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Outcome of newly-diagnosed epilepsy in older patients
Epilepsy & Behavior 27 (2013) 29–35
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Epilepsy & Behavior journal homepage: www.elsevier.com/locate/yebeh
Outcome of newly-diagnosed epilepsy in older patients A.G. Besocke a,⁎, B. Rosso a, E. Cristiano a, S.M. Valiensi a, M. del C. García a, S.E. Gonorazky b, L.M. Romano b a b
Neurology Department, Hospital Italiano de Buenos Aires, Argentina Neurology Department, Hospital Privado de Comunidad, Mar del Plata, Argentina
a r t i c l e
i n f o
Article history: Received 25 July 2012 Revised 14 November 2012 Accepted 17 November 2012 Available online 29 January 2013 Keywords: Epilepsy in older people Outcome of epilepsy Epilepsy prognosis in older people
a b s t r a c t Introduction: The annual incidence of seizure disorders rises sharply after the age of 60. Treatment is complicated by the normal physiological changes of aging, comorbid diseases, and polypharmacy. Despite this, approximately 80% of the patients become seizure-free. Objectives: The objectives of this study were to (1) analyze the outcome of a cohort of patients with newly-diagnosed epilepsy over the age of 65, (2) describe epilepsy etiology and seizure type, and (3) classify the outcome according to the latest ILAE classification proposal for drug-resistant epilepsy (2010). Methods: All patients with newly-diagnosed epilepsy over the age of 65 who were evaluated in two different institutions were included. Seizures and epilepsy syndromes were classified according to the International League Against Epilepsy proposal (2010). Epilepsy outcomes were also analyzed according to the proposal of the ILAE Commission on Therapeutic Strategies (2010). Results: One hundred and twenty-two patients were included with a median follow-up time of 15 months. Median age of diagnosis was 78 years. Seventy-seven patients (55%) had epilepsy of unknown cause, and 55 (45%) had structural–metabolic epilepsy. The proportions of seizure-free patients at 6, 12, 18, and 24 months were 90%, 77%, 74%, and 67%, respectively. Thirty percent of patients experienced adverse effects (AEs). We found a statistically significant trend toward a higher frequency of AEs as the number of concomitant medications rose and in younger patients. According to the 2010 ILAE classification proposal for drug-resistant epilepsy criteria, 55.8% of the patients were seizure-free, 12.3% had treatment failure, and 32% had undetermined seizure outcome. Conclusion: Patients with newly-diagnosed epilepsy after the age of 65 have very good chances of achieving seizure control with AED treatment. It seems that fulfilling the ILAE classification proposal for drug-resistant epilepsy (2010) criteria for seizure freedom was more difficult in our cohort. Older patients also seem to be more prone to suffering from AEs. © 2012 Elsevier Inc. All rights resrved.
1. Introduction The annual incidence of seizure disorders rises sharply after the age of 60 years old (yo), from 40 per 100,000 for people between 40 and 45 yo, to 80 per 100,000 for people between 60 and 65, to more than 150 per 100,000 in those older than 80 [1,2]. The clinical presentations of seizures in the elderly differ from those in other age groups, and underdiagnosis and misdiagnosis occur very frequently in this population [3,4]. Epilepsy can have profound physical and psychological consequences in older patients. The stigma surrounding the diagnosis can be hard to address at this time of life. Elderly people are particularly vulnerable to physical injury as a consequence of seizures. The situation may be complicated by a range of neurodegenerative, cerebrovascular, and neoplastic comorbidities; furthermore, problems with concomitant medications are common. Quality of life can be adversely affected, and ⁎ Corresponding author. E-mail address: [email protected] (A.G. Besocke). 1525-5050/$ – see front matter © 2012 Elsevier Inc. All rights resrved. http://dx.doi.org/10.1016/j.yebeh.2012.11.041
the unpredictable nature of the seizures can lead to social withdrawal. Loss of confidence and reduced independence can result in premature admission to nursing homes and residential care facilities. Despite this, approximately 80% of patients with new onset epilepsy beyond the age of 65 yo become seizure-free during a period of at least 12 months after being treated with one or two drugs in monotherapy [5]. Adverse effects (AEs) of antiepileptic drugs (AEDs) are causes for concern in the elderly population because they are common and can occur at lower blood levels than in younger patients [6]. Treatment is complicated by the normal physiological changes of aging, comorbid diseases, and polypharmacy. We describe the characteristics of a cohort of patients with newly-diagnosed epilepsy over the age of 65 yo, with a special focus on their outcome, treatment, and tolerability of AEDs. 1.1. Objectives The objectives of this study were to analyze the outcome of a cohort of patients with newly-diagnosed epilepsy over the age of
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AG Besocke et al. / Epilepsy & Behavior 27 (2013) 29–35
65 yo in two different neurology departments, describe epilepsy etiology and seizure type, and compare a classical clinical approach of defining epilepsy outcome with the latest ILAE classification proposal for drug-resistant epilepsy (2010) [7,8]. 2. Methods 2.1. Patients We retrospectively included all the patients with newly-diagnosed epilepsy over the age of 65 yo evaluated in two neurology departments from two different institutions: Hospital Privado de Comunidad de Mar del Plata, Argentina (November 1st, 2007 to June 30th, 2009) and Hospital Italiano de Buenos Aires, Argentina (November 1st, 2006 to June 30th, 2009). Patients with acute provoked seizures were not included in this cohort. Patients were interviewed by a neurologist every 6–8 weeks, until seizure freedom was achieved. Subsequently, patients were monitored every 3–6 months. Seizure outcome was established on the last visit to the neurologist's office. If no seizures were reported after one year of seizure freedom, the patient was assumed to be seizure-free. Furthermore, we classified outcomes according to the 2010 ILAE classification proposal for drug-resistant epilepsy, to compare the most recent definition with a classical, widely used clinical definition. All patients were initially treated with monotherapy. The objective of the treatment was to control seizures with the lowest drug dose necessary. Treatment was modified according to clinical response and tolerability. A second drug was prescribed if patients did not tolerate the first drug or if it was not effective. When there was a lack of efficacy after two drugs in monotherapy, combined treatment was established. 2.2. Definitions Seizures and epilepsy syndromes were classified according to the International League Against Epilepsy proposal (2010). Epileptic seizures were classified as focal seizures (FS), generalized seizures (GS), or unclassified seizures (US). FS are conceptualized as originating within networks limited to one hemisphere. They may be discretely localized or more widely distributed, and they may originate in subcortical structures. FS are further subdivided into FS with or without impairment of consciousness or awareness; FS evolving to a bilateral, convulsive seizure; and generalized seizures (involving tonic, clonic, or tonic and clonic components). GS are conceptualized as originating at some point within, and rapidly engaging, bilaterally distributed networks that can include cortical and subcortical structures but do not necessarily include the entire cortex. Although individual seizure onsets can appear localized, the location and lateralization are not consistent from one seizure to another [9]. Epilepsy syndromes were classified into the following: (1) “Genetic”: epilepsy as the direct result of a known or presumed genetic defect(s) in which seizures are the core symptom of the disorder. The knowledge regarding the genetic contributions may derive from specific molecular genetic studies that have been well replicated and have even become the basis of diagnostic tests. (2) “Structural/metabolic” (SE): epilepsy as the direct result of a distinct structural or metabolic condition or disease that has been demonstrated to be associated with a substantially increased risk of developing epilepsy in appropriately designed studies. SE syndromes include acquired disorders such as stroke, trauma, and infection. They may also be of genetic origin (e.g., tuberous sclerosis, many malformations of cortical development). (3) “Unknown cause” (UE): the nature of the underlying cause is currently unknown; it may have a fundamental genetic defect at its core or it may be the consequence of a separate unrecognized disorder [9].
Seizure freedom was defined as freedom from seizures or auras for a minimum of three times the longest pre-intervention inter-seizure interval, or 12 months, whichever was longer. Treatment failure was defined as recurrent seizure(s) after the intervention had been adequately applied. Both instances were further classified according to the presence or absence of adverse events. Undetermined seizure outcome was applied when the treatment had not been adequately established for a valid assessment of the outcome, or information was lacking to make the assessment [7]. Adverse effects (AEs) were defined as any harmful, unwanted effect of a medication used at therapeutic recommended doses [10,11]. 2.3. Statistical analysis Patients were divided into two groups according to the seizure freedom criteria. Categorical data were analyzed using the chisquare test and Fisher exact test. The Mann–Whitney test was used to compare ordinary and intervallic variables without normal distributions. The Kaplan–Meier method was applied to assess the proportion of seizure-free patients. The Wilcoxon (Peto–Prentice) method was used to compare two or more survival curves. All statistical tests were two-tailed. We used the 2008 version of STAT 2.7.2 for all statistical analyses. 3. Results 3.1. Patients One hundred and twenty-two patients were included, and all of them received their first AEDs. None of them had been previously treated with AEDs. The median follow-up time was 15 months (inferior quartile: 12–superior quartile: 24). Twenty-six patients (21%) died during the study period. The median age of diagnosis was 78 yo; 66% were female. Seventy-seven patients (55%) had UE, and 55 (45%) had SE. In the latter group, 50% (n = 28) of the cases were related to cerebrovascular disease (ischemic or hemorrhagic), 20% (n = 11) to brain tumors, 7.2% (4) to subdural hematomas, and 20% were associated with different causes (cerebral infections, previous neurosurgery, cavernous angioma, mesial temporal sclerosis). 3.2. Seizure type Seventeen patients (14%) suffered from focal seizures without impairment of consciousness, 41 (33.5%) had focal seizures with impairment of consciousness, 37 (30.3%) had focal seizures evolving to bilateral convulsive seizures, and 27 (22.2%) suffered from generalized tonic-clonic seizures. None of the patients had absences or myoclonic seizures. We performed an interictal electroencephalogram (EEG) in 95 patients (78%); 52% were normal, 14.4% had non-specific changes (mostly focal or generalized slowing), and 33.6% evidenced epileptiform abnormalities (Table 1). 3.3. Outcome The proportions of patients who attained remission for 6, 12, 18, and 24 months were 90%, 77%, 74%, and 67%, respectively (Fig. 1). Of the patients who attained a period of 12 months of seizure freedom (n = 76), 62 received one lifetime AED, 11 received two lifetime AEDs, and 3 received 3 or more lifetime AEDs. There were no statistically significant differences when comparing seizure freedom survival curves between the two neurology departments, sex, age at diagnosis, or seizure type (Table 2 and Fig. 2). However, we identified a trend toward higher seizure freedom in the SE group compared to the UE group, and in the normal EEG
AG Besocke et al. / Epilepsy & Behavior 27 (2013) 29–35 Table 1 Patient characteristics. Patients
Total (n: 122)
Age, median (years) Age IQ–SQ Sex, female Etiology • Unknown • Structural–metabolic • Vascular • Tumor • Subdural hematoma • Various Seizure type • Focal • Wo/IC • W/IC • Evolving to BCS • Generalized tonic-clonic EEG performed • Normal • Abnormal • Epileptiform • Non specific AEDs • Two or more AEDs • Monotherapy • DFH • LTG • VPA • LEV • CBZ • OXC • TPM • GBP • FB Adverse effects
78 72/83 65.5% (n: 80) 55% (n: 67) 44% (n: 55) 50% (n: 28) 20% (n: 11) 7% (n: 4) 21% (n: 12) 47.5% (n: 58) 14% (n: 17) 33.5% (n: 41) 30.3% (n: 37) 22.2% (n: 27) 78% (95/122) 52% (49/95) 48% (46/95) 33.6% (32/95) 14.4% (16/95) 6.7% (8) 93.3% (111a) 43.7% (52) 21% (25) 7.6% (9) 7.6% (9) 6.7 (8) 4.2% (5) 0.9% (1) 0.9% (1) 0.9% (1) 30% (37)
IC: inferior quartile, SC: superior quartile, Wo/IC: without impairment of consciousness, W/IC: with impairment of consciousness, BCS: bilateral convulsive seizure, DFH: phenytoin, LTG: lamotrigine, VPA: valproic acid, LEV: levetiracetam, CBZ: carbamazepine, OXC: oxcarbazepine, TPM: topiramate, GBP: gabapentin, FB: phenobarbital. a Three patients without AEDs.
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group compared to the abnormal EEG group (including epileptiform and non-specific changes), although these trends did not reach statistical significance. 3.4. Adverse effects Thirty-seven patients (30%) experienced AEs. We analyzed the association between AEs and the number of concomitant medications (CMs), and found a statistically significant trend (p b 0.0001) toward a higher proportion of patients with AEs as the number of CMs increased: AEs occurred in 0%, 13.5%, 54.7%, and 42.8% of patients with 0 CM, 1 to 3 CMs, 4 to 6 CMs, and more than 6 CMs, respectively. Furthermore, we found a trend (p = 0.045) toward higher proportions of AEs in younger patients (65–74 yo) (Fig. 3). 3.5. Epilepsy outcome classification According to the 2010 ILAE classification proposal for drugresistant epilepsy, 55.8% (n = 68) of our cohort was seizure-free. In this group, 59 patients (86.7%) received one lifetime AED, and 9 patients received 2 lifetime AEDs. In 45 patients (66.2%), seizure freedom was not associated with AEs. In this group, 43 patients received only one lifetime AED, 1 received two concomitant AEDs, and one decided not to be treated. In the seizure-free group associated with AEs (n = 23), 5 patients received 1 lifetime AED and tolerated the AEs, 14 patients received 2 lifetime AEDs, and 4 received three lifetime AEDs (either in monotherapy or in combination). Fifteen patients (12.3%) had treatment failure to two or more AEDs, 12 patients received 2 lifetime AEDs, and 3 patients received 3 or more lifetime AEDs. In 9 patients (60%), treatment failure was associated with AEs. In 39 patients (32%), the epilepsy outcome was undetermined, and in only 5 patients (12.8%), treatment outcome was associated with AE. In the undetermined group, 37 patients received one lifetime AED, and two decided not to receive treatment. Eighteen patients in this group died before sufficient time passed to establish outcome (Table 3).
Fig. 1. Kaplan–Meier, seizure-free patients.
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AG Besocke et al. / Epilepsy & Behavior 27 (2013) 29–35
Table 2 Prognostic variables. 12 months Variables Hospital: • HPC • HIBA Sex: • Female • Male Age (years) • 65–74 • 75–84 • ≥85 Etiology: • Unknown • Structural–metabolic Seizure type: • FS Wo/IC • FS W/IC • FS Ev BCS • GS EEG: • Normal • Abnormal
24 months
% Seizure-free patients
95% CI
% Seizure-free patients
95% CI
p
77.3 79.2
(63.2–86.5) (65.6–87.9)
54.3 72
(19.6–79.5) (55.2–83.4)
0.33a
76.8 79.7
(64.8–85.1) (62–89.8)
67.2 70.9
(49.5–79.8) (50.6–84)
0.71a
68.7 85.7 79.2
(51.5–80.9) (72.2–80.9) (53.4–91.7)
58.2 81.8 –
(37.6–74.1) (65.9–90.8) –
0.19a 0.35b
71.5 85.8
(58.1–81.2) (71–96.6)
66.4 64.4
(52.1–77.4) (32–84.3)
0.09a
79.6 83.7 67.1 81.8
(48.9–93) (67.3–92.3) (47.3–80.8) (57.8–92.2)
79.6 76.8 45.7 73.6
(48.9–93) (54.2–89.2) (16.7–71) (45.6–88.7)
0.32a
84.2 67.9
(69.6–92.1) (51.8–79.6)
73.8 56.9
(52.2–86.7) (30.8–75.8)
0.12a
HPC: Hospital Privado de Comunidad; HIBA: Hospital Italiano; FS Wo/IC: focal seizure without impairment of consciousness; FS W/IC: focal seizure with impairment of consciousness; FS Ev BCS: focal seizure evolving to bilateral convulsive seizure; GS: generalized seizure. a Wilcoxon (Peto–Prentice): chi-square equivalence. b Wilcoxon (Peto–Prentice): chi-square with trend.
4. Discussion After 12 months of follow-up, 77% of our cohort became seizurefree. A similar pattern has been noted in other patient populations, as in the cohort reported by Saetre et al. in which the primary endpoint was retention on treatment. Saetre et al. reported that the proportion of patients who remained on treatment at the end of the follow-up period (40 weeks) varied from 73 to 75% in the sensitivity analysis [12]. This finding seems to be similar to the Stephen et al. cohort where 79% of the patients attained remission [5]. Rowan et al. reported slightly lower proportions of seizure-free patients at 3, 6, and 12 months than in our cohort: 80.1% (LTG 80.3%, GBP 80.0%, CBZ 80.0%), 70.6% (LTG 68.2%, GBP 71.7%, CBZ 72.7%), and 63.4% (LTG 61.3%, GBP 60.0%, CBZ 71.4%), respectively, when seizures that occurred during the titration phase were excluded. Both populations were very similar in age, seizure types, and epilepsy syndromes. Interestingly, we had a higher proportion of patients at risk at 12 months than the Rowan cohort: 62% versus 46% [13]. Although we did not stratify our population according to the AED administered, only 33 of our patients were on monotherapy using one of the drugs analyzed by Rowan et al. Further investigation on response rates to different AEDs should be performed in our population. In the 12-month seizure-free group of our cohort, 81% of patients were on monotherapy, and 19% received 2 or more lifetime AEDs, alone or in combination. Slightly higher proportions of patients on monotherapy were reported by Stephen et al.: 93% on mono and 7% on dual therapy [5]. These findings suggest that older patients are good responders to AEDs. In agreement with this, SANAD findings demonstrated that the relationship between age and 12 months of remission was U-shaped: the chance of achieving a period of 12 months of remission is higher in children and elderly patients than in those in the mid-age range (approximately 20–50 yo). This relationship might be due to the different etiologies in different age groups, pharmacokinetics, or multiple other factors. A linear effect was noted in this cohort, with older patients being significantly less likely to have a treatment failure because of inadequate seizure control than were younger patients. However, older patients were significantly more likely to have a treatment failure because of unacceptable adverse events than were younger patients [14,15].
In our cohort, patient seizure type was independent of the chance of achieving 12 months of seizure freedom, although the majority of our patients had focal or focal evolving to bilateral convulsive seizures, suggesting a focal etiology of the epilepsy syndrome. In the SANAD cohort, treatment failure was significantly more likely in patients with simple or complex partial seizures without secondary generalization than in patients with secondary generalized tonic-clonic seizures [14]. This difference can be explained by our smaller sample size. Interestingly, we found a non-statistically significant trend toward a higher proportion of seizure-free patients in the SE group after 12 months of follow-up, compared with the UE group. These proportions became similar at 24 months of follow-up, although the number of patients at risk at this point was very low. These findings could be due to the initiation of treatment in patients with SE after having only one seizure and the exclusion of patients with unknown causes of isolated seizures, which led to an increase in the number of treated patients with structural causes that might not induce repeated seizures. We also found a non-statistically significant trend toward a lower chance of seizure freedom in patients with abnormal EEGs (either with epileptiform or non-epileptiform abnormalities) after one year of follow-up. This could be related to a functional abnormality in the brain that lowers seizure threshold. In the Stephen et al. cohorts, no association was found between outcome and EEG results [5], but with the more extensive approach of the SANAD study, treatment failure was significantly more likely in patients with epileptiform abnormalities on EEG [14]. In the SANAD study, the chance of treatment failure increased as the total number of seizures before randomization increased, was higher in women than in men, varied with respect to the AED prescribed, and was higher in patients with epilepsy that was not localized than in patients with temporal lobe epilepsy [14]. In our cohort, no differences in outcome were found with respect to sex, seizure type, or age at diagnosis. Our sample size was most likely too small to detect this association. When analyzing outcome according to the 2010 ILAE proposal for drug-resistant epilepsy, the percentage of seizure-free patients in our cohort decreased to 55.8%. This could be related to the insufficient follow-up time required to achieve the minimum of three times the longest pre-intervention inter-seizure interval to fulfill the criteria
AG Besocke et al. / Epilepsy & Behavior 27 (2013) 29–35
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Fig. 2. Kaplan–Meier analysis: seizure-free patients' proportion according to different variables. A): Hospital: HPC: Hospital Privado de Comunidad, HIBA: Hospital Italiano de Buenos Aires. B): Sex. C): Age group. D): Etiology. E): Seizure type. F): EEG. FS Wo/IC: focal seizure without impairment of consciousness; FS W/IC: focal seizure with impairment of consciousness; FS Ev BCS: focal seizure evolving to bilateral convulsive seizure.
of the undetermined group. In addition, a group of patients, especially with SE, initiated treatment after having only one seizure and were then re-classified into the undetermined group because no interseizure interval could be established. It seems that fulfilling the ILAE classification proposal for drug-resistant epilepsy (2010) criteria for seizure freedom is more difficult. However the ILAE classification is more clinically relevant in individual patients because it takes into account the particular inter-seizure interval for each person.
We found AEs in 30% of our total cohort, but they varied largely among the treatment response groups according to the 2010 ILAE proposal (12–60%). AEs were more frequent in younger patients (65–74 yo) and in patients using more than 4 concomitant medications. Although our analysis did not take AED dose or type into account, which could bias the causal relationship of a symptom to an AED, there was a clear temporal association between the beginning of the AED treatment and the AE. In the Saetre cohort, the frequency
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AG Besocke et al. / Epilepsy & Behavior 27 (2013) 29–35
Fig. 3. Adverse effects according to age group and concomitant medications. AE: adverse effects, CM: concomitant medications.
of AEs was 55% [12]. Elderly patients are more prone to side effects, and there is a high prevalence of comorbidities, comedications, and interactions with AEDs in this population [6,12]. Furthermore, AEDs may interfere with optimal functioning due to AEs that may be exaggerated or more severe in older adults compared with younger patients. In particular, the older, longer-established AEDs are more likely to lead to disability in older adults than the newer generation of antiepileptic compounds [15]. Geriatric training teaches that the average older adult has one chronic illness for each decade over 50. Therefore, one would expect that an individual who develops seizures in late life would likely have associated medical and/or neurologic conditions. Patients often have multiple co-morbidities and, therefore, require multiple medications [15–17]. In our cohort, 54.7% of patients with AEs were receiving between 4 and 6 concomitant medications. In previous reports of seizures in the elderly, the average number of prescribed drugs was seven [17]. We found a statistically significant association between the number of CMs used and the incidence of AEs, which supports the previous findings. It is important to note that the requirement for multiple drug treatments can often lead to poor medication adherence [15].
Table 3 Outcome category scheme according to ILAE 2010 proposal [7]. Outcome scheme
Outcome category
Outcome (N = 122)
Adverse effects (AEs) (n = 37)
1: Seizure-free
55.8% (68)
2: Treatment failure
12.3% (15)
3: Undetermined
32% (39)
A: no AE B: AE A: no AE B: AE A: no AE B: AE
66.2% 33.8% 40% 60% 87.2% 12.8%
(45) (23) (6) (9) (34) (5)
1: 1: 2: 2: 3: 3:
55.8% 55.8% 12.3% 12.3% 32.7% 32.7%
A: 66.2% B: 33.8% A: 40% B: 60% A: 87.2% B: 12.8%
5. Conclusion Patients with newly-diagnosed epilepsy after the age of 65 yo have a very good chance of achieving seizure control with AED treatment. It seems that fulfilling the ILAE classification proposal for drugresistant epilepsy (2010) criteria for seizure freedom was more difficult in our cohort compared to a classical approach of 12 months of seizure freedom. However, we agree that the 2010 ILAE classification is clinically more relevant because it takes into account the interseizure interval of individual patients. Older patients seem to be more prone to suffering from AEs that can be explained by concomitant illnesses, changes in pharmacokinetics and pharmacodynamics of drugs, and the number of CMs required. References [1] Hauser WA, Annegers JF, Kurland LT. The incidence of epilepsy and unprovoked seizures in Rochester, Minnesota, 1935–84. Epilepsia 1993;34:453–68. [2] Craig I, Tallis R. General practice management of adult-onset epilepsy analysed. Elder Care 1991;3:69–72. [3] Abuhuziefa A, Wambacq I. Seizures in the elderly: video/EEG monitoring analysis. Epilepsy Behav 2005;7:447–50. [4] Kellinghaus C, Loddenkemper T, Dinner D, Lachhwani D, Luders H. Seizure semiology in the elderly: a video analysis. Epilepsia 2004;45:263–7. [5] Stephen L, Kelly K, Mohanraj R, Brodie M. Pharmacological outcomes in older people with newly diagnosed epilepsy. Epilepsy Behav 2006;8:434–7. [6] Ramsay R, Rowan A, Pryor F. Special considerations in treating the elderly patient with epilepsy. Neurology 2004;62(Suppl. 2):24–9. [7] Kwan P, Arzimanoglou A, Berg AT, et al. Definition of drug resistant epilepsy: consensus proposal by the ad hoc Task Force of the ILAE Commission on Therapeutic Strategies. Epilepsia 2010;51(6):1069–77. [8] Kwan P, Brodie M. Definition of refractory epilepsy: defining the undefinable? Lancet Neurol 2010;9:27–9. [9] Berg A, Berkovic S, Brodie M, 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(4):676–85. [10] International drug monitoring: the role of national centres. Report of a WHO meeting, 498. World Health Organ Tech Rep Ser.; 1972. p. 1–25.
AG Besocke et al. / Epilepsy & Behavior 27 (2013) 29–35 [11] The use of computers in international drug monitoring. WHO Chron 1973;27(11): 476–80. [12] Saetre E, Perucca E, Isojarvi J. An international multicenter randomized double-blind controlled trial of lamotrigine and sustained-release carbamazepine in the treatment of newly diagnosed epilepsy in the elderly. Epilepsia 2007;48(7):1292–302. [13] Rowan AJ, Ramsay RE, Collins JF, et al. New onset geriatric epilepsy: a randomized study of gabapentin, lamotrigine and carbamazepine. Neurology 2005;64(11):1868–73. [14] Bonnett L, Smith C, Smith D, Williamson P, Chadwick D, Marson A. Prognostic factors for time to treatment failure and time to 12 months of remission for patients
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with focal epilepsy: post-hoc, subgroup analyses of data from the SANAD trial. Lancet Neurol 2012;4:331–40. [15] Rowan A. Epilepsy in older adults; common morbidities influence development, treatment strategies, and expected outcomes. Geriatrics 2005;60(12). [16] Pugh MJ, Cramer J, Knoefel J, et al. Potentially inappropriate antiepileptic drugs for elderly patients with epilepsy. J Am Geriatr Soc 2004;52:417–22. [17] Conway JM, Vloyd JC. Antiepileptic drug interactions in the elderly. In: Majkowski J, Bourgeois B, Patalos PN, Mattson R, editors. Antiepileptic drugs—combination therapy and interactions. Cambridge: Cambridge University Press; 2005. p. 273–93.
Contents lists available at SciVerse ScienceDirect
Epilepsy & Behavior journal homepage: www.elsevier.com/locate/yebeh
Outcome of newly-diagnosed epilepsy in older patients A.G. Besocke a,⁎, B. Rosso a, E. Cristiano a, S.M. Valiensi a, M. del C. García a, S.E. Gonorazky b, L.M. Romano b a b
Neurology Department, Hospital Italiano de Buenos Aires, Argentina Neurology Department, Hospital Privado de Comunidad, Mar del Plata, Argentina
a r t i c l e
i n f o
Article history: Received 25 July 2012 Revised 14 November 2012 Accepted 17 November 2012 Available online 29 January 2013 Keywords: Epilepsy in older people Outcome of epilepsy Epilepsy prognosis in older people
a b s t r a c t Introduction: The annual incidence of seizure disorders rises sharply after the age of 60. Treatment is complicated by the normal physiological changes of aging, comorbid diseases, and polypharmacy. Despite this, approximately 80% of the patients become seizure-free. Objectives: The objectives of this study were to (1) analyze the outcome of a cohort of patients with newly-diagnosed epilepsy over the age of 65, (2) describe epilepsy etiology and seizure type, and (3) classify the outcome according to the latest ILAE classification proposal for drug-resistant epilepsy (2010). Methods: All patients with newly-diagnosed epilepsy over the age of 65 who were evaluated in two different institutions were included. Seizures and epilepsy syndromes were classified according to the International League Against Epilepsy proposal (2010). Epilepsy outcomes were also analyzed according to the proposal of the ILAE Commission on Therapeutic Strategies (2010). Results: One hundred and twenty-two patients were included with a median follow-up time of 15 months. Median age of diagnosis was 78 years. Seventy-seven patients (55%) had epilepsy of unknown cause, and 55 (45%) had structural–metabolic epilepsy. The proportions of seizure-free patients at 6, 12, 18, and 24 months were 90%, 77%, 74%, and 67%, respectively. Thirty percent of patients experienced adverse effects (AEs). We found a statistically significant trend toward a higher frequency of AEs as the number of concomitant medications rose and in younger patients. According to the 2010 ILAE classification proposal for drug-resistant epilepsy criteria, 55.8% of the patients were seizure-free, 12.3% had treatment failure, and 32% had undetermined seizure outcome. Conclusion: Patients with newly-diagnosed epilepsy after the age of 65 have very good chances of achieving seizure control with AED treatment. It seems that fulfilling the ILAE classification proposal for drug-resistant epilepsy (2010) criteria for seizure freedom was more difficult in our cohort. Older patients also seem to be more prone to suffering from AEs. © 2012 Elsevier Inc. All rights resrved.
1. Introduction The annual incidence of seizure disorders rises sharply after the age of 60 years old (yo), from 40 per 100,000 for people between 40 and 45 yo, to 80 per 100,000 for people between 60 and 65, to more than 150 per 100,000 in those older than 80 [1,2]. The clinical presentations of seizures in the elderly differ from those in other age groups, and underdiagnosis and misdiagnosis occur very frequently in this population [3,4]. Epilepsy can have profound physical and psychological consequences in older patients. The stigma surrounding the diagnosis can be hard to address at this time of life. Elderly people are particularly vulnerable to physical injury as a consequence of seizures. The situation may be complicated by a range of neurodegenerative, cerebrovascular, and neoplastic comorbidities; furthermore, problems with concomitant medications are common. Quality of life can be adversely affected, and ⁎ Corresponding author. E-mail address: [email protected] (A.G. Besocke). 1525-5050/$ – see front matter © 2012 Elsevier Inc. All rights resrved. http://dx.doi.org/10.1016/j.yebeh.2012.11.041
the unpredictable nature of the seizures can lead to social withdrawal. Loss of confidence and reduced independence can result in premature admission to nursing homes and residential care facilities. Despite this, approximately 80% of patients with new onset epilepsy beyond the age of 65 yo become seizure-free during a period of at least 12 months after being treated with one or two drugs in monotherapy [5]. Adverse effects (AEs) of antiepileptic drugs (AEDs) are causes for concern in the elderly population because they are common and can occur at lower blood levels than in younger patients [6]. Treatment is complicated by the normal physiological changes of aging, comorbid diseases, and polypharmacy. We describe the characteristics of a cohort of patients with newly-diagnosed epilepsy over the age of 65 yo, with a special focus on their outcome, treatment, and tolerability of AEDs. 1.1. Objectives The objectives of this study were to analyze the outcome of a cohort of patients with newly-diagnosed epilepsy over the age of
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65 yo in two different neurology departments, describe epilepsy etiology and seizure type, and compare a classical clinical approach of defining epilepsy outcome with the latest ILAE classification proposal for drug-resistant epilepsy (2010) [7,8]. 2. Methods 2.1. Patients We retrospectively included all the patients with newly-diagnosed epilepsy over the age of 65 yo evaluated in two neurology departments from two different institutions: Hospital Privado de Comunidad de Mar del Plata, Argentina (November 1st, 2007 to June 30th, 2009) and Hospital Italiano de Buenos Aires, Argentina (November 1st, 2006 to June 30th, 2009). Patients with acute provoked seizures were not included in this cohort. Patients were interviewed by a neurologist every 6–8 weeks, until seizure freedom was achieved. Subsequently, patients were monitored every 3–6 months. Seizure outcome was established on the last visit to the neurologist's office. If no seizures were reported after one year of seizure freedom, the patient was assumed to be seizure-free. Furthermore, we classified outcomes according to the 2010 ILAE classification proposal for drug-resistant epilepsy, to compare the most recent definition with a classical, widely used clinical definition. All patients were initially treated with monotherapy. The objective of the treatment was to control seizures with the lowest drug dose necessary. Treatment was modified according to clinical response and tolerability. A second drug was prescribed if patients did not tolerate the first drug or if it was not effective. When there was a lack of efficacy after two drugs in monotherapy, combined treatment was established. 2.2. Definitions Seizures and epilepsy syndromes were classified according to the International League Against Epilepsy proposal (2010). Epileptic seizures were classified as focal seizures (FS), generalized seizures (GS), or unclassified seizures (US). FS are conceptualized as originating within networks limited to one hemisphere. They may be discretely localized or more widely distributed, and they may originate in subcortical structures. FS are further subdivided into FS with or without impairment of consciousness or awareness; FS evolving to a bilateral, convulsive seizure; and generalized seizures (involving tonic, clonic, or tonic and clonic components). GS are conceptualized as originating at some point within, and rapidly engaging, bilaterally distributed networks that can include cortical and subcortical structures but do not necessarily include the entire cortex. Although individual seizure onsets can appear localized, the location and lateralization are not consistent from one seizure to another [9]. Epilepsy syndromes were classified into the following: (1) “Genetic”: epilepsy as the direct result of a known or presumed genetic defect(s) in which seizures are the core symptom of the disorder. The knowledge regarding the genetic contributions may derive from specific molecular genetic studies that have been well replicated and have even become the basis of diagnostic tests. (2) “Structural/metabolic” (SE): epilepsy as the direct result of a distinct structural or metabolic condition or disease that has been demonstrated to be associated with a substantially increased risk of developing epilepsy in appropriately designed studies. SE syndromes include acquired disorders such as stroke, trauma, and infection. They may also be of genetic origin (e.g., tuberous sclerosis, many malformations of cortical development). (3) “Unknown cause” (UE): the nature of the underlying cause is currently unknown; it may have a fundamental genetic defect at its core or it may be the consequence of a separate unrecognized disorder [9].
Seizure freedom was defined as freedom from seizures or auras for a minimum of three times the longest pre-intervention inter-seizure interval, or 12 months, whichever was longer. Treatment failure was defined as recurrent seizure(s) after the intervention had been adequately applied. Both instances were further classified according to the presence or absence of adverse events. Undetermined seizure outcome was applied when the treatment had not been adequately established for a valid assessment of the outcome, or information was lacking to make the assessment [7]. Adverse effects (AEs) were defined as any harmful, unwanted effect of a medication used at therapeutic recommended doses [10,11]. 2.3. Statistical analysis Patients were divided into two groups according to the seizure freedom criteria. Categorical data were analyzed using the chisquare test and Fisher exact test. The Mann–Whitney test was used to compare ordinary and intervallic variables without normal distributions. The Kaplan–Meier method was applied to assess the proportion of seizure-free patients. The Wilcoxon (Peto–Prentice) method was used to compare two or more survival curves. All statistical tests were two-tailed. We used the 2008 version of STAT 2.7.2 for all statistical analyses. 3. Results 3.1. Patients One hundred and twenty-two patients were included, and all of them received their first AEDs. None of them had been previously treated with AEDs. The median follow-up time was 15 months (inferior quartile: 12–superior quartile: 24). Twenty-six patients (21%) died during the study period. The median age of diagnosis was 78 yo; 66% were female. Seventy-seven patients (55%) had UE, and 55 (45%) had SE. In the latter group, 50% (n = 28) of the cases were related to cerebrovascular disease (ischemic or hemorrhagic), 20% (n = 11) to brain tumors, 7.2% (4) to subdural hematomas, and 20% were associated with different causes (cerebral infections, previous neurosurgery, cavernous angioma, mesial temporal sclerosis). 3.2. Seizure type Seventeen patients (14%) suffered from focal seizures without impairment of consciousness, 41 (33.5%) had focal seizures with impairment of consciousness, 37 (30.3%) had focal seizures evolving to bilateral convulsive seizures, and 27 (22.2%) suffered from generalized tonic-clonic seizures. None of the patients had absences or myoclonic seizures. We performed an interictal electroencephalogram (EEG) in 95 patients (78%); 52% were normal, 14.4% had non-specific changes (mostly focal or generalized slowing), and 33.6% evidenced epileptiform abnormalities (Table 1). 3.3. Outcome The proportions of patients who attained remission for 6, 12, 18, and 24 months were 90%, 77%, 74%, and 67%, respectively (Fig. 1). Of the patients who attained a period of 12 months of seizure freedom (n = 76), 62 received one lifetime AED, 11 received two lifetime AEDs, and 3 received 3 or more lifetime AEDs. There were no statistically significant differences when comparing seizure freedom survival curves between the two neurology departments, sex, age at diagnosis, or seizure type (Table 2 and Fig. 2). However, we identified a trend toward higher seizure freedom in the SE group compared to the UE group, and in the normal EEG
AG Besocke et al. / Epilepsy & Behavior 27 (2013) 29–35 Table 1 Patient characteristics. Patients
Total (n: 122)
Age, median (years) Age IQ–SQ Sex, female Etiology • Unknown • Structural–metabolic • Vascular • Tumor • Subdural hematoma • Various Seizure type • Focal • Wo/IC • W/IC • Evolving to BCS • Generalized tonic-clonic EEG performed • Normal • Abnormal • Epileptiform • Non specific AEDs • Two or more AEDs • Monotherapy • DFH • LTG • VPA • LEV • CBZ • OXC • TPM • GBP • FB Adverse effects
78 72/83 65.5% (n: 80) 55% (n: 67) 44% (n: 55) 50% (n: 28) 20% (n: 11) 7% (n: 4) 21% (n: 12) 47.5% (n: 58) 14% (n: 17) 33.5% (n: 41) 30.3% (n: 37) 22.2% (n: 27) 78% (95/122) 52% (49/95) 48% (46/95) 33.6% (32/95) 14.4% (16/95) 6.7% (8) 93.3% (111a) 43.7% (52) 21% (25) 7.6% (9) 7.6% (9) 6.7 (8) 4.2% (5) 0.9% (1) 0.9% (1) 0.9% (1) 30% (37)
IC: inferior quartile, SC: superior quartile, Wo/IC: without impairment of consciousness, W/IC: with impairment of consciousness, BCS: bilateral convulsive seizure, DFH: phenytoin, LTG: lamotrigine, VPA: valproic acid, LEV: levetiracetam, CBZ: carbamazepine, OXC: oxcarbazepine, TPM: topiramate, GBP: gabapentin, FB: phenobarbital. a Three patients without AEDs.
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group compared to the abnormal EEG group (including epileptiform and non-specific changes), although these trends did not reach statistical significance. 3.4. Adverse effects Thirty-seven patients (30%) experienced AEs. We analyzed the association between AEs and the number of concomitant medications (CMs), and found a statistically significant trend (p b 0.0001) toward a higher proportion of patients with AEs as the number of CMs increased: AEs occurred in 0%, 13.5%, 54.7%, and 42.8% of patients with 0 CM, 1 to 3 CMs, 4 to 6 CMs, and more than 6 CMs, respectively. Furthermore, we found a trend (p = 0.045) toward higher proportions of AEs in younger patients (65–74 yo) (Fig. 3). 3.5. Epilepsy outcome classification According to the 2010 ILAE classification proposal for drugresistant epilepsy, 55.8% (n = 68) of our cohort was seizure-free. In this group, 59 patients (86.7%) received one lifetime AED, and 9 patients received 2 lifetime AEDs. In 45 patients (66.2%), seizure freedom was not associated with AEs. In this group, 43 patients received only one lifetime AED, 1 received two concomitant AEDs, and one decided not to be treated. In the seizure-free group associated with AEs (n = 23), 5 patients received 1 lifetime AED and tolerated the AEs, 14 patients received 2 lifetime AEDs, and 4 received three lifetime AEDs (either in monotherapy or in combination). Fifteen patients (12.3%) had treatment failure to two or more AEDs, 12 patients received 2 lifetime AEDs, and 3 patients received 3 or more lifetime AEDs. In 9 patients (60%), treatment failure was associated with AEs. In 39 patients (32%), the epilepsy outcome was undetermined, and in only 5 patients (12.8%), treatment outcome was associated with AE. In the undetermined group, 37 patients received one lifetime AED, and two decided not to receive treatment. Eighteen patients in this group died before sufficient time passed to establish outcome (Table 3).
Fig. 1. Kaplan–Meier, seizure-free patients.
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Table 2 Prognostic variables. 12 months Variables Hospital: • HPC • HIBA Sex: • Female • Male Age (years) • 65–74 • 75–84 • ≥85 Etiology: • Unknown • Structural–metabolic Seizure type: • FS Wo/IC • FS W/IC • FS Ev BCS • GS EEG: • Normal • Abnormal
24 months
% Seizure-free patients
95% CI
% Seizure-free patients
95% CI
p
77.3 79.2
(63.2–86.5) (65.6–87.9)
54.3 72
(19.6–79.5) (55.2–83.4)
0.33a
76.8 79.7
(64.8–85.1) (62–89.8)
67.2 70.9
(49.5–79.8) (50.6–84)
0.71a
68.7 85.7 79.2
(51.5–80.9) (72.2–80.9) (53.4–91.7)
58.2 81.8 –
(37.6–74.1) (65.9–90.8) –
0.19a 0.35b
71.5 85.8
(58.1–81.2) (71–96.6)
66.4 64.4
(52.1–77.4) (32–84.3)
0.09a
79.6 83.7 67.1 81.8
(48.9–93) (67.3–92.3) (47.3–80.8) (57.8–92.2)
79.6 76.8 45.7 73.6
(48.9–93) (54.2–89.2) (16.7–71) (45.6–88.7)
0.32a
84.2 67.9
(69.6–92.1) (51.8–79.6)
73.8 56.9
(52.2–86.7) (30.8–75.8)
0.12a
HPC: Hospital Privado de Comunidad; HIBA: Hospital Italiano; FS Wo/IC: focal seizure without impairment of consciousness; FS W/IC: focal seizure with impairment of consciousness; FS Ev BCS: focal seizure evolving to bilateral convulsive seizure; GS: generalized seizure. a Wilcoxon (Peto–Prentice): chi-square equivalence. b Wilcoxon (Peto–Prentice): chi-square with trend.
4. Discussion After 12 months of follow-up, 77% of our cohort became seizurefree. A similar pattern has been noted in other patient populations, as in the cohort reported by Saetre et al. in which the primary endpoint was retention on treatment. Saetre et al. reported that the proportion of patients who remained on treatment at the end of the follow-up period (40 weeks) varied from 73 to 75% in the sensitivity analysis [12]. This finding seems to be similar to the Stephen et al. cohort where 79% of the patients attained remission [5]. Rowan et al. reported slightly lower proportions of seizure-free patients at 3, 6, and 12 months than in our cohort: 80.1% (LTG 80.3%, GBP 80.0%, CBZ 80.0%), 70.6% (LTG 68.2%, GBP 71.7%, CBZ 72.7%), and 63.4% (LTG 61.3%, GBP 60.0%, CBZ 71.4%), respectively, when seizures that occurred during the titration phase were excluded. Both populations were very similar in age, seizure types, and epilepsy syndromes. Interestingly, we had a higher proportion of patients at risk at 12 months than the Rowan cohort: 62% versus 46% [13]. Although we did not stratify our population according to the AED administered, only 33 of our patients were on monotherapy using one of the drugs analyzed by Rowan et al. Further investigation on response rates to different AEDs should be performed in our population. In the 12-month seizure-free group of our cohort, 81% of patients were on monotherapy, and 19% received 2 or more lifetime AEDs, alone or in combination. Slightly higher proportions of patients on monotherapy were reported by Stephen et al.: 93% on mono and 7% on dual therapy [5]. These findings suggest that older patients are good responders to AEDs. In agreement with this, SANAD findings demonstrated that the relationship between age and 12 months of remission was U-shaped: the chance of achieving a period of 12 months of remission is higher in children and elderly patients than in those in the mid-age range (approximately 20–50 yo). This relationship might be due to the different etiologies in different age groups, pharmacokinetics, or multiple other factors. A linear effect was noted in this cohort, with older patients being significantly less likely to have a treatment failure because of inadequate seizure control than were younger patients. However, older patients were significantly more likely to have a treatment failure because of unacceptable adverse events than were younger patients [14,15].
In our cohort, patient seizure type was independent of the chance of achieving 12 months of seizure freedom, although the majority of our patients had focal or focal evolving to bilateral convulsive seizures, suggesting a focal etiology of the epilepsy syndrome. In the SANAD cohort, treatment failure was significantly more likely in patients with simple or complex partial seizures without secondary generalization than in patients with secondary generalized tonic-clonic seizures [14]. This difference can be explained by our smaller sample size. Interestingly, we found a non-statistically significant trend toward a higher proportion of seizure-free patients in the SE group after 12 months of follow-up, compared with the UE group. These proportions became similar at 24 months of follow-up, although the number of patients at risk at this point was very low. These findings could be due to the initiation of treatment in patients with SE after having only one seizure and the exclusion of patients with unknown causes of isolated seizures, which led to an increase in the number of treated patients with structural causes that might not induce repeated seizures. We also found a non-statistically significant trend toward a lower chance of seizure freedom in patients with abnormal EEGs (either with epileptiform or non-epileptiform abnormalities) after one year of follow-up. This could be related to a functional abnormality in the brain that lowers seizure threshold. In the Stephen et al. cohorts, no association was found between outcome and EEG results [5], but with the more extensive approach of the SANAD study, treatment failure was significantly more likely in patients with epileptiform abnormalities on EEG [14]. In the SANAD study, the chance of treatment failure increased as the total number of seizures before randomization increased, was higher in women than in men, varied with respect to the AED prescribed, and was higher in patients with epilepsy that was not localized than in patients with temporal lobe epilepsy [14]. In our cohort, no differences in outcome were found with respect to sex, seizure type, or age at diagnosis. Our sample size was most likely too small to detect this association. When analyzing outcome according to the 2010 ILAE proposal for drug-resistant epilepsy, the percentage of seizure-free patients in our cohort decreased to 55.8%. This could be related to the insufficient follow-up time required to achieve the minimum of three times the longest pre-intervention inter-seizure interval to fulfill the criteria
AG Besocke et al. / Epilepsy & Behavior 27 (2013) 29–35
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Fig. 2. Kaplan–Meier analysis: seizure-free patients' proportion according to different variables. A): Hospital: HPC: Hospital Privado de Comunidad, HIBA: Hospital Italiano de Buenos Aires. B): Sex. C): Age group. D): Etiology. E): Seizure type. F): EEG. FS Wo/IC: focal seizure without impairment of consciousness; FS W/IC: focal seizure with impairment of consciousness; FS Ev BCS: focal seizure evolving to bilateral convulsive seizure.
of the undetermined group. In addition, a group of patients, especially with SE, initiated treatment after having only one seizure and were then re-classified into the undetermined group because no interseizure interval could be established. It seems that fulfilling the ILAE classification proposal for drug-resistant epilepsy (2010) criteria for seizure freedom is more difficult. However the ILAE classification is more clinically relevant in individual patients because it takes into account the particular inter-seizure interval for each person.
We found AEs in 30% of our total cohort, but they varied largely among the treatment response groups according to the 2010 ILAE proposal (12–60%). AEs were more frequent in younger patients (65–74 yo) and in patients using more than 4 concomitant medications. Although our analysis did not take AED dose or type into account, which could bias the causal relationship of a symptom to an AED, there was a clear temporal association between the beginning of the AED treatment and the AE. In the Saetre cohort, the frequency
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Fig. 3. Adverse effects according to age group and concomitant medications. AE: adverse effects, CM: concomitant medications.
of AEs was 55% [12]. Elderly patients are more prone to side effects, and there is a high prevalence of comorbidities, comedications, and interactions with AEDs in this population [6,12]. Furthermore, AEDs may interfere with optimal functioning due to AEs that may be exaggerated or more severe in older adults compared with younger patients. In particular, the older, longer-established AEDs are more likely to lead to disability in older adults than the newer generation of antiepileptic compounds [15]. Geriatric training teaches that the average older adult has one chronic illness for each decade over 50. Therefore, one would expect that an individual who develops seizures in late life would likely have associated medical and/or neurologic conditions. Patients often have multiple co-morbidities and, therefore, require multiple medications [15–17]. In our cohort, 54.7% of patients with AEs were receiving between 4 and 6 concomitant medications. In previous reports of seizures in the elderly, the average number of prescribed drugs was seven [17]. We found a statistically significant association between the number of CMs used and the incidence of AEs, which supports the previous findings. It is important to note that the requirement for multiple drug treatments can often lead to poor medication adherence [15].
Table 3 Outcome category scheme according to ILAE 2010 proposal [7]. Outcome scheme
Outcome category
Outcome (N = 122)
Adverse effects (AEs) (n = 37)
1: Seizure-free
55.8% (68)
2: Treatment failure
12.3% (15)
3: Undetermined
32% (39)
A: no AE B: AE A: no AE B: AE A: no AE B: AE
66.2% 33.8% 40% 60% 87.2% 12.8%
(45) (23) (6) (9) (34) (5)
1: 1: 2: 2: 3: 3:
55.8% 55.8% 12.3% 12.3% 32.7% 32.7%
A: 66.2% B: 33.8% A: 40% B: 60% A: 87.2% B: 12.8%
5. Conclusion Patients with newly-diagnosed epilepsy after the age of 65 yo have a very good chance of achieving seizure control with AED treatment. It seems that fulfilling the ILAE classification proposal for drugresistant epilepsy (2010) criteria for seizure freedom was more difficult in our cohort compared to a classical approach of 12 months of seizure freedom. However, we agree that the 2010 ILAE classification is clinically more relevant because it takes into account the interseizure interval of individual patients. Older patients seem to be more prone to suffering from AEs that can be explained by concomitant illnesses, changes in pharmacokinetics and pharmacodynamics of drugs, and the number of CMs required. References [1] Hauser WA, Annegers JF, Kurland LT. The incidence of epilepsy and unprovoked seizures in Rochester, Minnesota, 1935–84. Epilepsia 1993;34:453–68. [2] Craig I, Tallis R. General practice management of adult-onset epilepsy analysed. Elder Care 1991;3:69–72. [3] Abuhuziefa A, Wambacq I. Seizures in the elderly: video/EEG monitoring analysis. Epilepsy Behav 2005;7:447–50. [4] Kellinghaus C, Loddenkemper T, Dinner D, Lachhwani D, Luders H. Seizure semiology in the elderly: a video analysis. Epilepsia 2004;45:263–7. [5] Stephen L, Kelly K, Mohanraj R, Brodie M. Pharmacological outcomes in older people with newly diagnosed epilepsy. Epilepsy Behav 2006;8:434–7. [6] Ramsay R, Rowan A, Pryor F. Special considerations in treating the elderly patient with epilepsy. Neurology 2004;62(Suppl. 2):24–9. [7] Kwan P, Arzimanoglou A, Berg AT, et al. Definition of drug resistant epilepsy: consensus proposal by the ad hoc Task Force of the ILAE Commission on Therapeutic Strategies. Epilepsia 2010;51(6):1069–77. [8] Kwan P, Brodie M. Definition of refractory epilepsy: defining the undefinable? Lancet Neurol 2010;9:27–9. [9] Berg A, Berkovic S, Brodie M, 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(4):676–85. [10] International drug monitoring: the role of national centres. Report of a WHO meeting, 498. World Health Organ Tech Rep Ser.; 1972. p. 1–25.
AG Besocke et al. / Epilepsy & Behavior 27 (2013) 29–35 [11] The use of computers in international drug monitoring. WHO Chron 1973;27(11): 476–80. [12] Saetre E, Perucca E, Isojarvi J. An international multicenter randomized double-blind controlled trial of lamotrigine and sustained-release carbamazepine in the treatment of newly diagnosed epilepsy in the elderly. Epilepsia 2007;48(7):1292–302. [13] Rowan AJ, Ramsay RE, Collins JF, et al. New onset geriatric epilepsy: a randomized study of gabapentin, lamotrigine and carbamazepine. Neurology 2005;64(11):1868–73. [14] Bonnett L, Smith C, Smith D, Williamson P, Chadwick D, Marson A. Prognostic factors for time to treatment failure and time to 12 months of remission for patients
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with focal epilepsy: post-hoc, subgroup analyses of data from the SANAD trial. Lancet Neurol 2012;4:331–40. [15] Rowan A. Epilepsy in older adults; common morbidities influence development, treatment strategies, and expected outcomes. Geriatrics 2005;60(12). [16] Pugh MJ, Cramer J, Knoefel J, et al. Potentially inappropriate antiepileptic drugs for elderly patients with epilepsy. J Am Geriatr Soc 2004;52:417–22. [17] Conway JM, Vloyd JC. Antiepileptic drug interactions in the elderly. In: Majkowski J, Bourgeois B, Patalos PN, Mattson R, editors. Antiepileptic drugs—combination therapy and interactions. Cambridge: Cambridge University Press; 2005. p. 273–93.