INTRODUCTION

 

Multiple sclerosis (MS) is a clinical diagnosis based on the dissemination of lesions of the central nervous system (CNS) in time and space¹. Some patients who suffered from initial demyelinating event (IDE) are at high risk for subsequent attacks. The initiation of disease modifying therapy (DMTs) may give better results rather than waiting for dissemination in time based on MRI or clinical outcomes². On the other hand, many patients do not start on DMTs after the first clinical event due to uncertain diagnosis, or the patient’s resistance to beginning injectable treatment.

Studies have identified prognostic factors for disability in the long-term³, predictors of relapse rate in patients with established MS^4-6, or magnetic resonance imaging (MRI) or other preclinical features that increase the risk of conversion to MS^7-9, but few have evaluated clinical risk factors for early relapse in MS^10,11.

 

The location of relapse may be one way to understand the etiology of relapsing – remitting multiple sclerosis (RRMS). If individual MS patients experience recurrent clinical exacerbations in a specific location of the central nervous system (CNS), one might hypothesize that it could be due to genetic and/or biological processes. Such a propensity for relapses to occur in a given CNS location has been demonstrated within families¹². 

The significant variability in the severity of demyelinating events in RRMS reflects patients’ heterogeneity^13,14.  IDE severity may be important predictor for both short-and long-term disability^13,15,16. It is unknown if a given patient has an inherent tendency to develop clinical demyelinating events of similar severity.

The aim of this study was to search for the possibility of presence of potential predictors of occurrence of the second demyelinating event to help in starting DMTs early. Also, the predictors of its location and severity may help in uncovering of some aspects of the etiology of RRMS.

 

SUBJECTS AND METHODS

   

This study was approved by the Medical Research Committee of Al-Rashid Hospital, Hail, and Kingdom of Saudi Arabia. The database for all IDE and RRMS patients seen within the first year of the disease, were collected^11,17. Follow-up visits were regularly occurring every 6 months, but if a patient has an exacerbation, there were unscheduled visits. Demyelinating events were defined as new or recurring neurological symptoms of the central nervous system (CNS) lasting for at least 48 hours after a remission of 30 days or more since the previous event.  Pseudo-exacerbations (transient, recurrent neurological symptoms in the context of infection or fever) and patients with neuromyelitis optica (NMO) were excluded¹⁸.

Based on clinical history and examination, the anatomical sites of each patient’s relapse were coded as occurring in the spinal cord, brainstem/cerebellum, optic nerve, or cerebrum. If the event involved at least two of these locations, it was considered polyregional. The number of functional systems (FS; e.g. sensory, motor, bladder/bowel) affected by the IDE was also calculated (possible range 1–7)¹⁹. Disease-modifying therapy (DMT) status was recorded. A patient was considered as being on DMT after he/she had at least 90 days of continuous treatment²⁰.

 

The severity of and recovery from the first event was determined as the following:^8,11.             

 -       Mild IDE severity was defined as FS scores of 0–1 in 1–3 FS, but no higher than 1 or visual acuity (VA) better  than  or equal to 20/40, EDSS score range of 0–1.5 inclusive. 

 -       Moderate severity was defined as a score of at least 2, but not higher than 2 in one or two FS or four or more scores of 1 or VA of 20/50–20/190, EDSS score of 2.0–2.5 inclusive.

 -       Severe was assigned for relapses exceeding prior criteria.

    

       Also, the IDE recovery was scored using the lowest EDSS and FS scores reported between two and 12 months after the attack. It was considered as the following:

-        Complete (no residual complaint, normal follow-up examination, all FS scores = 0, follow-up EDSS score = 0).

-        Fair (residual subjective complaint that does not impair activity, or at least one FS score of 1 at most or VA better or equal to 20/40, follow-up EDSS score = 1.0–1.5).

-              Poor (residual deficits exceeding prior criteria).

 

Increased risk of early second event was analyzed using the Cox proportional hazards model. Hazard ratios (HRs) were generated with 95% confidence intervals (CIs) and p-values.

To analyze whether IDE location predicted the second event location, multivariate logistic regression was performed, with the outcome defined as the second relapse location, and the two predictors defined as first relapse location and disease-modifying therapy (DMT). For example, for the optic nerve: the outcome was second relapse location (optic nerve or not), and the predictors were IDE location (optic nerve or not) and DMT. If the patient had a polyregional event, all involved locations were credited. To control for potential confounders, we then added covariates in turn to the multivariate model, including sex, race, ethnicity, age at IDE, polysymptomatic onset (yes or no), IDE severity and recovery, time to second event and disease duration at treatment initiation.

For second event, the severity was scored by the same way of the IDE. Multivariate models were generated to evaluate potential confounding. Since severity was measured on an ordered, three-level scale, ordinal logistic regression was used.  This method assumes a common odds ratio (OR) for each predictor's association with both severe versus mild or moderate severity and severe or moderate versus mild severity. When there was evidence against this assumption, we dichotomized the outcome and performed logistic regression. For the severity analyses, the dichotomized outcome was severe/moderate versus mild events.

 

RESULTS

 

We identified 88 patients (59 females and 29 males) seen at Alrashid Hospital within a year of initial MS symptoms. The mean age at IDE onset was 32±10 years. Fifty four (61.4%) patients were Asians mainly from India and Pakistan, 24 (27.3%) Africans mainly from Sudan, 4 (5.5%) Caucasian, and 6 (6.9%) others (unknown).  At onset, 78 (89%) of the 88 patients who had available brain imaging, had an abnormal brain MRI. Most IDEs (94%) were monoregional. The event location, severity, and recovery are presented in (Table-1). Within the first year, 32 patients (36%) experienced a second event.

Forty five (51%) patients received high dose steroid therapy for the IDE. DMT was initiated in 31% of patients (n = 27) during the entire follow-up period (Avonex 18%, Rebif 5%, Betaseron 3%, others 1%); 9 began therapy within 1 year of the IDE.

 

Factors associated with the risk of the second event:

        In the univariate Cox models, non-white race (HR = 2.37, 95% CI (1.53, 3.55), p < 0.0001) and younger age (HR for each 10-year decrease in age = 1.44, 95% CI (1.26, 1.74), p < 0.0001) were associated with a substantial increase in risk of a second event within the year after the IDE.

Fewer FS involved in the IDE predicted an increased risk of early second event (HR for each one less FS = 1.27, 95% CI (1.03, 1.67), p = 0.011). Fair versus complete IDE recovery conferred a reduction in the HR for a second event (HR = 0.72, 95% CI (0.46, 1.10), p = 0.160). Poor versus complete recovery seemed to be associated with an even lower risk (HR = 0.53, 95% CI 0.27, 1.01), p = 0.065, although there was substantial overlap of the CIs.

DMT status did not appear to substantially alter the HR for a second event within a year (HR = 0.96, 95% CI (0.44, 2.01), p = 0.96).  First event severity, sex, location of onset, abnormal versus normal brain MRI, polyregional onset, and steroid treatment for the IDE did not appear to strongly influence the hazard of an early second event. 

 

Predictors of second relapse location:

The predictors of early second event relapse were shown in (Table 2). There was a nearly fourfold increase in the odds of a patient’s relapse occurring in the spinal cord compared to the odds of occurring in another location, if the IDE was in the spinal cord (OR = 3.71 (2.01 to 6.92), p 0.001).

 

DMT: disease-modifying therapy

          This effect was independent of treatment (Table-2). Older age at IDE (p=0.03) and less severe IDE (p=0.04) were the only predictors that were independently associated with second event location in the cord.

Table (3) showed Odds ratios (ORs) of second event occurring in the same location as the initial demyelinating event. There was a more  than  five - fold  increase  in  the  odds of  a     patient’s  second  relapse   being  in the optic nerve compared with the odds of  a second relapse in a different location if  the IDE was in the optic nerve (OR=5.12(2.85 to 13.11), p  0.001).

This association was not substantially impacted by adding DMT or any of the additional potential confounders to the model. Only Asian race was independently associated with second event location in the optic nerve (p=0.040).

Brainstem/cerebellar IDE location tended to predict a second brainstem/cerebellar relapse (OR=1.61 (0.82 to 3.12) p=0.12). Adding DMT to the model, with or without the other potential confounders, did not substantially alter this relationship. African race was the only covariate that was independently associated with second event location in the brainstem/cerebellum (p=0.033).

Optic neuritis as the IDE was not associated with an increased odds of spinal cord involvement of the   second event (OR=0.47, 95% CI 0.24 to 0.91, p=0.025), nor did IDE in the spinal cord predict an increased odds of optic neuritis during the second event (OR=0.34, 95% CI 0.16 to 0.71, p=0.003).

 

Factors associated with second event severity

Univariate analyses

         Non-white and younger patients had higher odds of experiencing more severe first and second attacks. Treatment with DMT prior to the second attack was not meaningfully associated with severity (Table 4). A more severe preceding event was associated with a substantial increase in the odds of  a more severe second event, as there is  more than three-fold increase in the odds if  the first event was moderate compared to mild , and a greater  than  five- to six fold increase in the odds if the preceding event was severe compared to mild. Poor recovery of the first event predicted substantially increased odds of a more severe subsequent event (Table 4).

 

 

Multivariate analyses

In the multivariate analysis that evaluated predictors of IDE severity, which included age, location, and race, there were not substantial changes from the univariate analyses except that optic neuritis was more likely to be associated with IDE severity, whereas spinal cord onset did not seem to meaningfully predict severity (Table 5).

The multivariate model for second event severity included age, race, location, IDE severity and recovery, and DMT. The results were not meaningfully different than in the univariate analysis for non-white race, optic nerve or brainstem/cerebellar involvement, IDE severity, fair versus complete IDE recovery, and DMT (Table 5), but there was an attenuation of the association of age and of poor vs. complete IDE recovery with second event severity. Spinal cord involvement of the second event did not appear to be meaningfully associated with the event’s severity (Table 5).

 

Table 1. Location, severity, and recovery of first and second demyelinating events.

 

Event characteristic		First event  (n = 88)	Second event (n = 32)
1- Location, n (%)(*)	Spinal cord	42  (48)	20 (63)
	Brainstem/cerebellum	25 (28)	10 (31)
	Optic nerve	21 (24)	4 (13)
	Cerebrum	3 (3)	0
2- Severity, n (%)	Mild	38 (43)	16 (50)
	Moderate	39 (44)	12 (38)
	Severe	11 (13)	4 (12)
3-Recovery, n (%)(**)	Complete	39 (44)	15 (17)
	Fair	35 (40)	13 (42)
	Poor	14 (16)	4 (13)

(*)  Total does not add up to 100% since some patients had multiple sites affected.  (**) Could not be calculated for few individuals

 

 

Table 2. Results of the multivariate analysis for predictors of early second event relapse.

 

Predictors	Hazard ratio	95% CI	P-value
Age (10-year decrease)	1.39	1.20, 1.69	<0.0001**
Race/ethnicity (non-white vs. white)	2.04	1.29, 3.12	0.0010**
Functional systems (per one less)	1.28	1.02, 1.61	0.020*
Treatment of first attack with steroids	0.81	0.52, 1.28	0.50
Treatment with DMT	1.01	0.43, 2.11	0.92

* Significant at p<0.05 ** Significant at p<0.01

 

Table 3. Odds ratios (ORs) of second event occurring in the same location as the initial demyelinating event.

 

Model	Spinal Cord OR (95% CI)	Optic Nerve OR (95% CI)	Brain stem and Cerebellum OR (95% CI)
Non-Adjusted	3.71 (2.01 to 6.92)	5.12(2.85 to 13.11)	1.61 (0.82 to 3.12)
Adjusted for treatment	3.69 (2.01 to 6.89)	6.01(2.79 to 12.91)	1.68 (0.90 to 3.31)
Adjusted for treatment and most influential covariate	3.11 (1.62 to 5.93)	5.27 (2.39 to 11.67)	1.61 (0.81to 3.12)

The ORs and confidence intervals of the prediction models for second event location are demonstrated. For each unadjusted OR, the predictor is initial demyelinating event location. The outcome is second event location; the columns represent the three locations analyzed. The most attenuated association obtained of all the models evaluated that were adjusted for treatment and the covariates of interest is shown in the third row. The initial demyelinating event severity was the covariate that weakened the measure of association most substantially in the spinal cord and optic nerve models; the time to second event was the covariate that did so in the brainstem/cerebellum models

 

Table 4. Univariate Predictors of increased first and second events severity.

Predictor	First attack			Second attack
	OR	95% CI	p	OR	95% CI	p
Nonwhite race/ethnicity	1.71	1.01, 3.00	0.025	2.79	1.31, 5.87	0.005**
Age (10-year decrease)	1.27	1.06, 1.51	0.002	1.49	1.11, 2.01	0.003**
Spinal cord	0.39	0.27, 0.65	0.0002	0.41	0.21, 0.82	0.071
BS/CE	4.42	2.54, 7.66	<0.0001	2.18	1.02, 3.81	0.032*
Optic nerve	0.94	0.60, 1.64	0.96	1.16	0.51, 2.68	0.61
Cerebrum (a)	7.61	2.12, 27.11	0.002	N/A	N/A	N/A
Prior event severity (moderate vs. mild)	N/A	N/A	N/A	3.18	1.42, 6.16	0.002**
Prior event severity (severe vs. mild)	N/A	N/A	N/A	5.51	2.28, 13.14	<0.0001**
Prior event recovery (fair vs. complete)	N/A	N/A	N/A	0.61	0.29, 1.22	0.20
Prior event recovery (poor vs. complete)	N/A	N/A	N/A	2.23	0.88, 5.75	0.075
DMT  before event	N/A	N/A	N/A	0.90	0.42, 1.82	0.77

BS/CE brainstem/cerebellum, CI confidence interval, DMT disease-modifying therapy,N/A not applicable, OR odds ratio 

^a There were not enough second events in the cerebrum to generate an odds ratio.

* Significant at p<0.05 ** Significant at p<0.01

Table 5. Multivariate predictors of increased first and second events severity.

 

Predictor	First attack			Second attack
	OR	95% CI	p	OR	95% CI	p
Nonwhite race/ethnicity	1.65	0.89, 2.98	0.16	2.09	0.96, 4.63	0.084
Age (10-year decrease)	1.32	1.08, 1.62	0.036	1.18	0.83, 1.60	0.46
Spinal cord	1.61	0.76, 3.96	0.28	1.45	0.54, 3.99	0.56
BS/CE	7.19	2.99, 17.21	<0.0001	2.48	0.99, 6.26	0.059
Optic nerve	2.09	0.95, 4.76	0.094	1.46	0.48, 4.71	0.58
Cerebrum (*)	12.93	1.38, 126.88	0.029	N/A	N/A	N/A
Prior event severity (moderate vs. mild)	N/A	N/A	N/A	2.82	1.28, 6.15	0.016*
Prior event severity (severe vs. mild)	N/A	N/A	N/A	4.78	1.84, 12.62	0.002**
Prior event recovery (fair vs. complete)	N/A	N/A	N/A	0.58	0.28, 1.22	0.16
Prior event recovery (poor vs. complete)	N/A	N/A	N/A	1.39	0.52, 3.78	0.58
DMT  before event	N/A	N/A	N/A	0.99	0.46, 2.21	0.96

CI confidence interval, DMT disease-modifying therapy, N/A not applicable, OR odds ratio 

^a There were not enough second events in the cerebrum to generate an odds ratio.

* Significant at p<0.05 ** Significant at p<0.01

 

 

 

DISCUSSION

 

Patients with IDE may develop MS²¹. Clinically, the identification of patients with an IDE at high risk to develop clinically definite MS remains difficult²². This study supports that non-white race/ethnicity, younger age, and fewer FS associated with the IDE substantially increase the risk for early relapse in patients with IDE.

In previous studies, African-American patients had more rapid disease progression and/or were more likely to be disabled than were Caucasians, suggesting that the long-term course of MS may be more aggressive in the former group^23-26. Here, we included Africans, Asians, and Caucasian patients and demonstrated that non-white race/ethnicity was associated with a higher risk of early second event, independent of age or treatment status. In agree with that, our results suggest that more activity in the first year

Of disease onset has been associated with a poorer long-term prognosis^27,28. While some groups reported no difference in the percentage of African-American versus white patients who were treated with DMT^25,26, it is unknown if there are racial disparities in early initiation of DMT.

The association between the age and early risk of relapse is consistent with previous studies showing that new gadolinium-enhancing lesions are less likely to develop in older patients than in younger patients^29,30. The finding that older patients are less likely to have an early second event  after the IDE  may relate to the same factors  that are responsible for the different onset ages, whether genetic, biologic or both.

The higher number of FS involved, or a poor or moderate recovery from the IDE was associated with a lower risk of early relapse. Perhaps having more concurrent or destructive demyelinating lesions is more prone to temporarily suppress biologic disease processes compared with those with less aggressive disease onset. Alternatively, having more CNS territory involved in the IDE or poor recovery may lead to masking of subtle subsequent exacerbations, particularly if they occurred in similar anatomic areas.

Our study found that DMT did not appear to substantially change the risk of an early second event. Only a small number of patients are driving this finding as only 3 patients, who had a second event within a year of the IDE, actually began DMT before it occurred.

The genetic studies, such as HLA haplotype and gene expression, might also help to increase our ability to understand which patients are at greatest risk of early relapse and what is the mechanism of that.

The second result of this study is its strong evidence that at the individual level, early clinical demyelinating events in MS tend to recur in the same anatomic location within the CNS. The patients’ descriptions of their IDEs were less likely to be influenced by recall bias, since the IDEs had occurred within the year prior to the first clinic visit, and medical records were available to confirm most IDE descriptions. Subclinical lesions are often detected by MRI in patients with MS, but we only had access to a clinic-based cohort for whom standardized MRI protocols were not available; as such, including MRI features could introduce bias.

As few patients in our study initiated therapy, we could not investigate the differential effect of treatment on the likelihood of relapse in a specific location. We have established, however, that adding DMT to the prediction models generally did not substantially change the strong association between IDE and second relapse location.

Identifying genetic polymorphisms that could correlate with the individual tendency for recurrent disease in specific CNS locations is recommended. Whether, in the human, MS relapse location is purely explained by genetics or by the genetic influence on biological interactions remains to be determined.

The third result of the study was that individuals with MS inherently experience relatively similar severity of relapses over time, early in the disease course. This is supported by some previous reports that a given patient with RRMS is likely to have consecutive relapses in the same location within the nervous system and that there may be pathologic homogeneity within, but not between, individuals with MS^31,32. Whether stereotyped severity of exacerbations is explained by genetic polymorphisms or other underlying biologic processes remains to be determined.

Whether current DMTs modify relapse severity is uncertain. DMT reduced the annual rate of moderate and severe exacerbations in one study³³. Here, DMT did not seem to attenuate relapse severity. This was not a randomized study, so patients who received DMT may have been different from those who did not.

Here, I demonstrate that non-white race/ethnicity was associated with higher odds of more severe demyelinating events. I found elsewhere that non-whites have a two-fold increase of the risk of an early second demyelinating event³⁴. This study confirms previous reports that poor recovery of a first MS event is associated with severe presentation and polyregional onset³⁵. If the differential effect of age exists, perhaps younger patients have attacks associated with more edema such that symptoms are worse at their peak but also resolve more completely as the edema subsides. Younger patients may also have more plasticity and therefore better repair.

The effect of location, as evidenced in the multivariate models, was complex and requires further study in a larger cohort. Onset in the spinal cord did not appear to meaningfully influence relapse severity but was predictive of poor recovery of the IDE. Conversely, onset in the other three locations was associated with increased severity of the IDE (with a trend for the same when the second event involved the brainstem/cerebellum) but did not seem to meaningfully predict recovery. These data suggest that inflammation and repair processes are different in some CNS locations.

There are some limitations to our study.  When I was determining severity and recovery of attacks, I was not blinded to the assignations for previous attacks. While this could raise questions of whether misclassification bias was introduced, the fact that rigid definitions based on objective examination findings were used makes it unlikely. The sample sizes for the second event are small, resulting in widened CIs for predictors of these events severity and recovery. However, for the main predictors of interest, the point estimates were generally in the same direction as for the IDE model, and most of the wider CIs were similar to or encompassed those of the IDE models, indicating biologic consistency that bolsters the credibility of the findings.

Patients with a more severe presentation of and poor recovery from IDE may have an inherent tendency to continue on a similar trajectory for subsequent events. This opens the door to investigate if specific genetic polymorphisms are associated with severity of and recovery from demyelinating events.

 

[Disclosure: Authors report no conflict of interest]

 

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