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Prognostic factors associated with long-term disability and secondary progression in patients with Multiple Sclerosis
Multiple Sclerosis and Related Disorders, Volume 8, July 2016, Pages 27–34
Predicting the long-term prognosis of patients with multiple sclerosis (MS) remains an uncertain and difficult task, with most data having been obtained exclusively from Caucasian cohorts.
To investigate clinical prognostic factors in a Brazilian mixed-race cohort.
Demographic, clinical and therapeutic factors were investigated in 303 patients with relapsing-remitting MS in relation to the following outcomes: time until reaching Expanded Disability Status Scale (EDSS) 3 and EDSS 6, and until secondary progression.
Benign course was significantly more frequent among Caucasians when compared to Afrodescendants. Patients with a malignant course had more than one relapse in the first year of the disease and reached EDSS 3 faster if treatment was not started. In the multivariate analysis, the following factors were associated with a significantly shorter time until the established outcomes: male gender, being of African descent, non-recovery after the first relapse, two or more relapses during the first year, a short interval between initial relapses, initial polysymptomatic presentation of pyramidal and cerebellar dysfunction and no treatment prior to reaching EDSS 3.
Being of African descent was found to be an unfavorable factor for all outcomes, reinforcing the need to take ethnicity into consideration when defining treatment, particularly in mixed MS populations.
- African Ancestry is a risk factor for long-term disability and progression in MS.
- Caucasians were more significantly present among benign course of MS.
- African Ancestry should be considered in the initial therapeutic decision.
Keywords: Multiple Sclerosis, African Ancestry, Secondary progression, Prognostic factors, Risk factors, Disability.
Multiple Sclerosis (MS) was considered an inflammatory disease of the white matter of the central nervous system (CNS). Additionally, further aspects related to its pathogenesis such as axonal loss and neurodegeneration, often already present at the earliest stages of the disease, were subsequently identified (FERGUSON et al, 1997 and TRAPP et al, 1998) and associated with disease progression and irreversible disability (Vasconcelos et al., 2010). Studies on the natural history of MS (WEinshenker et al, 1989a and Weinshenker et al, 1989b) have revealed that a progressive course develops in 50% or more of patients after 10 years of the disease, irrespective of the presence or absence of relapses. Currently, it is known that, regardless of the initial clinical course, when a moderate degree of disability is reached, progression is similar for all affected individuals (Marrie et al., 2006).
Despite the availability of clinical and radiological criteria with which to diagnose the disease at an early stage, predicting the patient's long-term prognosis in daily practice remains difficult (Damasceno et al., 2013). Most studies on prognostic factors have been conducted with Caucasian North American and European cohorts. The extent of the influence of these factors on genetically mixed individuals and those exposed to different environmental factors requires confirmation. Due to its colonization, Brazil is a country with a genetically mixed population, principally European and African; however, there are variations in the population according to its geographical distribution. In the south of the country where the weather is cooler than in the north, exposure to sunlight is less and the influence of European colonization prevails. The north and northeastern regions are closer to the equator and are home to a greater percentage of individuals of African and indigenous descent (FERREIRA et al, 2004 and Finkelsztejn et al, 2014). Therefore, the objective of the present study was to investigate the extent of the influence of clinical aspects as prognostic factors in a Brazilian cohort of mixed race.
1.1. Patients and methods
This observational cohort study analyzed the prognosis of patients with relapsing-remitting MS (RRMS), defined according to the 2005 Revised McDonald Diagnostic Criteria (Polman et al., 2005). Patients who had the disease for at least two years and who were being followed up at the Hospital da Lagoa and at the Gaffrée and Guinle University Hospital, both in Rio de Janeiro, Brazil, were included. Cases with incomplete records and patients with initial optical and spinal clinical symptoms whose reviewed diagnosis was compatible with neuromyelitis optica were excluded from the study (Wingerchuk et al., 2006), as well as cases of primary-progressive MS. An additional 153 patients were added to a cohort of 150 patients previously analyzed in a study published in 2012 (Vasconcelos et al., 2012), making a total sample of 303 patients. Data on the disease course were obtained retrospectively from medical records and prospectively during follow-up visits. The methodology adopted was that used in the study conducted by Vasconcelos et al. (2012).
The onset of the disease was defined according to the date of the first relapse. The date defining the total duration of the disease was that of the patient's last visit. Data on relapses, recovery, disability progression and Expanded Disability Status Scale (EDSS) scores were obtained from the follow-up visits registered in the patients' medical records.
Relapses were defined as the presence of acute neurological symptoms or the worsening of preexisting symptoms lasting more than 24 h, followed by partial or complete recovery (Poser et al, 1983 and McDonald et al, 2001. Initial clinical manifestations were categorized according to the Functional Systems (FS) affected: pyramidal, cerebellar, pyramidal and cerebellar, sensory, visual, brainstem, sphincters or mental. Disability markers were evaluated according to the Kurtzke EDSS (Kurtzke, 1983). The clinical course was classified as benign if the EDSS score was ≤3 after 10 years of the disease (Kantarci and Weinshenker, 2005), and malignant if the EDSS score was ≥6 after 5 years of the disease (Perini et al., 2001). Secondary progressive MS was defined as a persistent increase in EDSS score, unassociated with relapses and sustained for six months or more, or a lack of improvement or progressive worsening at every assessment (Vasconcelos et al., 2012).
The outcome measures were time until reaching EDSS 3 and EDSS 6 and until the beginning of secondary progression. Factors investigated as independent variables for the outcomes were: gender, ancestry (of African descent, defined as the presence of blacks in the family for up to three previous generations, or white), age at onset (<30 years or ≥30 years), initial mono- or polysymptomatic presentation (1 or >1 FS affected, respectively), type of initial neurological manifestation (according to the FS included in the Kurtzke EDSS scale), number of relapses in the first year of the disease (1 or ≥2 relapses), the interval between the first and second relapses (<2 years or ≥2 years), full recovery after first relapse and the use of immunomodulatory therapy prior to reaching EDSS 3.
The study protocol was registered on the Plataforma Brasil research platform and approved by the Internal Review Board of the Gaffrée and Guinle University Teaching Hospital. A written informed consent form included a statement on the confidentiality of the data obtained and stored.
The Statistical Package for the Social Sciences (SPSS), version 13.0 for Windows, was used. Quantitative variables were expressed as frequencies (%). Skewness and kurtosis tests were applied to the continuous variables to confirm a normal distribution and results were expressed as means and standard deviations. The Mann-Whitney test was used to compare continuous and categorical variables, and Pearson's chi-square test or Fisher's exact test was used to evaluate the categorical variables. Odds ratios (OR) were calculated to identify factors associated with long-term disability and faster progression to the established outcomes. The Kaplan-Meier method was used to evaluate differences in the time until reaching EDSS 3, EDSS 6 and until the secondary progressive phase, according to demographic and clinical variables. The log rank test was used to measure the time difference between the variables.
In the univariate analysis, the median time in years until reaching EDSS 3, EDSS 6 and until secondary progression was calculated. Multivariate analysis was performed using Cox regression to determine the independent variables associated with a shorter period of time until reaching secondary progression and the established disability markers. Only variables with p-values <0.05 in the univariate analysis were selected for inclusion in the multivariate analysis. The Enter method was applied in the Cox regression model. The variables were inserted one by one and removed when found to have lost significance. Those with p-values <0.05 were maintained in the analysis. Results were considered statistically significant when p-values were <0.05.
Of the 303 patients, 76.2% were women and 66% were classified as white (Table 1). The youngest was 6 years old and the oldest, 58. Overall, 188 patients (62%) had their first relapse before 30 years of age.
In most patients (71%), onset of the disease was mono-symptomatic. The most common clinical presentations were sensory (41.6%) and pyramidal (35%). When analyzed according to gender, the first relapse of the disease was pyramidal in 68.9% of the women versus 31.1% of the men (p=0.03). The patients' clinical data are listed in Table 2 and Table 3.
|Age at onset|
|30 years or more||115||38|
|Pyramidal and cerebellar||16||5.3|
|Number of FS|
FS: Functional System.
|1 relapse||2 relapses||3 relapses||4 relapses||≥5 relapses|
|Years of evolution|
|1 year||231 (76.2)||48 (18.8)||14 (4.6)||7 (2.3)||3 (1.0)|
|2 years||119 (39.3)||48 (15.8)||25 (8.3)||9 (3.0)||8 (2.6)|
|5 years||71 (23.4)||55 (18.2)||54 (17.8)||38 (12.5)||134 (35.5)|
Analysis of the first year of the disease shows that 80% of patients recovered completely from their first relapse, while 17.5% made a partial recovery and 2.6% failed to recover. The interval between the first two relapses was less than two years in 56.4% of patients, with the longest interval being 25 years and the shortest, one month. When analyzed according to gender, the time interval between the first two relapses tended to be shorter in men (66.7% versus 53.2%; p=0.05). Concerning progression, 81 patients (26.7%) reached this stage of the disease at a median age of 42 years, with 38.3% reaching the progression stage prior to 40 years of age, 54.3% at 40–60 years of age, and 7.4% after 60 years of age. The youngest patient with progression was 20 years old and the oldest 69. Evolutive characteristics are listed in Table 4.
|Reach disability markers||N of patients||Frequency (%)|
|Recovery after first relapse||N of patients||Frequency (%)|
|Interval between 1° and 2° relapses||N of patients||Frequency (%)|
|2 years or more||132||43.6|
SPMS: Secondary Progressive Multiple Sclerosis.
A benign clinical course was more common in general, and significantly more common in white patients. A significantly higher number of patients with a malignant clinical course had more than one relapse in the first year of the disease and were more likely to have reached EDSS 3 prior to initiating treatment (Table 5).
|BMS (n=108–35.8%)||MMS (n=14–4.6%)|
|Characteristic||n||%||p value||N||%||p value|
|Age at onset|
|30 years or more||41||38||4||28.6|
|Recovery after 1 relapse|
|Interval between 1 and 2 relapse|
|2 years or more||59||54.6||0.005||3||21.4|
|Number of relapses in the 1 year|
|2 relapses or more||15||13.9||8||57.1||0.005|
|Number of FS affected in the 1 relapse|
|Pyramidal and cerebellar||3||2.8||0.2||1.0|
|Treated before EDSS 3|
MS: Multiple Sclerosis; BMS: Benign MS; MMS: Malignant MS; FS: Functional System.
At some point of the disease 74.6% of patients received treatment. Among treated patients, as first treatment immunomodulatory was used in 89.4%, immunosuppressive in 9.3% and monoclonal antibodies, in 1.3%.
In the univariate analysis, the following factors were found to be significantly associated with a shorter time until reaching EDSS 3, EDSS 6 and until secondary progression: being of African descent, not recovering from the first relapse, having had two or more relapses in the first year of the disease, initial presentation being pyramidal and cerebellar, polysymptomatic presentation and not having started treatment prior to reaching EDSS 3. Men reached EDSS 3 and EDSS 6 significantly faster than women. An interval of less than two years between the first two relapses was statistically significant only with respect to reaching EDSS 3 and progression (Table 6).
|Time in years (median)|
|Factors||EDSS 3||p value||EDSS 6||p value||Progression||p value|
|Age at onset||0.067||0.169||0.082|
|Recovery from 1° relapse||<0.001||<0.001|
|Interval between relapses||0.001||0.104||0.033|
|N relapses in the 1° years||<0.001||0.001||<0.001|
|FS pyramidal and cerebellar||0.015||0.001|
|Treatment before EDSS 3||0.001||<0.001||0.013|
FS: Functional System.
In the multivariate analysis (Cox regression) the following variables remained significantly associated with a shorter time until reaching EDSS 3 and EDSS 6: non-recovery after the first relapse, not having started treatment before reaching EDSS 3, more than one relapse in the first year of disease, male gender and African Ancestry. Initial presentation pyramidal and cerebellar remained significant to reach EDSS 6 and an interval of less than two years between first and second relapse remained significant to reach EDSS 3 (Table 7).
|Independent variable||EDSS 3||EDSS 6||SPMS|
|HR||95.0% CI||p value||HR||95.0% CI||p value||HR||95.0% CI||p value|
|Non recovery after first relapse||13.2||5.96–29.11||<0.001||5.3||2.04–13.80||0.001||5.9||2.31–15.08||<0.001|
|No treatment before reaching EDSS 3||2.1||1.48–2.97||<0.001||2.8||1.72–4.56||<0.001||1.8||1.14–2.80||0.011|
|≥2 relapses in the first year of disease||1.6||1.06–2.57||0.026||2.8||1.60–4.93||<0.001||2.9||1.71–4.84||<0.001|
|Interval <2 years between 1° and 2° relapses||1.8||1.24–2.71||0.002||NS||NS||NS||NS||NS||NS|
|FS pyramidal and cerebellar||NS||NS||NS||2.8||1.39–5.60||0.004||2.8||1.39–5.77||0.004|
FS: Functional System; NS: non-significant; CI: confidence interval.
Factors significantly associated with a shorter time until reaching secondary progression were not having started treatment prior to reaching EDSS 3, not having recovered from the initial relapse, being of African descent, pyramidal and cerebellar signs and two relapses or more in the first year of the disease (Table 7).
The most important studies on the natural history of MS were performed prior to the availability of faster diagnosis permitting earlier treatment with disease-modifying drugs. The same prognostic factors investigated in the context of the natural history of MS and/or its clinical course have been found in several studies (Damasceno et al, 2013, Vasconcelos et al, 2012, DEBOUVERIE, 2009, Scalfari et al, 2011, Scalfari et al, 2012, Scalfari et al, 2013, Cree et al, 2004, and SCALFARI et al, 2010). Some variations in the results can often be related to the cohort studied, the sample size or the statistical methodology (univariate or multivariate). In the mixed-race cohort in the present study, some of the results found for some of the factors evaluated reflected data reported from larger, predominantly Caucasian cohorts; however, with the additional factor that patients of African descent were included.
The most common initial clinical manifestation was of the sensory type, a finding that is in agreement with other reports (Vasconcelos et al, 2012, Scalfari et al, 2011, Scalfari et al, 2012, Scalfari et al, 2013, SCALFARI et al, 2010, Tremlett et al, 2009, and Baghizadeh et al, 2013). However, a comparative analysis between genders showed that the first relapse was more likely to be pyramidal in women, a finding already reported by Papais-Alvarenga et al. (1995) As in other cohorts, the most common presentation was mono-symptomatic (Scalfari et al, 2011, Scalfari et al, 2012, Scalfari et al, 2013, and SCALFARI et al, 2010).
In agreement with data from studies conducted by Confravreux et al. (2003) and Leray et al. (2013), most of the patients recovered completely from the first relapse. Regarding the number of relapses in the early years of the disease, the frequency found in the present study at the end of five years was in line with the results reported by Confravreux et al. (2003). The time interval found in the present study of less than two years between the first two relapses was observed in more than half the cases, and is similar to values reported from other studies (Damasceno et al, 2013, SCALFARI et al, 2010, Baghizadeh et al, 2013, and CONFRAVREUX et al, 2003.
Regarding the benign course of MS, the frequency in the present cohort is higher if compared to the study conducted by Naismith et al. (2006), but lower in comparison with the study performed by Leray et al. (2013).
Of the 303 patients, almost half reached EDSS 3 and a quarter reached EDSS 6. In a study conducted by Debouverie (2009), the frequencies of reaching EDSS 3 and EDSS 6 were slightly higher. Women took significantly longer to reach the established EDSS markers in the present study and also in the study conducted by Debouverie (2009). Less than 30% of the patients reached secondary progression of the disease, with around 40 years or more, a finding that is in agreement with data reported by Scalfari et al. in two separate studies (Scalfari et al, 2011 and SCALFARI et al, 2010.
Recognition of the risk factors associated with a more severe clinical course of the disease is useful when making early therapeutic decisions. Risk factors associated with a poorer prognosis that have already been identified in the literature are: male sex, older age at onset, a higher relapse rate in the early years of the disease, short interval between the first two relapses, polysymptomatic initial presentation, pyramidal and/or cerebellar relapses, non-recovery from the relapses, and more recently, being of African descent.
Both in the univariate analysis and in the multivariate analysis, associations were found between being male and a shorter time until reaching moderate disability (EDSS 3) and severe disability (EDSS 6), with a two-fold greater risk for these outcomes. In addition, the risk of reaching EDSS 6 has been reported to be 1.5-fold greater (Debouverie, 2009). In other studies, univariate analysis showed that the median time from the onset of the disease until reaching the established EDSS markers was significantly lower in men (Damasceno et al, 2013, DEBOUVERIE, 2009, Cree et al, 2004, Hammond et al, 2000, and Debouverie et al, 2007). Furthermore, the time until secondary progression was shorter in males (Scalfari et al, 2013 and Koch et al, 2010.
The presence of early cerebellar and pyramidal signs was significantly associated with a shorter time until EDSS 3, EDSS 6 and until secondary progression in the present cohort. Pyramidal and cerebellar signs have been described in several studies (Damasceno et al, 2013, Scalfari et al, 2013, Cree et al, 2004, Debouverie et al, 2007, Koch et al, 2010, AMATO and PONZIANI, 2000, and Kaufman et al, 2003) as being associated with a poorer long-term prognosis.
Age at first presentation of the disease was not identified as a prognostic factor in the present study. However, onset of the disease at a later age has been associated with a more severe course in many studies (Damasceno et al, 2013, DEBOUVERIE, 2009, Scalfari et al, 2011, Scalfari et al, 2012, Scalfari et al, 2013, Tremlett et al, 2009, Baghizadeh et al, 2013, and CONFRAVREUX et al, 2003). The probable explanation for this difference may be our smaller sample size.
The occurrence of two or more relapses in the first year of the disease increased the risk of reaching the established disability markers and progression outcomes within a shorter period of time. Similar findings have also been reported in other studies (Damasceno et al, 2013, Vasconcelos et al, 2012, DEBOUVERIE, 2009, Scalfari et al, 2011, Scalfari et al, 2012, Scalfari et al, 2013, SCALFARI et al, 2010, and Tremlett et al, 2009). A shorter interval between the initial relapses was also considered a factor indicative of poorer prognosis. In the present study, this was significantly associated with a shorter time until reaching disability markers, as well as with an increased risk of this outcome. (Scalfari et al, 2012) and (SCALFARI et al, 2010) found a statistically significant association between a short interval between relapses and reaching the secondary progressive phase and disability markers; however, those authors described this finding as a less reliable predictor than the number of relapses in the first two years of the disease. Three other studies (DEBOUVERIE, 2009, Debouverie et al, 2007, and AMATO and PONZIANI, 2000) reported similar findings, with a longer time interval between the first two relapses being indicative of a longer time until reaching the EDSS markers and secondary progression.
Non-recovery after the first relapse as a predictor of poor prognosis, with an increased risk, insofar as long-term disability and secondary progression are concerned, has been confirmed in five separate studies (Vasconcelos et al, 2012, DEBOUVERIE, 2009, Baghizadeh et al, 2013, CONFRAVREUX et al, 2003, and AMATO and PONZIANI, 2000). This association was also found in the present study, even after adjustment of the models.
Being of African descent has only recently been described as a risk factor. In the present study, it was found to constitute a risk factor for all established outcomes in both the univariate and multivariate models. It has been observed in some studies (Vasconcelos et al, 2010, MARRIE et al, 2006, Vasconcelos et al, 2012, Cree et al, 2004, NAISMITH et al, 2006, Kaufman et al, 2003, WEINSTOCK-GUTTMAN et al, 2003, Kister et al, 2010, and Koffman et al, 2013), that in individuals of African descent long-term EDSS scores are more likely to be higher, with a shorter mean time until reaching the outcomes evaluated. Four studies have reported that individuals of African descent reached the progressive phase faster than Caucasians (Vasconcelos et al, 2010, Vasconcelos et al, 2012, Cree et al, 2004, and Kaufman et al, 2003. In addition, the benign course was less common in patients of African descent (Kaufman et al., 2003).
In the last decade, a variety of treatment options for RRMS has emerged. None of the approved medications or experimental therapies has shown convincing evidence of slowing down or preventing disease progression in patients with SPMS or PPMS. All the approved medications have mainly anti-inflammatory effects and increasing evidence indicates that all of them are more effective in the early phases of disease (Coles et al, 2006 and Hauser et al, 2013). Large randomized controlled trials have demonstrated that disease modifying treatments (DMTs) can prolong the time from clinically isolated syndrome (CIS) to definite MS (Jacobs et al, 2000, Comi et al, 2001, Kappos et al, 2006, Comi et al, 2009, and ComI et al, 2012), however, if early treatment is be able to improve long-term disability outcome, this needs to be clarified (Kinkel et al, 2012 and Kappos et al, 2009).
In MS treatment, sometimes is necessary to use more than one therapeutic agent. Often patients receive several first-line therapies, while treatments that are more effective are still being introduced only after those have failed. In the face of sustained progression, treatment change is mandatory. The recognition of high-risk patients in whom breakthrough disease activity has occurred, treatment escalation to a more potent agent may be reasonable. A beneficial effect on either relapses or MRI can generally be observed within about three to six months after initiating a DMT, but to assess the progression, this period of time is not enough. Signs of progression may reflect disease activity that occurred prior to starting treatment rather than a failure of the treatment.
Not having initiated treatment prior to reaching EDSS 3 was another significant risk factor identified in this study, with a 2-fold risk of reaching EDSS 3, EDSS 6 and secondary progression. Leray et al. (2010) and Confravreux et al. (2003) suggested that the clinical course of MS consists of two stages. The first stage probably depends on the focal inflammation, while the second phase is unrelated to current focal inflammation but associated with diffuse inflammation. Following analysis of a large cohort, those authors noted that the speed of worsening during the second phase was unrelated to the first phase. Demographic and clinical factors that were predictive of the time until reaching EDSS 3 or EDSS 4 lost their force after reaching this disability marker and the speed of deterioration then remained similar for all patients who initiated the progressive phase. These findings reinforce the definition of a therapeutic window and, according to the results of the present study, treating the patient before he/she reaches EDSS 3 would reduce the risk of secondary progression.
When comparing the risks related to each factor, incomplete recovery after the initial manifestation of MS conferred risk up to 13 times to reach faster a moderate EDSS. In this situation, the high risk to reach EDSS 3 related to the residual deficit after first relapse can be easily understood by the greater chance of an initial severe relapse to cause sequelae. However, in long term, the influence of this factor in achieving high disability and progression (observed risk of five and six times respectively) could be explained by the fact that an incomplete recovery may be associated with the presence of neurodegeneration, already present in early stages of the disease, and/or by disruption of the balance of compensatory mechanisms of remyelination (Bjartmar and Trapp, 2001).
Other factors such as number of relapses in the first year showed an increased risk for long-term outcomes, probably because a high relapse rate in early stages translates greater inflammation and increased risk of axonal injury and neurodegenerative process (Compston, 2006).
Concomitant pyramidal and cerebellar initial manifestations conferred similar risk to achieve faster EDSS 6 and progression. Probably patients with higher EDSS, as the EDSS 6, have a higher chance of also developing disease progression. As it has been pointed out, the axonal loss specific to the corticospinal tract can be an early pathological substrate for progression (Kremenchutzky et al., 2006).
Although the risk related to African ancestry has been up twice, it was lower when compared to other factors; however, it was present to reach both disability landmarks and progression. The worse and faster evolution observed among African-Brazilian patients, as well as African-Americans and Afro-Europeans, suggest being a greater ethnic influence than environmental in MS progression, but the complex association between immunogenetic and racial factors is not fully elucidated.
The fact that approximately 30% of the patients in this cohort had the disease for less than 10 years constitutes one of the limitations of this study and may have caused a bias in the evaluation of the secondary progressive and benign forms. Another issue that has to be mentioned was the difficulty in obtaining accurate information on the number of relapses occurring in the second years of the disease, and for this reason that parameter was not taken into consideration in the analysis.
The demographic, clinical and treatment-related factors identified in the present cohort were largely similar to those reported from other studies.
The principal prognostic factors associated with a shorter time until reaching progression were being of African descent, a greater number of relapses in the first year of the disease, non-recovery from the first relapse, a short interval between the initial relapses, pyramidal and cerebellar signs as initial presentation, and not having initiated treatment before reaching EDSS 3. Some of these factors also affected the time until reaching disability markers such as EDSS 3 and EDSS 6. Being of African descent is a prognostic factor that has seldom been investigated in longitudinal studies; however, as shown by the present results, it proved to be unfavorable both for disability markers and for secondary progression, reinforcing the need to take this prognostic factor into consideration, particularly when dealing with a mixed-race population.
Declaration of conflicting interests
The authors declare that there is no conflict of interest.
This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
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a Universidade Federal do Estado do Rio de Janeiro, Rua Mariz e Barros 775, Departamento de Neurologia, Tijuca, Rio de Janeiro CEP: 20270-901, Brazil
b Universidade Federal do Estado do Rio de Janeiro and Instituto Nacional de Câncer, Rua André Cavalcanti, 37 - Centro, Rio de Janeiro, RJ CEP 20231050, Brazil
c Hospital Federal da Lagoa – Departamento de Neurologia, Rua Jardim Botânico, 501, Rio de Janeiro, Brazil
d Universidade Federal do Estado do Rio de Janeiro and Hospital Federal da Lagoa, Rua Mariz e Barros 775, Departamento de Neurologia, Tijuca, Rio de Janeiro CEP: 20270-901, Brazil
⁎ Corresponding author.
1 These authors contributed equally to the manuscript.
☆ This study did not receive any funding (industry, government, or institutional).
© 2016 Elsevier B.V., All rights reserved.