation is associated with a favorable prognosis ²⁶. These presentations can be used as prognostic markers of MS and guide the therapeutic approach.

We found that having a history of neurological diseases was associated with progression, this has been previously reported by studies that found that this type of patients is more prone to progression. Epilepsy seems particularly related to an increased risk of physical disability in patients with relapses and remissions ²⁷. The prevalence of psychiatric illness in the systematic review by Marrie et al. was quite high (i.e., 23.7% for depression, 21.9% for anxiety and 5.83% for bipolar disorder) ²⁸.

The simple model we used during the analysis showed that age at diagnosis influenced disability in MS patients. However, multivariate regression revealed that it did not influence MS disability. In a 2011 study, Scalfari et al. reported that age was an independent and important factor contributing to disease progression. These authors report that the age at onset of RR phenotype disease and advancing age (current age) affect the accumulation of disability, regardless of disease duration, largely by increasing the likelihood of experiencing a progressive course and shortening the latency to progression ²⁹. In addition, the authors also suggest that age stratification, which has been little used so far, may be advantageous, especially if the primary outcome is the occurrence of secondary progressive multiple sclerosis ²⁹. Early stages of the disease, especially during younger ages, represent a window of opportunity for future treatments that should focus on preventing or delaying the onset of secondary progression, the main determinant of the development of permanent disability.

Our results show that, for both, the simple regression model and the multivariate regression model, the RR phenotype was not a factor influencing MS disability progression. Stewart et al. conducted a prospective follow-up study on 136,462 patients with RR phenotype and found that a higher recurrence rate was related to a higher disability accumulation ³⁰. Studies suggest that the PP phenotype portends a worse prognosis than the RR phenotype or SP phenotype in terms of disability. However, progressive disease and the rate of post-progression disability accumulation appear to be age-dependent and do not correlate with the rate of pre-progression disability accumulation ²⁹. The previously mentioned studies that reported that patients with PP phenotype are more likely to progress in disability support our results, which show that more than 30% of patients had this phenotype.

Since this was a follow-up cohort study, some participants were lost during follow-up. In order to control for this type of bias, we considered that each patient contributed time while on follow-up, ensuring that we obtained the most accurate information. The analysis included the follow-up of 167 people for at least 20 months, which was equivalent to 77.3% of the study population. However, at 40 months about 50% of the population had been lost, which limits the identification of the time of disability progression in this group of participants. Additionally, we used non-probabilistic sampling, therefore, the results cannot be generalized to the department of Antioquia. Patients were not at the same stage of the disease when they entered the study, therefore, they had different levels of disability; in addition, there were cases lost during follow-up, although the data from the follow-up period was available in the medical records. However, this process was carried out in the framework of a clinical interview with a neurologist, who helped reviewing all reported consultations.

In conclusion, disability progression in MS patients is affected by several factors, with no single independent factor. The median time to progression was 72 months. Active lesions found on MRI and male sex were associated with greater disability progression, with statistically significant results in the multivariate model. Therefore, the correct and timely understanding of the risk factors associated with disability progression can help both to counsel patients and to improve the approach and provide evidence-based treatment recommendations, which helps to improve the prognosis and quality of life of patients.