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Epilepsy treatment as a predeterminant of psychosocial ill health
Epilepsy & Behavior 15 (2009) S46–S50
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Epilepsy treatment as a predeterminant of psychosocial ill health Piero Perucca a, Frank G. Gilliam a,*, Bettina Schmitz b a b
Department of Neurology, Columbia University, New York, NY, USA Department of Neurology, Vivantes Humboldt-Klinikum, Berlin, Germany
a r t i c l e
i n f o
Article history: Received 5 March 2009 Accepted 6 March 2009
Keywords: Epilepsy Quality of Life Anti epileptic Drug Side effects
a b s t r a c t Epilepsy is a chronic disorder with complex effects on social, vocational, physical, and psychological wellbeing. Patient-oriented research has demonstrated that recurrent seizures have a strong adverse effect on health-related quality of life, but also that seizure rate in persons with pharmacoresistant epilepsy has only a modest correlation with quality of life. Although treatment side effects have received limited attention in epilepsy research, available evidence indicates that adverse medication effects may explain more variance in quality of life than any other clinical variable in persons with pharmacoresistant epilepsy. Furthermore, systematic screening for adverse effects has been shown to be associated with significant reduction in subjective toxicity and improvement in quality of life. There has been only limited research on the relative contribution of specific adverse effects to impaired health-related quality of life. The relative importance of reduction of medication burden after resective epilepsy surgery or vagal nerve stimulation has similarly received sparse attention. Existing deficiencies in the available published research present challenges and opportunities to perform further investigations to define and improve best clinical practices in epilepsy care. Ó 2009 Published by Elsevier Inc.
1. Introduction
2. Antiepileptic drugs
Epilepsy is the most common disabling chronic illness of the central nervous system across the life span. In addition to experiencing the unpredictability of seizures, patients with epilepsy have to cope with adverse health effects of medications, psychiatric comorbidities, neuropsychological impairment, social and employment restrictions, stigmatization, injuries, and the possibility of sudden unexpected death in epilepsy (SUDEP) [1–9]. The global burden of the disorder is considered to be greater than that of other chronic illnesses, such as diabetes and hypertension [10]. In such a worrisome picture, epilepsy treatment plays a leading role. Antiepileptic drugs (AEDs) are the first-line treatment in epilepsy and usually control seizures in about 60–70% of the patients [11,12]. However, they are also a source of various types of adverse effects [1,13]. Recent evidence indicates that AED adverse effects negatively impact health-related quality of life (HRQOL), independent of seizure frequency [14]. Epilepsy surgery [15,16] and vagus nerve stimulation (VNS) [17,18] are effective treatment strategies whose value in reducing the burden of medication-related toxicity has received little investigation. In this review, we highlight the role of epilepsy treatments as predeterminants of limited health status.
As mentioned above, medical treatment of epilepsy is often complicated by adverse effects [13]. Data obtained from cross-sectional studies and randomized controlled trials indicate that up to 90% of persons with epilepsy taking AEDs experience adverse effects [1,19–21]. A large survey of more than 5000 patients from 15 different European countries found that approximately 50% reported fatigue and 40% concentration problems on each of the investigated AEDs [1]. Although complaints of AED side effects may be more frequent in patients with drug-resistant epilepsy [22,23], achievement of seizure freedom often implies tolerance of medication-related toxicity [24]. As the authors of the VA cooperative study concluded, ‘‘most patients whose epilepsy is reasonably controlled must tolerate some side effects” [20]. Adverse effects alone account for up to 40% of all initial treatment failures [20] but, more importantly, limit progressive increases of drug dosage up to a level where seizures are completely suppressed [11,25]. Although clinical experience suggests that adverse effects of AEDs may be more disabling to the patient than the seizures themselves [26], scant research has been dedicated to the relative contributions of side effects to HRQOL. Perhaps, the lack of investigations can be ascribed to the historical belief that seizure frequency is the major determinant of HRQOL and that adverse effects are merely a secondary endpoint. However, although patients free of seizures have a perception of their mental and physical well-being comparable to those of the general population [27], extensive re-
* Corresponding author. Address: Department of Neurology, Neurological Institute, Columbia University, 710 West 168th Street, 7th Floor, Room 719, New York, NY 10032, USA. Fax: +1 212 305 1450. E-mail address: [email protected] (F.G. Gilliam). 1525-5050/$ - see front matter Ó 2009 Published by Elsevier Inc. doi:10.1016/j.yebeh.2009.03.016
P. Perucca et al. / Epilepsy & Behavior 15 (2009) S46–S50
search over the past 15 years has demonstrated that changes in seizure rate among patients with drug-resistant epilepsy are only modestly correlated with HRQOL [14,28,29]. On the other hand, other factors, such as adverse effects of AEDs and depression, are rapidly emerging as additional determinants of subjective health status in individuals with epilepsy (Fig. 1) [30,31].
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A large prospective, randomized, multicenter study designed to compare clinical outcomes of immediate versus delayed pharmacological intervention for previously untreated seizures found that health status was significantly worse in subjects with recurrent seizures while taking AEDs, compared with all other groups [32]. As shown in Table 1, the sample at 2 years of follow-up who were treated with AEDs for seizure recurrence had the worst ratings of self-reported medication-related toxicity, anxiety, depression, cognitive function mastery, self-esteem, stigmatization, and social restrictions and employment. Although the authors conclude that there is a trade-off between seizure recurrence and AED exposure, the combination of both conditions in the same individual was clearly associated with the worst overall health status. These results indicate that persons with recurrent seizures requiring AED treatment are at risk of poor health within 2 years of beginning treatment. Two other prospective, population-based studies have shown significantly worse scores on HRQOL measures in individuals with epilepsy in remission still taking AEDs, compared with subjects in remission off AEDs [5,33]. In 2006 a cross-sectional, multicenter study of more than 200 subjects with epilepsy was conducted to elucidate some of these issues [34]. Each study participant completed a reliable and valid measure of self-perceived function and well-being, the Quality of Life in Epilepsy Inventory (QOLIE)-89, and two reliable and valid screening instruments for adverse effects of AEDs and depression, respectively the Adverse Event Profile (AEP) and the Neurological Disorder Depression Inventory for Epilepsy (NDDI-E). AEP and NDDI-E total scores independently correlated with QOLIE-89 total scores. Furthermore, a large majority (72%) of the variance of the QOLIE-89 was explained by the AEP and, to a lesser extent, the NDDI-E (Fig. 2). These findings are reinforced by a prospective, randomized controlled trial that compared systematic adverse AED effect assessment with the AEP to standard clinical practice [14]. Sixty-two consecutive outpatients with elevated medication-related toxicity (AEP total score P45) were randomized to two groups: one whose physicians had full access to the AEP completed at each visit, and another whose physicians were blinded to the AEP results. At the end of a relatively short 4-month follow-up, patients whose physicians were given the AEP results at the final clinic visit showed a significant reduction in medication-related toxicity and improvement in HRQOL compared with the other group (Fig. 3). 3. Epilepsy surgery
Fig. 1. Correlation of subjective health status (QOLIE-89 total score) with (A) adverse effects of AEDs (AEP total scores) (r = 0.76, P < 0.001); (B) depression (Beck Depression Inventory, BDI) (r = 0.49, P < 0.001); and (C) average monthly seizure rate (r = 0.01, P = 0.93) [30].
As reviewed in the American Academy of Neurology practice parameter for epilepsy surgery [35], one randomized controlled trial [15] and at least 24 observational studies [16,36] support the superior efficacy of temporal lobe resection in appropriately selected patients with pharmacoresistant epilepsy to continued medical therapy. The evidence for extratemporal lobe surgery is less definitive. At least one controlled study using a comprehensive battery of assessments following anterior/mesial temporal lobe resection indicated improvement in quality of life, adverse medication effects, driving status, and mood compared with nonsurgical controls [37]. Other studies also support improvement in overall quality of life, especially in persons rendered seizure free [15,29,38–40]. However, long-term outcomes may not be as favorable as those reported in studies of shorter duration [41]. The risk of permanent brain injury as a result of surgery remains a persistent concern to many physicians and patients. Multiple studies have reported worsened memory function following dominant mesial temporal lobe resection [42], which appears to be greater in the setting of normal preoperative MRI or mild mesial
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P. Perucca et al. / Epilepsy & Behavior 15 (2009) S46–S50
Table 1 Health outcomes by treatment policy, AED status, and seizure status at baseline and at 2 years postrandomization. Baseline
AEP score, median (IQR) Anxiety score, median (IQR) Depression score, median (IQR) CF score, median (IQR) Mastery score, median (IQR) Self-esteem score, median (IQR) Stigmatized (%) Socially restricted (%) In paid work (%)
2-Year follow-up
AED status at 2-year follow-up
Seizure status at 2-year follow-up
Immediate (n = 162)a
Deferred (n = 169)b
Immediate (n = 162)
Deferred (n = 169)
AED (n = 182)
No AED (n = 148)
Seizures (n = 121)c
No seizures (n = 209)d
36 (29–43) 5.5 (2–9) 3 (1–6) 3 (0–5) 8 (6–10) 8 (4–11) 29 33 50
33 (26–46) 6 (3–10) 3 (1–6) 3 (0–5) 8 (6–10) 8 (4–13) 24 33 47
32.5 (24–43) 4 (2–8) 3 (1–6) 2.5 (0–5) 7 (3–9.5) 6 (3–11) 29 23 51
34 (25–45) 5 (2–9) 3 (2–6) 3 (0–5) 7 (5–10) 7 (3–12) 21 25 48
35.5 (25–46) 5 (2–9) 3 (2–7)w 3 (0–6) 7 (3–10) 6 (3–11) 34§ 31 43w
32 (23–43) 4 (2–9) 2 (1–6) 2 (0–5) 7 (4–9) 7 (2–11) 15 16 59
42 (28.5–48)e 7 (3–11)e 5 (2–8)e 4 (2–6)e 8 (5–11)f 9 (4–13)e 44f 43f 39e
30 (23–39) 4 (1–8) 2 (1–5) 2 (0–4) 6 (3–9) 6 (2–10) 14 14 56
Note. For all scales, low scores represent a good outcome, and high scores, a poor outcome. CF, cognitive function; IQR, interquartile range. Source. Adapted from [32]. a 117/162 (72%) were on AEDs. b 65/169 (38%) were on AEDs. c 91/121 (75%) were on AEDs. d 91/209 (43%) were on AEDs. e P < 0.001. f P < 0.01
Fig. 2. Correlation of QOLIE-89 total scores with NDDI-E and AEP total scores. Adjusted r was 0.72 (P < 0.0001) for regression model with QOLIE-89 as the dependent variable.
temporal sclerosis [43]. It is noteworthy that studies of change in cognition over time in medically refractory temporal lobe epilepsy have observed a decline in memory, language and motor function in a substantial proportion of persons [3,44]; these observations indicate that a nonsurgical control group is required to fully interpret postoperative changes in cognition following epilepsy surgery. Although the association of change in quality of life and cognition with epilepsy surgery has received limited attention, a recent study reported that cognitive decline was not associated with worse quality of life in persons rendered free of seizures after surgery, and also that persons with both persistent seizures and cognitive decline had worse quality of life than other outcome groups [45]. Another study also suggested that memory decline had only a modest association with worsening quality of life after mesial temporal lobe resection [46]. Additional evidence from further investigations of cognitive, behavioral, and functional outcomes following epilepsy surgery is required to provide more definitive information to patients considering surgical intervention. Future studies should include appropriate controls and also comprehensive assessments and
Fig. 3. Change in the mean AEP total scores after 4 months of follow-up for the AEPprovided group and for the AEP-inaccessible group (25% vs. 4%, P = 0.01) [14].
outcome analyses to provide the most relevant information regarding the relative risks and benefits of surgery compared with continued medical management in refractory epilepsy. 4. Vagus nerve stimulation Following the first pilot trials in human beings in the late 1980s [47–49], several studies have investigated the effectiveness, safety, and tolerability of VNS in subjects with epilepsy [50–52], including two multicenter, double-blind, randomized, active-control, add-on trials [17,53]. In 1997, VNS received FDA approval for use as ‘‘an adjunctive therapy in reducing the frequency of seizures in adults and adolescents over 12 years of age with partial onset seizures that are refractory to antiepileptic medications” [54]. In the two randomized controlled trials that compared high and low levels of stimulation [17,53], while allowing changes in the concurrent AED therapy exclusively to maintain appropriate plasma concen-
P. Perucca et al. / Epilepsy & Behavior 15 (2009) S46–S50 Table 2 Rates of adverse effects in the two double-blind, randomized controlled trials (EO3 and EO5) evaluating the effectiveness, safety, and tolerability of adjunctive VNS treatment in medically refractory partial seizures. EO3 [53]
Voice alteration Coughing Throat pain Dyspnea Headache Paresthesia Dyspepsia Nausea Vomiting Muscle pain
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cations of these findings are unclear in patients with epilepsy with depression [66,67] or memory dysfunction [68]. Future studies are needed to elucidate the role of VNS in comorbid disorders in epilepsy.
EO5 [17]
High stimulation (n = 54)
Low stimulation (n = 60)
High stimulation (n = 95)
Low stimulation (n = 103)
37.2% 7.4% 11.1% 5.6% 1.8% 5.6% n/aa n/a n/a 5.6%
13.3% 8.3% 11.7% 1.7% 8.3% 3.3% n/a n/a n/a 1.7%
66.3% 45.3% 28.4% 25.3% 24.2% 17.9% 17.9% 14.7% 17.9% n/a
30.1% 42.7% 30.1% 10.7% 23.3% 25.2% 12.6% 20.4% 13.6% n/a
Source. Adapted from [17,53]. a Not available.
tration or to respond to apparent drug toxicity, mean reduction in seizure frequency was as high as 28% at the end of a 3-month follow-up. Of the 312 subjects evaluated in the two trials, only one became seizure free [17]. Open-label and retrospective studies report more encouraging estimates during longer periods of observation [50–52] and following early VNS implantation [18]. However, because treatment was unblinded and AED adjustments were permitted, these findings should be interpreted with caution [55]. Complications associated with VNS implantation include infections at incision (3–6% of patients) [51], which are often easily treated with antibiotics and rarely require removal of the device or electrodes, and, more infrequently, vocal cord paralyses, lower facial weakness, bradycardia, and transient ventricular asystole during implantation [56]. As shown in Table 2, the most common adverse effects related to long-term use of VNS are voice alteration/hoarseness (up to 66.3% of patients), coughing (up to 45.3%), throat pain (up to 30.1%), paresthesia (up to 25.2%), dyspnea (up to 25.3%), and headache (up to 24.2%). These side effects are most evident during stimulation, may be reduced by adjusting stimulation parameters, and tend to diminish over time [51,57]. Few studies have used reliable and valid instruments to measure the impact of VNS treatment on subjective health status. Growing evidence suggests that VNS may exert a positive effect on HRQOL, independent of reduction in seizure frequency [58– 60]. However, interpretation of these findings requires careful consideration of the inherent limitations of these studies, such as the open-label study design and the lack of non-VNS-treated control groups. Limited attention has been dedicated to the utility of VNS in reducing the number of concomitant AEDs and their adverse effects. A recent, single-center trial prospectively assessed drug reduction in 21 subjects implanted with vagus nerve stimulators for medically refractory epilepsy and compared results with those for a retrospectively identified cohort of 21 case-matched controls with a mean follow-up of 13.2 months [61]. Compared with only 2 of 21 (9%) controls, 15 of 21 (76.2%) vagus nerve stimulator-implanted subjects experienced a reduction in the number or dosage of their AEDs. The mean change in AED per patient was 0.43 in the VNS group and +0.86 in the control group. Most subjects reported an improvement in seizure severity and frequency. Interestingly, only 3 of 17 (18%) subjects reporting drug-related adverse effects prior to implantation noted no side effects at last follow-up interview. Two other studies failed to replicate these findings [52,62]. Recent evidence indicates that VNS may have a positive effect on mood [63,64] and cognitive function [65]. However, the impli-
5. Summary and considerations for the future Epilepsy exerts complex influences on a person’s health, especially when seizures recur after medical therapy is initiated. Health outcome studies in epilepsy that use valid and reliable assessments indicate that adverse AED effects have the strongest identifiable impact on subjective health. This observation poses both problems and opportunities. Nonpharmacological interventions, such as surgery and VNS, offer the possibility of stopping or substantially diminishing seizures and subsequently reducing doses or eliminating AEDs. Advances in the understanding of mechanisms of adverse effects should support the rational development of less toxic AEDs. Also, more effective health outcome research should provide knowledge of the most advantageous methods to use treatments in the least harmful way, and optimize overall health in persons with epilepsy. 6. Moderator’s comment Although it is universally accepted that the goal of the treatment of epilepsy is to prevent seizures, this should not be at the cost of unacceptable drug side effects and deleterious effects on the treated individual’s quality of life. A number of studies have demonstrated that scores on a patient-perceived AED side effect scale are correlated highly with HRQOL assessments and can account for a significant amount of variance in HRQOL scores. The authors draw attention to the outcome of epilepsy surgery and its impact on quality of life. They argue that to understand the impact of surgery, much more attention needs to be paid to the subtle psychological and neuropsychological changes that may occur and the implications of these changes for day-to-day functioning and HRQOL. There is need for more sophisticated studies incorporating evidence that allows fuller understanding of the risks and benefits of surgery compared with continued medical management. Likewise, more refined research is lacking on the effects of VNS, particularly with respect to comparison of outcomes with those of control groups. Further evidence of the impact of treatment on comorbid conditions such as mood would be beneficial in clarifying its role in the context of treatment. 7. Group discussion
It was agreed that the risk–benefit assessment of any treatment should take all physical and psychological effects into account. The importance of taking a wider perspective (emotional and cognitive) was noted, particularly in the case of children whose seizures are refractory, where use of a specific AED can sometimes bring improvements in alertness or mood, without necessarily reducing seizure frequency, and so might still be considered a valid treatment option. The importance of identifying both the benefits and the risks of treatment was emphasized. Concerns were raised about the issue of suicidality as a risk factor in treatment, what is meant by it, and how it is communicated to people with epilepsy. There was general agreement that the FDA’s AED Suicidality Report, published in January 2008, did a great disservice to the field of epilepsy. No substantial evidence was provided to support the FDA’s statements, and description of the method by which suicidality had been measured was omitted.
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Epilepsy treatment as a predeterminant of psychosocial ill health Piero Perucca a, Frank G. Gilliam a,*, Bettina Schmitz b a b
Department of Neurology, Columbia University, New York, NY, USA Department of Neurology, Vivantes Humboldt-Klinikum, Berlin, Germany
a r t i c l e
i n f o
Article history: Received 5 March 2009 Accepted 6 March 2009
Keywords: Epilepsy Quality of Life Anti epileptic Drug Side effects
a b s t r a c t Epilepsy is a chronic disorder with complex effects on social, vocational, physical, and psychological wellbeing. Patient-oriented research has demonstrated that recurrent seizures have a strong adverse effect on health-related quality of life, but also that seizure rate in persons with pharmacoresistant epilepsy has only a modest correlation with quality of life. Although treatment side effects have received limited attention in epilepsy research, available evidence indicates that adverse medication effects may explain more variance in quality of life than any other clinical variable in persons with pharmacoresistant epilepsy. Furthermore, systematic screening for adverse effects has been shown to be associated with significant reduction in subjective toxicity and improvement in quality of life. There has been only limited research on the relative contribution of specific adverse effects to impaired health-related quality of life. The relative importance of reduction of medication burden after resective epilepsy surgery or vagal nerve stimulation has similarly received sparse attention. Existing deficiencies in the available published research present challenges and opportunities to perform further investigations to define and improve best clinical practices in epilepsy care. Ó 2009 Published by Elsevier Inc.
1. Introduction
2. Antiepileptic drugs
Epilepsy is the most common disabling chronic illness of the central nervous system across the life span. In addition to experiencing the unpredictability of seizures, patients with epilepsy have to cope with adverse health effects of medications, psychiatric comorbidities, neuropsychological impairment, social and employment restrictions, stigmatization, injuries, and the possibility of sudden unexpected death in epilepsy (SUDEP) [1–9]. The global burden of the disorder is considered to be greater than that of other chronic illnesses, such as diabetes and hypertension [10]. In such a worrisome picture, epilepsy treatment plays a leading role. Antiepileptic drugs (AEDs) are the first-line treatment in epilepsy and usually control seizures in about 60–70% of the patients [11,12]. However, they are also a source of various types of adverse effects [1,13]. Recent evidence indicates that AED adverse effects negatively impact health-related quality of life (HRQOL), independent of seizure frequency [14]. Epilepsy surgery [15,16] and vagus nerve stimulation (VNS) [17,18] are effective treatment strategies whose value in reducing the burden of medication-related toxicity has received little investigation. In this review, we highlight the role of epilepsy treatments as predeterminants of limited health status.
As mentioned above, medical treatment of epilepsy is often complicated by adverse effects [13]. Data obtained from cross-sectional studies and randomized controlled trials indicate that up to 90% of persons with epilepsy taking AEDs experience adverse effects [1,19–21]. A large survey of more than 5000 patients from 15 different European countries found that approximately 50% reported fatigue and 40% concentration problems on each of the investigated AEDs [1]. Although complaints of AED side effects may be more frequent in patients with drug-resistant epilepsy [22,23], achievement of seizure freedom often implies tolerance of medication-related toxicity [24]. As the authors of the VA cooperative study concluded, ‘‘most patients whose epilepsy is reasonably controlled must tolerate some side effects” [20]. Adverse effects alone account for up to 40% of all initial treatment failures [20] but, more importantly, limit progressive increases of drug dosage up to a level where seizures are completely suppressed [11,25]. Although clinical experience suggests that adverse effects of AEDs may be more disabling to the patient than the seizures themselves [26], scant research has been dedicated to the relative contributions of side effects to HRQOL. Perhaps, the lack of investigations can be ascribed to the historical belief that seizure frequency is the major determinant of HRQOL and that adverse effects are merely a secondary endpoint. However, although patients free of seizures have a perception of their mental and physical well-being comparable to those of the general population [27], extensive re-
* Corresponding author. Address: Department of Neurology, Neurological Institute, Columbia University, 710 West 168th Street, 7th Floor, Room 719, New York, NY 10032, USA. Fax: +1 212 305 1450. E-mail address: [email protected] (F.G. Gilliam). 1525-5050/$ - see front matter Ó 2009 Published by Elsevier Inc. doi:10.1016/j.yebeh.2009.03.016
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search over the past 15 years has demonstrated that changes in seizure rate among patients with drug-resistant epilepsy are only modestly correlated with HRQOL [14,28,29]. On the other hand, other factors, such as adverse effects of AEDs and depression, are rapidly emerging as additional determinants of subjective health status in individuals with epilepsy (Fig. 1) [30,31].
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A large prospective, randomized, multicenter study designed to compare clinical outcomes of immediate versus delayed pharmacological intervention for previously untreated seizures found that health status was significantly worse in subjects with recurrent seizures while taking AEDs, compared with all other groups [32]. As shown in Table 1, the sample at 2 years of follow-up who were treated with AEDs for seizure recurrence had the worst ratings of self-reported medication-related toxicity, anxiety, depression, cognitive function mastery, self-esteem, stigmatization, and social restrictions and employment. Although the authors conclude that there is a trade-off between seizure recurrence and AED exposure, the combination of both conditions in the same individual was clearly associated with the worst overall health status. These results indicate that persons with recurrent seizures requiring AED treatment are at risk of poor health within 2 years of beginning treatment. Two other prospective, population-based studies have shown significantly worse scores on HRQOL measures in individuals with epilepsy in remission still taking AEDs, compared with subjects in remission off AEDs [5,33]. In 2006 a cross-sectional, multicenter study of more than 200 subjects with epilepsy was conducted to elucidate some of these issues [34]. Each study participant completed a reliable and valid measure of self-perceived function and well-being, the Quality of Life in Epilepsy Inventory (QOLIE)-89, and two reliable and valid screening instruments for adverse effects of AEDs and depression, respectively the Adverse Event Profile (AEP) and the Neurological Disorder Depression Inventory for Epilepsy (NDDI-E). AEP and NDDI-E total scores independently correlated with QOLIE-89 total scores. Furthermore, a large majority (72%) of the variance of the QOLIE-89 was explained by the AEP and, to a lesser extent, the NDDI-E (Fig. 2). These findings are reinforced by a prospective, randomized controlled trial that compared systematic adverse AED effect assessment with the AEP to standard clinical practice [14]. Sixty-two consecutive outpatients with elevated medication-related toxicity (AEP total score P45) were randomized to two groups: one whose physicians had full access to the AEP completed at each visit, and another whose physicians were blinded to the AEP results. At the end of a relatively short 4-month follow-up, patients whose physicians were given the AEP results at the final clinic visit showed a significant reduction in medication-related toxicity and improvement in HRQOL compared with the other group (Fig. 3). 3. Epilepsy surgery
Fig. 1. Correlation of subjective health status (QOLIE-89 total score) with (A) adverse effects of AEDs (AEP total scores) (r = 0.76, P < 0.001); (B) depression (Beck Depression Inventory, BDI) (r = 0.49, P < 0.001); and (C) average monthly seizure rate (r = 0.01, P = 0.93) [30].
As reviewed in the American Academy of Neurology practice parameter for epilepsy surgery [35], one randomized controlled trial [15] and at least 24 observational studies [16,36] support the superior efficacy of temporal lobe resection in appropriately selected patients with pharmacoresistant epilepsy to continued medical therapy. The evidence for extratemporal lobe surgery is less definitive. At least one controlled study using a comprehensive battery of assessments following anterior/mesial temporal lobe resection indicated improvement in quality of life, adverse medication effects, driving status, and mood compared with nonsurgical controls [37]. Other studies also support improvement in overall quality of life, especially in persons rendered seizure free [15,29,38–40]. However, long-term outcomes may not be as favorable as those reported in studies of shorter duration [41]. The risk of permanent brain injury as a result of surgery remains a persistent concern to many physicians and patients. Multiple studies have reported worsened memory function following dominant mesial temporal lobe resection [42], which appears to be greater in the setting of normal preoperative MRI or mild mesial
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Table 1 Health outcomes by treatment policy, AED status, and seizure status at baseline and at 2 years postrandomization. Baseline
AEP score, median (IQR) Anxiety score, median (IQR) Depression score, median (IQR) CF score, median (IQR) Mastery score, median (IQR) Self-esteem score, median (IQR) Stigmatized (%) Socially restricted (%) In paid work (%)
2-Year follow-up
AED status at 2-year follow-up
Seizure status at 2-year follow-up
Immediate (n = 162)a
Deferred (n = 169)b
Immediate (n = 162)
Deferred (n = 169)
AED (n = 182)
No AED (n = 148)
Seizures (n = 121)c
No seizures (n = 209)d
36 (29–43) 5.5 (2–9) 3 (1–6) 3 (0–5) 8 (6–10) 8 (4–11) 29 33 50
33 (26–46) 6 (3–10) 3 (1–6) 3 (0–5) 8 (6–10) 8 (4–13) 24 33 47
32.5 (24–43) 4 (2–8) 3 (1–6) 2.5 (0–5) 7 (3–9.5) 6 (3–11) 29 23 51
34 (25–45) 5 (2–9) 3 (2–6) 3 (0–5) 7 (5–10) 7 (3–12) 21 25 48
35.5 (25–46) 5 (2–9) 3 (2–7)w 3 (0–6) 7 (3–10) 6 (3–11) 34§ 31 43w
32 (23–43) 4 (2–9) 2 (1–6) 2 (0–5) 7 (4–9) 7 (2–11) 15 16 59
42 (28.5–48)e 7 (3–11)e 5 (2–8)e 4 (2–6)e 8 (5–11)f 9 (4–13)e 44f 43f 39e
30 (23–39) 4 (1–8) 2 (1–5) 2 (0–4) 6 (3–9) 6 (2–10) 14 14 56
Note. For all scales, low scores represent a good outcome, and high scores, a poor outcome. CF, cognitive function; IQR, interquartile range. Source. Adapted from [32]. a 117/162 (72%) were on AEDs. b 65/169 (38%) were on AEDs. c 91/121 (75%) were on AEDs. d 91/209 (43%) were on AEDs. e P < 0.001. f P < 0.01
Fig. 2. Correlation of QOLIE-89 total scores with NDDI-E and AEP total scores. Adjusted r was 0.72 (P < 0.0001) for regression model with QOLIE-89 as the dependent variable.
temporal sclerosis [43]. It is noteworthy that studies of change in cognition over time in medically refractory temporal lobe epilepsy have observed a decline in memory, language and motor function in a substantial proportion of persons [3,44]; these observations indicate that a nonsurgical control group is required to fully interpret postoperative changes in cognition following epilepsy surgery. Although the association of change in quality of life and cognition with epilepsy surgery has received limited attention, a recent study reported that cognitive decline was not associated with worse quality of life in persons rendered free of seizures after surgery, and also that persons with both persistent seizures and cognitive decline had worse quality of life than other outcome groups [45]. Another study also suggested that memory decline had only a modest association with worsening quality of life after mesial temporal lobe resection [46]. Additional evidence from further investigations of cognitive, behavioral, and functional outcomes following epilepsy surgery is required to provide more definitive information to patients considering surgical intervention. Future studies should include appropriate controls and also comprehensive assessments and
Fig. 3. Change in the mean AEP total scores after 4 months of follow-up for the AEPprovided group and for the AEP-inaccessible group (25% vs. 4%, P = 0.01) [14].
outcome analyses to provide the most relevant information regarding the relative risks and benefits of surgery compared with continued medical management in refractory epilepsy. 4. Vagus nerve stimulation Following the first pilot trials in human beings in the late 1980s [47–49], several studies have investigated the effectiveness, safety, and tolerability of VNS in subjects with epilepsy [50–52], including two multicenter, double-blind, randomized, active-control, add-on trials [17,53]. In 1997, VNS received FDA approval for use as ‘‘an adjunctive therapy in reducing the frequency of seizures in adults and adolescents over 12 years of age with partial onset seizures that are refractory to antiepileptic medications” [54]. In the two randomized controlled trials that compared high and low levels of stimulation [17,53], while allowing changes in the concurrent AED therapy exclusively to maintain appropriate plasma concen-
P. Perucca et al. / Epilepsy & Behavior 15 (2009) S46–S50 Table 2 Rates of adverse effects in the two double-blind, randomized controlled trials (EO3 and EO5) evaluating the effectiveness, safety, and tolerability of adjunctive VNS treatment in medically refractory partial seizures. EO3 [53]
Voice alteration Coughing Throat pain Dyspnea Headache Paresthesia Dyspepsia Nausea Vomiting Muscle pain
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cations of these findings are unclear in patients with epilepsy with depression [66,67] or memory dysfunction [68]. Future studies are needed to elucidate the role of VNS in comorbid disorders in epilepsy.
EO5 [17]
High stimulation (n = 54)
Low stimulation (n = 60)
High stimulation (n = 95)
Low stimulation (n = 103)
37.2% 7.4% 11.1% 5.6% 1.8% 5.6% n/aa n/a n/a 5.6%
13.3% 8.3% 11.7% 1.7% 8.3% 3.3% n/a n/a n/a 1.7%
66.3% 45.3% 28.4% 25.3% 24.2% 17.9% 17.9% 14.7% 17.9% n/a
30.1% 42.7% 30.1% 10.7% 23.3% 25.2% 12.6% 20.4% 13.6% n/a
Source. Adapted from [17,53]. a Not available.
tration or to respond to apparent drug toxicity, mean reduction in seizure frequency was as high as 28% at the end of a 3-month follow-up. Of the 312 subjects evaluated in the two trials, only one became seizure free [17]. Open-label and retrospective studies report more encouraging estimates during longer periods of observation [50–52] and following early VNS implantation [18]. However, because treatment was unblinded and AED adjustments were permitted, these findings should be interpreted with caution [55]. Complications associated with VNS implantation include infections at incision (3–6% of patients) [51], which are often easily treated with antibiotics and rarely require removal of the device or electrodes, and, more infrequently, vocal cord paralyses, lower facial weakness, bradycardia, and transient ventricular asystole during implantation [56]. As shown in Table 2, the most common adverse effects related to long-term use of VNS are voice alteration/hoarseness (up to 66.3% of patients), coughing (up to 45.3%), throat pain (up to 30.1%), paresthesia (up to 25.2%), dyspnea (up to 25.3%), and headache (up to 24.2%). These side effects are most evident during stimulation, may be reduced by adjusting stimulation parameters, and tend to diminish over time [51,57]. Few studies have used reliable and valid instruments to measure the impact of VNS treatment on subjective health status. Growing evidence suggests that VNS may exert a positive effect on HRQOL, independent of reduction in seizure frequency [58– 60]. However, interpretation of these findings requires careful consideration of the inherent limitations of these studies, such as the open-label study design and the lack of non-VNS-treated control groups. Limited attention has been dedicated to the utility of VNS in reducing the number of concomitant AEDs and their adverse effects. A recent, single-center trial prospectively assessed drug reduction in 21 subjects implanted with vagus nerve stimulators for medically refractory epilepsy and compared results with those for a retrospectively identified cohort of 21 case-matched controls with a mean follow-up of 13.2 months [61]. Compared with only 2 of 21 (9%) controls, 15 of 21 (76.2%) vagus nerve stimulator-implanted subjects experienced a reduction in the number or dosage of their AEDs. The mean change in AED per patient was 0.43 in the VNS group and +0.86 in the control group. Most subjects reported an improvement in seizure severity and frequency. Interestingly, only 3 of 17 (18%) subjects reporting drug-related adverse effects prior to implantation noted no side effects at last follow-up interview. Two other studies failed to replicate these findings [52,62]. Recent evidence indicates that VNS may have a positive effect on mood [63,64] and cognitive function [65]. However, the impli-
5. Summary and considerations for the future Epilepsy exerts complex influences on a person’s health, especially when seizures recur after medical therapy is initiated. Health outcome studies in epilepsy that use valid and reliable assessments indicate that adverse AED effects have the strongest identifiable impact on subjective health. This observation poses both problems and opportunities. Nonpharmacological interventions, such as surgery and VNS, offer the possibility of stopping or substantially diminishing seizures and subsequently reducing doses or eliminating AEDs. Advances in the understanding of mechanisms of adverse effects should support the rational development of less toxic AEDs. Also, more effective health outcome research should provide knowledge of the most advantageous methods to use treatments in the least harmful way, and optimize overall health in persons with epilepsy. 6. Moderator’s comment Although it is universally accepted that the goal of the treatment of epilepsy is to prevent seizures, this should not be at the cost of unacceptable drug side effects and deleterious effects on the treated individual’s quality of life. A number of studies have demonstrated that scores on a patient-perceived AED side effect scale are correlated highly with HRQOL assessments and can account for a significant amount of variance in HRQOL scores. The authors draw attention to the outcome of epilepsy surgery and its impact on quality of life. They argue that to understand the impact of surgery, much more attention needs to be paid to the subtle psychological and neuropsychological changes that may occur and the implications of these changes for day-to-day functioning and HRQOL. There is need for more sophisticated studies incorporating evidence that allows fuller understanding of the risks and benefits of surgery compared with continued medical management. Likewise, more refined research is lacking on the effects of VNS, particularly with respect to comparison of outcomes with those of control groups. Further evidence of the impact of treatment on comorbid conditions such as mood would be beneficial in clarifying its role in the context of treatment. 7. Group discussion
It was agreed that the risk–benefit assessment of any treatment should take all physical and psychological effects into account. The importance of taking a wider perspective (emotional and cognitive) was noted, particularly in the case of children whose seizures are refractory, where use of a specific AED can sometimes bring improvements in alertness or mood, without necessarily reducing seizure frequency, and so might still be considered a valid treatment option. The importance of identifying both the benefits and the risks of treatment was emphasized. Concerns were raised about the issue of suicidality as a risk factor in treatment, what is meant by it, and how it is communicated to people with epilepsy. There was general agreement that the FDA’s AED Suicidality Report, published in January 2008, did a great disservice to the field of epilepsy. No substantial evidence was provided to support the FDA’s statements, and description of the method by which suicidality had been measured was omitted.
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