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EEG monitoring between patients with epileptic seizures and those with psychogenic nonepileptic seizures
Epilepsy & Behavior 15 (2009) 303–307
Contents lists available at ScienceDirect
Epilepsy & Behavior journal homepage: www.elsevier.com/locate/yebeh
Comparison of outcomes of video/EEG monitoring between patients with epileptic seizures and those with psychogenic nonepileptic seizures Yi-Chen Zhang a,b, Edward B. Bromfield a, Shelley Hurwitz c, Aaron Nelson a, Kristen Sylvia a, Barbara A. Dworetzky a,* a
Department of Neurology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA Albert Einstein College of Medicine, Bronx, NY, USA c Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA b
a r t i c l e
i n f o
Article history: Received 11 January 2009 Revised 5 March 2009 Accepted 4 April 2009 Available online 7 May 2009 Keywords: Epileptic seizures Psychogenic nonepileptic seizures Video/EEG monitoring Quality of Life in Epilepsy inventory Outcome
a b s t r a c t We followed 103 patients for 6–16 months after discharge from elective long-term video/EEG monitoring to compare clinical outcomes and quality of life between patients diagnosed with epileptic (ES) and those diagnosed with psychogenic nonepileptic (PNES) seizures. Outcome measures determined at telephone or mail follow-up included seizure frequency, antiepileptic drug use, and self-reported quality of life using the Quality of Life in Epilepsy inventory. Of the 62 responders, 41 were diagnosed with ES and 11 with PNES, using strictly applied criteria. Those with ES reported significant improvement in Seizure Worry (P = 0.003), Medication Side Effects (P < 0.001), and Social Function (P < 0.001). In addition, both groups showed a decrease in seizure frequency. Furthermore, both groups showed a significant decrease in antiepileptic drug use at follow-up, with a greater, and sustained, decrease for the PNES group. Approximately half the patients in each group reported an improvement in overall condition. Ó 2009 Elsevier Inc. All rights reserved.
1. Introduction Long-term video/EEG monitoring (LTM) is the gold standard for diagnosing epileptic seizures (ES) and psychogenic nonepileptic seizures (PNES) in pharmacoresistant patients, primarily by correlating electrographic changes with clinical events, particularly with respect to patient responsiveness [1,2]. Video/EEG monitoring for 1–6 days has been shown to improve diagnostic accuracy compared with conventional EEG [3]. The extent to which this monitoring enhances treatment outcomes in patients with suspected seizures is less clear. Following LTM, approximately one-third of patients with PNES have no further events, one-third report that they are improved, and the remaining third show no response [4]. Favorable outcomes are associated with higher educational status, being accompanied to clinic visits [5], current friendships [6], and early diagnosis [7]. Poor prognoses are linked to substance abuse, psychiatric comorbidities including pseudostatus epilepticus [7], and posttraumatic stress disorder [8]. In one study, patients with PNES showed a statistically significant decline in seizure frequency in the 24-hour monitoring period * Corresponding author. Address: Department of Neurology, Brigham and Women’s Hospital, 75 Francis Street, Boston, MA 02115, USA. Fax: +1 617 278 6963. E-mail address: [email protected] (B.A. Dworetzky). 1525-5050/$ - see front matter Ó 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.yebeh.2009.04.008
after presentation of diagnosis [9]. Unfortunately, sustained reduction for PNES episodes is not ensured [10,11]. In a 10-year followup study, 71.2% of 164 patients with PNES still reported seizures [7]. However, another report of 22 patients with PNES in a tertiary epilepsy center demonstrated that 7 of 22 were in remission 4– 6 years after diagnosis, with associated improvements in psychosocial function [12]. Patients with ES also show a significant reduction in seizure frequency after LTM; 21% of 34 patients with ES in one study achieved seizure remission and remained seizure free for an average of 2.5 years. In addition, 44% felt more or much more satisfied with their lives, and 41% felt their quality of life was stable [13]. In a separate study, patients with concurrent ES and PNES had a higher percentage of spontaneously activated events, a shorter duration of disease, and a lower percentage lost at follow-up compared with those with only PNES [1]. Taken together, these results suggest an overall improvement in long-term prognosis for patients with ES following LTM. LTM is used to facilitate the diagnosis of patients with ES and PNES. The extent to which LTM impacts outcomes differently for these two patient groups is not known. The present study compares clinical outcomes after LTM for patients with PNES and ES with respect to seizure frequency, number of antiepileptic drugs, quality-of-life scores, and other measures.
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2. Methods Subjects were consecutively admitted patients who underwent elective LTM at a tertiary care epilepsy center between November 2006 and January 2008 and who responded to a 17-item questionnaire about their health within 6–16 months of discharge. Two board-certified neurologist/electroencephalographers (B.A.D., E.B.B.) independently confirmed the diagnoses for each patient, using the following criteria: patients with definite ES demonstrated clinical events with simultaneous ictal EEG abnormalities, whereas patients with probable epileptic seizures showed interictal epileptiform discharges and events consistent with ES that would not necessarily be expected to have an interpretable ictal scalp EEG correlate (e.g., simple partial seizures, frontal lobe seizures). In both situations, patients showed no clinical indications of PNES. These two groups were combined to form the ‘‘ES without PNES” group. Patients with definite PNES demonstrated clinical events with unresponsiveness and no ictal EEG change, and those with probable PNES had events that were inconsistent with epileptic seizures and had no definite interictal epileptiform discharges. These two groups were combined to form the ‘‘PNES without ES” group. The ES without PNES and PNES without ES groups were analyzed, whereas those who met less stringent criteria (classified as possible ES and/or PNES) were eliminated (n = 6), as were those who had strong evidence of concurrent ES and PNES (n = 11). At LTM discharge, the referring physician is contacted while the patient is still being monitored to discuss the preliminary results, the planned medications at discharge, and recommended next steps. All patients have a psychiatry consultation at the time of LTM by a specialist from our multidisciplinary team. Patients are usually informed of the possibility that their episodes might not be epileptic in origin before monitoring. Patients who prove to have PNES are referred for outpatient psychiatric follow-up. If there is already a counselor involved in their treatment, permission to contact him or her is requested by our consulting psychiatry team. Our epilepsy specialists strive to communicate the results of the LTM openly and directly and similarly to the nonjudgmental method outlined by Shen et al. [14]. We ask all monitored patients to follow up at our center at least once within 3–4 weeks to review the LTM results again, see how they have been doing since the hospitalization, and answer new questions or revise misunderstandings that may have arisen. Data were obtained from Quality of Life in Epilepsy inventory (QOLIE) surveys administered as the QOLIE-31 during LTM and the QOLIE-10 at follow-up. As these two versions have been shown to be correlated [15], both yielding valid subscores, we were able to calculate and compare subscales for the two time points. Data concerning number of antiepileptic drugs (AEDs), duration and quality of sleep, chronic pain, spell frequency, number of hospitalizations, and other variables were collected using a combination of medical records, clinic notes, and a questionnaire administered either by mail or by phone. Spell frequency was ranked as follows: none (0), fewer than one per year (1), monthly (2), weekly (3), daily (4). The ES and PNES groups were compared using the exact Jonckheere–Terpstra test for ordered categorical variables, Fisher’s exact test or exact {2 test for unordered categorical variables, and the Wilcoxon rank sum test for continuous variables. Within-group changes were tested using the Wilcoxon signed rank test. AEDs in all four groups were plotted, with statistical analyses limited to those with exclusively ES or PNES. The criterion for rejecting the null hypotheses for AEDs was adjusted for two main a priori focused tests of long-term benefit of LTM within ES and within PNES.
Statistical analyses were performed using SAS Version 9 and StatXact Version 5. 3. Results Of the total of 103 patients, 62 responded to the follow-up questionnaire 6–16 months after discharge. Forty-one (66%) were identified as having ES without PNES; 11 (18%) had PNES without ES. We did not further analyze the 6 (10%) who had both ES and PNES and the 4 (6%) whose diagnoses were indeterminate. Of the 41 patients who did not respond to the questionnaire, 25 (61%) had ES without PNES, 9 (22%) had PNES without ES, 5 (12%) had both ES and PNES, and 2 (5%) were indeterminate. There were no significant differences in demographics or diagnoses between responders and nonresponders. Given the small sample sizes within the ‘‘both” and ‘‘indeterminate” categories, statistical analysis was performed only on patients with ES and no PNES (ES group) and patients with PNES with no ES (PNES group). There were no statistically significant differences regarding gender, age, or follow-up duration between patients with ES and those with PNES (Table 1). However, patients with ES were significantly younger at seizure onset (17 ± 15 years) compared with those with PNES (34 ± 14 years) (P = 0.0015). Follow-up questionnaire responses for the ES and PNES groups are summarized in Table 2. At follow-up, there were no significant between-group differences in overall condition compared with admission. In each group, roughly half (ES 56% and PNES 45%) reported improvement, and few reporting worsening. There were significantly more patients with ES under current treatment for seizures (P = 0.008). Additionally, more patients with ES were treated with nonpharmacological therapies (P = 0.05). These included four with vagus nerve stimulators (VNS), one with magnesium supplements, one with a ventricular shunt, and seven with resective surgery. None of the patients with PNES reported nonpharmacological therapies. Notably, more than half of each group reported that LTM improved their understanding of their diagnosis. Social relationships following their LTM improved in a sizable minority of patients in both groups. More patients with ES reported getting adequate sleep (68% vs 36%, P = 0.08), while trouble falling asleep was significantly more prevalent in patients with PNES (P = 0.0004). There were no significant differences in reports of chronic pain or medical care utilization, with less than half reporting emergency visits or hospitalizations since their admission. The ES and PNES groups did not differ regarding change in occupational status following LTM (P = 0.17). QOLIE-31 subscale scores obtained at admission were compared with QOLIE-10 subscale scores obtained at follow-up using a validated transformation process [14], and are illustrated in Fig. 1. There were no significant group (ES vs PNES) differences
Table 1 Patient characteristics.
% Female (n) Age (years) Age at seizure onset (years) Follow-up time (months after LTM admission) a b
Definite or probable ES, not PNES. Definite or probable PNES, not ES.
ESa (N = 41)
PNESb (N = 11)
P value
54 (22) 39 ± 11 17 ± 15 9.4 ± 3.1
73 (8) 43 ± 10 34 ± 14 10.2 ± 3.0
0.32 0.24 0.002 0.45
Y.-C. Zhang et al. / Epilepsy & Behavior 15 (2009) 303–307 Table 2 Itemized questionnaire responses. P valuea
% (n) ES (N = 41)
PNES (N = 11)
56 (23) 34 (14) 10 (4)
45 (5) 27 (3) 27 (3)
Currently treated for seizures
100 (41)
73 (8)
0.008
Nonpharmacological seizure treatments
29 (12)
0 (0)
0.05
Increased understanding of condition
68 (28)
64 (7)
1.00
Change in social relationships For the better Not at all For the worse
37 (15) 54 (21) 8 (3)
40 (4) 30 (3) 30 (3)
Change in occupation Unemployed to working/student Disabled to working/student Working/student to unemployed Working/student to disabled Other change No change
2 (1) 0 (0) 2 (1) 10 (4) 7 (3) 78 (32)
0 (0) 9 (1) 9 (1) 18 (2) 18 (2) 45 (5)
Adequate sleep
68 (28)
36 (4)
0.08
Sleep problems Falling asleep Staying awake Waking up
14.6 (6) 14.6 (6) 9.8 (4)
72.7 (8) 9.1 (1) 27.3 (3)
0.0004 1.00 0.15
Chronic pain
39 (16)
64 (7)
0.18
Seen/called M.D. for seizures since LTM Never 1 or 2 times/year 3–6 times/year >6 times/year
17 22 37 24
45 (5) 9 (1) 18 (2) 27 (3)
Seen in emergency room since LTM
20 (8)
27 (3)
0.68
Hospitalized overnight for seizures
20 (8)
9 (1)
0.66
Overall condition Better Same Worse
a
0.36
0.54
0.17
0.36 (7) (9) (15) (10)
Exact Jonckheere–Terpstra test for ordered categories; Fisher’s exact test or exact {2 test for unordered categories.
305
on any QOLIE-31 domain at baseline. Patients with ES reported significant improvement in Seizure Worry, with average scores of 50 ± 28 at the time of LTM and 73 ± 30 at follow-up (P = 0.003). In addition, patients with ES reported significant improvement in Medication Side Effects (meaning fewer side effects), from 51 ± 35 to 83 ± 23 (P < 0.001), and in Social Function, from 48 ± 29 to 76 ± 27 (P < 0.001). In contrast, the PNES group did not show significant improvement on any subscale. Although the magnitude of changes in Medication Side Effects in the PNES group was similar to that in the ES group, the smaller size of the PNES group may have been a factor in the failure of this change to attain statistical significance. Neither group showed changes in global or Overall Quality of Life, Emotional Well-Being, Energy/Fatigue, or Cognitive Function from admission to follow-up. Self-reported seizure frequency at admission and at follow-up revealed a significant decrease in median rank for patients with ES (3.0 to 2.0, P = 0.0001), as well as a significant decrease for patients with PNES (3.5 to 1.5, P = 0.047). Both groups showed similar frequency reductions after accounting for differences in sample size (P = 0.33). Seven respondents who had epilepsy surgery within 12 months of LTM were not excluded from the analysis given the heterogeneity of patients who undergo LTM. On admission, all patients were taking one or more AEDs. The numbers of AEDs at admission, discharge, and follow-up are illustrated in Fig. 2. As expected, the number of AEDs decreased from admission to discharge for patients with PNES (P = 0.05), as it is part of our clinical protocol to reduce or eliminate AEDs in patients with PNES alone. Most noteworthy is the sustained reduction in number of AEDs for the PNES group at follow-up relative to admission (P = 0.05). The graph shows that there was less of a reduction for patients with ES (P = 0.05) and that this decrease was delayed. AED use in patients with ES remained significantly greater compared with that in patients with PNES from discharge until follow-up (P = 0.0001), with all 41 patients with ES taking at least one AED throughout, versus 4 of 11 (36%) patients with PNES stopping all AEDs (P = 0.001). Interestingly, though too small to
Fig. 1. QOLIE subscales in LTM admission (Adm) and follow-up (FU). QOLIE-31 and QOLIE-10 scores for Seizure Worry, Overall QOL, Emotional Well-Being, Energy, Cognitive Function, Medication Side Effects, and Social Function were gathered at LTM admission and at 6–16 months of follow-up, respectively, and converted to a common subscale for comparing seven outcome dimensions between patients with ES and those with PNES. A higher QOLIE score designates better outcome.
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Fig. 2. AED usage at admission, discharge, and follow-up. Effect of LTM on number of AEDs plotted at admission, discharge, and follow-up. In addition to the ES and PNES groups, patients with both ES and PNES and those with indeterminate diagnoses are included for comparison.
analyze, the indeterminate group had results qualitatively similar to those for the PNES group from admission to discharge, but this effect was no longer statistically significant at follow-up. In addition, the ES + PNES (both) group had findings similar to those of the ES group.
4. Discussion This study evaluated patients followed after LTM, tracking changes in self-reported quality of life, number of AEDs, seizure frequency, medical care utilization, sleep, pain, and other variables. The prevalence of ES and PNES in our population conforms to what is reported in the literature, supporting our diagnostic criteria. Patients with PNES were taking significantly fewer AEDs than those with ES at admission, discharge, and follow-up. The greater decline in AED use between admission and discharge in the PNES group can be attributed to our common practice of decreasing or discontinuing medication for this group once a definitive diagnosis is rendered. Of more interest, however, is the sustained decline in AED use from discharge to follow-up, suggesting that LTM may contribute to a beneficial elimination of unnecessary medications in the PNES group once definitively diagnosed. The absolute number of AEDs for patients with ES also showed a small reduction, suggesting that LTM can play a role in simplifying the treatment regimen for these patients as well. The observation that patients whose diagnoses were ‘‘indeterminate” reported a small increase in AED use over time suggests that a convincing diagnosis may be required for LTM to persistently reduce AED use, though it remains possible that some of these patients had epilepsy. Interestingly, in addition to reduction of AEDs, each group exhibited a significant decline in seizure frequency at LTM follow-up. The number of patients undergoing surgery between admission and follow-up was small and did not significantly skew the results. This, together with the global reports of improvement and modest improvements in measured quality of life, suggests a beneficial effect of the admission that may be more evident in those with ES, though the small size of the PNES group may have contributed to the failure to attain statistical significance here. Reasons for these self-reported improvements may markedly differ
for the two diagnostic groups, but may include establishing a definitive diagnosis, simplifying or changing the medical regimen, and providing additional subspecialty consultation and support that would otherwise not have been arranged in the outpatient setting. LTM is usually a necessary precursor for surgery and VNS implantation, and outcomes for these have been well studied [16]. Our sample was not large enough to comment on these separately. In some cases, LTM may have resulted in the initiation of new supportive psychotherapy or other psychiatric care. We explored the possibility of questionnaire response bias and found that patients who participated in the follow-up assessment were representative of the baseline study sample. Similar proportions of people with ES and PNES reported improvement at follow-up after LTM. However, on the QOLIEs, patients with ES reported significant improvements in Seizure Worry, Medication Side Effects, and Social Function; patients with PNES showed a trend toward improvement in Medication Side Effects. There was no significant improvement in occupational status for either group, similar to what others have found [17]. There are some limitations to this retrospective study. The PNES group size was small, so statistical power is limited. However, the cases were carefully chosen from a larger group, and strictly defined so as not to include any doubtful cases. There were no nonLTM controls. Therefore, the differences in outcome between patients with ES and those with PNES may be attributed to factors other than the LTM, including subsequent changes in lifestyle. Subjects may have been more unwell at the time of admission than at follow-up, for example. Improvement may therefore have had less to do with the LTM than with life circumstances. However, our 6to 8-week waiting list for admission and the exclusion of patients admitted urgently should have minimized this possible confound. It is interesting to note that the indeterminate group at followup, although not analyzed, behaved somewhat like the PNES group except that AEDs increased over time, suggesting that definitive diagnosis on LTM may be important to sustained improvement. It is appropriate as previously mentioned [14] to consider definitive diagnosis of PNES during LTM as the start of treatment. Future efforts to understand and improve long-term outcomes are necessary, with more research focused on the specific role of LTM in this process.
Y.-C. Zhang et al. / Epilepsy & Behavior 15 (2009) 303–307
Ethical approval We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. Conflict of interest statement None of the authors has any conflict of interest to disclose. Acknowledgments This project was supported in part by a research stipend from the Albert Einstein College of Medicine. The authors also acknowledge the help of Sonia Replansky, who completed the institutional review board consents and helped initiate data collection for this study. The Brigham and Women’s Hospital Center for Clinical Investigation provided statistical analysis. References [1] Mari F, Di Bonaventura C, Vanacore N, et al. Video-EEG study of psychogenic nonepileptic seizures: differential characteristics in patients with and without epilepsy. Epilepsia 2006;475:64–7. [2] Ribaï P, Tugendhaft P, Legros B. Usefulness of prolonged video-EEG monitoring and provocative procedure with saline injection for the diagnosis of non epileptic seizures of psychogenic origin. J Neurol 2006;3:328–32. [3] Park KI, Lee SK, Chu K, Lee JJ, Kim DW, Nan H. The value of video-EEG monitoring to diagnose juvenile myoclonic epilepsy. Seizure 2009;18:94–9. [4] Hovorka J, Nezádal T, Herman E, Nemcová I, Bajacek M. Psychogenic nonepileptic seizures, prospective clinical experience: diagnosis, clinical features, risk factors, psychiatric comorbidity, treatment outcome. Epileptic Disord 2007;9(Suppl. 1):S52–8.
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[5] Arain AM, Hamadani AM, Islam S, Abou-Khalil BW. Predictors of early seizure remission after diagnosis of psychogenic nonepileptic seizures. Epilepsy Behav 2007;11:409–12. [6] Ettinger AB, Dhoon A, Weisbrot DM, Devinsky O. Predictive factors for outcome of nonepileptic seizures after diagnosis. J Neuropsychiatry Clin Neurosci 1999;11:458–63. [7] Reuber M, Pukrop R, Bauer J, Helmstaedter C, Tessendorf N, Elger CE. Outcome in psychogenic nonepileptic seizures: 1 to 10-year follow-up in 164 patients. Ann Neurol 2003;53:305–11. [8] Lesser RP. Treatment and outcome of psychogenic nonepileptic seizures. Epilepsy Curr 2003;3:198–200. [9] Farias ST, Thieman C, Alsaadi TM. Psychogenic nonepileptic seizures: acute change in event frequency after presentation of the diagnosis. Epilepsy Behav 2003;4:424–9. [10] O’Sullivan SS, Spillane JE, McMahon EM, et al. Clinical characteristics and outcome of patients diagnosed with psychogenic nonepileptic seizures: a 5year review. Epilepsy Behav 2007;1:77–84. [11] Quigg M, Armstrong RF, Farace E, Fountain NB. Quality of life outcome is associated with cessation rather than reduction of psychogenic nonepileptic seizures. Epilepsy Behav 2002;3:455–9. [12] Bodde NM, Janssen AM, Theuns C, Vanhoutvin JF, Boon PA, Aldenkamp AP. Factors involved in the long-term prognosis of psychogenic nonepileptic seizures. J Psychosom Res 2007;62:545–51. [13] Selwa LM, Schmidt SL, Malow BA, Beydoun A. Long-term outcome of nonsurgical candidates with medically refractory localization-related epilepsy. Epilepsia 2003;44:1568–72. [14] Shen W, Bowman ES, Markand ON. Presenting the diagnosis of pseudoseizure. Neurology 1990;40:756–9. [15] Cramer JA, Arrigo C, van Hammee G, Bromfield EB. Comparison between the QOLIE-31 and derived QOLIE-10 in a clinical trial of levetiracetam. Epilepsy Res 2000;41:29–38. [16] Spencer SS, Berg AT, Vickrey BG, Sperling MR, Bazil CW, Shinnar S, Langfitt JT, Walczak TS, Pacia SV, Ebrahimi N, Frobish D. Multicenter study of epilepsy surgery. Initial outcomes in the Multicenter study of Epilepsy Surgery. Neurology 2003;61:1680–5. [17] Walczak TS, Papacostas S, Williams DT, Scheuer ML, Lebowitz N, Notarfrancesco A. Outcome after diagnosis of psychogenic nonepileptic seizures. Epilepsia 1995;36:1131–7.
Contents lists available at ScienceDirect
Epilepsy & Behavior journal homepage: www.elsevier.com/locate/yebeh
Comparison of outcomes of video/EEG monitoring between patients with epileptic seizures and those with psychogenic nonepileptic seizures Yi-Chen Zhang a,b, Edward B. Bromfield a, Shelley Hurwitz c, Aaron Nelson a, Kristen Sylvia a, Barbara A. Dworetzky a,* a
Department of Neurology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA Albert Einstein College of Medicine, Bronx, NY, USA c Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA b
a r t i c l e
i n f o
Article history: Received 11 January 2009 Revised 5 March 2009 Accepted 4 April 2009 Available online 7 May 2009 Keywords: Epileptic seizures Psychogenic nonepileptic seizures Video/EEG monitoring Quality of Life in Epilepsy inventory Outcome
a b s t r a c t We followed 103 patients for 6–16 months after discharge from elective long-term video/EEG monitoring to compare clinical outcomes and quality of life between patients diagnosed with epileptic (ES) and those diagnosed with psychogenic nonepileptic (PNES) seizures. Outcome measures determined at telephone or mail follow-up included seizure frequency, antiepileptic drug use, and self-reported quality of life using the Quality of Life in Epilepsy inventory. Of the 62 responders, 41 were diagnosed with ES and 11 with PNES, using strictly applied criteria. Those with ES reported significant improvement in Seizure Worry (P = 0.003), Medication Side Effects (P < 0.001), and Social Function (P < 0.001). In addition, both groups showed a decrease in seizure frequency. Furthermore, both groups showed a significant decrease in antiepileptic drug use at follow-up, with a greater, and sustained, decrease for the PNES group. Approximately half the patients in each group reported an improvement in overall condition. Ó 2009 Elsevier Inc. All rights reserved.
1. Introduction Long-term video/EEG monitoring (LTM) is the gold standard for diagnosing epileptic seizures (ES) and psychogenic nonepileptic seizures (PNES) in pharmacoresistant patients, primarily by correlating electrographic changes with clinical events, particularly with respect to patient responsiveness [1,2]. Video/EEG monitoring for 1–6 days has been shown to improve diagnostic accuracy compared with conventional EEG [3]. The extent to which this monitoring enhances treatment outcomes in patients with suspected seizures is less clear. Following LTM, approximately one-third of patients with PNES have no further events, one-third report that they are improved, and the remaining third show no response [4]. Favorable outcomes are associated with higher educational status, being accompanied to clinic visits [5], current friendships [6], and early diagnosis [7]. Poor prognoses are linked to substance abuse, psychiatric comorbidities including pseudostatus epilepticus [7], and posttraumatic stress disorder [8]. In one study, patients with PNES showed a statistically significant decline in seizure frequency in the 24-hour monitoring period * Corresponding author. Address: Department of Neurology, Brigham and Women’s Hospital, 75 Francis Street, Boston, MA 02115, USA. Fax: +1 617 278 6963. E-mail address: [email protected] (B.A. Dworetzky). 1525-5050/$ - see front matter Ó 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.yebeh.2009.04.008
after presentation of diagnosis [9]. Unfortunately, sustained reduction for PNES episodes is not ensured [10,11]. In a 10-year followup study, 71.2% of 164 patients with PNES still reported seizures [7]. However, another report of 22 patients with PNES in a tertiary epilepsy center demonstrated that 7 of 22 were in remission 4– 6 years after diagnosis, with associated improvements in psychosocial function [12]. Patients with ES also show a significant reduction in seizure frequency after LTM; 21% of 34 patients with ES in one study achieved seizure remission and remained seizure free for an average of 2.5 years. In addition, 44% felt more or much more satisfied with their lives, and 41% felt their quality of life was stable [13]. In a separate study, patients with concurrent ES and PNES had a higher percentage of spontaneously activated events, a shorter duration of disease, and a lower percentage lost at follow-up compared with those with only PNES [1]. Taken together, these results suggest an overall improvement in long-term prognosis for patients with ES following LTM. LTM is used to facilitate the diagnosis of patients with ES and PNES. The extent to which LTM impacts outcomes differently for these two patient groups is not known. The present study compares clinical outcomes after LTM for patients with PNES and ES with respect to seizure frequency, number of antiepileptic drugs, quality-of-life scores, and other measures.
304
Y.-C. Zhang et al. / Epilepsy & Behavior 15 (2009) 303–307
2. Methods Subjects were consecutively admitted patients who underwent elective LTM at a tertiary care epilepsy center between November 2006 and January 2008 and who responded to a 17-item questionnaire about their health within 6–16 months of discharge. Two board-certified neurologist/electroencephalographers (B.A.D., E.B.B.) independently confirmed the diagnoses for each patient, using the following criteria: patients with definite ES demonstrated clinical events with simultaneous ictal EEG abnormalities, whereas patients with probable epileptic seizures showed interictal epileptiform discharges and events consistent with ES that would not necessarily be expected to have an interpretable ictal scalp EEG correlate (e.g., simple partial seizures, frontal lobe seizures). In both situations, patients showed no clinical indications of PNES. These two groups were combined to form the ‘‘ES without PNES” group. Patients with definite PNES demonstrated clinical events with unresponsiveness and no ictal EEG change, and those with probable PNES had events that were inconsistent with epileptic seizures and had no definite interictal epileptiform discharges. These two groups were combined to form the ‘‘PNES without ES” group. The ES without PNES and PNES without ES groups were analyzed, whereas those who met less stringent criteria (classified as possible ES and/or PNES) were eliminated (n = 6), as were those who had strong evidence of concurrent ES and PNES (n = 11). At LTM discharge, the referring physician is contacted while the patient is still being monitored to discuss the preliminary results, the planned medications at discharge, and recommended next steps. All patients have a psychiatry consultation at the time of LTM by a specialist from our multidisciplinary team. Patients are usually informed of the possibility that their episodes might not be epileptic in origin before monitoring. Patients who prove to have PNES are referred for outpatient psychiatric follow-up. If there is already a counselor involved in their treatment, permission to contact him or her is requested by our consulting psychiatry team. Our epilepsy specialists strive to communicate the results of the LTM openly and directly and similarly to the nonjudgmental method outlined by Shen et al. [14]. We ask all monitored patients to follow up at our center at least once within 3–4 weeks to review the LTM results again, see how they have been doing since the hospitalization, and answer new questions or revise misunderstandings that may have arisen. Data were obtained from Quality of Life in Epilepsy inventory (QOLIE) surveys administered as the QOLIE-31 during LTM and the QOLIE-10 at follow-up. As these two versions have been shown to be correlated [15], both yielding valid subscores, we were able to calculate and compare subscales for the two time points. Data concerning number of antiepileptic drugs (AEDs), duration and quality of sleep, chronic pain, spell frequency, number of hospitalizations, and other variables were collected using a combination of medical records, clinic notes, and a questionnaire administered either by mail or by phone. Spell frequency was ranked as follows: none (0), fewer than one per year (1), monthly (2), weekly (3), daily (4). The ES and PNES groups were compared using the exact Jonckheere–Terpstra test for ordered categorical variables, Fisher’s exact test or exact {2 test for unordered categorical variables, and the Wilcoxon rank sum test for continuous variables. Within-group changes were tested using the Wilcoxon signed rank test. AEDs in all four groups were plotted, with statistical analyses limited to those with exclusively ES or PNES. The criterion for rejecting the null hypotheses for AEDs was adjusted for two main a priori focused tests of long-term benefit of LTM within ES and within PNES.
Statistical analyses were performed using SAS Version 9 and StatXact Version 5. 3. Results Of the total of 103 patients, 62 responded to the follow-up questionnaire 6–16 months after discharge. Forty-one (66%) were identified as having ES without PNES; 11 (18%) had PNES without ES. We did not further analyze the 6 (10%) who had both ES and PNES and the 4 (6%) whose diagnoses were indeterminate. Of the 41 patients who did not respond to the questionnaire, 25 (61%) had ES without PNES, 9 (22%) had PNES without ES, 5 (12%) had both ES and PNES, and 2 (5%) were indeterminate. There were no significant differences in demographics or diagnoses between responders and nonresponders. Given the small sample sizes within the ‘‘both” and ‘‘indeterminate” categories, statistical analysis was performed only on patients with ES and no PNES (ES group) and patients with PNES with no ES (PNES group). There were no statistically significant differences regarding gender, age, or follow-up duration between patients with ES and those with PNES (Table 1). However, patients with ES were significantly younger at seizure onset (17 ± 15 years) compared with those with PNES (34 ± 14 years) (P = 0.0015). Follow-up questionnaire responses for the ES and PNES groups are summarized in Table 2. At follow-up, there were no significant between-group differences in overall condition compared with admission. In each group, roughly half (ES 56% and PNES 45%) reported improvement, and few reporting worsening. There were significantly more patients with ES under current treatment for seizures (P = 0.008). Additionally, more patients with ES were treated with nonpharmacological therapies (P = 0.05). These included four with vagus nerve stimulators (VNS), one with magnesium supplements, one with a ventricular shunt, and seven with resective surgery. None of the patients with PNES reported nonpharmacological therapies. Notably, more than half of each group reported that LTM improved their understanding of their diagnosis. Social relationships following their LTM improved in a sizable minority of patients in both groups. More patients with ES reported getting adequate sleep (68% vs 36%, P = 0.08), while trouble falling asleep was significantly more prevalent in patients with PNES (P = 0.0004). There were no significant differences in reports of chronic pain or medical care utilization, with less than half reporting emergency visits or hospitalizations since their admission. The ES and PNES groups did not differ regarding change in occupational status following LTM (P = 0.17). QOLIE-31 subscale scores obtained at admission were compared with QOLIE-10 subscale scores obtained at follow-up using a validated transformation process [14], and are illustrated in Fig. 1. There were no significant group (ES vs PNES) differences
Table 1 Patient characteristics.
% Female (n) Age (years) Age at seizure onset (years) Follow-up time (months after LTM admission) a b
Definite or probable ES, not PNES. Definite or probable PNES, not ES.
ESa (N = 41)
PNESb (N = 11)
P value
54 (22) 39 ± 11 17 ± 15 9.4 ± 3.1
73 (8) 43 ± 10 34 ± 14 10.2 ± 3.0
0.32 0.24 0.002 0.45
Y.-C. Zhang et al. / Epilepsy & Behavior 15 (2009) 303–307 Table 2 Itemized questionnaire responses. P valuea
% (n) ES (N = 41)
PNES (N = 11)
56 (23) 34 (14) 10 (4)
45 (5) 27 (3) 27 (3)
Currently treated for seizures
100 (41)
73 (8)
0.008
Nonpharmacological seizure treatments
29 (12)
0 (0)
0.05
Increased understanding of condition
68 (28)
64 (7)
1.00
Change in social relationships For the better Not at all For the worse
37 (15) 54 (21) 8 (3)
40 (4) 30 (3) 30 (3)
Change in occupation Unemployed to working/student Disabled to working/student Working/student to unemployed Working/student to disabled Other change No change
2 (1) 0 (0) 2 (1) 10 (4) 7 (3) 78 (32)
0 (0) 9 (1) 9 (1) 18 (2) 18 (2) 45 (5)
Adequate sleep
68 (28)
36 (4)
0.08
Sleep problems Falling asleep Staying awake Waking up
14.6 (6) 14.6 (6) 9.8 (4)
72.7 (8) 9.1 (1) 27.3 (3)
0.0004 1.00 0.15
Chronic pain
39 (16)
64 (7)
0.18
Seen/called M.D. for seizures since LTM Never 1 or 2 times/year 3–6 times/year >6 times/year
17 22 37 24
45 (5) 9 (1) 18 (2) 27 (3)
Seen in emergency room since LTM
20 (8)
27 (3)
0.68
Hospitalized overnight for seizures
20 (8)
9 (1)
0.66
Overall condition Better Same Worse
a
0.36
0.54
0.17
0.36 (7) (9) (15) (10)
Exact Jonckheere–Terpstra test for ordered categories; Fisher’s exact test or exact {2 test for unordered categories.
305
on any QOLIE-31 domain at baseline. Patients with ES reported significant improvement in Seizure Worry, with average scores of 50 ± 28 at the time of LTM and 73 ± 30 at follow-up (P = 0.003). In addition, patients with ES reported significant improvement in Medication Side Effects (meaning fewer side effects), from 51 ± 35 to 83 ± 23 (P < 0.001), and in Social Function, from 48 ± 29 to 76 ± 27 (P < 0.001). In contrast, the PNES group did not show significant improvement on any subscale. Although the magnitude of changes in Medication Side Effects in the PNES group was similar to that in the ES group, the smaller size of the PNES group may have been a factor in the failure of this change to attain statistical significance. Neither group showed changes in global or Overall Quality of Life, Emotional Well-Being, Energy/Fatigue, or Cognitive Function from admission to follow-up. Self-reported seizure frequency at admission and at follow-up revealed a significant decrease in median rank for patients with ES (3.0 to 2.0, P = 0.0001), as well as a significant decrease for patients with PNES (3.5 to 1.5, P = 0.047). Both groups showed similar frequency reductions after accounting for differences in sample size (P = 0.33). Seven respondents who had epilepsy surgery within 12 months of LTM were not excluded from the analysis given the heterogeneity of patients who undergo LTM. On admission, all patients were taking one or more AEDs. The numbers of AEDs at admission, discharge, and follow-up are illustrated in Fig. 2. As expected, the number of AEDs decreased from admission to discharge for patients with PNES (P = 0.05), as it is part of our clinical protocol to reduce or eliminate AEDs in patients with PNES alone. Most noteworthy is the sustained reduction in number of AEDs for the PNES group at follow-up relative to admission (P = 0.05). The graph shows that there was less of a reduction for patients with ES (P = 0.05) and that this decrease was delayed. AED use in patients with ES remained significantly greater compared with that in patients with PNES from discharge until follow-up (P = 0.0001), with all 41 patients with ES taking at least one AED throughout, versus 4 of 11 (36%) patients with PNES stopping all AEDs (P = 0.001). Interestingly, though too small to
Fig. 1. QOLIE subscales in LTM admission (Adm) and follow-up (FU). QOLIE-31 and QOLIE-10 scores for Seizure Worry, Overall QOL, Emotional Well-Being, Energy, Cognitive Function, Medication Side Effects, and Social Function were gathered at LTM admission and at 6–16 months of follow-up, respectively, and converted to a common subscale for comparing seven outcome dimensions between patients with ES and those with PNES. A higher QOLIE score designates better outcome.
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Fig. 2. AED usage at admission, discharge, and follow-up. Effect of LTM on number of AEDs plotted at admission, discharge, and follow-up. In addition to the ES and PNES groups, patients with both ES and PNES and those with indeterminate diagnoses are included for comparison.
analyze, the indeterminate group had results qualitatively similar to those for the PNES group from admission to discharge, but this effect was no longer statistically significant at follow-up. In addition, the ES + PNES (both) group had findings similar to those of the ES group.
4. Discussion This study evaluated patients followed after LTM, tracking changes in self-reported quality of life, number of AEDs, seizure frequency, medical care utilization, sleep, pain, and other variables. The prevalence of ES and PNES in our population conforms to what is reported in the literature, supporting our diagnostic criteria. Patients with PNES were taking significantly fewer AEDs than those with ES at admission, discharge, and follow-up. The greater decline in AED use between admission and discharge in the PNES group can be attributed to our common practice of decreasing or discontinuing medication for this group once a definitive diagnosis is rendered. Of more interest, however, is the sustained decline in AED use from discharge to follow-up, suggesting that LTM may contribute to a beneficial elimination of unnecessary medications in the PNES group once definitively diagnosed. The absolute number of AEDs for patients with ES also showed a small reduction, suggesting that LTM can play a role in simplifying the treatment regimen for these patients as well. The observation that patients whose diagnoses were ‘‘indeterminate” reported a small increase in AED use over time suggests that a convincing diagnosis may be required for LTM to persistently reduce AED use, though it remains possible that some of these patients had epilepsy. Interestingly, in addition to reduction of AEDs, each group exhibited a significant decline in seizure frequency at LTM follow-up. The number of patients undergoing surgery between admission and follow-up was small and did not significantly skew the results. This, together with the global reports of improvement and modest improvements in measured quality of life, suggests a beneficial effect of the admission that may be more evident in those with ES, though the small size of the PNES group may have contributed to the failure to attain statistical significance here. Reasons for these self-reported improvements may markedly differ
for the two diagnostic groups, but may include establishing a definitive diagnosis, simplifying or changing the medical regimen, and providing additional subspecialty consultation and support that would otherwise not have been arranged in the outpatient setting. LTM is usually a necessary precursor for surgery and VNS implantation, and outcomes for these have been well studied [16]. Our sample was not large enough to comment on these separately. In some cases, LTM may have resulted in the initiation of new supportive psychotherapy or other psychiatric care. We explored the possibility of questionnaire response bias and found that patients who participated in the follow-up assessment were representative of the baseline study sample. Similar proportions of people with ES and PNES reported improvement at follow-up after LTM. However, on the QOLIEs, patients with ES reported significant improvements in Seizure Worry, Medication Side Effects, and Social Function; patients with PNES showed a trend toward improvement in Medication Side Effects. There was no significant improvement in occupational status for either group, similar to what others have found [17]. There are some limitations to this retrospective study. The PNES group size was small, so statistical power is limited. However, the cases were carefully chosen from a larger group, and strictly defined so as not to include any doubtful cases. There were no nonLTM controls. Therefore, the differences in outcome between patients with ES and those with PNES may be attributed to factors other than the LTM, including subsequent changes in lifestyle. Subjects may have been more unwell at the time of admission than at follow-up, for example. Improvement may therefore have had less to do with the LTM than with life circumstances. However, our 6to 8-week waiting list for admission and the exclusion of patients admitted urgently should have minimized this possible confound. It is interesting to note that the indeterminate group at followup, although not analyzed, behaved somewhat like the PNES group except that AEDs increased over time, suggesting that definitive diagnosis on LTM may be important to sustained improvement. It is appropriate as previously mentioned [14] to consider definitive diagnosis of PNES during LTM as the start of treatment. Future efforts to understand and improve long-term outcomes are necessary, with more research focused on the specific role of LTM in this process.
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Ethical approval We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. Conflict of interest statement None of the authors has any conflict of interest to disclose. Acknowledgments This project was supported in part by a research stipend from the Albert Einstein College of Medicine. The authors also acknowledge the help of Sonia Replansky, who completed the institutional review board consents and helped initiate data collection for this study. The Brigham and Women’s Hospital Center for Clinical Investigation provided statistical analysis. References [1] Mari F, Di Bonaventura C, Vanacore N, et al. Video-EEG study of psychogenic nonepileptic seizures: differential characteristics in patients with and without epilepsy. Epilepsia 2006;475:64–7. [2] Ribaï P, Tugendhaft P, Legros B. Usefulness of prolonged video-EEG monitoring and provocative procedure with saline injection for the diagnosis of non epileptic seizures of psychogenic origin. J Neurol 2006;3:328–32. [3] Park KI, Lee SK, Chu K, Lee JJ, Kim DW, Nan H. The value of video-EEG monitoring to diagnose juvenile myoclonic epilepsy. Seizure 2009;18:94–9. [4] Hovorka J, Nezádal T, Herman E, Nemcová I, Bajacek M. Psychogenic nonepileptic seizures, prospective clinical experience: diagnosis, clinical features, risk factors, psychiatric comorbidity, treatment outcome. Epileptic Disord 2007;9(Suppl. 1):S52–8.
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