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Changes in seizure severity and quality of life in patients with refractory partial epilepsy
Epilepsy & Behavior 19 (2010) 409–413
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Epilepsy & Behavior j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / ye b e h
Changes in seizure severity and quality of life in patients with refractory partial epilepsy Jerónimo Sancho a, Vicente Iváñez b, Albert Molins c, Vanessa López Gómez d, Xavier Masramón e, María Pérez d,⁎ a
Department of Neurology, General University Hospital, Valencia, Spain Epilepsy Unit, Neurology Department, Hospital Universitario La Paz, Madrid, Spain Department of Neurology, Hospital Josep Trueta, Girona, Spain d Pfizer España, Medical Unit, Alcobendas, Spain e Department of Biometrics, European Biometrics Institute, Barcelona, Spain b c
a r t i c l e
i n f o
Article history: Received 14 June 2010 Revised 5 August 2010 Accepted 9 August 2010 Available online 19 September 2010 Keywords: Epilepsy Seizure severity Quality of life Antiepileptic Refractory Sleep Depression Anxiety
a b s t r a c t This 6-month observational, prospective, multicenter study assessed the influence of changes in seizure severity on quality of life in patients with refractory partial epilepsy. Patients (N = 262) diagnosed with partial epilepsy and receiving two antiepileptic drugs as determined by usual clinical practice were enrolled in this study. The primary endpoint was the mean seizure severity score obtained from the Seizure Severity Questionnaire. Reductions in seizure severity were detected from baseline to months 3 and 6 (P b 0.0001). Improvements compared with baseline were found for several secondary measures: Hamilton Anxiety and Depression scales (P b 0.0001), most Medical Outcomes Study—Sleep subscales (P b 0.05), and seven subscales of the Quality of Life in Epilepsy Inventory-31 (QOLIE-31; P b 0.0005). Seizure severity correlated directly with anxiety (P b 0.0001) and inversely with QOLIE-31 measures (P b 0.0001). In conclusion, reducing seizure severity with appropriate medication may lead to improvement in the overall quality of life of patients with refractory partial epilepsy. © 2010 Elsevier Inc. All rights reserved.
1. Introduction Seizure measurement after new antiepileptic treatment was traditionally based on two major outcomes: seizure type and seizure frequency [1]. Increasing research has demonstrated that seizure frequency alone is not sufficient to assess efficacy of treatment, as antiepileptic therapy can modify seizure severity, as perceived by the patient, without altering seizure frequency [2]. Although it is important to reduce the frequency of seizures in the treatment of epilepsy, it is just as important to consider patients' perception of the severity of their seizures in determining their well-being [3]. Indeed, it was found that seizure frequency was not significantly associated with quality of life in people with refractory partial epilepsy [4]. Mood disturbance is a key factor in patients’ judgment of their quality of life [5]. Patients with epilepsy have a high psychiatric morbidity, with prevalent anxiety (30.4%) and mood (21.8%) disorders [6,7]. Depression and anxiety were independently associated with reduced health-related quality of life in patients with temporal lobe epilepsy [8]. Sleep disturbance is also associated with impairment of ⁎ Corresponding author. Pfizer España, Avenida de Europa, 20 B, Parque Empresarial de la Moraleja, 28108 Alcobendas, Madrid, Spain. Fax: + 34 91 4909750. E-mail address: maria.perez2@pfizer.com (M. Pérez). 1525-5050/$ – see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.yebeh.2010.08.011
quality of life in patients with epilepsy. Sleep disturbance was found to be more than twice as prevalent in patients with partial epilepsy as in controls, and most domains of sleep were significantly disturbed [9]. Improving quality of life by treating psychiatric disorders and sleep disturbance may assist in the management of seizures. Various scales have been developed to assess seizure severity both objectively, from the clinician's perspective on several aspects of the seizures, and subjectively, from the patient's perspective. The development of quality-of-life measures using subjective, patient-based opinion has changed the approach to seizure severity assessment [1]. Using the Seizure Severity Questionnaire (SSQ) to assess seizure severity as a treatment response [10], we sought to evaluate, in daily clinical practice, the evolution of seizure severity and the impact on the quality of life in patients with refractory partial epilepsy. 2. Patients and methods 2.1. Study population Enrolled patients were men or women ≥18 years of age who were diagnosed with refractory partial epilepsy, as defined by the International League Against Epilepsy criteria, and were receiving
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two antiepileptic drugs (AEDs) as determined by usual clinical practice. This study took place from April 16, 2008 to July 6, 2009.
2.2. Study design This was a 6-month, observational, prospective, and multicenter study. Overall, 68 researchers from neurology settings at 54 Spanish hospitals participated in the study. The study did not interfere with the investigators’ treatment decisions for their patients, and medication changes were allowed as needed throughout the study. The study was developed in agreement with legal stipulations in Spain for observational epidemiological studies and with the Declaration of Helsinki, and it was approved by the Research Ethics Committee of Hospital Universitario La Paz (Madrid). All patients gave written informed consent prior to entering the study.
Table 1 Patient demographic and clinical characteristics. Characteristic
N
Sex Female Male Age (years) Duration of epilepsy (years) Number of seizures over 8 weeks preceding baseline Type of epilepsy Symptomatic Cryptogenic Idiopathic
261
Mean (SD)/number (%) 139 (53.3%) 122 (46.7%) 40.8 (13.8) 18.5 (13.1%) 6.6 (10.2)
260 248
258 120 (46.5%) 89 (34.5%) 49 (19.0%)
3. Results 2.3. Assessments The primary endpoint of this study was the mean seizure severity score obtained from the 16-item SSQ, which assesses severity and bothersomeness of seizures [10]. Each item is scored on a 7-point Likert scale, with lower scores representing lesser impact [severity: very mild (1) to very severe (7); bothersome: no bother (1) to very bothersome (7)]. Severity of seizures (before, during, and after seizures) is assessed with the first 13 items, for which the total score ranges from 0 to 91. Overall assessment of seizure severity is measured with the last two items (8 and 9), for which the total score ranges from 0 (minimum severity) to 7 (maximum severity). The item that measures change in seizure severity or bothersomeness after changing seizure treatment is scored from 1 (much better) to 7 (much worse). The Hamilton Anxiety Rating Scale (HAM-A), a secondary endpoint, comprises 14 items, each defined by a series of symptoms [11]. Each item is rated on a 5-point scale, which ranges from 0 (not present) to 4 (severe). Total subscale scores range from 0 to 56. The Hamilton Depression Rating Scale (HAM-D), another secondary endpoint, comprises 17 items; 9 items are scored from 0 to 4, whereas the remaining 8 items are scored from 0 to 2 [12]. Total subscale scores range from 0 to 52. Additional secondary endpoints included the Medical Outcomes Study—Sleep Scale (MOS-Sleep), a selfadministered questionnaire composed of an index and seven subscales [global index score range from 0 (no interference) to 100 (maximum interference)] [13]; the Quality of Life in Epilepsy Inventory-31 (QOLIE-31), which is composed of 31 items grouped into seven domains (Seizure Worry, Overall Quality of Life, Emotional Well-Being, Energy/Fatigue, Cognitive Function, Adverse Events, and Social Function; the total score ranges from 0 to 100, with higher scores equating to higher quality of life); and the visual analog scale (VAS), visually represented as a calibrated (0–100) thermometer [14]. To assess treatment compliance, patients had to confirm they did not stop taking their medication in the circumstances assessed by the Morisky–Green test [15]. 2.4. Statistical analyses Quantitative and qualitative variables were analyzed using measurements of central tendency (mean, median) and dispersion (95% confidence interval). All quantitative variables were tested for gaussian distribution with the Kolmogorov–Smirnov test. Based on our sample size of 222 patients and an effect size of 0.25, the study had 95% power to detect the change in SSQ. Student's t test was used to compare score changes on quantitative variables, and the McNemar test was used to compare score changes on qualitative variables. Tests were two-tailed with a significance level of 5%. Data were analyzed using SAS 8.2 statistical software (SAS Institute, Cary, NC, USA).
In total, 262 patients were enrolled and 237 (90.5%) patients completed the study. Twenty-five patients discontinued: 11 (44.0%) patients discontinued at month 3, and 14 (56.0%) patients discontinued at month 6. Of those patients who discontinued the study, 18 (72.0%) were lost to follow-up, 4 (16.0%) discontinued at the patient's request, 2 (8.0%) discontinued owing to the patient's death, and 1 (4.0%) discontinued owing to adverse events. Demographic and clinical patient characteristics are listed in Table 1. Seizure characteristics at baseline, month 3, and month 6 are listed in Table 2. The mean (SD) seizure severity score (SSQ) was 25.3 (20.9) at baseline, 20.0 (18.6) at month 3, and 19.0 (18.2) at month 6. All score changes compared with baseline were statistically significant (P b 0.0001) (Table 3). The mean (SD) overall assessment of the SSQ was 3.5 (1.6) at baseline, 3.1 (1.5) at month 3, and 2.9 (1.5) at month 6. All score changes compared with baseline were statistically significant (P b 0.0001) (Table 3). However, SSQ scores assessing patient perception of possible treatment-related changes at months 3 and 6 compared with baseline were unchanged (Table 3). HAM-A and
Table 2 Seizure characteristics. Characteristic
N
Number (%)/mean (SD) Baseline
Simple partial seizures Partial seizures with secondary generalization Complex partial seizures Total number of seizures over last 8 weeks Mean (SD) 95% Cl Median (P25/P75) Change in total number of seizures over last 8 weeks Mean (SD) 95% Cl Median (P25/P75) Duration of seizures b1 min 1–3 min N3 min Seizure recovery time b1 min 1–5 min 5–10 min N10 min Loss of consciousness a b c
Month 3
242 40 (16.5%) 43 (17.8%) 242 118 (48.8%) 100 (41.3%)a 242 129 (53.3) 242
120 (49.6)b
6.6 (10.2) 4.7 (8.9) 5.3–7.9 3.5–5.8 3.0 (1.0/8.0) 2.0 (1.0/5.0)
Month 6 51 (21.1%) 100 (41.3%)a 117 (48.3)b
4.4 (8.5) 3.3–5.4 2.0 (0.0/5.0)
242 –1.9 (6.8)a –2.2 (8.4)a –2.8 to –1.0 –3.3 to –1.2 –1.0 (–3.0/0.0) –1.0 (–4.0/0.0) 206 54 (26.2%) 68 (33.0%)a 115 (55.8%) 105 (51.0%)a 37 (18.0%) 33 (16.0%)a
74 (35.9%)c 10 (49.0%)c 31 (15.0%)c
205 36 (17.6%) 66 (32.2%) 62 (30.2%) 41 (20.0%) 203 150 (73.9%)
P b 0.0001, compared with baseline. P b 0.05, compared with baseline. P b 0.005 compared with baseline.
47 (22.9%)a 83 (40.5%)a 42 (20.5%)a 33 (16.1%)a 140 (69.0%)b
51 (24.9%)a 81 (39.5%)a 42 (20.5%)a 31 (15.1%)a 137 (67.5%)b
J. Sancho et al. / Epilepsy & Behavior 19 (2010) 409–413 Table 3 Effect of treatment on questionnaire-based outcomes. Possible N range Seizure severity, SSQ Mean (SD) Change Overall assessment of seizure severity Mean (SD) Change Change in seizures after changing treatment Mean (SD) Change Hamilton Anxiety Rating Scale total score Mean (SD) Change Hamilton Depression Rating Scale total score Mean (SD) Change Global Medical Outcomes Study— Sleep Scale Index Mean (SD) Change Quality of Life in Epilepsy-31 score Mean (SD) Change a b c
0–91
Baseline
Table 4 Correlations between seizure severity score (SSQ) and scores on other instruments. Month 3
Month 6
222 25.3 (20.9) 20.0 (18.6) 19.0 (18.2) –5.3 (17.0)a –6.2 (17.7)a
0–7
0–7
0–56
0–52
0–100
208 3.5 (1.6)
3.1 (1.5) –0.4 (1.3)a
2.9 (1.5) –0.6 (1.5)a
1.4 (2.2)
1.3 (2.0) –0.2 (1.8)
1.3 (2.1) –0.1 (2.0)
11.4 (9.4)
9.7 (9.2) –1.7 (4.8)a
8.9 (8.7) –2.5 (5.6)a
8.4 (6.9)
7.4 (5.9) –1.0 (3.4)a
6.7 (5.7) –1.7 (4.6)a
218
250
221
243
27.0 (18.5) 25.1 (17.7) 24.5 (17.6) –1.8 (10.9)b –2.5 (13.0)b 0–100
246 62.4 (17.7) 64.2 (17.8) 1.8 (7.9)c
65.7 (16.8) 3.3 (10.7)c
P b 0.0001. P b 0.05. P b 0.0005.
Hamilton Anxiety Rating Scale Psychic Anxiety Somatic Anxiety Total Anxiety Hamilton Depression Rating Scale Depression total score Melancholy domain Sleep domain Anxiety domain Medical Outcomes Study—Sleep Scale Quantity of Sleep Sleep Disturbance Snoring Abrupt Awakening Optimal Sleep Sleep Adequacy Somnolence Sleep Problems Overall Sleep Problems Index Quality of Life in Epilepsy-31 Seizure Worry Overall Quality Of Life Well-Being Energy/Fatigue Cognitive Function Adverse Events Social Function Visual analog scale total score Visual analog scale b
HAM-D scores decreased at months 3 and 6 compared with baseline (P b 0.0001) (Table 3). Additionally, Psychic Anxiety and Somatic Anxiety scores (HAM-A scales) improved during the 6-month followup (P b 0.0001) (Fig. 1). On all the MOS-Sleep subscales, except for Abrupt Awakening, there were improvements in quality and quantity of sleep at months 3 and 6 compared with baseline (P b 0.05); the mean global MOS-Sleep Index also improved at months 3 and 6 (P b 0.05) (Table 3). In addition, the QOLIE-31 scores showed improvements at month 6 compared with baseline (P b 0.0005) on all except the Cognitive Function and Adverse Events subscales. The mean QOLIE-31 total score improved at months 3 and 6 compared with baseline (P b 0.0005) (Table 3).
8 7
Mean score HAM-A scale
N
a
6 5 4 3 2 1 0 Baseline
Month 3 Psychic anxiety
411
Month 6 Somatic anxiety
Baseline
Month 6
221 221 221
0.5148a 0.3276a 0.4587a
0.3970a 0.2759a 0.3815a
195 215 215 219
0.4749a 0.4923a 0.2810a 0.4030a
0.333a 0.3620a 0.2628a 0.2807a
218 219 217 219 218 216 219 214 214
–0.1131 0.3176a 0.0270 0.1936b –0.1014 –0.3688a 0.2819a 0.4008a 0.4024a
–0.1251 0.2931a –0.0154 0.1915b –0.1025 –0.2885a 0.2741a 0.3296a 0.3818a
221 222 220 222 222 222 222 218 206
–0.5134a –0.4896a –0.5337a –0.4943a –0.4175a –0.2855a –0.4357a –0.5843a –0.5005a
–0.2463a –0.4574a –0.3570a –0.3728a –0.3067a –0.0958 –0.2363a –0.4407a –0.3493a
P b 0.0005. P b 0.005.
Table 5 Correlations between overall seizure severity score (SSQ) and scores on other instruments. N
Hamilton Anxiety Rating Scale Psychic Anxiety Somatic Anxiety Total Anxiety Hamilton Depression Rating Scale Depression total score Melancholy domain Sleep domain Anxiety domain Medical Outcomes Study—Sleep Scale Quantity of Sleep Sleep Disturbance Snoring Abrupt Awakening Optimal Sleep Sleep Adequacy Somnolence Sleep Problems Overall Sleep Problems Index Quality of Life in Epilepsy-31 Seizure Worry Overall Quality Of Life Mood Well-Being Energy/Fatigue Cognitive Function Adverse Events Social Function Visual analog scale total score Visual analog scale a
Fig 1. Psychic and somatic anxiety (range, 0–28, n = 250). aP b 0.0006, bP b 0.0001. HAM-A, Hamilton Anxiety Rating Scale.
Correlation, r
b c
P b 0.0005. P b 0.005. P b 0.05.
Correlation, r Baseline
Month 6
208 208 208
0.4019a 0.2532a 0.3562a
0.3923a 0.3360a 0.4075a
181 201 202 205
0.3442a 0.3577a 0.2254b 0.2570a
0.3415a 0.3514a 0.2259b 0.3492a
204 205 204 205 204 203 205 201 201
–0.0895 0.2208b –0.0527 0.1615c –0.0737 –0.2489b 0.1580c 0.2805a 0.2852a
–0.0527 0.2660a –0.0026 0.2246b –0.0979 –0.2123b 0.2105b 0.2777 0.3128a
207 208 206 208 208 208 208 204 193
–0.5849a –0.4380a –0.4348a –0.4113a –0.3043a –0.2914a –0.3451a –0.4811a –0.4303
–0.3673a –0.3382a –0.2527a –0.2384a –0.2754a –0.1168 –0.2207b –0.3610a –0.2963a
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Table 6 Pharmacological treatments. Number (%)
Carbamazepine Valproic acid Phenytoin Lamotrigine Levetiracetam Pregabalin
Baseline (N = 249)
During study (N = 249)
96 (38.5%) 75 (30.1%) 62 (24.8%) 52 (20.8%) 49 (19.6%) 25 (10.0%)
59 (27.6%) 41 (19.2%) 18 (8.9%) 52 (24.4%) 76 (35.6%) 67 (31.4%)
Significant correlations were found between most quality-oflife measures and mean seizure severity (Table 4) and overall seizure severity (Table 5) scores at baseline and 6 months. Strong correlations (r ≥ I0.5I) were found between mean seizure severity at baseline and several quality-of-life measures: greater seizure severity correlated with higher levels of HAM-A Psychic Anxiety (r = 0.5148; P b 0.0001); conversely, less severe seizures correlated (all P b 0.0001) with less Seizure Worry (r = –0.5134), greater WellBeing (r = –0.5337), higher VAS score (r = –0.5005), and higher VAS total score (r = –0.5843) on the QOLIE-31. Only QOLIE-31 Seizure Worry showed a strong correlation with overall evaluation of seizure severity (r = –0.5849, P b 0.0001). The most frequent AEDs administered at baseline were carbamazepine (38.5%), valproic acid (30.1%), and phenytoin (24.8%); however, over the course of the study, newer AEDs, levetiracetam (35.6%) and pregabalin (31.4%), were the most frequently used agents (Table 6). For nonpharmacological treatments, statistically significant differences were observed between the number of patients who had surgery at or before baseline (20, 8.1%) and those who had surgery over the 6 months of the study, 2 (0.8%) at month 3 and 5 (2.0%) at month 6 (P b 0.0001). The Morisky–Green test indicated that 142 (56.8%) patients were compliant with treatment at baseline, and that compliance significantly increased to 180 (72.0%) patients at month 3 and 186 (74.4%) at month 6 (P b 0.0001). 4. Discussion In this observational study, we found strong correlations between seizure severity and poorer reports on several quality-of-life measures in patients with refractory partial epilepsy receiving AEDs as determined by clinical practice. In particular, we have shown that seizure severity directly correlates with psychic anxiety and worrying about recurrent seizures, whereas there is an inverse relationship between seizure severity and quality of life. Treatment with AEDs resulted in better control of seizure severity as perceived by the patients and by objective measures such as a significant reduction in total number of seizures, duration of seizures, and recovery time at months 3 and 6 compared with baseline. Treatment success can be attributed to the continued attendance of patients at the clinic and the change in treatment, as needed, to medication with a better efficacy and/or tolerability profile or better compliance by the patient. We observed strong correlations of seizure severity score with anxiety as indicated by the HAM-A scale and the Seizure Worry subscale of the QOLIE-31, which are in agreement with previous studies showing a positive correlation between seizure severity and anxiety [8,16]. Similarly, higher seizure severity scores correlated with greater depression as indicated by all subscales of the HAM-D. A previous study that evaluated the relationship between depressive symptoms and seizure severity found that clinically depressed people with epilepsy reported higher levels of all aspects of seizure severity, as well as increased difficulties with overall seizure recovery, when
compared with non-depressed controls with epilepsy [17]. Our findings further emphasize the strong correlation between seizure severity and depression. Because anxiety and depression are associated with significantly poorer health-related quality of life [18], it is important to reduce seizure severity in patients with refractory partial epilepsy to reduce their anxiety and depression levels and eventually improve their quality of life. Furthermore, our study indicates a significant correlation between seizure severity and several aspects of sleep as measured by the MOS-Sleep scale and the HAM-D Sleep subscale. A previous study showed that sleep disturbance was more than twice as prevalent in patients with partial epilepsy as in healthy controls and was associated with poorer quality of life in both controls and patients with epilepsy [9]. AEDs have the potential to either improve or worsen sleep and sleep disorders in patients with epilepsy [19]. Because sleep disturbance clearly contributes to the poorer quality of life of patients with refractory partial epilepsy, management of sleep disturbance should be an integral part of their treatment and could impact the choice of treatment provided to patients. Patients with epilepsy often experience cognitive dysfunction [20]. Many of the drugs prescribed for epilepsy can either impair or improve cognitive functioning, which is a major concern for patients taking medications [20]. In this study, as indicated from the Cognitive Function domain of the QOLIE-31 (from the patient's subjective perception of performance), there was a significant inverse correlation between seizure severity score and cognitive function. As seizure severity improved with the change in antiepileptic treatment, it is likely that the AEDs used in this study would not have worsened the cognitive function of the patients. Additionally, it suggests that reducing seizure severity in patients with epilepsy increases their quality of life by improving their cognitive function as well. Throughout the study physicians changed patients’ medication to achieve better efficacy and/or tolerability, with the result that by the end of the study, the majority of the patients were using newer AEDs such as pregabalin and levetiracetam. Pregabalin, independent of its effect on seizure severity, has been shown to reduce sleep latency and awakenings, improve rapid eye movement sleep, and reduce psychic and somatic anxiety symptoms in patients with partial epilepsy [21,22]. Levetiracetam improved several measures on the QOLIE-31, including Seizure Worry, Overall Quality of Life, and Cognitive Function, which also supports improvements in quality of life for patients with refractory partial epilepsy [23]. Improvement in seizure severity and quality of life may in part be attributable to the use of these new AEDs. When interpreting this study, some limitations should be noted. First, this was an observational and noncomparative study; therefore, conclusions should be considered of low level of evidence. Second, it is not clear from this study if greater seizure severity caused anxiety, depression, and sleep disturbance, or if these comorbid conditions caused greater seizure severity. However, it is very clear that greater seizure severity or comorbid conditions lead to poor quality of life in patients with refractory partial epilepsy. In conclusion, the findings herein suggest that reducing seizure severity significantly improves the quality of life of patients with refractory partial epilepsy. Additionally, our results emphasize the importance of identifying and treating anxiety, depression, and sleep disorders among patients with epilepsy to improve their seizure severity perception and their quality of life.
Acknowledgments This study was funded by Pfizer Inc. Editorial support was provided by Vardit Dror of UBC Scientific Solutions and funded by Pfizer Inc.
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Epilepsy & Behavior j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / ye b e h
Changes in seizure severity and quality of life in patients with refractory partial epilepsy Jerónimo Sancho a, Vicente Iváñez b, Albert Molins c, Vanessa López Gómez d, Xavier Masramón e, María Pérez d,⁎ a
Department of Neurology, General University Hospital, Valencia, Spain Epilepsy Unit, Neurology Department, Hospital Universitario La Paz, Madrid, Spain Department of Neurology, Hospital Josep Trueta, Girona, Spain d Pfizer España, Medical Unit, Alcobendas, Spain e Department of Biometrics, European Biometrics Institute, Barcelona, Spain b c
a r t i c l e
i n f o
Article history: Received 14 June 2010 Revised 5 August 2010 Accepted 9 August 2010 Available online 19 September 2010 Keywords: Epilepsy Seizure severity Quality of life Antiepileptic Refractory Sleep Depression Anxiety
a b s t r a c t This 6-month observational, prospective, multicenter study assessed the influence of changes in seizure severity on quality of life in patients with refractory partial epilepsy. Patients (N = 262) diagnosed with partial epilepsy and receiving two antiepileptic drugs as determined by usual clinical practice were enrolled in this study. The primary endpoint was the mean seizure severity score obtained from the Seizure Severity Questionnaire. Reductions in seizure severity were detected from baseline to months 3 and 6 (P b 0.0001). Improvements compared with baseline were found for several secondary measures: Hamilton Anxiety and Depression scales (P b 0.0001), most Medical Outcomes Study—Sleep subscales (P b 0.05), and seven subscales of the Quality of Life in Epilepsy Inventory-31 (QOLIE-31; P b 0.0005). Seizure severity correlated directly with anxiety (P b 0.0001) and inversely with QOLIE-31 measures (P b 0.0001). In conclusion, reducing seizure severity with appropriate medication may lead to improvement in the overall quality of life of patients with refractory partial epilepsy. © 2010 Elsevier Inc. All rights reserved.
1. Introduction Seizure measurement after new antiepileptic treatment was traditionally based on two major outcomes: seizure type and seizure frequency [1]. Increasing research has demonstrated that seizure frequency alone is not sufficient to assess efficacy of treatment, as antiepileptic therapy can modify seizure severity, as perceived by the patient, without altering seizure frequency [2]. Although it is important to reduce the frequency of seizures in the treatment of epilepsy, it is just as important to consider patients' perception of the severity of their seizures in determining their well-being [3]. Indeed, it was found that seizure frequency was not significantly associated with quality of life in people with refractory partial epilepsy [4]. Mood disturbance is a key factor in patients’ judgment of their quality of life [5]. Patients with epilepsy have a high psychiatric morbidity, with prevalent anxiety (30.4%) and mood (21.8%) disorders [6,7]. Depression and anxiety were independently associated with reduced health-related quality of life in patients with temporal lobe epilepsy [8]. Sleep disturbance is also associated with impairment of ⁎ Corresponding author. Pfizer España, Avenida de Europa, 20 B, Parque Empresarial de la Moraleja, 28108 Alcobendas, Madrid, Spain. Fax: + 34 91 4909750. E-mail address: maria.perez2@pfizer.com (M. Pérez). 1525-5050/$ – see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.yebeh.2010.08.011
quality of life in patients with epilepsy. Sleep disturbance was found to be more than twice as prevalent in patients with partial epilepsy as in controls, and most domains of sleep were significantly disturbed [9]. Improving quality of life by treating psychiatric disorders and sleep disturbance may assist in the management of seizures. Various scales have been developed to assess seizure severity both objectively, from the clinician's perspective on several aspects of the seizures, and subjectively, from the patient's perspective. The development of quality-of-life measures using subjective, patient-based opinion has changed the approach to seizure severity assessment [1]. Using the Seizure Severity Questionnaire (SSQ) to assess seizure severity as a treatment response [10], we sought to evaluate, in daily clinical practice, the evolution of seizure severity and the impact on the quality of life in patients with refractory partial epilepsy. 2. Patients and methods 2.1. Study population Enrolled patients were men or women ≥18 years of age who were diagnosed with refractory partial epilepsy, as defined by the International League Against Epilepsy criteria, and were receiving
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two antiepileptic drugs (AEDs) as determined by usual clinical practice. This study took place from April 16, 2008 to July 6, 2009.
2.2. Study design This was a 6-month, observational, prospective, and multicenter study. Overall, 68 researchers from neurology settings at 54 Spanish hospitals participated in the study. The study did not interfere with the investigators’ treatment decisions for their patients, and medication changes were allowed as needed throughout the study. The study was developed in agreement with legal stipulations in Spain for observational epidemiological studies and with the Declaration of Helsinki, and it was approved by the Research Ethics Committee of Hospital Universitario La Paz (Madrid). All patients gave written informed consent prior to entering the study.
Table 1 Patient demographic and clinical characteristics. Characteristic
N
Sex Female Male Age (years) Duration of epilepsy (years) Number of seizures over 8 weeks preceding baseline Type of epilepsy Symptomatic Cryptogenic Idiopathic
261
Mean (SD)/number (%) 139 (53.3%) 122 (46.7%) 40.8 (13.8) 18.5 (13.1%) 6.6 (10.2)
260 248
258 120 (46.5%) 89 (34.5%) 49 (19.0%)
3. Results 2.3. Assessments The primary endpoint of this study was the mean seizure severity score obtained from the 16-item SSQ, which assesses severity and bothersomeness of seizures [10]. Each item is scored on a 7-point Likert scale, with lower scores representing lesser impact [severity: very mild (1) to very severe (7); bothersome: no bother (1) to very bothersome (7)]. Severity of seizures (before, during, and after seizures) is assessed with the first 13 items, for which the total score ranges from 0 to 91. Overall assessment of seizure severity is measured with the last two items (8 and 9), for which the total score ranges from 0 (minimum severity) to 7 (maximum severity). The item that measures change in seizure severity or bothersomeness after changing seizure treatment is scored from 1 (much better) to 7 (much worse). The Hamilton Anxiety Rating Scale (HAM-A), a secondary endpoint, comprises 14 items, each defined by a series of symptoms [11]. Each item is rated on a 5-point scale, which ranges from 0 (not present) to 4 (severe). Total subscale scores range from 0 to 56. The Hamilton Depression Rating Scale (HAM-D), another secondary endpoint, comprises 17 items; 9 items are scored from 0 to 4, whereas the remaining 8 items are scored from 0 to 2 [12]. Total subscale scores range from 0 to 52. Additional secondary endpoints included the Medical Outcomes Study—Sleep Scale (MOS-Sleep), a selfadministered questionnaire composed of an index and seven subscales [global index score range from 0 (no interference) to 100 (maximum interference)] [13]; the Quality of Life in Epilepsy Inventory-31 (QOLIE-31), which is composed of 31 items grouped into seven domains (Seizure Worry, Overall Quality of Life, Emotional Well-Being, Energy/Fatigue, Cognitive Function, Adverse Events, and Social Function; the total score ranges from 0 to 100, with higher scores equating to higher quality of life); and the visual analog scale (VAS), visually represented as a calibrated (0–100) thermometer [14]. To assess treatment compliance, patients had to confirm they did not stop taking their medication in the circumstances assessed by the Morisky–Green test [15]. 2.4. Statistical analyses Quantitative and qualitative variables were analyzed using measurements of central tendency (mean, median) and dispersion (95% confidence interval). All quantitative variables were tested for gaussian distribution with the Kolmogorov–Smirnov test. Based on our sample size of 222 patients and an effect size of 0.25, the study had 95% power to detect the change in SSQ. Student's t test was used to compare score changes on quantitative variables, and the McNemar test was used to compare score changes on qualitative variables. Tests were two-tailed with a significance level of 5%. Data were analyzed using SAS 8.2 statistical software (SAS Institute, Cary, NC, USA).
In total, 262 patients were enrolled and 237 (90.5%) patients completed the study. Twenty-five patients discontinued: 11 (44.0%) patients discontinued at month 3, and 14 (56.0%) patients discontinued at month 6. Of those patients who discontinued the study, 18 (72.0%) were lost to follow-up, 4 (16.0%) discontinued at the patient's request, 2 (8.0%) discontinued owing to the patient's death, and 1 (4.0%) discontinued owing to adverse events. Demographic and clinical patient characteristics are listed in Table 1. Seizure characteristics at baseline, month 3, and month 6 are listed in Table 2. The mean (SD) seizure severity score (SSQ) was 25.3 (20.9) at baseline, 20.0 (18.6) at month 3, and 19.0 (18.2) at month 6. All score changes compared with baseline were statistically significant (P b 0.0001) (Table 3). The mean (SD) overall assessment of the SSQ was 3.5 (1.6) at baseline, 3.1 (1.5) at month 3, and 2.9 (1.5) at month 6. All score changes compared with baseline were statistically significant (P b 0.0001) (Table 3). However, SSQ scores assessing patient perception of possible treatment-related changes at months 3 and 6 compared with baseline were unchanged (Table 3). HAM-A and
Table 2 Seizure characteristics. Characteristic
N
Number (%)/mean (SD) Baseline
Simple partial seizures Partial seizures with secondary generalization Complex partial seizures Total number of seizures over last 8 weeks Mean (SD) 95% Cl Median (P25/P75) Change in total number of seizures over last 8 weeks Mean (SD) 95% Cl Median (P25/P75) Duration of seizures b1 min 1–3 min N3 min Seizure recovery time b1 min 1–5 min 5–10 min N10 min Loss of consciousness a b c
Month 3
242 40 (16.5%) 43 (17.8%) 242 118 (48.8%) 100 (41.3%)a 242 129 (53.3) 242
120 (49.6)b
6.6 (10.2) 4.7 (8.9) 5.3–7.9 3.5–5.8 3.0 (1.0/8.0) 2.0 (1.0/5.0)
Month 6 51 (21.1%) 100 (41.3%)a 117 (48.3)b
4.4 (8.5) 3.3–5.4 2.0 (0.0/5.0)
242 –1.9 (6.8)a –2.2 (8.4)a –2.8 to –1.0 –3.3 to –1.2 –1.0 (–3.0/0.0) –1.0 (–4.0/0.0) 206 54 (26.2%) 68 (33.0%)a 115 (55.8%) 105 (51.0%)a 37 (18.0%) 33 (16.0%)a
74 (35.9%)c 10 (49.0%)c 31 (15.0%)c
205 36 (17.6%) 66 (32.2%) 62 (30.2%) 41 (20.0%) 203 150 (73.9%)
P b 0.0001, compared with baseline. P b 0.05, compared with baseline. P b 0.005 compared with baseline.
47 (22.9%)a 83 (40.5%)a 42 (20.5%)a 33 (16.1%)a 140 (69.0%)b
51 (24.9%)a 81 (39.5%)a 42 (20.5%)a 31 (15.1%)a 137 (67.5%)b
J. Sancho et al. / Epilepsy & Behavior 19 (2010) 409–413 Table 3 Effect of treatment on questionnaire-based outcomes. Possible N range Seizure severity, SSQ Mean (SD) Change Overall assessment of seizure severity Mean (SD) Change Change in seizures after changing treatment Mean (SD) Change Hamilton Anxiety Rating Scale total score Mean (SD) Change Hamilton Depression Rating Scale total score Mean (SD) Change Global Medical Outcomes Study— Sleep Scale Index Mean (SD) Change Quality of Life in Epilepsy-31 score Mean (SD) Change a b c
0–91
Baseline
Table 4 Correlations between seizure severity score (SSQ) and scores on other instruments. Month 3
Month 6
222 25.3 (20.9) 20.0 (18.6) 19.0 (18.2) –5.3 (17.0)a –6.2 (17.7)a
0–7
0–7
0–56
0–52
0–100
208 3.5 (1.6)
3.1 (1.5) –0.4 (1.3)a
2.9 (1.5) –0.6 (1.5)a
1.4 (2.2)
1.3 (2.0) –0.2 (1.8)
1.3 (2.1) –0.1 (2.0)
11.4 (9.4)
9.7 (9.2) –1.7 (4.8)a
8.9 (8.7) –2.5 (5.6)a
8.4 (6.9)
7.4 (5.9) –1.0 (3.4)a
6.7 (5.7) –1.7 (4.6)a
218
250
221
243
27.0 (18.5) 25.1 (17.7) 24.5 (17.6) –1.8 (10.9)b –2.5 (13.0)b 0–100
246 62.4 (17.7) 64.2 (17.8) 1.8 (7.9)c
65.7 (16.8) 3.3 (10.7)c
P b 0.0001. P b 0.05. P b 0.0005.
Hamilton Anxiety Rating Scale Psychic Anxiety Somatic Anxiety Total Anxiety Hamilton Depression Rating Scale Depression total score Melancholy domain Sleep domain Anxiety domain Medical Outcomes Study—Sleep Scale Quantity of Sleep Sleep Disturbance Snoring Abrupt Awakening Optimal Sleep Sleep Adequacy Somnolence Sleep Problems Overall Sleep Problems Index Quality of Life in Epilepsy-31 Seizure Worry Overall Quality Of Life Well-Being Energy/Fatigue Cognitive Function Adverse Events Social Function Visual analog scale total score Visual analog scale b
HAM-D scores decreased at months 3 and 6 compared with baseline (P b 0.0001) (Table 3). Additionally, Psychic Anxiety and Somatic Anxiety scores (HAM-A scales) improved during the 6-month followup (P b 0.0001) (Fig. 1). On all the MOS-Sleep subscales, except for Abrupt Awakening, there were improvements in quality and quantity of sleep at months 3 and 6 compared with baseline (P b 0.05); the mean global MOS-Sleep Index also improved at months 3 and 6 (P b 0.05) (Table 3). In addition, the QOLIE-31 scores showed improvements at month 6 compared with baseline (P b 0.0005) on all except the Cognitive Function and Adverse Events subscales. The mean QOLIE-31 total score improved at months 3 and 6 compared with baseline (P b 0.0005) (Table 3).
8 7
Mean score HAM-A scale
N
a
6 5 4 3 2 1 0 Baseline
Month 3 Psychic anxiety
411
Month 6 Somatic anxiety
Baseline
Month 6
221 221 221
0.5148a 0.3276a 0.4587a
0.3970a 0.2759a 0.3815a
195 215 215 219
0.4749a 0.4923a 0.2810a 0.4030a
0.333a 0.3620a 0.2628a 0.2807a
218 219 217 219 218 216 219 214 214
–0.1131 0.3176a 0.0270 0.1936b –0.1014 –0.3688a 0.2819a 0.4008a 0.4024a
–0.1251 0.2931a –0.0154 0.1915b –0.1025 –0.2885a 0.2741a 0.3296a 0.3818a
221 222 220 222 222 222 222 218 206
–0.5134a –0.4896a –0.5337a –0.4943a –0.4175a –0.2855a –0.4357a –0.5843a –0.5005a
–0.2463a –0.4574a –0.3570a –0.3728a –0.3067a –0.0958 –0.2363a –0.4407a –0.3493a
P b 0.0005. P b 0.005.
Table 5 Correlations between overall seizure severity score (SSQ) and scores on other instruments. N
Hamilton Anxiety Rating Scale Psychic Anxiety Somatic Anxiety Total Anxiety Hamilton Depression Rating Scale Depression total score Melancholy domain Sleep domain Anxiety domain Medical Outcomes Study—Sleep Scale Quantity of Sleep Sleep Disturbance Snoring Abrupt Awakening Optimal Sleep Sleep Adequacy Somnolence Sleep Problems Overall Sleep Problems Index Quality of Life in Epilepsy-31 Seizure Worry Overall Quality Of Life Mood Well-Being Energy/Fatigue Cognitive Function Adverse Events Social Function Visual analog scale total score Visual analog scale a
Fig 1. Psychic and somatic anxiety (range, 0–28, n = 250). aP b 0.0006, bP b 0.0001. HAM-A, Hamilton Anxiety Rating Scale.
Correlation, r
b c
P b 0.0005. P b 0.005. P b 0.05.
Correlation, r Baseline
Month 6
208 208 208
0.4019a 0.2532a 0.3562a
0.3923a 0.3360a 0.4075a
181 201 202 205
0.3442a 0.3577a 0.2254b 0.2570a
0.3415a 0.3514a 0.2259b 0.3492a
204 205 204 205 204 203 205 201 201
–0.0895 0.2208b –0.0527 0.1615c –0.0737 –0.2489b 0.1580c 0.2805a 0.2852a
–0.0527 0.2660a –0.0026 0.2246b –0.0979 –0.2123b 0.2105b 0.2777 0.3128a
207 208 206 208 208 208 208 204 193
–0.5849a –0.4380a –0.4348a –0.4113a –0.3043a –0.2914a –0.3451a –0.4811a –0.4303
–0.3673a –0.3382a –0.2527a –0.2384a –0.2754a –0.1168 –0.2207b –0.3610a –0.2963a
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Table 6 Pharmacological treatments. Number (%)
Carbamazepine Valproic acid Phenytoin Lamotrigine Levetiracetam Pregabalin
Baseline (N = 249)
During study (N = 249)
96 (38.5%) 75 (30.1%) 62 (24.8%) 52 (20.8%) 49 (19.6%) 25 (10.0%)
59 (27.6%) 41 (19.2%) 18 (8.9%) 52 (24.4%) 76 (35.6%) 67 (31.4%)
Significant correlations were found between most quality-oflife measures and mean seizure severity (Table 4) and overall seizure severity (Table 5) scores at baseline and 6 months. Strong correlations (r ≥ I0.5I) were found between mean seizure severity at baseline and several quality-of-life measures: greater seizure severity correlated with higher levels of HAM-A Psychic Anxiety (r = 0.5148; P b 0.0001); conversely, less severe seizures correlated (all P b 0.0001) with less Seizure Worry (r = –0.5134), greater WellBeing (r = –0.5337), higher VAS score (r = –0.5005), and higher VAS total score (r = –0.5843) on the QOLIE-31. Only QOLIE-31 Seizure Worry showed a strong correlation with overall evaluation of seizure severity (r = –0.5849, P b 0.0001). The most frequent AEDs administered at baseline were carbamazepine (38.5%), valproic acid (30.1%), and phenytoin (24.8%); however, over the course of the study, newer AEDs, levetiracetam (35.6%) and pregabalin (31.4%), were the most frequently used agents (Table 6). For nonpharmacological treatments, statistically significant differences were observed between the number of patients who had surgery at or before baseline (20, 8.1%) and those who had surgery over the 6 months of the study, 2 (0.8%) at month 3 and 5 (2.0%) at month 6 (P b 0.0001). The Morisky–Green test indicated that 142 (56.8%) patients were compliant with treatment at baseline, and that compliance significantly increased to 180 (72.0%) patients at month 3 and 186 (74.4%) at month 6 (P b 0.0001). 4. Discussion In this observational study, we found strong correlations between seizure severity and poorer reports on several quality-of-life measures in patients with refractory partial epilepsy receiving AEDs as determined by clinical practice. In particular, we have shown that seizure severity directly correlates with psychic anxiety and worrying about recurrent seizures, whereas there is an inverse relationship between seizure severity and quality of life. Treatment with AEDs resulted in better control of seizure severity as perceived by the patients and by objective measures such as a significant reduction in total number of seizures, duration of seizures, and recovery time at months 3 and 6 compared with baseline. Treatment success can be attributed to the continued attendance of patients at the clinic and the change in treatment, as needed, to medication with a better efficacy and/or tolerability profile or better compliance by the patient. We observed strong correlations of seizure severity score with anxiety as indicated by the HAM-A scale and the Seizure Worry subscale of the QOLIE-31, which are in agreement with previous studies showing a positive correlation between seizure severity and anxiety [8,16]. Similarly, higher seizure severity scores correlated with greater depression as indicated by all subscales of the HAM-D. A previous study that evaluated the relationship between depressive symptoms and seizure severity found that clinically depressed people with epilepsy reported higher levels of all aspects of seizure severity, as well as increased difficulties with overall seizure recovery, when
compared with non-depressed controls with epilepsy [17]. Our findings further emphasize the strong correlation between seizure severity and depression. Because anxiety and depression are associated with significantly poorer health-related quality of life [18], it is important to reduce seizure severity in patients with refractory partial epilepsy to reduce their anxiety and depression levels and eventually improve their quality of life. Furthermore, our study indicates a significant correlation between seizure severity and several aspects of sleep as measured by the MOS-Sleep scale and the HAM-D Sleep subscale. A previous study showed that sleep disturbance was more than twice as prevalent in patients with partial epilepsy as in healthy controls and was associated with poorer quality of life in both controls and patients with epilepsy [9]. AEDs have the potential to either improve or worsen sleep and sleep disorders in patients with epilepsy [19]. Because sleep disturbance clearly contributes to the poorer quality of life of patients with refractory partial epilepsy, management of sleep disturbance should be an integral part of their treatment and could impact the choice of treatment provided to patients. Patients with epilepsy often experience cognitive dysfunction [20]. Many of the drugs prescribed for epilepsy can either impair or improve cognitive functioning, which is a major concern for patients taking medications [20]. In this study, as indicated from the Cognitive Function domain of the QOLIE-31 (from the patient's subjective perception of performance), there was a significant inverse correlation between seizure severity score and cognitive function. As seizure severity improved with the change in antiepileptic treatment, it is likely that the AEDs used in this study would not have worsened the cognitive function of the patients. Additionally, it suggests that reducing seizure severity in patients with epilepsy increases their quality of life by improving their cognitive function as well. Throughout the study physicians changed patients’ medication to achieve better efficacy and/or tolerability, with the result that by the end of the study, the majority of the patients were using newer AEDs such as pregabalin and levetiracetam. Pregabalin, independent of its effect on seizure severity, has been shown to reduce sleep latency and awakenings, improve rapid eye movement sleep, and reduce psychic and somatic anxiety symptoms in patients with partial epilepsy [21,22]. Levetiracetam improved several measures on the QOLIE-31, including Seizure Worry, Overall Quality of Life, and Cognitive Function, which also supports improvements in quality of life for patients with refractory partial epilepsy [23]. Improvement in seizure severity and quality of life may in part be attributable to the use of these new AEDs. When interpreting this study, some limitations should be noted. First, this was an observational and noncomparative study; therefore, conclusions should be considered of low level of evidence. Second, it is not clear from this study if greater seizure severity caused anxiety, depression, and sleep disturbance, or if these comorbid conditions caused greater seizure severity. However, it is very clear that greater seizure severity or comorbid conditions lead to poor quality of life in patients with refractory partial epilepsy. In conclusion, the findings herein suggest that reducing seizure severity significantly improves the quality of life of patients with refractory partial epilepsy. Additionally, our results emphasize the importance of identifying and treating anxiety, depression, and sleep disorders among patients with epilepsy to improve their seizure severity perception and their quality of life.
Acknowledgments This study was funded by Pfizer Inc. Editorial support was provided by Vardit Dror of UBC Scientific Solutions and funded by Pfizer Inc.
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