Abstracts
Objective
The study aims to investigate the presence of pain amongst multiple sclerosis (MS) patients.
Method
One hundred MS patients responded to questionnaires evaluating neuropathic and nociceptive pain, depression and anxiety. Statistical analysis was performed using the Mann–Whitney U, Chi-Square and two-tailed Fisher’s exact tests and multivariate logistic regression.
Results
Women had a statistically higher prevalence of pain (p = 0.037), and chances of having pain after the age of 50 reduced. Women with pain had a statistically significant lower number of relapses (p = 0.003), restricting analysis to those patients with more than one relapse. After the second relapse, each relapse reduced the chance of having pain by 46%. Presence of pain was independent of Expanded Disability Status Scale (EDSS) anxiety, and depression.
Conclusion
Our findings suggest a strong inverse association between relapses and pain indicating a possible protective role of focal inflammation in the control of pain.
multiple sclerosis; pain; prevalence; relapses; gender
Objetivo
O estudo tem como objetivo investigar a presença de dor entre pacientes com esclerose múltipla (EM).
Método
Cem pacientes com EM responderam a questionários avaliando dor neuropática e nociceptiva, depressão e ansiedade. A análise estatística foi realizada através dos testes de Mann-Whitney U, Qui-Quadrado, two tailed Fisher exact test e regressão logística multivariada.
Resultados
As mulheres apresentaram estatisticamente uma maior prevalência de dor (p = 0,037), e as chances de ter dor após a idade de 50 reduziram. As mulheres com dor tinham um número com significância estatística reduzido de surtos (p = 0,003), restringindo a análise aos pacientes com mais de um surto. Após o segundo surto, cada surto reduziu a chance de ter dor em 46%. A presença de dor foi independente da Expanded Disability Status Scale (EDSS) ansiedade e depressão.
Conclusão
Nossos resultados sugerem uma forte associação inversa entre o surto e a dor, indicando um possível papel protetor da inflamação focal no controle da dor.
esclerose múltipla; dor; prevalência; surto; sexo
While several studies have found a relationship for the development of pain related to one or
more multiple sclerosis (MS) factors such as patient’s age, duration of disease, disease
course, and disability11 Solaro C, Brichetto G, Amato MP, Cocco E, Colombo B, D’Aleo G et al. The
prevalence of pain in multiple sclerosis: a multicenter cross-sectional study. Neurology.
2004;63(5):919-21. http://dx.doi.org/10.1212/01.WNL.0000137047.85868.D6
https://doi.org/10.1212/01.WNL.000013704...
,22 Hadjimichael O, Kerns RD, Rizzo MA, Cutter G, Vollmer T. Persistent pain and
uncomfortable sensations in persons with multiple sclerosis. Pain. 2007;127(1-2):35-41.
http://dx.doi.org/10.1016/j.pain.2006.07.015
https://doi.org/10.1016/j.pain.2006.07.0...
,33 Grau-López L, Sierra S, Martínez-Cáceres E, Ramo-Tello C. Analysis of the
pain in multiple sclerosis patients. Neurologia. 2011;26(4):208-13.
http://dx.doi.org/10.1016/j.nrl.2010.07.014
https://doi.org/10.1016/j.nrl.2010.07.01...
, virtually an equal number have not44 Kalia LV, O’Connor PW. Severity of chronic pain and its relationship to
quality of life in multiple sclerosis. Mult Scler. 2005;11(3):322-7.
http://dx.doi.org/10.1191/1352458505ms1168oa
https://doi.org/10.1191/1352458505ms1168...
,55 Osterberg A, Boivie J, Thuomas KA. Central pain in multiple sclerosis:
prevalence and clinical characteristics. Eur J Pain. 2005;9(5):531-42.
http://dx.doi.org/10.1016/j.ejpain.2004.11.005
https://doi.org/10.1016/j.ejpain.2004.11...
. Pain
clearly has a role in the disease as its prevalence has been reported ranging up to 74% in MS
outpatients66 Truini A, Barbanti P, Pozzilli C, Cruccu G. A mechanism-based classification
of pain in multiple sclerosis. J Neurol. 2013;260(2):351-67.
http://dx.doi.org/10.1007/s00415-012-6579-2
https://doi.org/10.1007/s00415-012-6579-...
. While research does implicate
factors that may be related to pain, multivariate analyses are lacking, which leaves the issue
unclear as to the role of the various risk factors in the development of pain66 Truini A, Barbanti P, Pozzilli C, Cruccu G. A mechanism-based classification
of pain in multiple sclerosis. J Neurol. 2013;260(2):351-67.
http://dx.doi.org/10.1007/s00415-012-6579-2
https://doi.org/10.1007/s00415-012-6579-...
. The development of MS pain and its severity
has implications into the general evolution of the disease which itself varies amongst the
different clinical forms [relapsing-remitting- (RR), primary progressive- (PP) and secondary
progressive- (SP)] as well as its gender-specific presentation.
This study investigates the prevalence and severity of pain amongst multiple variables in attempt to further elucidate the role of pain within the evolution of MS. Our goal is to evaluate these results within the context of the recent mechanisms of MS that have addressed not only gender issues but also the relationship of relapses to long term disability and the progression of RR to SP, implicating two distinct disease phases related to late outcome. We hope to provide further insight into the relationship of pain to these end-points and its possible role in the natural history of the disease.
METHOD
Procedure
In this cross-sectional clinic based study we administered a questionnaire to 100
consecutive MS patients. The questionnaire included a total of 65 questions, which
included the Brazilian-portuguese validated questionnaires DN477 Santos JG, Brito JO, de Andrade DC, Kaziyama VM, Ferreira KA, Souza I et al.
Translation to Portuguese and validation of the Douleur Neuropathique 4 questionnaire. J
Pain. 2010;11(5):484-90. http://dx.doi.org/10.1016/j.jpain.2009.09.014
https://doi.org/10.1016/j.jpain.2009.09....
(Neuropathic Pain in 4 questions), the
LANSS88 Schestatsky P, Félix-Torres V, Chaves ML, Câmara-Ehlers B, Mucenic T, Caumo
W et al. Brazilian Portuguese validation of the Leeds Assessment of Neuropathic Symptoms
and Signs for patients with chronic pain. Pain Med. 2011; 12(10):1544-50.
http://dx.doi.org/10.1111/j.1526-4637.2011.01221.x
https://doi.org/10.1111/j.1526-4637.2011...
(Leeds assessment of neuropathic
symptoms and signs), Beck Depression Inventory (BDI)99 Cunha J. Manual da versão em português das escalas Beck. São Paulo: Casa do
Psicólogo; 2001. and Anxiety (BAI)99 Cunha J. Manual da versão em português das escalas Beck. São Paulo: Casa do
Psicólogo; 2001., a pain questionnaire and disease related information. The survey
was given to each patient at the end of their physician consult to complete independently,
with no time constraints. Statistical analysis was then performed. This study was approved
by the Ethics committee of the Department of Neurology at the Antonio Pedro University
Hospital – Fluminense Federal University in Rio de Janeiro, Brazil and obtained according
to the Declaration of Helsinki. Informed consent was obtained from all patients.
Study sample
One-hundred consecutive MS patients met the inclusion and exclusion criteria at the
Antonio Pedro University Hospital in the Department of Neuro-immunology. Inclusion
criteria: diagnosis of multiple sclerosis (all clinical courses) based upon the
McDonald’s criteria1010 Polman CH, Reingold SC, Banwell B, Clanet M, Cohen JA, Filippi M et al.
Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann
Neurol 2011;69(2):292-302. http://dx.doi.org/10.1002/ana.22366
https://doi.org/10.1002/ana.22366...
age between 18
and 80 years old, medication possession rate > 80%. Exclusion criteria: having other
known neurological conditions, cancer, renal disorders, psychiatric disorder and
diabetes.
Pain questionnaire
The 13 questions structured questionnaire was based on Grau-López33 Grau-López L, Sierra S, Martínez-Cáceres E, Ramo-Tello C. Analysis of the
pain in multiple sclerosis patients. Neurologia. 2011;26(4):208-13.
http://dx.doi.org/10.1016/j.nrl.2010.07.014
https://doi.org/10.1016/j.nrl.2010.07.01...
. This self-reported data evaluated the presence of pain; its
location including head, upper extremities, lower extremities, back or generalized; its
classification as constant or intermittent; its frequency (daily, more than 3 times per
week, less than 3 times per week, or 1-3 times per month); presence of Lhermitte’s
phenomenon; types of head pain including migraine, tensional and trigeminal neuralgia;
medication used for MS; medication used for pain.
Classification of pain type
Pain was classified as either neuropathic or nociceptive. Neuropathic pain was defined as having a score of 4 or greater on the DN4 or greater than 12 on the LANSS. All other pain was otherwise classified as nociceptive.
Statistical analysis
Descriptive statistics were performed to illustrate the study population demographic characteristics (gender and age) and the MS aspects (clinical form, Expanded Disability Status Scale (EDSS) medication, onset of disease and relapses) as well as the characteristics of pain (localization, type of pain, types of headache and Lhermitte’s sign) and humor status (depression and anxiety). The prevalence was estimated by gender and total population. The Mann–Whitney U test was used to compare continuous variables between groups. The two-tailed Fisher’s exact test and Chi-Square was used for categorical variable comparison. Logistic regression models were used to estimate the associations between pain and co-variables, such as gender, age (older or younger than 50 years old), EDSS, medication, clinical form, onset of disease, relapses, depression and anxiety. In the bivariate analysis, the variables associated with pain to significance level of 10% were included in the multivariate analysis to calculate adjusted estimates of Odds Ratio (OR). In multivariate analysis, the differences lower than 0.05 were accepted as significant. All statistical analyses were performed using program support language R (The R Foundation for Statistical Computing, Vienna, Austria; http://www.r-project.org) and SPSS 16.0 (SPSS Inc., Chicago, IL, USA).
RESULTS
All 100 patients met the inclusion criteria. There were three questions that were not completed by all of the patients: presence of Lhermitte’s phenomenon, 83 out of 100 responded; another two individuals did not complete the BDI (98/100) and 97/100 completed the BAI.
Descriptive statistics of prevalence rates are displayed in Table 1. Most notably, men showed statistically higher EDSS than women (p = 0.008) with 5.4 and 3.9, respectively. The clinical forms of MS were statistically different amongst men (PP and SP) and women (RR) (p = 0.022). While women had a statistically higher prevalence of pain (p = 0.037), men had significantly higher scores on the DN4 (p = 0.016) and LANSS (p = 0.021), indicating greater severity in neuropathic pain (Table 1). Neither depression nor anxiety was associated with the presence of pain.
The prevalence rates and gender distribution of the type of pain experienced by those patients with pain (n = 71) are shown in Table 1. Within this group, men maintained their significantly higher EDSS than women (p = 0.056) as in the overall population. However, pain was found to be independent of EDSS (Figure 1a and 1b). There was a significant difference in the mean number of relapses and pain in females, as seen in Figure 1 c and d (p = 0.001).
(A) Difference of average Expanded Disability Status Scale (EDSS) by gender (p-value = 0.008); (B) Difference of average EDSS by gender in subjects with pain (p-value = 0.056) and without pain (p-value = 0.045). Difference of average EDSS by pain in subjects male (p-value = 0.814) and in female (p-value = 0.843); (C) Difference of average relapse number by gender (p-value = 0.048); (D) Difference of average relapse number by gender in subjects with pain (p-value = 0.120) and without pain (p-value = 0.780). Difference of average relapse number by pain in subjects’ male (p-value = 0.491) and in female (p-value = 0.003).
Upon comparing those patients under the age of 50 to those patients over the age of 50, we observed a statistically significant difference with younger women (under the age of 50) having a higher prevalence of pain than men and older women, whereas older men (over the age of 50) had a higher prevalence of pain than women and younger men. These results are illustrated in Figure 2.
Differences in prevalence of “presence of pain” over age of multiple sclerosis (MS) patients, stratified by gender.
Logistical regression analysis found that females had a 2.7 greater chance of having pain than men (95%CI: 1.04-7) and older than 50 had only a minimal affect, 1.3 greater chance of having pain than not (95%CI: 1.07-3.2). Clinical forms showed no difference other than SP MS patients have a 67% lower risk of having pain than PP (95%CI: 0.09-1.2). However, the most indicative factor predicting the development of pain was a lower absolute number of relapses, instead of the annualized relapse rate. Excluding those with only one relapse (13/16 having PP), each relapse after the second reduced in 46% the chance of experiencing pain [OR 0.54 (95%CI:0.33-0.88)] adjusted for age and sex, but there was an interaction between sex and age as demonstrated in Table 2 - Model 1 and 2; this was found to be independent of relapse rate as shown in Figure 3, which demonstrates the number of relapses by pain (yes or no) and by medication/treatment type. Besides, no statistical relationship was found between different medications. The complete results from the logistical analysis are demonstrated in Table 2.
We both excluded and included those patients with one relapse, and found that our results were statistically significant in both cases. There were 16 patients with one relapse, 13 of which were diagnosed with PP, one of which was diagnosed with SP and two of which had RR, one of whom was 46 years old and was painless, another 24 years old who had pain. All those with one relapse were excluded, as we did not have the MRI data and, based upon only self-reported data, we felt that including the PP and the other three patients had a greater chance of skewing the data, as there is a chance of these three cases being either PP or a clinically isolated syndrome (CIS). PP was eliminated so the data would more clearly represent the phase 1 – relapsing phase and the impact on pain.
DISCUSSION
Our population displayed similar characteristics found in other studies, including the higher prevalence among women and prevalence of pain in general. Presence of pain was independent of EDSS and had a negative association with relapses experienced. While the tendency was seen far greater in women, we believe the causes could be due to the greater number of women in our study or a gender or sex-related explanation. Though it should be noted that men showed the same trends found among women when stratified in a similar representation as showed in Figure 4, we grouped together the sexes as the sample size is limited. Our exclusion of PP and the three cases with one relapse was to attempt to eliminate any element of confounding that could be caused by patients that may be misdiagnosed with RR-MS rather than a CIS or PP. While the statistical significance in our finding was present whether we included or excluded PP, we felt that the inclusion of PP may too strongly influence the results and as such it remained excluded from our analysis. Our results were unexpected, yet not completely out of the realm of reason and had strong support in recent MS literature. Nevertheless, we have done our due diligence in our statistical analysis, data collection, recording and interpretation to state with certainty our findings and have tried to account for any confound or aspect of the disease that may have been overlooked and that would provide an alternative hypothesis. Of course, there are always factors that cannot be controlled and should be considered when relying upon self-reported data from patients, which answers may be exaggerated and present biases such as social desirability or suggestion. We have no evidence of such a bias in our study and attempted to use the DN4, LANSS, BAI and BDI to assist in this error.
The incidence of RR-MS has been close to 2-3 times greater for women than for men, whereas the PP is a 1:1 ratio. While incidence of RR has been predominantly associated with women, severity of the disease has been linked to men. As such, the role of this gender bias has typically been considered in congruous with relapses occurring more in women than in men, though men being more severe. However, with recent studies on disability and disease progression invalidating the long held belief that relapses were indicative or related to disease/disability progression or severity, questions as to the role of relapses in MS or this first relapsing phase within the natural progression of the disease have been raised.
Our results propose that relapses are related to diminished prevalence of pain, suggesting
that the first relapsing phase of MS may be protective against pain in the underlying second
phase which appears to be more age-related33 Grau-López L, Sierra S, Martínez-Cáceres E, Ramo-Tello C. Analysis of the
pain in multiple sclerosis patients. Neurologia. 2011;26(4):208-13.
http://dx.doi.org/10.1016/j.nrl.2010.07.014
https://doi.org/10.1016/j.nrl.2010.07.01...
,1111 Scalfari A, Neuhaus A, Degenhardt A, Rice GP, Muraro PA, Daumer M et al. The
natural history of multiple sclerosis: a geographically based study 10: relapses and
long-term disability. Brain. 2010;133(7):1914-29.
http://dx.doi.org/10.1093/brain/awq118
https://doi.org/10.1093/brain/awq118...
,1212 Voskuhl RR. Gender issues and multiple sclerosis. Curr Neurol Neurosci Rep.
2002;2(3):277-86. http://dx.doi.org/10.1007/s11910-002-0087-1
https://doi.org/10.1007/s11910-002-0087-...
,1313 Kremenchutzky M, Rice GP, Baskerville J, Wingerchuk DM, Ebers GC. The
natural history of multiple sclerosis: a geographically based study 9: observations on the
progressive phase of the disease. Brain. 2006;129(3):584-94.
http://dx.doi.org/10.1093/brain/awh721
https://doi.org/10.1093/brain/awh721...
,1414 Stankoff B, Mrejen S, Tourbah A, Fontaine B, Lyon-Caen O, Lubetzki C et al.
Age at onset determines the occurrence of the progressive phase of multiple sclerosis.
Neurology. 2007;68(10):779-81.
http://dx.doi.org/10.1212/01.wnl.0000256732.36565.4a
https://doi.org/10.1212/01.wnl.000025673...
.
This would imply that the increase in relapses that women undergo in their premenstrual
cycle1515 Zorgdrager A, De Keyser J. The premenstrual period and exacerbations in
multiple sclerosis. Eur Neurol 2002;48(4):204-6.
http://dx.doi.org/10.1159/000066166
https://doi.org/10.1159/000066166...
, postpartum period1616 Paavilainen T, Kurki T, Parkkola R, Färkkilä M, Salonen O, Dastidar P et al.
Magnetic resonance imaging of the brain used to detect early post-partum activation of
multiple sclerosis. Eur J Neurol. 2007;14(11):1216-21.
http://dx.doi.org/10.1111/j.1468-1331.2007.01927.x
https://doi.org/10.1111/j.1468-1331.2007...
and assisted reproductive technology (ART)
with gonadotropin releasing hormone agonists1717 Michel L, Foucher Y, Vukusic S, Confavreux C, Sèze J, Brassat D et al.
Increased risk of multiple sclerosis relapse after in vitro fertilisation. J Neurol
Neurosurg Psychiatry. 2012;83(8):796-802.
http://dx.doi.org/10.1136/jnnp-2012-302235
https://doi.org/10.1136/jnnp-2012-302235...
are all indicative of the female sex related hormones/genes causing
increased relapses and their surrogate lesions as a possible “protective” function by
reducing pain-related brain activation in anticipation of the underlying “dormant” disease
(second phase) when more debilitating progression will occur. This would also clarify the
reason that more severe disability is found in men early on and greater prevalence of pain
in the second phase of the disease, as it is exposure to female steroid hormones that
increases the susceptibility for relapses1212 Voskuhl RR. Gender issues and multiple sclerosis. Curr Neurol Neurosci Rep.
2002;2(3):277-86. http://dx.doi.org/10.1007/s11910-002-0087-1
https://doi.org/10.1007/s11910-002-0087-...
. Unfortunately, our finding remain speculative as we have found few
studies on pain in multiple sclerosis and none that have stratified based upon sex.
While MRI analysis and lesion load is beyond the scope of our study, MRI T2 or
gadolinium enhancing lesions have long been established as the surrogates of focal
inflammation1818 Frischer JM, Bramow S, Dal-Bianco A, Lucchinetti CF, Rauschka H, Schmidbauer
M et al. The relation between inflammation and neurodegeneration in multiple sclerosis
brains. Brain. 2009;132(5):1175-89.
http://dx.doi.org/10.1093/brain/awp070
https://doi.org/10.1093/brain/awp070...
. Even though pain has
been associated with various pain syndromes in MS (i.e. extremity pain, back pain, etc.),
there has not been an association found between pain and the site of demyelination1919 Borsook D. Neurological diseases and pain. Brain. 2012;135(2):320-44.
http://dx.doi.org/10.1093/brain/awr271
https://doi.org/10.1093/brain/awr271...
though it has been associated with
depression, spinal cord involvement at the onset and the presence of spinal cord
lesions33 Grau-López L, Sierra S, Martínez-Cáceres E, Ramo-Tello C. Analysis of the
pain in multiple sclerosis patients. Neurologia. 2011;26(4):208-13.
http://dx.doi.org/10.1016/j.nrl.2010.07.014
https://doi.org/10.1016/j.nrl.2010.07.01...
. The damage to the pain pathways
has been theorized to possibly involve glia and cytokines2020 Merson TD, Binder MD, Kilpatrick TJ. Role of cytokines as mediators and
regulators of microglial activity in inflammatory demyelination of the CNS. Neuromolecular
Med. 2010;12(2):99-132. http://dx.doi.org/10.1007/s12017-010-8112-z
https://doi.org/10.1007/s12017-010-8112-...
, which has been linked to the possible mechanism of central
pain2121 Graeber MB. Changing face of microglia. Science. 2010;330(6005):783-8.
http://dx.doi.org/10.1126/science.1190929
https://doi.org/10.1126/science.1190929...
. However, no significant pain
relief has been found with any of the disease modifying medications that target the immune
system. Furthermore, our results are supported by recent work in neuroimaging, which
suggests that intrinsic brain connectivity is associated with chronic pain intensity2222 Napadow V, LaCount L, Park K, As-Sanie S, Clauw DJ, Harris RE. Intrinsic
brain connectivity in fibromyalgia is associated with chronic pain intensity. Arthritis
Rheum. 2010;62(8):2545-55. http://dx.doi.org/10.1002/art.27497
https://doi.org/10.1002/art.27497...
, implying that lesions or demyelinating
neuro-degeneration may reduce or eliminate pain sensation. This concept directly contradicts
the formerly held belief of the role of relapses and supports other work in Neurology which
proposes that pain is a multimodal evaluative or distributed process in the brain2222 Napadow V, LaCount L, Park K, As-Sanie S, Clauw DJ, Harris RE. Intrinsic
brain connectivity in fibromyalgia is associated with chronic pain intensity. Arthritis
Rheum. 2010;62(8):2545-55. http://dx.doi.org/10.1002/art.27497
https://doi.org/10.1002/art.27497...
. Recent studies investigating brain lesions
support the hypothesis that they may serve as a function of the body to reduce pain-related
cortical activity2323 Starr CJ, Sawaki L, Wittenberg GF, Burdette JH, Oshiro Y, Quevedo AS et al.
The contribution of the putamen to sensory aspects of pain: insights from structural
connectivity and brain lesions. Brain. 2011;134(7):1987-2004.
http://dx.doi.org/10.1093/brain/awr117
https://doi.org/10.1093/brain/awr117...
, or the
sensory-discriminative processing of pain2323 Starr CJ, Sawaki L, Wittenberg GF, Burdette JH, Oshiro Y, Quevedo AS et al.
The contribution of the putamen to sensory aspects of pain: insights from structural
connectivity and brain lesions. Brain. 2011;134(7):1987-2004.
http://dx.doi.org/10.1093/brain/awr117
https://doi.org/10.1093/brain/awr117...
meanwhile maintaining intact tactile thresholds2323 Starr CJ, Sawaki L, Wittenberg GF, Burdette JH, Oshiro Y, Quevedo AS et al.
The contribution of the putamen to sensory aspects of pain: insights from structural
connectivity and brain lesions. Brain. 2011;134(7):1987-2004.
http://dx.doi.org/10.1093/brain/awr117
https://doi.org/10.1093/brain/awr117...
thus serving as a protective measure against pain or aid in
its tolerability.
We postulate that with the increase of lesion load, associated with a higher number of
relapses, it is possible that the interpretation of painful stimuli by the brain is impaired
or that the arrival of those stimuli to somatosensorial pathways is decreased. One
study2424 Tremlett H, Yousefi M, Devonshire V, Rieckmann P, Zhao Y. Impact of multiple
sclerosis relapses on progression diminishes with time. Neurology. 2009;73(20):1616-23.
http://dx.doi.org/10.1212/WNL.0b013e3181c1e44f
https://doi.org/10.1212/WNL.0b013e3181c1...
found that, in a long-term
basis, accumulation of relapses and their consequences are less evident in patients with MS.
Furthermore, with the advent of more powerful MRI scans, the confirmation of involvement of
the gray matter became more sensitive. Harrison et al2525 Harrison DM, Oh J, Roy S, Wood ET, Whetstone A, Seigo MA et al. Thalamic
lesions in multiple sclerosis by 7T MRI: clinical implications and relationship to
cortical pathology. Mult Scler. 2015 [Forthcoming]. conducted a study with 34 patients and demonstrated through
7-Tesla MRI scan that thalamic lesions were present in 24 patients. It is known that such
lesions are associated with a higher EDSS score, cortical lesions and progressive forms.
Regarding the thalamus as a major relay of pain, its involvement in patients with MS
diminish the arrival of nociceptive inputs to cortical regions.
Studies of pain in MS patients have attempted to link the location of lesions to related
pain and have found difficulty in defending this theory. For example, ongoing extremity pain
is more common in patients with primary progressive or the progressive-relapsing (PR) types
of MS, and lowest in the RR type2626 Nurmikko TJ, Gupta S, Maclver K. Multiple sclerosis-related central pain
disorders. Curr Pain Headache Rep. 2010;14(3):189-95.
http://dx.doi.org/10.1007/s11916-010-0108-8
https://doi.org/10.1007/s11916-010-0108-...
. MRI
studies usually show plaques in the cervical and thoracic spinal cord, however the bilateral
and relatively distal distribution is difficult to explain as there is ample evidence that
excludes peripheral nerve involvement55 Osterberg A, Boivie J, Thuomas KA. Central pain in multiple sclerosis:
prevalence and clinical characteristics. Eur J Pain. 2005;9(5):531-42.
http://dx.doi.org/10.1016/j.ejpain.2004.11.005
https://doi.org/10.1016/j.ejpain.2004.11...
.
MS-related trigeminal neuralgia (TN) has long been attributed to a demyelinating plaque in
the pons, as seen in postmortem specimens2727 Athanasiou TC, Patel NK, Renowden SA, Coakham HB. Some patients with
multiple sclerosis have neurovascular compression causing their trigeminal neuralgia and
can be treated effectively with MVD: report of five cases. Br J Neurosurg.
2005;19(6):463-8. http://dx.doi.org/10.1080/02688690500495067
https://doi.org/10.1080/0268869050049506...
, however this contrasts with the frequent neuroimaging finding of a
neurovascular contact with the trigeminal root in patients with TN and MS and the existence
of some patients with MS who have TN as the sole clinical manifestation and the
microvascular decompression outcome of neurosurgical studies results in considerable pain
relief2727 Athanasiou TC, Patel NK, Renowden SA, Coakham HB. Some patients with
multiple sclerosis have neurovascular compression causing their trigeminal neuralgia and
can be treated effectively with MVD: report of five cases. Br J Neurosurg.
2005;19(6):463-8. http://dx.doi.org/10.1080/02688690500495067
https://doi.org/10.1080/0268869050049506...
. Lhermitte’s phenomenon, which
is thought to come from a demyelinating plaque in the dorsal columns at the cervical level,
is for many patients a transient symptom, manifesting for some weeks then resolving
spontaneously2626 Nurmikko TJ, Gupta S, Maclver K. Multiple sclerosis-related central pain
disorders. Curr Pain Headache Rep. 2010;14(3):189-95.
http://dx.doi.org/10.1007/s11916-010-0108-8
https://doi.org/10.1007/s11916-010-0108-...
. Painful tonic spasms
are more MS-specific. They are involuntary muscle contractions that last less than 2 minutes
sometimes several times per day and usually continue for weeks or months and then disappear.
They are more common in PP and SP forms and are positively correlated with age, disease
duration, and disability2626 Nurmikko TJ, Gupta S, Maclver K. Multiple sclerosis-related central pain
disorders. Curr Pain Headache Rep. 2010;14(3):189-95.
http://dx.doi.org/10.1007/s11916-010-0108-8
https://doi.org/10.1007/s11916-010-0108-...
, although never
found to be linked to relapses and appear to be linked to the second phase of MS.
Inasmuch as our study may provide a drastic shift in the role of relapses, it supports the
recent two distinct phase model of MS1111 Scalfari A, Neuhaus A, Degenhardt A, Rice GP, Muraro PA, Daumer M et al. The
natural history of multiple sclerosis: a geographically based study 10: relapses and
long-term disability. Brain. 2010;133(7):1914-29.
http://dx.doi.org/10.1093/brain/awq118
https://doi.org/10.1093/brain/awq118...
, 2424 Tremlett H, Yousefi M, Devonshire V, Rieckmann P, Zhao Y. Impact of multiple
sclerosis relapses on progression diminishes with time. Neurology. 2009;73(20):1616-23.
http://dx.doi.org/10.1212/WNL.0b013e3181c1e44f
https://doi.org/10.1212/WNL.0b013e3181c1...
, 2828 Leray E, Yaouanq J, Le Page E, Coustans M, Laplaud D, Oger J et al. Evidence
for a two-stage disability progression in multiple sclerosis. Brain. 2010;133(7):1900-13.
http://dx.doi.org/10.1093/brain/awq076
https://doi.org/10.1093/brain/awq076...
,
gender1212 Voskuhl RR. Gender issues and multiple sclerosis. Curr Neurol Neurosci Rep.
2002;2(3):277-86. http://dx.doi.org/10.1007/s11910-002-0087-1
https://doi.org/10.1007/s11910-002-0087-...
and age related2929 Confavreux C, Vukusic S. Age at disability milestones in multiple sclerosis.
Brain. 2006;129(3):595-605. http://dx.doi.org/10.1093/brain/awh714
https://doi.org/10.1093/brain/awh714...
findings. However, it remains difficult to
interpret drug trials, as relapses have typically been an end-point and as such creates a
mind-boggling task of applying these trial results to the mechanism of action of these
drugs. Even so, our results concur with several well-designed trials in SP multiple
sclerosis3030 Rice GP, Filippi M, Comi G. Cladribine and progressive MS: clinical and MRI
outcomes of a multicenter controlled trial. Neurology. 2000;54(5):1145-55.
http://dx.doi.org/10.1212/WNL.54.5.1145
https://doi.org/10.1212/WNL.54.5.1145...
, which showed an unrelated
impact of treatments focusing on focal inflammation (frequency of relapses and MRI activity)
on delaying disability progression. This implies that therapeutics focusing on these
end-points rather than disability progression are actually working against the immune system
to preserve the individual from later MS related pain developed in the second phase. By no
means are we able to state that relapses hold a beneficial function, however our results
indicate that further studies need to be done to investigate the relationship between a
possibly protective role of relapses for later developed pain. As well, while we stratified
our results by medication use, this is not to imply that any relationship was found in use
of medication. The fact remains that our population size is extremely limited and the use of
medication, pain and relapse is confounded by the specific physician choice of therapeutic
treatment. Treatment choices have a variety of considerations that are unable to be
stratified or listed, as they are patient specific. We stress that our results cannot be
used to draw conclusion about drug treatments used and that larger longitudinal studies
would be able to offer more insight. Our findings do support that the progressive phase is
the core phenotype of MS, and its probability, slope, and latency should be the targets for
MS treatment and investigations.
The most obvious limitation of our study is the size of our sample. While we still reached statistical significance, our findings should be verified in larger longitudinal studies and stratified per sex to verify if the same patterns exist. On this same note, as our sample was a clinic based study, it did not have an equal number of men and women, and reflects the gender bias in incidence. We believe the intensity and location of pain, though done only general in our study should be investigated in relation to the presence of MRI T2 or gadolinium enhancing lesions. Moreover, we did not perform a regression analysis adjusted for time of disease, what we believe to be a critical limitation of study, once the greater the disease duration, the higher the relapses occurrence. Our next step will consist of analyzing the annualized relapse rate and its relationship to pain frequency.
In our sample, 64 patients were on immunomodulatory therapy. Among those, 48 were in regular use of interferons. Taking into account the difficulty of MS patients to adhere to treatment, we included in our study only patients with medication possession rate above 80%, thus avoiding a possible selection bias.
In conclusion, regardless the number of limitations of our study, it shows a statistically significant relationship between MS relapses experienced and prevalence of painless MS patients.
References
-
1Solaro C, Brichetto G, Amato MP, Cocco E, Colombo B, D’Aleo G et al. The prevalence of pain in multiple sclerosis: a multicenter cross-sectional study. Neurology. 2004;63(5):919-21. http://dx.doi.org/10.1212/01.WNL.0000137047.85868.D6
» https://doi.org/10.1212/01.WNL.0000137047.85868.D6 -
2Hadjimichael O, Kerns RD, Rizzo MA, Cutter G, Vollmer T. Persistent pain and uncomfortable sensations in persons with multiple sclerosis. Pain. 2007;127(1-2):35-41. http://dx.doi.org/10.1016/j.pain.2006.07.015
» https://doi.org/10.1016/j.pain.2006.07.015 -
3Grau-López L, Sierra S, Martínez-Cáceres E, Ramo-Tello C. Analysis of the pain in multiple sclerosis patients. Neurologia. 2011;26(4):208-13. http://dx.doi.org/10.1016/j.nrl.2010.07.014
» https://doi.org/10.1016/j.nrl.2010.07.014 -
4Kalia LV, O’Connor PW. Severity of chronic pain and its relationship to quality of life in multiple sclerosis. Mult Scler. 2005;11(3):322-7. http://dx.doi.org/10.1191/1352458505ms1168oa
» https://doi.org/10.1191/1352458505ms1168oa -
5Osterberg A, Boivie J, Thuomas KA. Central pain in multiple sclerosis: prevalence and clinical characteristics. Eur J Pain. 2005;9(5):531-42. http://dx.doi.org/10.1016/j.ejpain.2004.11.005
» https://doi.org/10.1016/j.ejpain.2004.11.005 -
6Truini A, Barbanti P, Pozzilli C, Cruccu G. A mechanism-based classification of pain in multiple sclerosis. J Neurol. 2013;260(2):351-67. http://dx.doi.org/10.1007/s00415-012-6579-2
» https://doi.org/10.1007/s00415-012-6579-2 -
7Santos JG, Brito JO, de Andrade DC, Kaziyama VM, Ferreira KA, Souza I et al. Translation to Portuguese and validation of the Douleur Neuropathique 4 questionnaire. J Pain. 2010;11(5):484-90. http://dx.doi.org/10.1016/j.jpain.2009.09.014
» https://doi.org/10.1016/j.jpain.2009.09.014 -
8Schestatsky P, Félix-Torres V, Chaves ML, Câmara-Ehlers B, Mucenic T, Caumo W et al. Brazilian Portuguese validation of the Leeds Assessment of Neuropathic Symptoms and Signs for patients with chronic pain. Pain Med. 2011; 12(10):1544-50. http://dx.doi.org/10.1111/j.1526-4637.2011.01221.x
» https://doi.org/10.1111/j.1526-4637.2011.01221.x -
9Cunha J. Manual da versão em português das escalas Beck. São Paulo: Casa do Psicólogo; 2001.
-
10Polman CH, Reingold SC, Banwell B, Clanet M, Cohen JA, Filippi M et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol 2011;69(2):292-302. http://dx.doi.org/10.1002/ana.22366
» https://doi.org/10.1002/ana.22366 -
11Scalfari A, Neuhaus A, Degenhardt A, Rice GP, Muraro PA, Daumer M et al. The natural history of multiple sclerosis: a geographically based study 10: relapses and long-term disability. Brain. 2010;133(7):1914-29. http://dx.doi.org/10.1093/brain/awq118
» https://doi.org/10.1093/brain/awq118 -
12Voskuhl RR. Gender issues and multiple sclerosis. Curr Neurol Neurosci Rep. 2002;2(3):277-86. http://dx.doi.org/10.1007/s11910-002-0087-1
» https://doi.org/10.1007/s11910-002-0087-1 -
13Kremenchutzky M, Rice GP, Baskerville J, Wingerchuk DM, Ebers GC. The natural history of multiple sclerosis: a geographically based study 9: observations on the progressive phase of the disease. Brain. 2006;129(3):584-94. http://dx.doi.org/10.1093/brain/awh721
» https://doi.org/10.1093/brain/awh721 -
14Stankoff B, Mrejen S, Tourbah A, Fontaine B, Lyon-Caen O, Lubetzki C et al. Age at onset determines the occurrence of the progressive phase of multiple sclerosis. Neurology. 2007;68(10):779-81. http://dx.doi.org/10.1212/01.wnl.0000256732.36565.4a
» https://doi.org/10.1212/01.wnl.0000256732.36565.4a -
15Zorgdrager A, De Keyser J. The premenstrual period and exacerbations in multiple sclerosis. Eur Neurol 2002;48(4):204-6. http://dx.doi.org/10.1159/000066166
» https://doi.org/10.1159/000066166 -
16Paavilainen T, Kurki T, Parkkola R, Färkkilä M, Salonen O, Dastidar P et al. Magnetic resonance imaging of the brain used to detect early post-partum activation of multiple sclerosis. Eur J Neurol. 2007;14(11):1216-21. http://dx.doi.org/10.1111/j.1468-1331.2007.01927.x
» https://doi.org/10.1111/j.1468-1331.2007.01927.x -
17Michel L, Foucher Y, Vukusic S, Confavreux C, Sèze J, Brassat D et al. Increased risk of multiple sclerosis relapse after in vitro fertilisation. J Neurol Neurosurg Psychiatry. 2012;83(8):796-802. http://dx.doi.org/10.1136/jnnp-2012-302235
» https://doi.org/10.1136/jnnp-2012-302235 -
18Frischer JM, Bramow S, Dal-Bianco A, Lucchinetti CF, Rauschka H, Schmidbauer M et al. The relation between inflammation and neurodegeneration in multiple sclerosis brains. Brain. 2009;132(5):1175-89. http://dx.doi.org/10.1093/brain/awp070
» https://doi.org/10.1093/brain/awp070 -
19Borsook D. Neurological diseases and pain. Brain. 2012;135(2):320-44. http://dx.doi.org/10.1093/brain/awr271
» https://doi.org/10.1093/brain/awr271 -
20Merson TD, Binder MD, Kilpatrick TJ. Role of cytokines as mediators and regulators of microglial activity in inflammatory demyelination of the CNS. Neuromolecular Med. 2010;12(2):99-132. http://dx.doi.org/10.1007/s12017-010-8112-z
» https://doi.org/10.1007/s12017-010-8112-z -
21Graeber MB. Changing face of microglia. Science. 2010;330(6005):783-8. http://dx.doi.org/10.1126/science.1190929
» https://doi.org/10.1126/science.1190929 -
22Napadow V, LaCount L, Park K, As-Sanie S, Clauw DJ, Harris RE. Intrinsic brain connectivity in fibromyalgia is associated with chronic pain intensity. Arthritis Rheum. 2010;62(8):2545-55. http://dx.doi.org/10.1002/art.27497
» https://doi.org/10.1002/art.27497 -
23Starr CJ, Sawaki L, Wittenberg GF, Burdette JH, Oshiro Y, Quevedo AS et al. The contribution of the putamen to sensory aspects of pain: insights from structural connectivity and brain lesions. Brain. 2011;134(7):1987-2004. http://dx.doi.org/10.1093/brain/awr117
» https://doi.org/10.1093/brain/awr117 -
24Tremlett H, Yousefi M, Devonshire V, Rieckmann P, Zhao Y. Impact of multiple sclerosis relapses on progression diminishes with time. Neurology. 2009;73(20):1616-23. http://dx.doi.org/10.1212/WNL.0b013e3181c1e44f
» https://doi.org/10.1212/WNL.0b013e3181c1e44f -
25Harrison DM, Oh J, Roy S, Wood ET, Whetstone A, Seigo MA et al. Thalamic lesions in multiple sclerosis by 7T MRI: clinical implications and relationship to cortical pathology. Mult Scler. 2015 [Forthcoming].
-
26Nurmikko TJ, Gupta S, Maclver K. Multiple sclerosis-related central pain disorders. Curr Pain Headache Rep. 2010;14(3):189-95. http://dx.doi.org/10.1007/s11916-010-0108-8
» https://doi.org/10.1007/s11916-010-0108-8 -
27Athanasiou TC, Patel NK, Renowden SA, Coakham HB. Some patients with multiple sclerosis have neurovascular compression causing their trigeminal neuralgia and can be treated effectively with MVD: report of five cases. Br J Neurosurg. 2005;19(6):463-8. http://dx.doi.org/10.1080/02688690500495067
» https://doi.org/10.1080/02688690500495067 -
28Leray E, Yaouanq J, Le Page E, Coustans M, Laplaud D, Oger J et al. Evidence for a two-stage disability progression in multiple sclerosis. Brain. 2010;133(7):1900-13. http://dx.doi.org/10.1093/brain/awq076
» https://doi.org/10.1093/brain/awq076 -
29Confavreux C, Vukusic S. Age at disability milestones in multiple sclerosis. Brain. 2006;129(3):595-605. http://dx.doi.org/10.1093/brain/awh714
» https://doi.org/10.1093/brain/awh714 -
30Rice GP, Filippi M, Comi G. Cladribine and progressive MS: clinical and MRI outcomes of a multicenter controlled trial. Neurology. 2000;54(5):1145-55. http://dx.doi.org/10.1212/WNL.54.5.1145
» https://doi.org/10.1212/WNL.54.5.1145
-
Funding: This research was partially funded by Biogen Idec, Inc. Grant number:BRA-AVX-11-10219.
Publication Dates
-
Publication in this collection
July 2015
History
-
Received
06 Jan 2015 -
Reviewed
27 Feb 2015 -
Accepted
20 Mar 2015