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Summary: Purpose: To examine whether seizure remission is a comprehensive marker of outcome in psychogenic nonepileptic seizures (PNESs).
Methods: A postal questionnaire was returned by 147 patients with PNESs a mean of 4.2 years after diagnosis (mean age at follow-up, 38.1 years). The proportion of patients who were “unproductive” (receiving health-related state benefits) at follow-up was determined, with a comparison of markers of ongoing psychopathology (Global Severity Index, anxiety and depression scores of the Symptom Checklist 90, Somatization Index DSM of the SOMS-2) in three outcome groups: group 1, continuing seizures; group 2, seizures stopped but patients “unproductive;” and group 3, seizures stopped, patients “productive.”
Results: Of the patients, 71.4% continued to have seizures, and 28.6% had achieved seizure remission; 60.0% of patients with continuing seizures and 42.7% of patients in remission were “unproductive” (difference, NS). Ongoing psychopathology was related to the factor “group membership” with higher values in groups 2 and 3 than in group 1 (GSI, p < 0.001; anxiety, p = 0.01; depression, p = 0.02; Somatization Index DSM, p < 0.001). Across all patients and in the subgroup with PNESs and additional epilepsy, differences were significant only between groups 2 and 3, not between groups 1 and 2. In patients with PNESs alone, differences were significant only between groups 1 and 2.
Conclusions: Seizure remission is not a comprehensive measure of good medical or psychosocial outcome in PNESs. Nearly half the patients who become seizure free remain unproductive. Many of these patients continue to report symptoms of psychopathology. Seizure control should not be the only focus of treatment in clinical practice or outcome observation in research studies.
Psychogenic nonepileptic seizures (PNESs) can be defined as a form of paroxysmal behavior that mimics epileptic seizures and is characterized by a sudden and time-limited disturbance of motor, sensory, autonomic, cognitive, and emotional functions, or a combination of these. PNESs are usually thought to represent an automatic expression of psychological distress rather than a wilfully simulated event, but establishing underlying intentionality is difficult (1–3).
Since the introduction of video-EEG into routine clinical practice, it has become clear that PNESs are more common than expected. Five percent of patients who carried a diagnosis of epilepsy in primary care (4), 10% referred to an epilepsy clinic with seizures refractory to antiepileptic drugs (AEDs) (5) and 30% of patients referred to an American epilepsy center for prolonged video-EEG monitoring had PNESs rather than epilepsy (6). What is more, patients with PNESs have a greater tendency than do those with epilepsy to develop seizure status, causing emergency admissions to hospital (7). One fourth of patients with PNESs seen at an epilepsy centre had been taken to an intensive care unit to control their seizures (8). This means that PNES patients are at high risk of iatrogenic harm or even death from inappropriate or inadvertent medication administration (9–12).
PNESs are costly to patients and to society at large. The mean proportion of patients reporting complete cessation of seizures in a range of outcome studies was 31%, and only 43% of patients were living independently at the time of follow-up (Table 1) (13–25). One large study showed that 69% of patients with PNESs were working at the time of initial manifestation of seizures, but only 20% were still working at the time the diagnosis was made (26). Another study revealed that the proportion of patients receiving disability benefits increased from 33% at the time of diagnosis to 60% after a mean follow-up interval of 17 months (15). The cost of the misdiagnosis of PNESs as epilepsy has been estimated as $100,000 per patient (26). The indirect costs through loss of employment of patients and carers are likely to be much greater than the direct costs of inappropriately prescribed AEDs or professional time (27).
Table 1. Overview of studies examining outcome of PNES in adults
| Number||Mean follow-up after diagnosis (mo)|| Concurrent epilepsy*|| % PNES-free||% living independently|
|Krumholz 1983 (25)|| 34||60||+||29||NR|
|Lempert et al. 1990 (24)|| 50||24||+||34||28|
|Meierkord 1991 (23)|| 70||60||+||40||31|
|Kristensen 1992 (22)|| 28||70||+||45||45|
|Betts 1992 (21)||121||24||+||31||NR|
|McDade 1992 (20)|| 13||12||+||33||NR|
|Walczak 1995 (19)|| 51||16||+||35||NR|
|Krahn 1997 (27)|| 71||17||−||24||55|
|Ettinger 1999 (18)|| 56||18||−||52||32|
|Kanner et al. 1999 (17)|| 45||14||+||29||NR|
|Quigg et al. 2002 (15)|| 30||17||+||33||40|
|Carton et al. 2003 (14)|| 85||30||−||28||70|
|Reuber et al. 2003 (13)||164||49||+||29||44|
|Mean, M; Total, T||T, 818||M, 31.6||N/A||M, 31||M, 43|
The realization that PNESs are common, serious, and costly has stimulated increasing interest in effective treatments. Randomized controlled studies of different psychotherapeutic interventions are finally under way, and the results of a National Institutes of Health (NIH)-supported study of antidepressant therapy are awaited (28,29). Yet it remains unclear how the outcome of treatments for PNESs should be measured. Although some of the most recent treatment studies have included a range of outcome measures, the existing literature shows that the number of seizures or the proportion of patients becoming seizure free after intervention have been the most popular outcome measures (20,21,28,30–38). However, some evidence indicates that patients can remain disabled by psychosocial problems and dependent on state benefits although they have stopped having seizures. For instance, one study showed that although PNESs had fully remitted in 35% and decreased substantially in a further 41% of patients 16 months after diagnosis, occupational status had either not changed or deteriorated in 80% of patients (19).
In epilepsy, the complete remission of seizures is an important treatment goal for several reasons. These include the reduction of the risk of seizure-related injury and sudden unexpected death (39), reduction of stigma (40), and improvement of socioeconomic status and quality of life (41,42). However, it is not clear whether the achievement of seizure remission is a similarly important indicator of outcome in PNESs. To approach this question, we focused on measures of continuing psychopathology in patients with PNESs whose long-term outcome we described previously (13). In this study, we compare psychopathology in patients whose seizures were continuing with that in those whose seizures had stopped but also examine employment status as a cofactor.
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We previously showed that the long-term outcome in patients with PNESs seen in an epilepsy center is poor. At a mean age of 38 years, and just over 4 years from the time of diagnosis, 71% of the patients continued to have seizures, and 51% were dependent on state benefits (13). In this study, we examined whether the achievement of complete cessation of seizures for >1 year was a meaningful, comprehensive marker of outcome.
In line with other outcome studies (see Table 1) (14,15,17–25,27), almost a third of patients with PNESs achieved seizure remission. Yet, even in this group, >40% were in receipt of health-related benefits at the time of follow-up and did not enter (or reenter) full-time employment or education. The observation that no significant difference occurred in the risk of continuing nonproductivity between patients whose seizures had stopped versus those whose seizures had not, does not mean that seizure status is of no importance to patients or benefit agencies. However, this observation does suggest that seizure control is not a major factor in the self-assessment and third-party assessment of disability in this patient group.
The comparison of measures of ongoing psychiatric symptoms, somatization, depression, and anxiety showed that mean scores tended to be lower in patients whose PNESs had stopped. However, across the whole patient group and in the subgroup with PNES+E, scores were significantly lower only in those patients who were seizure free and productive. Little difference was noted between patients whose seizures continued and patients whose attacks had stopped but who remained nonproductive. In the subgroup of patients with PNES-only (Table 3b), the achievement of seizure control may be a more meaningful marker of psychopathology, but even in this subgroup, nine (39.1%) of 23 patients remained unproductive, indicating that seizure control does not necessarily equate with good overall outcome.
Given that a significant interaction was found between age at manifestation and seizure and productivity outcome, it is possible that the differences between the PNES-only and PNES+E subgroups were related to the fact that the age at onset of PNES was lower in the PNES+E group. Conversely, real differences may exist in terms of psychopathology between patients with PNES-only and PNES+E (46), although such differences have not been found by all groups who have examined this issue (47).
The most important finding of this study, however, is that nearly half the patients whose PNESs had stopped remained disabled and continued to have symptoms of psychiatric disorders. This is in keeping with a study of 56 patients with PNESs that found evidence of depression in 52%, suicidal ideation in 39%, and a history of a recent suicide attempt in 20% of patients a mean of 18 months after diagnosis (48). Suicide attempts were as common in patients who continued to have seizures as they were in those whose seizures had stopped.
Evidence from studies in patients with epilepsy suggests that measures of psychopathology are correlated more closely with Quality of Life (QoL) than with physical markers of severity of the seizure disorder (49–52). One would therefore expect the findings of this study to mirror those of a previous investigation examining the relation between seizure frequency or remission and QoL in 30 patients with PNESs a mean of 17 months after diagnosis (15). Although patients who had achieved complete remission of seizures in this study showed greater improvements in QoL than did those with continuing seizures, the study also revealed a very substantial group of patients in whom seizures stopped but life did not improve. Only 50% of those with complete remission experienced a subjective improvement in QoL, and about half of those who achieved full seizure control had significant psychiatric symptoms or an unproductive occupational status. Furthermore, no significant correlation of QoL and seizure frequency overall was noted (15).
Given that the value of seizure frequency or control appears limited, what outcome measures would be more relevant? In view of the heterogeneity of PNES disorders and related interventions, we suggest the following:
Outcome measures must be chosen with the specific condition in mind. PNESs involve unpredictable, disabling attacks that often lead to dependence on carers and state benefits, which are associated with other psychiatric and medically unexplained physical symptoms and high health care utilization.
Measures must be suitable for particular patient groups; those suitable for children may not be applicable to men or women.
Outcome measures of PNESs treatment studies should include psychosocial domains such as self-efficacy, activities, and perceived support.
Measures should have face validity for the particular intervention: a score measuring change in illness representations may be a good choice for a brief intervention tackling patients' beliefs and assumptions about their condition, whereas such an intervention may not effect changes of social and work adjustment in the short term.
Both subjective measures and objective measures should be considered because the two reveal different aspects of HRQoL (15,53
), and subjective measures cannot be relied on in isolation (54
The applicability of outcome measures may depend on the health care system they are applied in. A person funding his or her own health care may be interested in significant subjective improvements, whereas public health purchasers may only be prepared to fund interventions that reduce health care costs. In countries where health care and social budgets are financed by tax income, interventions may be funded only if reductions in direct and indirect health care costs can be demonstrated.
Some of the more recent intervention studies have used a range of suitable measures in addition to seizure counts. For instance, a pilot study of a 12-session cognitive behavioural therapy programme demonstrated significant psychosocial improvements on the Work and Social Adjustment Scale (55), Hospital Anxiety and Depression Scale (56), and positive changes of beliefs and assumptions on the Illness Perceptions Questionnaire (57). Another small but innovative open-ended group psychotherapy program that failed to show appreciable effect on seizure control (31) demonstrated significant benefits in posttraumatic and dissociative symptoms and emotionally based coping by using the Coping Inventory for Stressful Situations (58), the Davidson Trauma Scale (59), the Curios Experiences Survey (60), and the State-Trait Anger Expression Inventory-2 (61). Our own experience suggests that a count of unexplained physical symptoms that have caused patients to consult a doctor over the previous 6 months is a measure that may be closely correlated with seizure severity and longer-term global outcome (45,62).
This study has several limitations. The analysis was based on postal returns of a self-report questionnaire. Because of this, it was not possible to distinguish clearly between patients with ongoing epileptic and nonepileptic seizures in the PNES+E group. Although the overall response rate was satisfactory, and no identifiable differences were seen between those PNES patients who did and those who did not return the questionnaire, it is possible that the patient sample described here is biased in some way. It should be pointed out that elevated scores in self-report measures do not mean that patients are necessarily symptomatic or would pass the threshold of a DSM-based psychiatric diagnosis. It may be relevant that significant differences were found between the three patient groups with regard to education and age, although we did not think that these differences would be relevant to the comparisons made here. Although the results in the whole group would not have been different, the results of the analysis in the PNES+E and PNES-only subgroups clearly depend on the definition of “additional epilepsy.” The PNES+E group would have been smaller and the PNES-only group bigger if we had included only patients with ictal EEG or video-EEG evidence of epilepsy or a specific interictal EEG focus. Finally, we did not have sufficient data to analyse the impact of seizure freedom on health care costs. However, no significant difference was found in the rate of patients still taking (inappropriate) AEDs. Yet the effect may have been much more significant had the more relevant indirect costs been taken into account
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Traditional outcome measures of both epilepsy and PNESs have been based on the frequency of seizures. Although seizure control is important in both disorders, it is not the strongest predictor of QoL (49). In addition, distinct differences appear to exist between patients with epilepsy and PNESs with regard to the relevance of seizure remission. In epilepsy, seizure-free individuals can return to near-normal levels of functioning (63). In patients with PNESs, this does not appear to be the case. In fact, the long-term outcomes in PNESs appear to be worse than those in epilepsy but comparable to those with dissociative and somatization presentations (64,65).
Seizure remission cannot be considered a comprehensive measure of medical or psychosocial outcome in PNESs. Nearly half the patients who become seizure free remain unproductive. Many of these patients continue to have symptoms of psychopathology including other somatoform, depressive, and anxiety disorders. This suggests that seizure counts should be complemented by other outcome measures in trials of medical and nonpharmacologic interventions in PNESs. It also implies that seizure control should not be the only focus of treatment programmes. Further work is required to elucidate differences in psychopathology between patients with PNES-only and those with additional epilepsy. We also must discover not only how to improve seizure control but also how to improve QoL in patients with PNESs.