- Email: [email protected]
Neurological comorbidity and survival in multiple sclerosis
Multiple Sclerosis and Related Disorders (2014) 3, 72–77
Available online at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/msard
Neurological comorbidity and survival in multiple sclerosis Olga Krökkia, Risto Bloigub, Hanna Ansakorpia, Mauri Reunanena, Anne M. Remesc,d,n a
Institute of Clinical Medicine, Neurology, University of Oulu, Oulu, Finland Medical Informatics Group, University of Oulu, Oulu, Finland c Institute of Clinical Medicine, Neurology, University of Eastern Finland, Finland d Department of Neurology, Kuopio University Hospital, Kuopio, Finland b
Received 6 March 2013; received in revised form 13 June 2013; accepted 17 June 2013
KEYWORDS Neurological comorbidity; Migraine; Epilepsy; Stroke; Peripheral nervous system disorders; Survival
Abstract Objective: There is increasing interest in the survival of multiple sclerosis (MS). MS itself may decrease life expectancy; however, several other comorbid diseases may also influence survival. We aimed to evaluate frequency of other neurological conditions and survival in the population-based Finnish Northern Ostrobothnia MS cohort. Methods: The frequencies of neurological comorbid diseases and their associations with gender, clinical course, disability level (EDSS) and duration of MS were evaluated in population based cohort of 491 patients with clinically definite MS that was diagnosed between 1990 and 2010. The survival rate of the patients was also analysed. Results: One or more neurological comorbid disease was present in 17.1% of patients (n=84). The prevalence of epilepsy in MS patients was 4.7%, which is greater than that in the general population. Migraine was significantly more common in women with a benign MS course when compared to other types of MS (p=0.046). A significant association between peripheral nervous system disorders and primary progressive MS was found (p=0.027). The 21-year survival rate from time of diagnosis was 90.5%. Stroke decreased the 21-year survival rate of the patients (p=0.003). An association between stroke prevalence and the duration of MS disease was also detected (p=0.023). Conclusions: This is the first report of multifaceted neurological comorbidities in MS patients. Neurological comorbidity is rather common in MS. However, only the prevalence of epilepsy was increased in MS patients compared to the general population. An association between peripheral nervous system disorders and primary progressive MS was also found. The 21-year survival rate was greater in the present population based cohort compared in other studies, but stroke seems to decrease the survival rate in MS patients. & 2013 Elsevier B.V. All rights reserved.
n
Correspondence to: University of Eastern Finland, Department of Neurology, Institute of Clinical Medicine, P.O. Box 1627, 70211 Kuopio, Finland. Tel.: +358 44 717 4655; fax: +358 17 172305. E-mail address: anne.remes@uef.fi (A.M. Remes). 2211-0348/$ - see front matter & 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.msard.2013.06.006
Neurological comorbidity and survival in MS
1.
Introduction
Multiple sclerosis (MS) is a lifelong, autoimmune demyelinating disease of the central nervous system with unexplained heterogeneity in outcomes that leads to the accumulation of physical and mental disabilities. The estimated life expectancy of MS patients is decreased, although several recent studies suggest improved MS survival (Bronnum-Hansen et al., 2004; Sumelahti et al., 2010). Comorbid diseases may adversely influence the quality of life, disabilities and life expectancies of MS patients. Comorbidity has recently been recognised as a relatively common problem in patients with MS (Marrie et al., 2008). Physical (vascular, autoimmune, musculoskeletal, gastrointestinal and visual and cancers) or mental (depression, anxiety, bipolar disorder and schizophrenia) comorbidities are present more than 50% of individuals with MS. While physical and mental comorbid conditions are increasingly being investigated, there is a dearth of information concerning the associations of comorbid neurological diseases with MS (Christiansen et al., 2010; Handel and Ramagopalan, 2010; Byatt et al., 2011). Several studies have shown that the frequency of epilepsy in patients with MS is elevated compared to the general population (Zaccara, 2009; Koch et al., 2009; Kang et al., 2010; Catenoix et al., 2011). Some studies have revealed an increased risk for primary headaches such as migraine and tension-type headache in MS patients (D'Amico et al., 2004; La Mantia, 2009; Kister et al., 2010). However, these findings are controversial (Putzki et al., 2009). The prevalence of other neurological diseases, such as stroke, movement disorders, peripheral nervous system disorders or brain tumours, in patients with MS is still unclear. Previous reports have focused on single specific neurological comorbid disease in MS, and data regarding composite neurological comorbidities in MS are not available. The aim of the present study was to evaluate the strain and developing of neurological comorbidity in the Finnish Northern Ostrobothnia MS cohort. We also evaluated the associations of neurological comorbid diseases with gender, clinical course, disability level and duration of MS. The influence of comorbid neurological diseases to the survival rates of MS patients was also analysed.
2. 2.1.
Materials and methods Locale of the study population
Northern Ostrobothnia is situated in Northern Finland. The area of study has been detailed elsewhere (Krokki et al., 2011). The population of the region on the 31st of December, 2010 was 398,335, which amounted to 7.4% of the total population of Finland, and the female/male ratio was 0.99. The region is served by Oulu University Hospital (OUH). The diagnosis and treatment of MS and other neurological diseases is concentrated in OUH; thus, OUH provided broad information about the comorbidity of other neurological diseases. The population data were obtained from Statistics Finland (http://www.tilastokeskus.fi).
73
2.2.
Data collection
The study was carried out in the Outpatient Department of Neurology at OUH with the approval of the Northern Ostrobothnia Ethics Committee and following the principles of the Declaration of Helsinki. Cases were identified from hospital records by reference to code 3400A (multiple sclerosis) in the ICD 9 (1st January 1990–31st December 1995) and code G35 (multiple sclerosis) in the ICD 10 (1st January 1996–31st December 2010). All new, clinically definite MS cases during the 21-year time interval were included in the study. The diagnoses of MS were made by a neurologist who verified diagnoses according to the Poser criteria (Poser et al., 1983), early McDonald criteria of 2001 (McDonald et al., 2001) or the McDonald criteria of 2005 (Polman et al., 2005). Data from brain MRIs (n= 490/99.8%), CSF IgG-indices (n = 463/94.7%) and CSF oligoclonal bands (n = 454/92.8%) were available for almost every case. The following clinical data were collected: sex, age at onset, age at MS-diagnosis, age at death, clinical course type (i.e., relapsing remitting (RRMS), primary progressive (PPMS) or benign), and expanded disability status score levels (EDSS) at the last evaluation, at 10 years from the onset and from the year of MS diagnosis. The classification of MS as benign was based on EDSS scores of 0–3 over a duration 10 years from the verified MS diagnosis as defined by Weinshenker (1995). Data concerning neurological comorbidity were identified by systematic review of hospital records according to the following criteria: doctor diagnosed migraine (both without and with aura), clinically verified epilepsy, anamnesis and/or typical clinical status of movement disorders (e.g., Parkinson's disease, essential tremor and restless legs syndrome), ischaemic stroke with diagnostic findings based on brain imaging, peripheral nervous system involvement verified by ENMG, cranial neuralgias with typical anamnesis, and MRI-verified brain tumours. The evaluation period for comorbid diseases was 2010–2012.
2.3.
Statistical methods
Statistical analyses were performed using SPSS for Windows, (IBM Corp. Released 2010. IBM SPSS Statistics for Windows, version 19.0. Armonk, NY: IBM Corp.). The significance level was set at p= 0.05. The derivation of p values was made by application of proper statistical tests. We used parametric t-tests to analyse baseline differences among study groups. Associations between neurological comorbidities and MS by duration, gender, disability level and course were systematically analysed for each neurological comorbid nosology and for overall neurological comorbidity by nonparametric tests (Chi-squared or Fisher's exact test). We compared associations with duration of MS disease based on four groups: less than 5 years, from 5 to 10 years, from 10 to 15 years and more than 15 years from MS diagnosis. To analyse the association with disability, patients were divided into two groups. In group one, the EDSS levels were equal or less than 3, and EDSS levels were greater than 3 at the time of the last evaluation in group two. The survival rate was analysed using Kaplan–Meier curves and the logrank test. The points of valuation time were 21 years from the first symptom and time of MS diagnosis. The use of
74
O. Krökki et al.
Table 1
Characteristics of the MS cohort (all new cases 1990–2010).
Total N (%)
Female
Male
Total
340 (69.2)
151 (30.8)
491 (100)
Age at onset mean/range Age at diagnosis mean/range Dead Age at death mean/range
31.0/11–65 35.3/12–67 7 (2.1) 45.0/25–70
33.9/15–65 38.2/16–70 10 (6.6) 57.1/45–74
32.0/11–65 36.2/12–70 17 (3.5) 52.1/25–74
RRMS Age at onset mean/range Age at diagnosis mean/range Dead Age at death mean/range
254 (74.7) 30.8/11–65nn 35.0/12–67 4(1.6) 34.0/25–49nnn
122 (80.8) 32.9/15–59 37.3/17–67 7 (5.7) 54.6/45–68
376 (76.6) 31.5/11–65n 35.8/12–67 11(2.9) 47.125–68
PPMS Age at onset mean/range Age at diagnosis mean/range Dead Age at death mean/range
19 (5.6) 40.8/21–58 44.6/21–59 3 (15.8) 59.7/54–70
14 (9.3) 47.9/22–65 53.2/34–70 3 (21.4) 63.0/57–74
33 (6.7) 43.9/21–65n 48.3/21–70 6 (18.2) 61.3/54–74
Benign Age at onset mean/range Age at diagnosis mean/range Dead
67 (20.9) 29.5/18–49 33.9/20–65 0
15 (10.9) 28.1/16–49 31.4/16–50 0
82 (17.9) 29.2/16–49 33.5/16–65 0
RRMS=relapsing-remitting MS; PPMS=primary progressive MS and Benign=‘benign’ cases. n po0.005 (total, RRMS vs. PPMS). nn p=0.05 (male vs. female). nnn p =0.005 (male vs. female).
Kaplan–Meier curves is beneficial because of the time factor, especially when that factor has a major impact on mortality rate. All analyses were performed using a univariate rather than a multivariate approach due to the relatively small subgroup sample sizes.
3. 3.1.
Results Characteristics of the MS cohort
A total of 491 clinically definite MS diagnoses (69.2% female) were made during the study period (Table 1). 93. 3% of patients suffered from RRMS, and 6.7% of cases were diagnosed as PPMS. The criteria for benign MS were fulfilled in 17.9% of RRMS cases. There were no gender differences in the age at onset or the age at death across the whole cohort or in the cases with PPMS. However, the mean age at onset was lower in patients with RRMS compared to patients with PPMS (po0.005), and the mean age at onset of MS was lower in females than in the males with RRMS (p= 0.05). The mean age at death was also lower in females than males with RRMS (p= 0.005).
3.2.
Neurological comorbidity in general
One or more neurological comorbid disease was present in 17.1% of patients (n= 84). Most cases suffered one (94%, n= 79) neurological comorbid disease at the time of
evaluation. However, there were also cases with two (6%, n = 5) neurological comorbid diseases.
3.3. Characteristics of the neurological comorbidity cohort by nosology Migraine was the most common neurological disease in patients with MS. Doctor-diagnosed migraine was observed in 10.4% of MS patients (female 78.4%). Migraine was more prevalent in women with benign MS compared to other types of the disease (p= 0.046). The frequency of epilepsy was 4.7%, and epilepsy was the second most common comorbid disease. The mean age at the first epileptic seizure was 36.6 years (range 16–62). The mean age at MS onset of the epilepsy patients was 29.4 years (range 15–49). Epilepsy was diagnosed before MS onset in 20% of cases. An epileptic seizure was the first symptom of MS disease in one case. EEGs were available from 83% of the patients with epilepsy. EEGs were normal in 26.3% and related to epilepsy in 73.7% of cases. The most common type of seizure was a focal seizure that evolved to a bilateral tonic–clonic seizure (47.8%). Generalised tonic– clonic, generalised myoclonic and focal seizures were also diagnosed. Seizure terms were assigned according to the ILAE Revised Classification of Seizures 2010 (Berg et al., 2010). Status epilepticus was observed in only one case with a focal seizure that evolved to a bilateral tonic–clonic seizures. Antiepileptic treatment had been started in 91% (n =21) of the patients with epilepsy. Epilepsy was
Neurological comorbidity and survival in MS diagnosed, and antiepileptic treatment had been started after the first seizure in 25% of the patients. At the last evaluation, 61% of all MS patients with epilepsy were seizure-free for at least 3 years (mean 7.7 years, range 3– 17 years ). One patient had less than one seizure per year and three cases (14.3%) had more than one seizure per year. One patient had seizures at a rate of more than 1 per month. Recent data were not available for three cases (14.3%) as a result of relocation to another region. The frequency of stroke was 1.2% (n =6, five females) in the cohort. Five of the patients had had an acute ischaemic stroke in the large vessels, and one patient had a transient ischaemic attack with a few hours of aphasia. The mean age at stroke occurrence was 43.1 years (range 30–57). The mean age at MS onset in the stroke patients was 39.7 years (range 17–58). Two patients suffered a stroke before MS onset (one 10 years before, the other at 24 years before MS onset). One patient had both an MRI-verified stroke and the first MS symptoms in the same year. MS onset preceded stroke in three patients. The aetiologies of the ischaemic strokes remained unknown. However, heart diseases and risks for cardiac embolism were present in two patients in the follow-up. There was a correlation between stroke and
75 the duration of MS disease (p =0.023). Two cases died after the stroke; one of these cased died two years after the stroke, and the other died 31 years after the stroke. We identified five MS patients with peripheral nervous system disorders. Two of these cases had PPMS, and three suffered from RRMS. Electrophysiological investigations were performed in all of these cases. Four patients had polyneuropathy, and one had a bilateral L-5 radiculopathy due to spinal stenosis. Peripheral nervous system disease was diagnosed after MS onset in all cases. The mean time between MS onset and peripheral nervous disease onset was 7.8 years (range 2–14). There was a significant correlation between peripheral nervous system disease and PPMS (p =0.027). Both of the PPMS patients were males, and one suffered from distal sensorimotor polyneuropathy, while the other had a bilateral ulnar demyelinating neuropathy. Four patients with movement disorders were identified in the cohort. Idiopathic Parkinson's disease was diagnosed in one patient 8 years after PPMS onset. One patient suffered from essential tremor, and two patients had restless legs syndrome. The prevalence of restless legs syndrome in our cohort was 0.4% (n = 2). Four patients suffered from unilateral trigeminal neuralgia. These patients were excluded
Fig. 1 21-Year survival rates (a) from time of MS onset and from time of MS-diagnosis in the Finnish Northern Ostrobothnia MS-cohort, (b) with stroke as neurological comorbid disease and (c) with neurological comorbid disease.
76
O. Krökki et al.
from our calculations because, in all cases, the trigeminal neuralgia occurred prior to the age of 50 years and was indistinguishable from neuropathic pain syndrome in MS. Malignant brain tumours were not detected in the cohort.
3.4.
Survival
Over a 21 year period, 17 deaths occurred in the cohort. The mean age at death was 52.1 (range 25–74 years). The age at death for females was lower than that for males with RRMS (p= 0.005). All cases with benign MS were still alive. The 21year survival rate was 90.5% from the time of MS diagnosis. The 21-year survival rate from the time of MS onset was fairly good; however, this rate declined to 73% after 40 years from the onset of MS (Fig. 1a). The 21-year survival rate was significantly lower (p= 0.003) in MS patients with stroke compared with those patients without stroke (Fig. 1b). No other differences in survival were observed between MS patients with and without neurological comorbidity (Fig. 1c).
4.
Discussion
This is the first report of integrated neurological comorbidity. Neurological comorbidity was rather common in MS patients; however, most patients suffered from only one neurological condition other than MS. This epidemiology of neurological comorbid disease is in line with earlier reports in which only epilepsy was found to be more prevalent in MS patients compared to other populations (Poser and Brinar, 2003; Forsgren et al., 2005; Zaccara, 2009; Catenoix et al., 2011). Epilepsy may be over-diagnosed in MS patients, and this possibility should be considered when interpreting present study because the diagnosis of epilepsy was made after the first seizure in 25% of the patients. All patients were seizure-free during treatment. In addition, more than 60% of our MS patients with epilepsy were seizure-free at the time of the last evaluation. These results confirm a previous finding that the prognosis of epilepsy in patients with MS is favourable (Knox, 2010). Migraine was the most common neurological disease in MS patients. Several studies have shown an increase in the risk of migraine in patients with MS (Kang et al., 2010; Doi et al., 2009); however, these findings are controversial (Putzki and Katsarava, 2010). There is no epidemiological data regarding migraine in the Finnish population, but the frequency of migraine in the present MS cohort was similar to that in the general western population (Breslau and Rasmussen, 2001). Migraine may have been under-diagnosed in our cohort, because only doctor-diagnosed migraine was considered, and migraine specific self-questionnaires were not used. Our study confirms previous findings that the prevalence of migraine is not associated with the duration of MS disease or EDSS level (Kister et al., 2010). We found that migraine was significantly more common in women with a benign course of MS. In a previous study, a significant correlation between migraine and RRMS was found (D'Amico et al., 2004); however, this tendency was not observed in the present study. An increased frequency of peripheral nervous system diseases in PPMS was also observed. The reason for this
phenomenon is unknown. The involvement of the peripheral nervous system in MS has been previously described in only one study in which standard nerve conduction velocity abnormalities were found in one-third of RRMS and SPMS patients (Gartzen et al., 2011). However, patients with PPMS were not included in that study. Further investigations with larger PPMS cohorts are needed to confirm this finding. We found only one case of Parkinson's disease in our cohort. Parkinson's disease seems to be rarely comorbid with MS, as a French study of neurological comorbidity in parkinsonism found no cases of MS in the study cohort (Bodenmann et al., 2001). RLS is reported to be more prevalent in patients with MS than in the general population (Fleming and Pollak, 2005). However, the prevalence of RLS in our cohort was lower than the recently estimated 5.5% in the general European population (Ohayon and Roth, 2002). RLS may have been under-diagnosed in our cohort because no specific questionnaires for restless legs syndrome were used, and mild symptoms may not have been reported. The estimated life expectancy of MS patients is reduced (Poser et al., 1989; Sumelahti et al., 2002). Interestingly, the 21-year survival rate in our cohort was greater than in previously published reports; the 21-year survival rate in our cohort exceed that in a study examining interferon-β treated patients (Goodin et al., 2012). In a previous Finnish study, the 25-year survival rate from the time of diagnosis to death by any cause was 62% (Sumelahti et al., 2002). However, that MS cohort was analysed before the use of immunomodulatory treatments began in Finland and reflects the survival rate of the natural course of MS; whereas in our study, most of the patients had received immunomodulatory treatments. Thus immunomodulatory may have influence in survival of MS patients. Also a fair limited cohort size may have influence to survival analysis. Our study revealed that comorbidity with stroke decreased the 21-year survival rate of patients with MS. Epidemiological studies suggest that patients with MS have a greater risk of ischaemic stroke than those without MS (Christiansen et al., 2010; Allen et al., 2008). Increased mortality from cardiovascular diseases, but not from ischaemic stroke, in MS patients has also been reported (Bronnum-Hansen et al., 2004). The prevalence of stroke in the present cohort was 1.2%, which is similar to the age-matched Finnish population (Meretoja et al., 2010). The duration of MS disease, but not the age of the MS patient, significantly increased the risk of stroke occurrence. In the present cohort, the number of stroke cases was limited, and stroke itself is an independent cause of death; however, both deaths due to stroke in our cohort occurred years after the initial stroke.
5.
Conclusions
Single neurological comorbidities seem to be common in patients with MS, but only epilepsy was more frequently present in MS patients compared to the known epidemiological data of the general population. Interestingly, MS survival in the cohort of the present study was better than that in previous studies, which may reflect the impact of the use of immunomodulatory treatments. Stroke associated with MS decreased survival; however, the size of the cohort
Neurological comorbidity and survival in MS was small, and comprehensive neurological comorbidity analyses should be carried out in larger cohorts.
Conflict of interest The authors disclose no conflicts of interest. This manuscript presents original work and is not in press or under consideration in any other journal. The research protocols have been approved by the local ethics committee. All the authors have reviewed the final version of the submitted manuscript and approved it for submission. The authors take full responsibility for the data, the analyses and interpretation, and the conduct of the research.
Funding source This work was supported by clinical EVO grants from Oulu University Hospital.
References Allen NB, Lichtman JH, Cohen HW, Fang J, Brass LM, Alderman MH. Vascular disease among hospitalized multiple sclerosis patients. Neuroepidemiology 2008;30:234–8. Berg AT, Berkovic SF, Brodie MJ, Buchhalter J, Cross JH, van Emde Boas W, et al. Revised terminology and concepts for organization of seizures and epilepsies: report of the ILAE commission on classification and terminology, 2005–2009. Epilepsia 2010;51:676–85. Bodenmann P, Ghika J, Van Melle G, Bogousslavsky J. Neurological comorbidity in parkinsonism. Revue Neurologique 2001;157:45–54. Breslau N, Rasmussen BK. The impact of migraine: epidemiology, risk factors, and co-morbidities. Neurology 2001;56:S4–12. Bronnum-Hansen H, Koch-Henriksen N, Stenager E. Trends in survival and cause of death in danish patients with multiple sclerosis. Brain 2004;127:844–50. Byatt N, Rothschild AJ, Riskind P, Ionete C, Hunt AT. Relationships between multiple sclerosis and depression. Journal of Neuropsychiatry and Clinical Neurosciences 2011;23:198–200. Catenoix H, Marignier R, Ritleng C, Dufour M, Mauguiere F, Confavreux C, et al. Multiple sclerosis and epileptic seizures. Multiple Sclerosis 2011;17:96–102. Christiansen CF, Christensen S, Farkas DK, Miret M, Sorensen HT, Pedersen L. Risk of arterial cardiovascular diseases in patients with multiple sclerosis: A population-based cohort study. Neuroepidemiology 2010;35:267–74. D'Amico D, La Mantia L, Rigamonti A, Usai S, Mascoli N, Milanese C, et al. Prevalence of primary headaches in people with multiple sclerosis. Cephalalgia 2004;24:980–4. Doi H, Matsushita T, Isobe N, Ishizu T, Ohyagi Y, Kira J. Frequency of chronic headaches in japanese patients with multiple sclerosis: with special reference to opticospinal and common forms of multiple sclerosis. Headache 2009;49:1513–20. Fleming WE, Pollak CP. Sleep disorders in multiple sclerosis. Seminars in Neurology 2005;25:64–8. Forsgren L, Beghi E, Oun A, Sillanpää M. The epidemiology of epilepsy in Europe—a systematic review. European Journal of Neurology 2005;12:245–53. Gartzen K, Katzarava Z, Diener HC, Putzki N. Peripheral nervous system involvement in multiple sclerosis. European Journal of Neurology 2011;18:789–91. Goodin DS, Reder AT, Ebers GC, Cutter G, Kremenchutzky M, Oger J, et al. Survival in MS: a randomized cohort study 21 years after
77 the start of the pivotal IFNbeta-1b trial. Neurology 2012;78: 1315–22. Handel AE, Ramagopalan SV. Multiple sclerosis and risk of cancer: a meta-analysis. Journal of Neurology, Neurosurgery and Psychiatry 2010;81:1413–4. Kang JH, Chen YH, Lin HC. Comorbidities amongst patients with multiple sclerosis: a population-based controlled study. European Journal of Neurology 2010;17:1215–9. Kister I, Caminero AB, Herbert J, Lipton RB. Tension-type headache and migraine in multiple sclerosis. Current Pain and Headache Reports 2010;14:441–8. Knox KB. Validating the assessment of comorbidity in multiple sclerosis: another step towards comprehensive health care. Neuroepidemiology 2010;35:91–2. Koch MW, Polman SK, Uyttenboogaart M, De Keyser J. Treatment of seizures in multiple sclerosis. Cochrane Database of Systematic Reviews (Online) 2009(3): CD007150. Krokki O, Bloigu R, Reunanen M, Remes AM. Increasing incidence of multiple sclerosis in women in northern Finland. Multiple sclerosis 2011;17:133–8. La Mantia L. Headache and multiple sclerosis: Clinical and therapeutic correlations. Neurological Sciences 2009;30(Suppl. 1): S23–S26. Marrie R, Horwitz R, Cutter G, Tyry T, Campagnolo D, Vollmer T. Comorbidity, socioeconomic status and multiple sclerosis. Multiple Sclerosis 2008;14:1091–8. McDonald WI, Compston A, Edan G, Goodkin D, Hartung HP, Lublin FD, et al. Recommended diagnostic criteria for multiple sclerosis: guidelines from the international panel on the diagnosis of multiple sclerosis. Annals of Neurology 2001;50:121–7. Meretoja A, Roine RO, Kaste M, Linna M, Juntunen M, Erila T, et al. Stroke monitoring on a national level: PERFECT stroke, a comprehensive, registry-linkage stroke database in Finland. Stroke 2010;41:2239–46. Ohayon MM, Roth T. Prevalence of restless legs syndrome and periodic limb movement disorder in the general population. Journal of Psychosomatic Research 2002;53:547–54. Polman CH, Reingold SC, Edan G, Filippi M, Hartung HP, Kappos L, et al. Diagnostic criteria for multiple sclerosis: 2005 revisions to the “McDonald criteria”. Annals of Neurology 2005;58:840–6. Poser CM, Brinar VV. Epilepsy and multiple sclerosis. Epilepsy Behavior 2003;4:6–12. Poser CM, Paty DW, Scheinberg L, McDonald WI, Davis FA, Ebers GC, et al. New diagnostic criteria for multiple sclerosis: Guidelines for research protocols. Annals of Neurology 1983;13:227–31. Poser S, Kurtzke JF, Poser W, Schlaf G. Survival in multiple sclerosis. Journal of Clinical Epidemiology 1989;42:159–68. Putzki N, Katsarava Z. Headache in multiple sclerosis. Current Pain and Headache Reports 2010;14:316–20. Putzki N, Pfriem A, Limmroth V, Yaldizli O, Tettenborn B, Diener HC, et al. Prevalence of migraine, tension-type headache and trigeminal neuralgia in multiple sclerosis. European Journal of Neurology 2009;16:262–7. Sumelahti ML, Hakama M, Elovaara I, Pukkala E. Causes of death among patients with multiple sclerosis. Multiple Sclerosis 2010;16:1437–42. Sumelahti ML, Tienari PJ, Wikstrom J, Salminen TM, Hakama M. Survival of multiple sclerosis in Finland between 1964 and 1993. Multiple Sclerosis 2002;8:350–5. Weinshenker BG. The natural history of multiple sclerosis. Neurologic Clinics 1995;13:119–46. Zaccara G. Neurological comorbidity and epilepsy: implications for treatment. Acta Neurologica Scandinavica 2009;120:1–15.
Available online at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/msard
Neurological comorbidity and survival in multiple sclerosis Olga Krökkia, Risto Bloigub, Hanna Ansakorpia, Mauri Reunanena, Anne M. Remesc,d,n a
Institute of Clinical Medicine, Neurology, University of Oulu, Oulu, Finland Medical Informatics Group, University of Oulu, Oulu, Finland c Institute of Clinical Medicine, Neurology, University of Eastern Finland, Finland d Department of Neurology, Kuopio University Hospital, Kuopio, Finland b
Received 6 March 2013; received in revised form 13 June 2013; accepted 17 June 2013
KEYWORDS Neurological comorbidity; Migraine; Epilepsy; Stroke; Peripheral nervous system disorders; Survival
Abstract Objective: There is increasing interest in the survival of multiple sclerosis (MS). MS itself may decrease life expectancy; however, several other comorbid diseases may also influence survival. We aimed to evaluate frequency of other neurological conditions and survival in the population-based Finnish Northern Ostrobothnia MS cohort. Methods: The frequencies of neurological comorbid diseases and their associations with gender, clinical course, disability level (EDSS) and duration of MS were evaluated in population based cohort of 491 patients with clinically definite MS that was diagnosed between 1990 and 2010. The survival rate of the patients was also analysed. Results: One or more neurological comorbid disease was present in 17.1% of patients (n=84). The prevalence of epilepsy in MS patients was 4.7%, which is greater than that in the general population. Migraine was significantly more common in women with a benign MS course when compared to other types of MS (p=0.046). A significant association between peripheral nervous system disorders and primary progressive MS was found (p=0.027). The 21-year survival rate from time of diagnosis was 90.5%. Stroke decreased the 21-year survival rate of the patients (p=0.003). An association between stroke prevalence and the duration of MS disease was also detected (p=0.023). Conclusions: This is the first report of multifaceted neurological comorbidities in MS patients. Neurological comorbidity is rather common in MS. However, only the prevalence of epilepsy was increased in MS patients compared to the general population. An association between peripheral nervous system disorders and primary progressive MS was also found. The 21-year survival rate was greater in the present population based cohort compared in other studies, but stroke seems to decrease the survival rate in MS patients. & 2013 Elsevier B.V. All rights reserved.
n
Correspondence to: University of Eastern Finland, Department of Neurology, Institute of Clinical Medicine, P.O. Box 1627, 70211 Kuopio, Finland. Tel.: +358 44 717 4655; fax: +358 17 172305. E-mail address: anne.remes@uef.fi (A.M. Remes). 2211-0348/$ - see front matter & 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.msard.2013.06.006
Neurological comorbidity and survival in MS
1.
Introduction
Multiple sclerosis (MS) is a lifelong, autoimmune demyelinating disease of the central nervous system with unexplained heterogeneity in outcomes that leads to the accumulation of physical and mental disabilities. The estimated life expectancy of MS patients is decreased, although several recent studies suggest improved MS survival (Bronnum-Hansen et al., 2004; Sumelahti et al., 2010). Comorbid diseases may adversely influence the quality of life, disabilities and life expectancies of MS patients. Comorbidity has recently been recognised as a relatively common problem in patients with MS (Marrie et al., 2008). Physical (vascular, autoimmune, musculoskeletal, gastrointestinal and visual and cancers) or mental (depression, anxiety, bipolar disorder and schizophrenia) comorbidities are present more than 50% of individuals with MS. While physical and mental comorbid conditions are increasingly being investigated, there is a dearth of information concerning the associations of comorbid neurological diseases with MS (Christiansen et al., 2010; Handel and Ramagopalan, 2010; Byatt et al., 2011). Several studies have shown that the frequency of epilepsy in patients with MS is elevated compared to the general population (Zaccara, 2009; Koch et al., 2009; Kang et al., 2010; Catenoix et al., 2011). Some studies have revealed an increased risk for primary headaches such as migraine and tension-type headache in MS patients (D'Amico et al., 2004; La Mantia, 2009; Kister et al., 2010). However, these findings are controversial (Putzki et al., 2009). The prevalence of other neurological diseases, such as stroke, movement disorders, peripheral nervous system disorders or brain tumours, in patients with MS is still unclear. Previous reports have focused on single specific neurological comorbid disease in MS, and data regarding composite neurological comorbidities in MS are not available. The aim of the present study was to evaluate the strain and developing of neurological comorbidity in the Finnish Northern Ostrobothnia MS cohort. We also evaluated the associations of neurological comorbid diseases with gender, clinical course, disability level and duration of MS. The influence of comorbid neurological diseases to the survival rates of MS patients was also analysed.
2. 2.1.
Materials and methods Locale of the study population
Northern Ostrobothnia is situated in Northern Finland. The area of study has been detailed elsewhere (Krokki et al., 2011). The population of the region on the 31st of December, 2010 was 398,335, which amounted to 7.4% of the total population of Finland, and the female/male ratio was 0.99. The region is served by Oulu University Hospital (OUH). The diagnosis and treatment of MS and other neurological diseases is concentrated in OUH; thus, OUH provided broad information about the comorbidity of other neurological diseases. The population data were obtained from Statistics Finland (http://www.tilastokeskus.fi).
73
2.2.
Data collection
The study was carried out in the Outpatient Department of Neurology at OUH with the approval of the Northern Ostrobothnia Ethics Committee and following the principles of the Declaration of Helsinki. Cases were identified from hospital records by reference to code 3400A (multiple sclerosis) in the ICD 9 (1st January 1990–31st December 1995) and code G35 (multiple sclerosis) in the ICD 10 (1st January 1996–31st December 2010). All new, clinically definite MS cases during the 21-year time interval were included in the study. The diagnoses of MS were made by a neurologist who verified diagnoses according to the Poser criteria (Poser et al., 1983), early McDonald criteria of 2001 (McDonald et al., 2001) or the McDonald criteria of 2005 (Polman et al., 2005). Data from brain MRIs (n= 490/99.8%), CSF IgG-indices (n = 463/94.7%) and CSF oligoclonal bands (n = 454/92.8%) were available for almost every case. The following clinical data were collected: sex, age at onset, age at MS-diagnosis, age at death, clinical course type (i.e., relapsing remitting (RRMS), primary progressive (PPMS) or benign), and expanded disability status score levels (EDSS) at the last evaluation, at 10 years from the onset and from the year of MS diagnosis. The classification of MS as benign was based on EDSS scores of 0–3 over a duration 10 years from the verified MS diagnosis as defined by Weinshenker (1995). Data concerning neurological comorbidity were identified by systematic review of hospital records according to the following criteria: doctor diagnosed migraine (both without and with aura), clinically verified epilepsy, anamnesis and/or typical clinical status of movement disorders (e.g., Parkinson's disease, essential tremor and restless legs syndrome), ischaemic stroke with diagnostic findings based on brain imaging, peripheral nervous system involvement verified by ENMG, cranial neuralgias with typical anamnesis, and MRI-verified brain tumours. The evaluation period for comorbid diseases was 2010–2012.
2.3.
Statistical methods
Statistical analyses were performed using SPSS for Windows, (IBM Corp. Released 2010. IBM SPSS Statistics for Windows, version 19.0. Armonk, NY: IBM Corp.). The significance level was set at p= 0.05. The derivation of p values was made by application of proper statistical tests. We used parametric t-tests to analyse baseline differences among study groups. Associations between neurological comorbidities and MS by duration, gender, disability level and course were systematically analysed for each neurological comorbid nosology and for overall neurological comorbidity by nonparametric tests (Chi-squared or Fisher's exact test). We compared associations with duration of MS disease based on four groups: less than 5 years, from 5 to 10 years, from 10 to 15 years and more than 15 years from MS diagnosis. To analyse the association with disability, patients were divided into two groups. In group one, the EDSS levels were equal or less than 3, and EDSS levels were greater than 3 at the time of the last evaluation in group two. The survival rate was analysed using Kaplan–Meier curves and the logrank test. The points of valuation time were 21 years from the first symptom and time of MS diagnosis. The use of
74
O. Krökki et al.
Table 1
Characteristics of the MS cohort (all new cases 1990–2010).
Total N (%)
Female
Male
Total
340 (69.2)
151 (30.8)
491 (100)
Age at onset mean/range Age at diagnosis mean/range Dead Age at death mean/range
31.0/11–65 35.3/12–67 7 (2.1) 45.0/25–70
33.9/15–65 38.2/16–70 10 (6.6) 57.1/45–74
32.0/11–65 36.2/12–70 17 (3.5) 52.1/25–74
RRMS Age at onset mean/range Age at diagnosis mean/range Dead Age at death mean/range
254 (74.7) 30.8/11–65nn 35.0/12–67 4(1.6) 34.0/25–49nnn
122 (80.8) 32.9/15–59 37.3/17–67 7 (5.7) 54.6/45–68
376 (76.6) 31.5/11–65n 35.8/12–67 11(2.9) 47.125–68
PPMS Age at onset mean/range Age at diagnosis mean/range Dead Age at death mean/range
19 (5.6) 40.8/21–58 44.6/21–59 3 (15.8) 59.7/54–70
14 (9.3) 47.9/22–65 53.2/34–70 3 (21.4) 63.0/57–74
33 (6.7) 43.9/21–65n 48.3/21–70 6 (18.2) 61.3/54–74
Benign Age at onset mean/range Age at diagnosis mean/range Dead
67 (20.9) 29.5/18–49 33.9/20–65 0
15 (10.9) 28.1/16–49 31.4/16–50 0
82 (17.9) 29.2/16–49 33.5/16–65 0
RRMS=relapsing-remitting MS; PPMS=primary progressive MS and Benign=‘benign’ cases. n po0.005 (total, RRMS vs. PPMS). nn p=0.05 (male vs. female). nnn p =0.005 (male vs. female).
Kaplan–Meier curves is beneficial because of the time factor, especially when that factor has a major impact on mortality rate. All analyses were performed using a univariate rather than a multivariate approach due to the relatively small subgroup sample sizes.
3. 3.1.
Results Characteristics of the MS cohort
A total of 491 clinically definite MS diagnoses (69.2% female) were made during the study period (Table 1). 93. 3% of patients suffered from RRMS, and 6.7% of cases were diagnosed as PPMS. The criteria for benign MS were fulfilled in 17.9% of RRMS cases. There were no gender differences in the age at onset or the age at death across the whole cohort or in the cases with PPMS. However, the mean age at onset was lower in patients with RRMS compared to patients with PPMS (po0.005), and the mean age at onset of MS was lower in females than in the males with RRMS (p= 0.05). The mean age at death was also lower in females than males with RRMS (p= 0.005).
3.2.
Neurological comorbidity in general
One or more neurological comorbid disease was present in 17.1% of patients (n= 84). Most cases suffered one (94%, n= 79) neurological comorbid disease at the time of
evaluation. However, there were also cases with two (6%, n = 5) neurological comorbid diseases.
3.3. Characteristics of the neurological comorbidity cohort by nosology Migraine was the most common neurological disease in patients with MS. Doctor-diagnosed migraine was observed in 10.4% of MS patients (female 78.4%). Migraine was more prevalent in women with benign MS compared to other types of the disease (p= 0.046). The frequency of epilepsy was 4.7%, and epilepsy was the second most common comorbid disease. The mean age at the first epileptic seizure was 36.6 years (range 16–62). The mean age at MS onset of the epilepsy patients was 29.4 years (range 15–49). Epilepsy was diagnosed before MS onset in 20% of cases. An epileptic seizure was the first symptom of MS disease in one case. EEGs were available from 83% of the patients with epilepsy. EEGs were normal in 26.3% and related to epilepsy in 73.7% of cases. The most common type of seizure was a focal seizure that evolved to a bilateral tonic–clonic seizure (47.8%). Generalised tonic– clonic, generalised myoclonic and focal seizures were also diagnosed. Seizure terms were assigned according to the ILAE Revised Classification of Seizures 2010 (Berg et al., 2010). Status epilepticus was observed in only one case with a focal seizure that evolved to a bilateral tonic–clonic seizures. Antiepileptic treatment had been started in 91% (n =21) of the patients with epilepsy. Epilepsy was
Neurological comorbidity and survival in MS diagnosed, and antiepileptic treatment had been started after the first seizure in 25% of the patients. At the last evaluation, 61% of all MS patients with epilepsy were seizure-free for at least 3 years (mean 7.7 years, range 3– 17 years ). One patient had less than one seizure per year and three cases (14.3%) had more than one seizure per year. One patient had seizures at a rate of more than 1 per month. Recent data were not available for three cases (14.3%) as a result of relocation to another region. The frequency of stroke was 1.2% (n =6, five females) in the cohort. Five of the patients had had an acute ischaemic stroke in the large vessels, and one patient had a transient ischaemic attack with a few hours of aphasia. The mean age at stroke occurrence was 43.1 years (range 30–57). The mean age at MS onset in the stroke patients was 39.7 years (range 17–58). Two patients suffered a stroke before MS onset (one 10 years before, the other at 24 years before MS onset). One patient had both an MRI-verified stroke and the first MS symptoms in the same year. MS onset preceded stroke in three patients. The aetiologies of the ischaemic strokes remained unknown. However, heart diseases and risks for cardiac embolism were present in two patients in the follow-up. There was a correlation between stroke and
75 the duration of MS disease (p =0.023). Two cases died after the stroke; one of these cased died two years after the stroke, and the other died 31 years after the stroke. We identified five MS patients with peripheral nervous system disorders. Two of these cases had PPMS, and three suffered from RRMS. Electrophysiological investigations were performed in all of these cases. Four patients had polyneuropathy, and one had a bilateral L-5 radiculopathy due to spinal stenosis. Peripheral nervous system disease was diagnosed after MS onset in all cases. The mean time between MS onset and peripheral nervous disease onset was 7.8 years (range 2–14). There was a significant correlation between peripheral nervous system disease and PPMS (p =0.027). Both of the PPMS patients were males, and one suffered from distal sensorimotor polyneuropathy, while the other had a bilateral ulnar demyelinating neuropathy. Four patients with movement disorders were identified in the cohort. Idiopathic Parkinson's disease was diagnosed in one patient 8 years after PPMS onset. One patient suffered from essential tremor, and two patients had restless legs syndrome. The prevalence of restless legs syndrome in our cohort was 0.4% (n = 2). Four patients suffered from unilateral trigeminal neuralgia. These patients were excluded
Fig. 1 21-Year survival rates (a) from time of MS onset and from time of MS-diagnosis in the Finnish Northern Ostrobothnia MS-cohort, (b) with stroke as neurological comorbid disease and (c) with neurological comorbid disease.
76
O. Krökki et al.
from our calculations because, in all cases, the trigeminal neuralgia occurred prior to the age of 50 years and was indistinguishable from neuropathic pain syndrome in MS. Malignant brain tumours were not detected in the cohort.
3.4.
Survival
Over a 21 year period, 17 deaths occurred in the cohort. The mean age at death was 52.1 (range 25–74 years). The age at death for females was lower than that for males with RRMS (p= 0.005). All cases with benign MS were still alive. The 21year survival rate was 90.5% from the time of MS diagnosis. The 21-year survival rate from the time of MS onset was fairly good; however, this rate declined to 73% after 40 years from the onset of MS (Fig. 1a). The 21-year survival rate was significantly lower (p= 0.003) in MS patients with stroke compared with those patients without stroke (Fig. 1b). No other differences in survival were observed between MS patients with and without neurological comorbidity (Fig. 1c).
4.
Discussion
This is the first report of integrated neurological comorbidity. Neurological comorbidity was rather common in MS patients; however, most patients suffered from only one neurological condition other than MS. This epidemiology of neurological comorbid disease is in line with earlier reports in which only epilepsy was found to be more prevalent in MS patients compared to other populations (Poser and Brinar, 2003; Forsgren et al., 2005; Zaccara, 2009; Catenoix et al., 2011). Epilepsy may be over-diagnosed in MS patients, and this possibility should be considered when interpreting present study because the diagnosis of epilepsy was made after the first seizure in 25% of the patients. All patients were seizure-free during treatment. In addition, more than 60% of our MS patients with epilepsy were seizure-free at the time of the last evaluation. These results confirm a previous finding that the prognosis of epilepsy in patients with MS is favourable (Knox, 2010). Migraine was the most common neurological disease in MS patients. Several studies have shown an increase in the risk of migraine in patients with MS (Kang et al., 2010; Doi et al., 2009); however, these findings are controversial (Putzki and Katsarava, 2010). There is no epidemiological data regarding migraine in the Finnish population, but the frequency of migraine in the present MS cohort was similar to that in the general western population (Breslau and Rasmussen, 2001). Migraine may have been under-diagnosed in our cohort, because only doctor-diagnosed migraine was considered, and migraine specific self-questionnaires were not used. Our study confirms previous findings that the prevalence of migraine is not associated with the duration of MS disease or EDSS level (Kister et al., 2010). We found that migraine was significantly more common in women with a benign course of MS. In a previous study, a significant correlation between migraine and RRMS was found (D'Amico et al., 2004); however, this tendency was not observed in the present study. An increased frequency of peripheral nervous system diseases in PPMS was also observed. The reason for this
phenomenon is unknown. The involvement of the peripheral nervous system in MS has been previously described in only one study in which standard nerve conduction velocity abnormalities were found in one-third of RRMS and SPMS patients (Gartzen et al., 2011). However, patients with PPMS were not included in that study. Further investigations with larger PPMS cohorts are needed to confirm this finding. We found only one case of Parkinson's disease in our cohort. Parkinson's disease seems to be rarely comorbid with MS, as a French study of neurological comorbidity in parkinsonism found no cases of MS in the study cohort (Bodenmann et al., 2001). RLS is reported to be more prevalent in patients with MS than in the general population (Fleming and Pollak, 2005). However, the prevalence of RLS in our cohort was lower than the recently estimated 5.5% in the general European population (Ohayon and Roth, 2002). RLS may have been under-diagnosed in our cohort because no specific questionnaires for restless legs syndrome were used, and mild symptoms may not have been reported. The estimated life expectancy of MS patients is reduced (Poser et al., 1989; Sumelahti et al., 2002). Interestingly, the 21-year survival rate in our cohort was greater than in previously published reports; the 21-year survival rate in our cohort exceed that in a study examining interferon-β treated patients (Goodin et al., 2012). In a previous Finnish study, the 25-year survival rate from the time of diagnosis to death by any cause was 62% (Sumelahti et al., 2002). However, that MS cohort was analysed before the use of immunomodulatory treatments began in Finland and reflects the survival rate of the natural course of MS; whereas in our study, most of the patients had received immunomodulatory treatments. Thus immunomodulatory may have influence in survival of MS patients. Also a fair limited cohort size may have influence to survival analysis. Our study revealed that comorbidity with stroke decreased the 21-year survival rate of patients with MS. Epidemiological studies suggest that patients with MS have a greater risk of ischaemic stroke than those without MS (Christiansen et al., 2010; Allen et al., 2008). Increased mortality from cardiovascular diseases, but not from ischaemic stroke, in MS patients has also been reported (Bronnum-Hansen et al., 2004). The prevalence of stroke in the present cohort was 1.2%, which is similar to the age-matched Finnish population (Meretoja et al., 2010). The duration of MS disease, but not the age of the MS patient, significantly increased the risk of stroke occurrence. In the present cohort, the number of stroke cases was limited, and stroke itself is an independent cause of death; however, both deaths due to stroke in our cohort occurred years after the initial stroke.
5.
Conclusions
Single neurological comorbidities seem to be common in patients with MS, but only epilepsy was more frequently present in MS patients compared to the known epidemiological data of the general population. Interestingly, MS survival in the cohort of the present study was better than that in previous studies, which may reflect the impact of the use of immunomodulatory treatments. Stroke associated with MS decreased survival; however, the size of the cohort
Neurological comorbidity and survival in MS was small, and comprehensive neurological comorbidity analyses should be carried out in larger cohorts.
Conflict of interest The authors disclose no conflicts of interest. This manuscript presents original work and is not in press or under consideration in any other journal. The research protocols have been approved by the local ethics committee. All the authors have reviewed the final version of the submitted manuscript and approved it for submission. The authors take full responsibility for the data, the analyses and interpretation, and the conduct of the research.
Funding source This work was supported by clinical EVO grants from Oulu University Hospital.
References Allen NB, Lichtman JH, Cohen HW, Fang J, Brass LM, Alderman MH. Vascular disease among hospitalized multiple sclerosis patients. Neuroepidemiology 2008;30:234–8. Berg AT, Berkovic SF, Brodie MJ, Buchhalter J, Cross JH, van Emde Boas W, et al. Revised terminology and concepts for organization of seizures and epilepsies: report of the ILAE commission on classification and terminology, 2005–2009. Epilepsia 2010;51:676–85. Bodenmann P, Ghika J, Van Melle G, Bogousslavsky J. Neurological comorbidity in parkinsonism. Revue Neurologique 2001;157:45–54. Breslau N, Rasmussen BK. The impact of migraine: epidemiology, risk factors, and co-morbidities. Neurology 2001;56:S4–12. Bronnum-Hansen H, Koch-Henriksen N, Stenager E. Trends in survival and cause of death in danish patients with multiple sclerosis. Brain 2004;127:844–50. Byatt N, Rothschild AJ, Riskind P, Ionete C, Hunt AT. Relationships between multiple sclerosis and depression. Journal of Neuropsychiatry and Clinical Neurosciences 2011;23:198–200. Catenoix H, Marignier R, Ritleng C, Dufour M, Mauguiere F, Confavreux C, et al. Multiple sclerosis and epileptic seizures. Multiple Sclerosis 2011;17:96–102. Christiansen CF, Christensen S, Farkas DK, Miret M, Sorensen HT, Pedersen L. Risk of arterial cardiovascular diseases in patients with multiple sclerosis: A population-based cohort study. Neuroepidemiology 2010;35:267–74. D'Amico D, La Mantia L, Rigamonti A, Usai S, Mascoli N, Milanese C, et al. Prevalence of primary headaches in people with multiple sclerosis. Cephalalgia 2004;24:980–4. Doi H, Matsushita T, Isobe N, Ishizu T, Ohyagi Y, Kira J. Frequency of chronic headaches in japanese patients with multiple sclerosis: with special reference to opticospinal and common forms of multiple sclerosis. Headache 2009;49:1513–20. Fleming WE, Pollak CP. Sleep disorders in multiple sclerosis. Seminars in Neurology 2005;25:64–8. Forsgren L, Beghi E, Oun A, Sillanpää M. The epidemiology of epilepsy in Europe—a systematic review. European Journal of Neurology 2005;12:245–53. Gartzen K, Katzarava Z, Diener HC, Putzki N. Peripheral nervous system involvement in multiple sclerosis. European Journal of Neurology 2011;18:789–91. Goodin DS, Reder AT, Ebers GC, Cutter G, Kremenchutzky M, Oger J, et al. Survival in MS: a randomized cohort study 21 years after
77 the start of the pivotal IFNbeta-1b trial. Neurology 2012;78: 1315–22. Handel AE, Ramagopalan SV. Multiple sclerosis and risk of cancer: a meta-analysis. Journal of Neurology, Neurosurgery and Psychiatry 2010;81:1413–4. Kang JH, Chen YH, Lin HC. Comorbidities amongst patients with multiple sclerosis: a population-based controlled study. European Journal of Neurology 2010;17:1215–9. Kister I, Caminero AB, Herbert J, Lipton RB. Tension-type headache and migraine in multiple sclerosis. Current Pain and Headache Reports 2010;14:441–8. Knox KB. Validating the assessment of comorbidity in multiple sclerosis: another step towards comprehensive health care. Neuroepidemiology 2010;35:91–2. Koch MW, Polman SK, Uyttenboogaart M, De Keyser J. Treatment of seizures in multiple sclerosis. Cochrane Database of Systematic Reviews (Online) 2009(3): CD007150. Krokki O, Bloigu R, Reunanen M, Remes AM. Increasing incidence of multiple sclerosis in women in northern Finland. Multiple sclerosis 2011;17:133–8. La Mantia L. Headache and multiple sclerosis: Clinical and therapeutic correlations. Neurological Sciences 2009;30(Suppl. 1): S23–S26. Marrie R, Horwitz R, Cutter G, Tyry T, Campagnolo D, Vollmer T. Comorbidity, socioeconomic status and multiple sclerosis. Multiple Sclerosis 2008;14:1091–8. McDonald WI, Compston A, Edan G, Goodkin D, Hartung HP, Lublin FD, et al. Recommended diagnostic criteria for multiple sclerosis: guidelines from the international panel on the diagnosis of multiple sclerosis. Annals of Neurology 2001;50:121–7. Meretoja A, Roine RO, Kaste M, Linna M, Juntunen M, Erila T, et al. Stroke monitoring on a national level: PERFECT stroke, a comprehensive, registry-linkage stroke database in Finland. Stroke 2010;41:2239–46. Ohayon MM, Roth T. Prevalence of restless legs syndrome and periodic limb movement disorder in the general population. Journal of Psychosomatic Research 2002;53:547–54. Polman CH, Reingold SC, Edan G, Filippi M, Hartung HP, Kappos L, et al. Diagnostic criteria for multiple sclerosis: 2005 revisions to the “McDonald criteria”. Annals of Neurology 2005;58:840–6. Poser CM, Brinar VV. Epilepsy and multiple sclerosis. Epilepsy Behavior 2003;4:6–12. Poser CM, Paty DW, Scheinberg L, McDonald WI, Davis FA, Ebers GC, et al. New diagnostic criteria for multiple sclerosis: Guidelines for research protocols. Annals of Neurology 1983;13:227–31. Poser S, Kurtzke JF, Poser W, Schlaf G. Survival in multiple sclerosis. Journal of Clinical Epidemiology 1989;42:159–68. Putzki N, Katsarava Z. Headache in multiple sclerosis. Current Pain and Headache Reports 2010;14:316–20. Putzki N, Pfriem A, Limmroth V, Yaldizli O, Tettenborn B, Diener HC, et al. Prevalence of migraine, tension-type headache and trigeminal neuralgia in multiple sclerosis. European Journal of Neurology 2009;16:262–7. Sumelahti ML, Hakama M, Elovaara I, Pukkala E. Causes of death among patients with multiple sclerosis. Multiple Sclerosis 2010;16:1437–42. Sumelahti ML, Tienari PJ, Wikstrom J, Salminen TM, Hakama M. Survival of multiple sclerosis in Finland between 1964 and 1993. Multiple Sclerosis 2002;8:350–5. Weinshenker BG. The natural history of multiple sclerosis. Neurologic Clinics 1995;13:119–46. Zaccara G. Neurological comorbidity and epilepsy: implications for treatment. Acta Neurologica Scandinavica 2009;120:1–15.