Acta Neurol Scand 2014: 130: 368–373 DOI: 10.1111/ane.12276
© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd ACTA NEUROLOGICA SCANDINAVICA
Multiple sclerosis and seizures: incidence and prevalence over 40 years Lund C, Nakken KO, Edland A, Celius EG. Multiple sclerosis and seizures: incidence and prevalence over 40 years. Acta Neurol Scand: 2014: 130: 368–373. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd. Objectives – The prevalence of multiple sclerosis (MS) is increasing worldwide. Epileptic seizures are more common in MS patients than in the general population. The aim of this study was to investigate changes in the prevalence and incidence of MS in a well-defined population over several decades and estimate the occurrence of epilepsy in the same cohort. Materials and methods – Patients diagnosed with MS in the County of Vestfold, Norway in the period of 1983–2003 were identified. Point prevalence for MS and epilepsy was calculated for January 1, 2003. The average annual incidence rates were calculated in five-year periods from 1983 to 2002. These numbers were compared to previously published figures of prevalence from 1963 and incidence from 1953. Results – On prevalence day, we identified 364 patients diagnosed with MS living in Vestfold. Thus, the prevalence increased from 61.6/100,000 in 1963 to 166.8/100,000 in 2003. In the period 1983–2002, the annual incidence fluctuated between 4.2 and 7.3/100,000/year (mean 4.5, 95% CI 3.6 – 5.5). In 2003, the portion of MS patients with epileptic seizures was 7.4%, compared to 2.9% in 1963. Conclusions – During the 40 years followup of this population, the incidence of MS was stable, while the prevalence of MS and the share of MS patients with epileptic seizures increased. Compared to the general population, the risk of having active epilepsy was increased fourfold. We assume that this is a consequence of an increased survival in MS patients.
Introduction
The prevalence of multiple sclerosis (MS) is increasing worldwide (1–9), and this is assumed mainly to be due to increased survival, improvement in case ascertainment and changes in diagnostic criteria (2, 6). Two previous epidemiological studies in Vestfold, Norway demonstrated an increase in MS prevalence from 61.6/100,000 in 1963 to 86.4/100,000 in 1983 (7, 8). Incidence data were available for the period 1953–1983 and demonstrated a fluctuating pattern (8). Epileptic seizures occur more commonly in patients with MS than in the general population, although the exact prevalence is not known. In recent population-based studies, the frequency of epileptic seizures in MS patients varies between 1.5 and 7.8% (10–20), while the occurrence of 368
C. Lund1,2, K. O. Nakken1, A. Edland3, E. G. Celius4 1 National Center for Epilepsy, Oslo University Hospital, Oslo, Norway; 2Department of Neurology, Vestfold County Hospital, Tønsberg, Norway; 3Department of Neurology, Vestre Viken Hospital, Drammen, Norway; 4 Department of Neurology, Oslo University Hospital, Oslo, Norway
Key words: epilepsy; multiple sclerosis; prevalence; incidence C. Lund, National Center for Epilepsy, P.O. Box 853, 1306 Bærum Postterminal, Norway Tel.: +47 67501000 Fax: +47 67540496 e-mail: [email protected] Accepted for publication June 10, 2014
active epilepsy in MS patients has been estimated to be 1.0–3.2% (11, 12, 15). In 1963, 2.9% of the MS patients in Vestfold had experienced epileptic seizures (7). The aim of this study was to update earlier assessments, allowing calculations of the prevalence and incidence of MS and the occurrence of epileptic seizures in this cohort. Materials and methods Patient material
MS patients in Vestfold County, Norway (218,171 inhabitants on January 1st 2003) were identified through retrospective chart reviews at the Department of Neurology at Vestfold County Hospital in Tønsberg, Norway. Information was also requested from private neurological
Multiple sclerosis and epileptic seizures practices, nursing homes, a rehabilitation institution, the neurological departments in the two neighboring counties, Telemark and Buskerud, as well as from the National Multiple Sclerosis Registry. Files from previous surveys of MS in Vestfold were available for scrutiny (7, 8). A questionnaire was sent to all patients to obtain additional demographic and clinical data. All hospital records were reviewed by the same neurologist (CL). The Regional Committee for Medical Research Ethics in Southern Norway and the Norwegian Data Inspectorate approved the study. Prevalence of MS
The patients were classified according to the Poser criteria (21), and for comparison with previous studies also the McAlpine criteria (22). Only cases of definite and probable MS, according to the Poser criteria, were included. MRI abnormalities were not included as paraclinical evidence of MS. Data on year of onset, place of residence at onset, type of debut symptom, year of diagnosis, and disease course were obtained. Year of onset was defined as the year of the first symptoms that were most probably related to the disease. The clinical course at diagnosis was classified as relapsing-remitting (RR), secondary progressive (SP), or primary progressive (PP). Patients classified as RR-MS and SP-MS were pooled in the analysis as time of conversion to SP-MS were unavailable. Prevalence of epilepsy
Epilepsy and active epilepsy were defined according to International League Against Epilepsy’s (ILAE) definition of 1993: Epilepsy is a condition characterized by recurrent (two or more) epileptic seizures, unprovoked by any immediate identified cause (23). In the current study, epileptic seizures occurring both at the time of a MS relapse and between MS relapses were included. Multiple seizures occurring within a 24-h period, or an episode of status epilepticus were considered as a single event. The term ‘active epilepsy’ was employed for persons who had experienced at least one epileptic seizure in the previous 5 years, regardless of antiepileptic drug (AED) use. The prevalence of active epilepsy in the general population was derived from a population-based study carried out in Oppland County, Norway (24). This study had used the same definition of active epilepsy as in our study, and the populations in the two counties are comparable regarding size
and socioeconomic composition. Drug resistant epilepsy was defined as failure of adequate trials of two tolerated and appropriately chosen AED schedules (25). According to Matthews (26), patients with MS and epileptic seizures may be classified into three groups: (1) Patients with seizures associated with MS relapse, who rarely have recurrent attacks, (2) Patients with infrequent seizures in whom seizures are not related to MS relapse, and (3) Patients with progressive cognitive deterioration in whom seizures are recurrent and sometimes complicated with status epilepticus. In this study, we have included a new group; (4) Patients with epilepsy due to other etiologies, probably not related to MS. Statistical analysis
Statistical calculations were performed using the Public Domain Software for Epidemiology and Disease Surveillance Epi-info Version 6.0 (Center for Disease Control, Epidemiology Program Office, Atlanta, GA, USA) and OpenEpi (www. OpenEpi.com). The prevalence data were calculated using the chi-squared likelihood ratio test. Results Prevalence of MS
A total of 504 patients with a diagnosis of definite or probable MS, according to the Poser criteria (11), were identified between 1983 and 2003. Of these, 364 patients were alive and living in Vestfold on the prevalence day, 1. January 2003, yielding a prevalence rate of 166.8/100,000. This is a significant increase compared to the numbers from 1963 (61.6/100,000) (P < 0.0001). The female:male ratio was 1.7:1. Definite MS was diagnosed in 332 patients and 32 patients had probable MS. Demographic and clinical characteristics of the cohort are shown in Table 1. 67.4% responded to our questionnaire. Incidence of MS
In the period 1983–2002, the mean annual incidence of MS was 4.5/100,000 (95% CI 3.6–5.5). The average annual incidence rates of definite and probable MS in Vestfold County for 5-year interval in the period 1953–2002 are shown in Fig. 1. The incidence shows a non-significant fluctuating pattern, varying between 1.9 and 7.3/ 100,000/year. 369
Lund et al. Table 1 Demographic and clinical characteristics of patients with multiple sclerosis in Vestfold County on prevalence day (January 1, 2003)
Total Female Male RR PP Mean age at onset of MS (years) Mean age at diagnosis (years) Mean time from onset to diagnosis (years)
All patients n = (%)
Definite MS n = (%)
Patients with Probable MS epileptic seizures n = (%) n= (%)
364 233 131 327 37 32.5
332 210 122 297 35 32.4
32 23 9 30 2 33.6
(64) (36) (89.8) (10.2) (7–81)
(63) (37) (89) (11) (7–67)
38.8 (12–82) 38.5 (12–70)
6.2
6.2
(72) (28) (94) (6) (17–81)
41.0 (19–82)
6.2
27 15 12 22 5 30.1
(56) (44) (89) (11) (19–48)
34.4 (22–52)
4.3
RR, relapsing-remitting; PP, primary progressive.
8 7 Per 100,000
6 5
Of the 27 patients with epileptic seizures, eight had experienced only one single seizure. Three patients were considered drug resistant, and all these patients had experienced one or several episodes of status epilepticus, along with cognitive deterioration. As previously described, the patients were classified into four different groups (two patients could not be classified due to lack of information): Group 1 (infrequent seizures associated with MS relapse): five patients; Group 2 (infrequent seizures not related to MS relapse): 14 patients; Group 3 (recurrent seizures, progressive cognitive deterioration, status epilepticus): three patients; Group 4 (epilepsy probably not related to MS): three patients (Table 3). Of the 27 patients with epileptic seizures, 20 were using or had used AEDs. Of these, five only experienced one single seizure. Thirteen patients had tried only one drug, six had tried two different drugs, and one had tried four different drugs. EEG-reports were available for 22 cases; in eight described as normal, and in 14 described with focal pathology, including dysrhythmia and/or suspected epileptiform activity.
4 3 2 1
19 53 –5 19 7 58 –6 19 2 63 –6 19 7 68 –7 19 2 73 –7 19 7 78 –8 19 2 83 –8 19 7 88 –9 19 2 93 –9 19 7 98 –0 2
0
Figure 1. Incidence of multiple sclerosis diagnosed in Vestfold County, Norway from 1953–2002 divided into 5-year intervals.
Prevalence of epileptic seizures
Of the 364 patients with definite or probable MS on prevalence day, 27 (7.4%) had experienced epileptic seizures. This is a significant increase compared to the numbers from 1963 (P = 0.045). Of the 27 patients, 19 (5.2%) fulfilled the criteria of epilepsy, and 13 (3.6%) fulfilled the criteria of active epilepsy. We excluded three patients in whom seizures started in childhood and as a consequence regarded as unlikely to be related to MS. This left us with 24 (6.6%) patients with epileptic seizures, 16 (4.4%) with epilepsy, and 12 (3.3%) with active epilepsy. The mean age of onset of epileptic seizures was 39.4 years (22– 59 years), and the mean delay from onset of MS to onset of epilepsy was 8.8 years (Table 2). 370
Prognosis of epileptic seizures
Discussion Prevalence and incidence of MS
In the period 1963–2003, the prevalence of MS in Vestfold County, Norway increased significantly from 61.6/100,000 to 166.8/100,000. This is most likely due to an increased survival of these patients over the last decades. The incidence of MS in Vestfold County has fluctuated over the last 50 years. In other counties in Norway, and also other parts of the world, the incidence has gradually increased up to a certain point, and then stabilized (3–5, 9). The fluctuating pattern in Vestfold is similar to that reported in the 50-year follow-up of the Danish Multiple Sclerosis Registry (5). Edland et al. (8) proposed that such fluctuations over time indi-
Table 2 Number (%) of patients with epileptic seizures on prevalence day MS patients n = 364 Total (single seizures and epilepsy) Epilepsy Active epilepsy Single seizures
All patients (%)
Excluding patients with epilepsy of other etiologies (%)
27 (7.4)
24 (6.6)
19 (5.2) 13 (3.6) 8 (2.2)
16 (4.4) 12 (3.3) 8 (2.2)
Multiple sclerosis and epileptic seizures Table 3 Classification of relationship beween seizures and MS*
Group Number of patients
Infrequent Infrequent Frequent seizures Seizures, but seizures seizures not and progressive probably associated with associated with cognitive not related MS relapses MS relapses deterioriation to MS 5
14
3
3
*Two patients could not be classified due to lack of information.
cates that the incidence is influenced by exogenous factors. However, a fluctuating pattern over a period as long as 50 years might argue against changing exogenous factors. In contrast to other Norwegian studies (3, 27), the time from symptom onset to diagnosis had not decreased, being 5.5 years in 1963, 4.8 years in 1983, and 6.2 years in 2003. This discrepancy is difficult to explain, but might indicate that the population is stable and the clinical work-up of these patients have been rather similar throughout the years in spite of changing guidelines and increased availability of magnetic resonance imaging. Prevalence of epileptic seizures in MS patients
Increased survival implies that more patients remain alive with a more advanced disease state, and thus being at an increased risk of complications, including epileptic seizures. Indeed, the prevalence of epileptic seizures in this cohort increased from 2.9% to 7.4% during the 40-year period. Repeated surveys in a defined geographic area are likely to ensure good case ascertainment, and this might explain a higher prevalence of epileptic seizures in this population compared to figures from recent population-based studies (11, 13, 15, 17–19). In this study, 3.6% of the patients had active epilepsy, which is 4.4 times higher than would be expected in the general population in Norway (24). Prognosis of epilepsy in patients with MS
Of the 27 patients with epileptic seizures, eight (30%) had only one single seizure. Of the 19 patients fulfilling the criteria of epilepsy, three (16%) were drug resistant. Counting only patients with epilepsy of no assumed etiology other than MS, the percentage of pharmacoresistant cases is 19. According to studies of drug sensitivity in epilepsy, about 30% of patients with newly diagnosed epilepsy are drug resistant (25). Thus, our results indicate that epilepsy associated with MS might have a favorable outcome. This is
not surprising considering the inclusion of acute symptomatic seizures, which most often are associated with a good prognosis (28). Nevertheless, a subgroup of the patients had severe, chronic epilepsy with recurrent episodes of status epilepticus combined with cognitive deterioration. The relationship between MS and epilepsy – and classification of seizures
Previously, a causal association between epilepsy and MS was difficult to explain (10). Whereas in epilepsy the epileptic discharges arise from hyperexcitable neurons in the cerebral cortex, i.e., the gray matter, MS is considered a disease of the white matter of the central nervous system. However, novel MRI techniques with improved sensitivity to gray matter changes have demonstrated that both atrophy and lesions in the gray matter are more prevalent in MS than previously estimated (29). Plaques situated within the cortical gray matter may comprise 26–30% of all lesions in MS (30). Recently, a longitudinal MRI-study demonstrated an increased number of cortical lesions and extent of cortical atrophy in MS patients with epilepsy compared to MS patients without epilepsy (31). Thus, the increased occurrence of epileptic seizures is probably due to epileptogenic changes in the cortex arising from both cortical and subcortical lesions. Therefore, epilepsy associated with MS should be classified as symptomatic focal epilepsy (16). It has been argued that acute symptomatic seizures are due to new MS lesions, and that chronic epilepsy is unrelated to new attacks of the disease, but rather to the epileptogenic effect of chronic cortical plaques (32). New definitions suggest that acute symptomatic seizures occur as the first presenting symptom or within 7 days of a relapse (33). According to guidelines (23), acute symptomatic seizures are excluded from analysis of epilepsy prevalence (13–15). Epileptic seizures may be the only clinical manifestation of a relapse (32, 34) which can be verified only by the presence of active lesions on cerebral MRI. As MRI cannot be performed after every epileptic seizure, this is not possible to assess in a clinical setting. As the incidence of epileptic seizures in MS is low, it is important to remember that co-occurrence of MS and epilepsy could simply be a chance association. In some cases, seizures may occur long before MS becomes clinically apparent (17), and the longer the interval between the first seizure and the clinical onset of MS, the weaker the causal relationship (35). In retrospect, it 371
Lund et al. might be hard to differ between seizures due to MS and seizures due to other etiologies. The epidemiology of epileptic seizures in MS has been the subject of numerous investigations, but without consensus regarding inclusion and exclusion criteria (36). To standardize epidemiological studies of seizures in patients with MS, we suggest including all patients with seizures. Limitations and strengths
The major limitation of this study is the small number of patients. However, the county of Vestfold is a small and densely populated area with easy access to public health service facilities. Therefore, repeated surveys covering 40 years should ensure close to complete case ascertainment and enable reliable conclusions to be drawn. Conclusions
In conclusion, the prevalence of MS has increased in Vestfold County over 40 years. At the same time, the occurrence of epilepsy in this MS-cohort also increased, and epilepsy was four times more common than in the general population. It is highly probable that the prolonged survival of MS patients make them more susceptible to complications like epileptic seizures, increasing the total burden of their disease. Acknowledgements The authors gratefully acknowledge the patients for participating in this study.
Conflict of interest Caroline Lund has been funded by: Unrestricted grants from Biogen Idec, The Legacy of Reberg, and The Legacy of the Stray Sisters. The other authors report no conflict of interests.
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Multiple sclerosis and seizures: incidence and prevalence over 40 years Lund C, Nakken KO, Edland A, Celius EG. Multiple sclerosis and seizures: incidence and prevalence over 40 years. Acta Neurol Scand: 2014: 130: 368–373. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd. Objectives – The prevalence of multiple sclerosis (MS) is increasing worldwide. Epileptic seizures are more common in MS patients than in the general population. The aim of this study was to investigate changes in the prevalence and incidence of MS in a well-defined population over several decades and estimate the occurrence of epilepsy in the same cohort. Materials and methods – Patients diagnosed with MS in the County of Vestfold, Norway in the period of 1983–2003 were identified. Point prevalence for MS and epilepsy was calculated for January 1, 2003. The average annual incidence rates were calculated in five-year periods from 1983 to 2002. These numbers were compared to previously published figures of prevalence from 1963 and incidence from 1953. Results – On prevalence day, we identified 364 patients diagnosed with MS living in Vestfold. Thus, the prevalence increased from 61.6/100,000 in 1963 to 166.8/100,000 in 2003. In the period 1983–2002, the annual incidence fluctuated between 4.2 and 7.3/100,000/year (mean 4.5, 95% CI 3.6 – 5.5). In 2003, the portion of MS patients with epileptic seizures was 7.4%, compared to 2.9% in 1963. Conclusions – During the 40 years followup of this population, the incidence of MS was stable, while the prevalence of MS and the share of MS patients with epileptic seizures increased. Compared to the general population, the risk of having active epilepsy was increased fourfold. We assume that this is a consequence of an increased survival in MS patients.
Introduction
The prevalence of multiple sclerosis (MS) is increasing worldwide (1–9), and this is assumed mainly to be due to increased survival, improvement in case ascertainment and changes in diagnostic criteria (2, 6). Two previous epidemiological studies in Vestfold, Norway demonstrated an increase in MS prevalence from 61.6/100,000 in 1963 to 86.4/100,000 in 1983 (7, 8). Incidence data were available for the period 1953–1983 and demonstrated a fluctuating pattern (8). Epileptic seizures occur more commonly in patients with MS than in the general population, although the exact prevalence is not known. In recent population-based studies, the frequency of epileptic seizures in MS patients varies between 1.5 and 7.8% (10–20), while the occurrence of 368
C. Lund1,2, K. O. Nakken1, A. Edland3, E. G. Celius4 1 National Center for Epilepsy, Oslo University Hospital, Oslo, Norway; 2Department of Neurology, Vestfold County Hospital, Tønsberg, Norway; 3Department of Neurology, Vestre Viken Hospital, Drammen, Norway; 4 Department of Neurology, Oslo University Hospital, Oslo, Norway
Key words: epilepsy; multiple sclerosis; prevalence; incidence C. Lund, National Center for Epilepsy, P.O. Box 853, 1306 Bærum Postterminal, Norway Tel.: +47 67501000 Fax: +47 67540496 e-mail: [email protected] Accepted for publication June 10, 2014
active epilepsy in MS patients has been estimated to be 1.0–3.2% (11, 12, 15). In 1963, 2.9% of the MS patients in Vestfold had experienced epileptic seizures (7). The aim of this study was to update earlier assessments, allowing calculations of the prevalence and incidence of MS and the occurrence of epileptic seizures in this cohort. Materials and methods Patient material
MS patients in Vestfold County, Norway (218,171 inhabitants on January 1st 2003) were identified through retrospective chart reviews at the Department of Neurology at Vestfold County Hospital in Tønsberg, Norway. Information was also requested from private neurological
Multiple sclerosis and epileptic seizures practices, nursing homes, a rehabilitation institution, the neurological departments in the two neighboring counties, Telemark and Buskerud, as well as from the National Multiple Sclerosis Registry. Files from previous surveys of MS in Vestfold were available for scrutiny (7, 8). A questionnaire was sent to all patients to obtain additional demographic and clinical data. All hospital records were reviewed by the same neurologist (CL). The Regional Committee for Medical Research Ethics in Southern Norway and the Norwegian Data Inspectorate approved the study. Prevalence of MS
The patients were classified according to the Poser criteria (21), and for comparison with previous studies also the McAlpine criteria (22). Only cases of definite and probable MS, according to the Poser criteria, were included. MRI abnormalities were not included as paraclinical evidence of MS. Data on year of onset, place of residence at onset, type of debut symptom, year of diagnosis, and disease course were obtained. Year of onset was defined as the year of the first symptoms that were most probably related to the disease. The clinical course at diagnosis was classified as relapsing-remitting (RR), secondary progressive (SP), or primary progressive (PP). Patients classified as RR-MS and SP-MS were pooled in the analysis as time of conversion to SP-MS were unavailable. Prevalence of epilepsy
Epilepsy and active epilepsy were defined according to International League Against Epilepsy’s (ILAE) definition of 1993: Epilepsy is a condition characterized by recurrent (two or more) epileptic seizures, unprovoked by any immediate identified cause (23). In the current study, epileptic seizures occurring both at the time of a MS relapse and between MS relapses were included. Multiple seizures occurring within a 24-h period, or an episode of status epilepticus were considered as a single event. The term ‘active epilepsy’ was employed for persons who had experienced at least one epileptic seizure in the previous 5 years, regardless of antiepileptic drug (AED) use. The prevalence of active epilepsy in the general population was derived from a population-based study carried out in Oppland County, Norway (24). This study had used the same definition of active epilepsy as in our study, and the populations in the two counties are comparable regarding size
and socioeconomic composition. Drug resistant epilepsy was defined as failure of adequate trials of two tolerated and appropriately chosen AED schedules (25). According to Matthews (26), patients with MS and epileptic seizures may be classified into three groups: (1) Patients with seizures associated with MS relapse, who rarely have recurrent attacks, (2) Patients with infrequent seizures in whom seizures are not related to MS relapse, and (3) Patients with progressive cognitive deterioration in whom seizures are recurrent and sometimes complicated with status epilepticus. In this study, we have included a new group; (4) Patients with epilepsy due to other etiologies, probably not related to MS. Statistical analysis
Statistical calculations were performed using the Public Domain Software for Epidemiology and Disease Surveillance Epi-info Version 6.0 (Center for Disease Control, Epidemiology Program Office, Atlanta, GA, USA) and OpenEpi (www. OpenEpi.com). The prevalence data were calculated using the chi-squared likelihood ratio test. Results Prevalence of MS
A total of 504 patients with a diagnosis of definite or probable MS, according to the Poser criteria (11), were identified between 1983 and 2003. Of these, 364 patients were alive and living in Vestfold on the prevalence day, 1. January 2003, yielding a prevalence rate of 166.8/100,000. This is a significant increase compared to the numbers from 1963 (61.6/100,000) (P < 0.0001). The female:male ratio was 1.7:1. Definite MS was diagnosed in 332 patients and 32 patients had probable MS. Demographic and clinical characteristics of the cohort are shown in Table 1. 67.4% responded to our questionnaire. Incidence of MS
In the period 1983–2002, the mean annual incidence of MS was 4.5/100,000 (95% CI 3.6–5.5). The average annual incidence rates of definite and probable MS in Vestfold County for 5-year interval in the period 1953–2002 are shown in Fig. 1. The incidence shows a non-significant fluctuating pattern, varying between 1.9 and 7.3/ 100,000/year. 369
Lund et al. Table 1 Demographic and clinical characteristics of patients with multiple sclerosis in Vestfold County on prevalence day (January 1, 2003)
Total Female Male RR PP Mean age at onset of MS (years) Mean age at diagnosis (years) Mean time from onset to diagnosis (years)
All patients n = (%)
Definite MS n = (%)
Patients with Probable MS epileptic seizures n = (%) n= (%)
364 233 131 327 37 32.5
332 210 122 297 35 32.4
32 23 9 30 2 33.6
(64) (36) (89.8) (10.2) (7–81)
(63) (37) (89) (11) (7–67)
38.8 (12–82) 38.5 (12–70)
6.2
6.2
(72) (28) (94) (6) (17–81)
41.0 (19–82)
6.2
27 15 12 22 5 30.1
(56) (44) (89) (11) (19–48)
34.4 (22–52)
4.3
RR, relapsing-remitting; PP, primary progressive.
8 7 Per 100,000
6 5
Of the 27 patients with epileptic seizures, eight had experienced only one single seizure. Three patients were considered drug resistant, and all these patients had experienced one or several episodes of status epilepticus, along with cognitive deterioration. As previously described, the patients were classified into four different groups (two patients could not be classified due to lack of information): Group 1 (infrequent seizures associated with MS relapse): five patients; Group 2 (infrequent seizures not related to MS relapse): 14 patients; Group 3 (recurrent seizures, progressive cognitive deterioration, status epilepticus): three patients; Group 4 (epilepsy probably not related to MS): three patients (Table 3). Of the 27 patients with epileptic seizures, 20 were using or had used AEDs. Of these, five only experienced one single seizure. Thirteen patients had tried only one drug, six had tried two different drugs, and one had tried four different drugs. EEG-reports were available for 22 cases; in eight described as normal, and in 14 described with focal pathology, including dysrhythmia and/or suspected epileptiform activity.
4 3 2 1
19 53 –5 19 7 58 –6 19 2 63 –6 19 7 68 –7 19 2 73 –7 19 7 78 –8 19 2 83 –8 19 7 88 –9 19 2 93 –9 19 7 98 –0 2
0
Figure 1. Incidence of multiple sclerosis diagnosed in Vestfold County, Norway from 1953–2002 divided into 5-year intervals.
Prevalence of epileptic seizures
Of the 364 patients with definite or probable MS on prevalence day, 27 (7.4%) had experienced epileptic seizures. This is a significant increase compared to the numbers from 1963 (P = 0.045). Of the 27 patients, 19 (5.2%) fulfilled the criteria of epilepsy, and 13 (3.6%) fulfilled the criteria of active epilepsy. We excluded three patients in whom seizures started in childhood and as a consequence regarded as unlikely to be related to MS. This left us with 24 (6.6%) patients with epileptic seizures, 16 (4.4%) with epilepsy, and 12 (3.3%) with active epilepsy. The mean age of onset of epileptic seizures was 39.4 years (22– 59 years), and the mean delay from onset of MS to onset of epilepsy was 8.8 years (Table 2). 370
Prognosis of epileptic seizures
Discussion Prevalence and incidence of MS
In the period 1963–2003, the prevalence of MS in Vestfold County, Norway increased significantly from 61.6/100,000 to 166.8/100,000. This is most likely due to an increased survival of these patients over the last decades. The incidence of MS in Vestfold County has fluctuated over the last 50 years. In other counties in Norway, and also other parts of the world, the incidence has gradually increased up to a certain point, and then stabilized (3–5, 9). The fluctuating pattern in Vestfold is similar to that reported in the 50-year follow-up of the Danish Multiple Sclerosis Registry (5). Edland et al. (8) proposed that such fluctuations over time indi-
Table 2 Number (%) of patients with epileptic seizures on prevalence day MS patients n = 364 Total (single seizures and epilepsy) Epilepsy Active epilepsy Single seizures
All patients (%)
Excluding patients with epilepsy of other etiologies (%)
27 (7.4)
24 (6.6)
19 (5.2) 13 (3.6) 8 (2.2)
16 (4.4) 12 (3.3) 8 (2.2)
Multiple sclerosis and epileptic seizures Table 3 Classification of relationship beween seizures and MS*
Group Number of patients
Infrequent Infrequent Frequent seizures Seizures, but seizures seizures not and progressive probably associated with associated with cognitive not related MS relapses MS relapses deterioriation to MS 5
14
3
3
*Two patients could not be classified due to lack of information.
cates that the incidence is influenced by exogenous factors. However, a fluctuating pattern over a period as long as 50 years might argue against changing exogenous factors. In contrast to other Norwegian studies (3, 27), the time from symptom onset to diagnosis had not decreased, being 5.5 years in 1963, 4.8 years in 1983, and 6.2 years in 2003. This discrepancy is difficult to explain, but might indicate that the population is stable and the clinical work-up of these patients have been rather similar throughout the years in spite of changing guidelines and increased availability of magnetic resonance imaging. Prevalence of epileptic seizures in MS patients
Increased survival implies that more patients remain alive with a more advanced disease state, and thus being at an increased risk of complications, including epileptic seizures. Indeed, the prevalence of epileptic seizures in this cohort increased from 2.9% to 7.4% during the 40-year period. Repeated surveys in a defined geographic area are likely to ensure good case ascertainment, and this might explain a higher prevalence of epileptic seizures in this population compared to figures from recent population-based studies (11, 13, 15, 17–19). In this study, 3.6% of the patients had active epilepsy, which is 4.4 times higher than would be expected in the general population in Norway (24). Prognosis of epilepsy in patients with MS
Of the 27 patients with epileptic seizures, eight (30%) had only one single seizure. Of the 19 patients fulfilling the criteria of epilepsy, three (16%) were drug resistant. Counting only patients with epilepsy of no assumed etiology other than MS, the percentage of pharmacoresistant cases is 19. According to studies of drug sensitivity in epilepsy, about 30% of patients with newly diagnosed epilepsy are drug resistant (25). Thus, our results indicate that epilepsy associated with MS might have a favorable outcome. This is
not surprising considering the inclusion of acute symptomatic seizures, which most often are associated with a good prognosis (28). Nevertheless, a subgroup of the patients had severe, chronic epilepsy with recurrent episodes of status epilepticus combined with cognitive deterioration. The relationship between MS and epilepsy – and classification of seizures
Previously, a causal association between epilepsy and MS was difficult to explain (10). Whereas in epilepsy the epileptic discharges arise from hyperexcitable neurons in the cerebral cortex, i.e., the gray matter, MS is considered a disease of the white matter of the central nervous system. However, novel MRI techniques with improved sensitivity to gray matter changes have demonstrated that both atrophy and lesions in the gray matter are more prevalent in MS than previously estimated (29). Plaques situated within the cortical gray matter may comprise 26–30% of all lesions in MS (30). Recently, a longitudinal MRI-study demonstrated an increased number of cortical lesions and extent of cortical atrophy in MS patients with epilepsy compared to MS patients without epilepsy (31). Thus, the increased occurrence of epileptic seizures is probably due to epileptogenic changes in the cortex arising from both cortical and subcortical lesions. Therefore, epilepsy associated with MS should be classified as symptomatic focal epilepsy (16). It has been argued that acute symptomatic seizures are due to new MS lesions, and that chronic epilepsy is unrelated to new attacks of the disease, but rather to the epileptogenic effect of chronic cortical plaques (32). New definitions suggest that acute symptomatic seizures occur as the first presenting symptom or within 7 days of a relapse (33). According to guidelines (23), acute symptomatic seizures are excluded from analysis of epilepsy prevalence (13–15). Epileptic seizures may be the only clinical manifestation of a relapse (32, 34) which can be verified only by the presence of active lesions on cerebral MRI. As MRI cannot be performed after every epileptic seizure, this is not possible to assess in a clinical setting. As the incidence of epileptic seizures in MS is low, it is important to remember that co-occurrence of MS and epilepsy could simply be a chance association. In some cases, seizures may occur long before MS becomes clinically apparent (17), and the longer the interval between the first seizure and the clinical onset of MS, the weaker the causal relationship (35). In retrospect, it 371
Lund et al. might be hard to differ between seizures due to MS and seizures due to other etiologies. The epidemiology of epileptic seizures in MS has been the subject of numerous investigations, but without consensus regarding inclusion and exclusion criteria (36). To standardize epidemiological studies of seizures in patients with MS, we suggest including all patients with seizures. Limitations and strengths
The major limitation of this study is the small number of patients. However, the county of Vestfold is a small and densely populated area with easy access to public health service facilities. Therefore, repeated surveys covering 40 years should ensure close to complete case ascertainment and enable reliable conclusions to be drawn. Conclusions
In conclusion, the prevalence of MS has increased in Vestfold County over 40 years. At the same time, the occurrence of epilepsy in this MS-cohort also increased, and epilepsy was four times more common than in the general population. It is highly probable that the prolonged survival of MS patients make them more susceptible to complications like epileptic seizures, increasing the total burden of their disease. Acknowledgements The authors gratefully acknowledge the patients for participating in this study.
Conflict of interest Caroline Lund has been funded by: Unrestricted grants from Biogen Idec, The Legacy of Reberg, and The Legacy of the Stray Sisters. The other authors report no conflict of interests.
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