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Treatment of epilepsy in multiple sclerosis

Open ArchivePublished:April 05, 2018DOI:https://doi.org/10.1016/j.seizure.2018.04.001

      Highlights

      • We describe clinical course of epilepsy in 62 patients with MS.
      • At the first seizure, most had secondary progressive MS and considerable disability.
      • The majority were currently on monotherapy and 46% were seizure-free.
      • Carbamazepine was the most commonly used first AED.
      • The most common reason for discontinuation of the first AED was side-effects.

      Abstract

      Purpose

      The prevalence of epilepsy is increased in multiple sclerosis (MS), but information on AED treatment and seizure outcome is scarce. We describe epilepsy characteristics including the use of AEDs and proportion of seizure-free patients at two tertiary hospitals in Sweden.

      Method

      We retrospectively studied electronic medical records of all patients with a diagnosis of MS and seizures at Sahlgrenska university hospital and Uppsala university hospital. Clinical data were reviewed until 2017.

      Results

      We identified a total of 62 MS patients with at least one seizure. Median age at the first seizure (before or after MS) was 41 years (range 0–80). The most common MS disease course at the first seizure was secondary progressive MS, the neurological disability was considerable, and most patients had several MRI lesions at their first seizure. The first EEG demonstrated epileptiform discharges in 38% and unspecific pathology in 40%. Current seizure status could be determined for 37 patients. Out of these, 46% had been seizure free for more than one year at last follow-up. The majority of patients (65%) were on monotherapy at last follow-up. Carbamazepine was the most commonly used first AED, with a retention rate of 52%. No individual AED was associated with a particularly high rate of seizure freedom. The most common reason for discontinuation of the first AED was side-effects.

      Conclusion

      Seizure freedom rates were low, perhaps indicating a need for higher ambitions in management. Side effects of AEDs may be a particular concern when treating epilepsy in patients with MS.

      Keywords

      1. Introduction

      The new ILAE classification of epilepsies emphasizes aetiology and comorbidities [
      • Scheffer I.E.
      • Berkovic S.
      • Capovilla G.
      • Connolly M.B.
      • French J.
      • Guilhoto L.
      • et al.
      ILAE classification of the epilepsies: position paper of the ILAE Commission for Classification and Terminology.
      ]. Epilepsy in several distinct patient groups previously studied together under the term “partial epilepsy” are now studied in an aetiology-stratified manner; examples include poststroke epilepsy [
      • Zelano J.
      Poststroke epilepsy: update and future directions.
      ], autoimmune epilepsy [
      • Feyissa A.M.
      • Lopez Chiriboga A.S.
      • Britton J.W.
      Antiepileptic drug therapy in patients with autoimmune epilepsy.
      ], or epilepsy after infectious encephalitis [
      • Pillai S.C.
      • Mohammad S.S.
      • Hacohen Y.
      • Tantsis E.
      • Prelog K.
      • Barnes E.H.
      • et al.
      Postencephalitic epilepsy and drug-resistant epilepsy after infectious and antibody-associated encephalitis in childhood: clinical and etiologic risk factors.
      ,
      • Singh T.D.
      • Fugate J.E.
      • Hocker S.E.
      • Rabinstein A.A.
      Postencephalitic epilepsy: clinical characteristics and predictors.
      ]. In the era of person-centered care, such evidence is of great value for clinicians and health care providers trying to tailor therapy and management.
      The prevalence of epilepsy is increased approximately threefold in multiple sclerosis (MS) [
      • Gasparini S.
      • Ferlazzo E.
      • Ascoli M.
      • Sueri C.
      • Cianci V.
      • Russo C.
      • et al.
      Risk factors for unprovoked epileptic seizures in multiple sclerosis: a systematic review and meta-analysis.
      ,
      • Marrie R.A.
      • Reider N.
      • Cohen J.
      • Trojano M.
      • Sorensen P.S.
      • Cutter G.
      • et al.
      A systematic review of the incidence and prevalence of sleep disorders and seizure disorders in multiple sclerosis.
      ]. Seizures are more common in severe MS, which suggests a causal relationship between accumulated brain damage and epilepsy [
      • Martinez-Juarez I.E.
      • Lopez-Meza E.
      • Gonzalez-Aragon Mdel C.
      • Ramirez-Bermudez J.
      • Corona T.
      Epilepsy and multiple sclerosis: increased risk among progressive forms.
      ]. In contrast to the acquired epilepsies listed above, investigators have so far focused on describing the co-existence of MS and seizures, and as pointed out in thorough reviews, little information is available on optimal AED treatment and epilepsy outcome [
      • Koch M.W.
      • Polman S.K.
      • Uyttenboogaart M.
      • De Keyser J.
      Treatment of seizures in multiple sclerosis.
      ]. This most likely reflects the relative rarity of epilepsy in MS and the subsequent low number of subjects available for study at individual centers. One study identified ten cases of epilepsy among 310 MS patients, seven of whom had good seizure control (defined as “few seizures”) [
      • Uribe-San-Martin R.
      • Ciampi-Diaz E.
      • Suarez-Hernandez F.
      • Vasquez-Torres M.
      • Godoy-Fernandez J.
      • Carcamo-Rodriguez C.
      Prevalence of epilepsy in a cohort of patients with multiple sclerosis.
      ]. Another study reported that seizure control was easily achieved in 22/36 patients (61.1%), but did not provide information on AED treatment [
      • Durmus H.
      • Kurtuncu M.
      • Tuzun E.
      • Pehlivan M.
      • Akman-Demir G.
      • Yapici Z.
      • et al.
      Comparative clinical characteristics of early- and adult-onset multiple sclerosis patients with seizures.
      ]. An attempt at a Cochrane review showed no eligible studies [
      • Koch M.W.
      • Polman S.K.
      • Uyttenboogaart M.
      • De Keyser J.
      Treatment of seizures in multiple sclerosis.
      ,
      • Koch M.
      • Uyttenboogaart M.
      • Polman S.
      • De Keyser J.
      Seizures in multiple sclerosis.
      ]. Recently, characteristics of epilepsy in MS was reported for 19 patients in a Norwegian single-center study, but the focus was not on epilepsy treatment and current seizure status [
      • Benjaminsen E.
      • Myhr K.M.
      • Alstadhaug K.B.
      The prevalence and characteristics of epilepsy in patients with multiple sclerosis in Nordland county, Norway.
      ]. In summary, there is shortage of systematic knowledge on management of epilepsy in MS. Given the increasing focus on aetiology in epilepsy, this is a considerable shortcoming − especially since worrying reports indicate that epilepsy in MS may have particular clinical characteristics; an unexpectedly high proportion of patients with status epilepticus and increased sensitivity to AED side effects [
      • Martinez-Juarez I.E.
      • Lopez-Meza E.
      • Gonzalez-Aragon Mdel C.
      • Ramirez-Bermudez J.
      • Corona T.
      Epilepsy and multiple sclerosis: increased risk among progressive forms.
      ,
      • Koch M.
      • Uyttenboogaart M.
      • Polman S.
      • De Keyser J.
      Seizures in multiple sclerosis.
      ].
      We therefore performed a retrospective observational study on patients with seizures and MS at two of Sweden’s larger tertiary neurology centers, with focus on seizure prognosis and AED response.

      2. Methods

      2.1 Cohort

      The electronic patient registers at Sahlgrenska University Hospital, Gothenburg and Uppsala University Hospital, Sweden, contain information on all outpatient and inpatient contacts at each hospital. We searched the databases for all contacts with the neurology department during available years (Gothenburg 2000–2013, Uppsala 2007–2016) and selected all patients with MS and at lest one code for seizure (R56.8) or epilepsy (G40.0-40.9). The search yielded 52 patients in Gothenburg and 15 patients in Uppsala. Among these, 47 patients in Gothenburg and 15 patients in Uppsala fulfilled the inclusion criteria (the records supporting at least one seizure and a diagnosis of MS). In five patients, the medical records revealed that the codes were erroneous, since either MS (n = 1) or seizures (n = 4) had not been present. These were excluded.

      2.2 Review of records

      Data were extracted from the medical records by use of a predefined clinical report form. EEG and MRI findings were categorized based on reports. Medical records were reviewed until April 2017 in Gothenburg and November 2017 in Uppsala and anonymized prior to analysis.

      2.3 Statistics

      Data are expressed as median and range for continuous variables and frequencies for categorical variables. Dates were approximated to the first day of the month or the year if the records did not contain exact information. If information was missing, the patient was omitted from that particular analysis. The exact number of patients in each analysis is given in tables or text. All analyses were performed using IBM SPSS version 23.

      2.4 Ethical permission

      The regional ethics committees of Gothenburg and Uppsala approved the study and waived the need for informed consent (Decisions Gothenburg 988-17 and Uppsala 397-17).

      3. Results

      3.1 Cohort and the first seizure

      We identified 62 MS patients with seizures. Twenty-three patients were deceased. The median age at the first seizure was 41 years (Table 1). The first seizure type was focal with impaired awareness or focal to bilateral tonic-clonic in most cases, but tonic-clonic without clear focal onset in one third of cases (Table 2). The year of the first seizure and the year of onset of MS symptoms could be determined for 60 patients. In 82% of cases, the first seizure was considered unprovoked and in 87% of cases the seizure occurred after the MS-diagnosis (Table 2). For one patient in Gothenburg, a seizure was the presenting symptom of MS. The median time from diagnosis of MS to the first seizure was ten years, and from the onset of MS symptoms eleven years (Fig. 1). The most common disease stage at the time of the first seizure was secondary progressive MS, and the median expanded disability status scale (EDSS) score was 6.5 (0 = no disability, 10 = death in MS).
      Table 1Cohort and follow-up time.
      DemographicsGothenburgUppsalaTotal
      n = 47%n = 15%n = 62%
      Male12256401829
      Female35759604471
      Deceased21462132338
      Age and follow-upYears, medianmin-maxYears, medianmin-maxYears, medianmin-max
      Age at 1st seizure429–80360–72410–80
      Age at last-follow-up5124–825322–725122–82
      Time from 1st seizure80–39110–5380–53
      Table 2The first seizure. Semiology, MS characteristics and results of investigations. RRMS = relapsing remitting MS, SPMS = secondary progressive MS, PPMS = primary progressive MS. EDSS = Expanded disability status scale (0 = no disability, 10 = death in MS).
      Gothenburg, N = 47Uppsala, N = 15Total, N = 62
      Seizure typeN = 45%N = 12%N = 57%
      Focal aware10222171221
      Focal impaired awareness or focal to bilateral tonic-clonic21476502747
      Tonic-clonic without clear focal onset14314331832
      CauseN=47%N=15%N=62%
      Unprovoked388113875182
      Provoked (incl possibly)9192131118
       – MS relapse24.30023
       – Abstinence24.30023
       – Other511213711
      TimingN=45%N=15%N=60%
      Before MS48.5320711
      Same year as MS110011.7
      After MS408512805287
      MS courseN=37%N=12%N=49%
      RRMS15414331939
      SPMS21575422653
      PPMS12.732548
      EDSSN=37Median

      (min-max)
      N=11Median (min-max)N=48Median

      (min-max)
      All376,5 (1–8)116.5 (1–8)486.5 (1–8)
      RRMS133.5 (2–6.5)43.5 (1–5.5)173.5 (1–6.5)
      SPMS217.5 (1–8)58.0 (6.5–8)267.5 (1–8)
      PPMS17.524.8 (3–6.5)36.5 (3–7.5)
      Unknown23.5 (2.5-4.5)023.5 (2.5-4.5)
      MRI beforeN=20%N=9%N=29%
      No lesions000000
      Few lesions (<5)2100027
      Several lesions (>5)189091002793
      MRI afterN=31%N=11%N=42%
      No lesions13.21924.8
      Few lesions (<5)26.51938.4
      Several lesions (>5)28909823788
      EEG (first after seizure)N=39%N=14%N=52%
      Normal7185361223
      Unspecific pathology15396432140
      Epileptiform discharges17443212038
      Fig. 1
      Fig. 1Time from MS diagnosis to the first seizure in the cohort. Time 0 represents the diagnosis of MS.

      3.2 MRI and EEG findings

      Twenty-nine patients had MRI results documented prior to their first seizure, with 93% demonstrating several lesions (semi-quantitatively assessed from reports or images, refers to all lesions – not just juxtacortical). An MRI after the first seizure was available for 42 patients, 88% of which had more than five lesions (unfortunately, most MRI reports did not specify lesion distribution). EEG was available for 52 patients; 40% demonstrated unspecific pathology such as slowing, and 38% had epileptiform discharges. Forty-four patients with EEG results available had more seizures, including all twelve patients with normal EEGs. Among the six patients that did not have more than one seizure, three had epileptiform discharges and three had unspecific pathology.

      3.3 AED choice

      Out of all 62 patients, 54 had additional documented seizures. Sixteen patients had other possible reasons for an epilepsy diagnosis such as CNS tumor (n = 4), head trauma (n = 7), stroke (n = 2), or other (n = 3). We next characterized the treatment and treatment response to AEDs in patients with seizures and no other aetiology than MS (Table 3). Information on the first AED could be found for 44 patients. The most commonly selected first drug was carbamazepine, followed by phenytoin, lamotrigine, and levetiracetam. Carbamazepine had been discontinued in almost half of the patients starting with this drug. For remaining AEDs, the numbers were small. The overall retention rate for the older AEDs carbamazepine, phenytoin, or valproic acid was 50% and that of newer AEDs lamotrigin, levetiracetam, gabapentin was 75% (p = 0.184, Fishers exact test).
      Table 3Epilepsy and AED treatment. 1. First AED selection and retention rate in patients without other possible seizure cause than MS. 2. Current treatment and proportion of seizure-free patients in patients with known seizure status.
      1. AED choice and retention rate
      First AEDN = 44%discontinuedRetention rate%
      Carbamazepine23521152
      Phenytoin716357
      Valproic acid24.520
      Lamotrigine614350
      Levetiracetam490100
      Gabapentin24.50100
      2. Current treatmentN=37%seizure-free%
      Untreated38.13100
      Monotherapy24651250
      Combination1027220
      All371001746
      On first AED2022840
      Current AEDN=37%seizure −free%
      Carbamazepine1232542
      Phenytoin514240
      Lamotrigine924333
      Levetiracetam1130327
      Gabapentin514240
      Valproic acid25.4150
      Other41100

      3.4 Seizure outcome

      At the time of last follow-up, seizure status could be determined for 37 patients (28 in Gothenburg and 9 in Uppsala). Among these, 50% had been seizure free for more than one year in Gothenburg and 33% in Uppsala. In total, 46% of patients were seizure free at last follow-up. Out of 20 patients being prescribed their first AED, 8 (40%) were seizure free. The majority of patients were on monotherapy, 10 patients were on a combination of AEDs and 3 patients were untreated. No single AED was associated with a particularly high proportion of seizure-free patients. We also analyzed the reason for discontinuation of the first AEDs, which was side effect of the AED in the majority of patients (Fig. 2).
      Fig. 2
      Fig. 2Reason for discontinuation of the first AED.

      3.5 AAN quality parameters

      We finally assessed AAN quality parameters in all patients with no alternative cause of epilepsy and outpatient follow-up information (n = 36). The year of last follow-up was 2015 (2000–2017, min-max). We focused only on seven out of eight AAN recommendations, as surgical referral was deemed not applicable to this patient population. Our data presents low rates of documentation for aetiology of epilepsy, as well as MRI and EEG review, and no patients were counseled regarding safety or reproductive health (Fig. 3). Seizure type/frequency was documented at a higher rate (61%).
      Fig. 3
      Fig. 3Documentation of AAN quality measures at most recent visit.

      4. Discussion

      Epilepsy in MS has mainly been studied as an outcome, most recently in a world-wide meta-analysis and in a large register-based population-wide study in Sweden [
      • Gasparini S.
      • Ferlazzo E.
      • Ascoli M.
      • Sueri C.
      • Cianci V.
      • Russo C.
      • et al.
      Risk factors for unprovoked epileptic seizures in multiple sclerosis: a systematic review and meta-analysis.
      ,
      • Burman J.
      • Zelano J.
      Epilepsy in multiple sclerosis: a nationwide cohort study.
      ]. Epidemiological studies give excellent information on the prevalence and risk of epilepsy in MS, but are based on administrative data and cannot provide clinical detail. Such studies must therefore be supplemented by information from primary sources like medical records. There are currently very few studies describing the epilepsy per se in MS. The widespread and long-standing use of electronic health records in Sweden allowed us to identify 62 MS patients with seizures and describe the clinical course of their epilepsies. Although normally of limited value, retrospective observational studies are motivated in rare conditions where future RCTs are unlikely and similar studies have recently been published on autoimmune epilepsy [
      • Feyissa A.M.
      • Lopez Chiriboga A.S.
      • Britton J.W.
      Antiepileptic drug therapy in patients with autoimmune epilepsy.
      ] and postencephalitic epilepsy [
      • Pillai S.C.
      • Mohammad S.S.
      • Hacohen Y.
      • Tantsis E.
      • Prelog K.
      • Barnes E.H.
      • et al.
      Postencephalitic epilepsy and drug-resistant epilepsy after infectious and antibody-associated encephalitis in childhood: clinical and etiologic risk factors.
      ,
      • Singh T.D.
      • Fugate J.E.
      • Hocker S.E.
      • Rabinstein A.A.
      Postencephalitic epilepsy: clinical characteristics and predictors.
      ].
      Overall, our findings are well in line with the existing knowledge on epilepsy in MS. As in the epidemiological studies, the first seizure in our cohort occurred most often occurred some time after MS onset and a majority of patients were in secondary progressive MS at the time of their first seizure. Seizures very long before MS are probably unrelated to MS. The high proportion of focal seizure types is also in agreement with the literature [
      • Kelley B.J.
      • Rodriguez M.
      Seizures in patients with multiple sclerosis: epidemiology, pathophysiology and management.
      ]. The median EDSS score at the time of the first seizure was 6.5, indicating a high disability level. These findings fit well with the notion that severity of MS is associated with risk of epilepsy. Our findings are also in agreement with those recently reported from a smaller cohort of 19 patients in a Norwegian single-center study [
      • Benjaminsen E.
      • Myhr K.M.
      • Alstadhaug K.B.
      The prevalence and characteristics of epilepsy in patients with multiple sclerosis in Nordland county, Norway.
      ].
      Most patients received carbamazepine as the first AED. The retention rate was higher for newer AEDs when used as the first drug compared to older AEDs, but the difference was not statistically significant and the shorter time in the market for newer drugs may have resulted in a shorter exposure time.
      More than 60% of patients received carbamazepine or phenytoin as their first AED, and almost half the population were currently being treated with either compound at the time of the investigation. The widespread use of older sodium-channel blockers is interesting given the reports on increased side-effect sensitivity to such drugs in patients with MS [
      • Koch M.W.
      • Polman S.K.
      • Uyttenboogaart M.
      • De Keyser J.
      Treatment of seizures in multiple sclerosis.
      ,
      • Ramsaransing G.
      • Zwanikken C.
      • De Keyser J.
      Worsening of symptoms of multiple sclerosis associated with carbamazepine.
      ]. The enzyme-inducing properties of these drugs may also make them less suitable given other concomitant medication in severely affected MS patients, such as antidepressants. Treatment pattern and retention rates found in such a small patient material as ours is merely hypothesis-generating and we intend to investigate retention rates in a future nation-wide register-based investigation. Importantly, we report AED treatment for all patients with a seizure diagnosis and no other aetiology than MS that explains seizures. We cannot be certain that all seizures in the material were because of MS; seizures and or epilepsy can in rare cases occur by chance in patients with MS.
      The most important finding of our study is the low rate of seizure freedom. Overall, two thirds of patients with epilepsy are expected to become seizure-free on AEDs, but only 44% of patients were seizure-free in our study population. This contrasts to some other reports, in which a majority of patients are described as having a benign seizure course [
      • Nyquist P.A.
      • Cascino G.D.
      • Rodriguez M.
      Seizures in patients with multiple sclerosis seen at Mayo Clinic, Rochester, Minn, 1990–1998.
      ]. The literature as a whole report very diverging results, but methodology such as follow-up time differs markedly [
      • Kelley B.J.
      • Rodriguez M.
      Seizures in patients with multiple sclerosis: epidemiology, pathophysiology and management.
      ]. Presumably, the introduction of electronic health records and raised therapeutic ambitions in both MS and epilepsy have improved data capture, giving contemporary reports an advantage over the older literature. We suggest at least three possible explanations for our finding of low rates of seizure freedom. The participating hospitals are tertiary centers, treating severely affected MS-patients in their respective regions. The low rate of seizure freedom could therefore reflect selection bias. Second, sensitivity to side effects may limit adequate dosing of AEDs and clinicians may not consider high doses justified in patients that are non-ambulatory and at low risk of seizure-related injuries. However, the doses used in our study population were not particularly low. Finally, it is possible that the low rates of seizure freedom reflect lower ambitions in management of seizures in patients with MS compared to the general epilepsy population. In poststroke epilepsy, another form of acquired epilepsy, the rate of seizure freedom at a Swedish tertiary center was considerably lower than those reported in clinical trials performed in the same patient group [
      • Zelano J.
      • Lundberg R.G.
      • Baars L.
      • Hedegard E.
      • Kumlien E.
      Clinical course of poststroke epilepsy: a retrospective nested case-control study.
      ,
      • Zelano J.
      Comment on epilepsy in cerebrovascular diseases: review of experimental and clinical data with meta-analysis of risk factors.
      ]. In our study, low rates of seizure freedom were seen at both Swedish hospitals. One possible interpretation is that seizure freedom is not pursued as vigorously in the presence of another neurological disorder. Before independent replication in another country, this remains a concerning observation limited to Sweden. A low seizure freedom rate is of particular concern given the findings that patients with MS have repeatedly been shown to have an increased risk of status epilepticus [
      • Burman J.
      • Zelano J.
      Epilepsy in multiple sclerosis: a nationwide cohort study.
      ,
      • Catenoix H.
      • Marignier R.
      • Ritleng C.
      • Dufour M.
      • Mauguiere F.
      • Confavreux C.
      • et al.
      Multiple sclerosis and epileptic seizures.
      ,
      • Sokic D.V.
      • Stojsavljevic N.
      • Drulovic J.
      • Dujmovic I.
      • Mesaros S.
      • Ercegovac M.
      • et al.
      Seizures in multiple sclerosis.
      ]. Status epilepticus was not a predefined outcome measure in our investigation, but at least six patients (9.7%) in our cohort had status epilepticus (three EEG-verified in Gothenburg, and three clinically diagnosed in Uppsala).
      We also assessed the American Academy of Neurology (AAN) epilepsy quality measures [
      • Fountain N.B.
      • Van Ness P.C.
      • Swain-Eng R.
      • Tonn S.
      • Bever Jr., C.T.
      Quality improvement in neurology: AAN epilepsy quality measures: report of the quality measurement and reporting subcommittee of the American Academy of Neurology.
      ]. The first four measures (seizure type/frequency, aetiology, EEG, and neuroimaging) support the diagnostic approach and the last four measures (surgical referral, counseling about side effects, safety issues and reproductive health) supports quality of care. Our findings show limited documentation of quality parameters, indicating a need for raised ambitions in care of epilepsy in patients with MS, at least in Sweden.
      In summary, we present the largest study of epilepsy and its treatment in patients with MS. Our findings validate recent register-based investigation and underline that epilepsy seems closely linked to MS severity. Like other investigators, we found that onset of epilepsy occurred mainly after MS. An interesting question is therefore if disease modifying therapy (DMT) of MS can prevent or mitigate epilepsy [
      • Kelley B.J.
      • Rodriguez M.
      Seizures in patients with multiple sclerosis: epidemiology, pathophysiology and management.
      ]. We did not address DMT in our material, since we only studied patients with seizures – but future studies are needed to elucidate if more aggressive management of MS can prevent epilepsy. From our current incomplete understanding of the pathophysiology of epilepsy in MS the relative contributions of inflammation and structural damage to epileptogenesis are not known, and may well differ in individual patients. We found low rates of seizure freedom in our material, with no indication of any particular AED being more effective than others. The retention rate for newer AEDs was higher than that of older AEDs, but not significantly so. This needs to be investigated further in larger patient materials – ideally large prospective trials.

      Declarations of interest

      None. The donors of the disclosed research grants had no influence over study idea, design, or results.

      Funding sources

      The work was funded by the authors institutions, the Jeansson Foundations , Magnus Bergvalls Foundation , and the Swedish Society of Medicine .

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