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Purpose: To determine whether withdrawal of antiepileptic drugs (AEDs) in patients with psychogenic nonepileptic attacks (PNEAs) improves outcome.
Methods: Randomized controlled trial of AED withdrawal in patients with PNEAs. Patients were randomized to immediate or delayed (9 months) withdrawal of AEDs. We recorded spell frequency, changes in work status, use of emergency medical services, and psychological status at baseline, 9 months, and 18 months.
Results: Of 193 patients screened, 38 fulfilled entry criteria, 13 declined participation, and 25 were randomized. Fourteen patients were randomized to immediate withdrawal (IW) and 11 patients to delayed withdrawal (DW). There was a significant reduction in spell frequency from baseline to 9 months in the IW group but not in the DW group (p = 0.028). There was a significantly greater reduction in use of rescue medication in the IW group compared to the DW group between baseline and 9 months (p = 0.002). Emergency health care utilization dropped to zero in both groups by the end of the study. Psychological measures reflecting internal locus of control increased significantly more in the IW group (p = 0.005).
Discussion: Stringent diagnostic criteria and an increasing tendency for patients to be referred before AED prescription limited the recruitment and the power of the study. Our data nonetheless provide evidence that some outcomes are improved by AED withdrawal in patients with PNEAs.
Psychogenic nonepileptic attacks (PNEAs) may be defined as paroxysmal events that resemble or may be mistaken for epileptic seizures, are not associated with any measurable alteration in brain electrical activity, and could plausibly be attributed to a psychological cause. PNEAs present to virtually all health care professionals, account for approximately 18% of patients presenting with spells, and represent a significant management problem for epilepsy specialists (Kotsopoulos et al., 2003). A variety of psychological interpretative paradigms have been proposed to explain PNEAs (Gates & Erdahl, 1993; Bowman & Markand, 1996; Krishnamoorthy et al., 2001).
A recent Cochrane review concluded that there was no reliable evidence to support the use of any specific treatment (Brooks et al., 2007). There is, however, increasing consensus that an initial clear and unambiguous communication of the diagnosis of PNEAs and the withdrawal of an erroneous diagnosis of epilepsy is a necessary part of management and may be the only required intervention for some patients (Aboukasm et al., 1998; Hall-Patch et al., 2010).
Up to 80% of patients with PNEAs are exposed to anti-epileptic drugs (AEDs), and up to 40% remain on AEDs after the diagnosis has been established (Benbadis, 1999; Reuber & Elger, 2003; O’Sullivan et al., 2007; Hall-Patch et al., 2010). Studies across a range of physical and psychological disorders have indicated that inconsistency between diagnosis and management undermines compliance and prejudices outcome (Barsky & Borus, 1999). Therefore, it is possible that failure to withdraw AEDs, by undermining the clarity of a communicated diagnosis of “no epilepsy,” may have a negative effect on outcome in PNEAs.
In a previous study we showed that AED withdrawal in the context of PNEAs can be carried out safely (Oto et al., 2005). In the present study we investigate the potential therapeutic effect of planned withdrawal of AEDs following the diagnosis of PNEAs, by carrying out an exploratory randomized, controlled trial comparing outcomes in patients who had immediate withdrawal of AEDs at diagnosis with those who had withdrawal delayed by 9 months.
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This is the first randomized controlled trial aimed at determining the possible therapeutic effect of a scheduled AED withdrawal at the time of the diagnosis of PNEAs.
We detected no significant between-group differences that would support a therapeutic effect of AED withdrawal on our primary outcome measure, spell frequency. The fact that we achieved a significant drop in spell frequency in the IW group but not in the DW group, hints at an effect, however.
One obvious possible reason for the preceding result was our small sample size. The only available data on which to base a preliminary power calculation came from cohort studies that suggested that up to one third of the patients become attack free regardless of management (Iriarte et al., 2003). A power calculation based on an alpha of <0.05 suggested we would have required 87 patients per group to have 80% probability of detecting a medium-sized effect. We thought it unlikely that we would achieve this, but elected to proceed with an exploratory trial which, in the event, was indeed underpowered. The lack of significant differences between IW and DW groups in terms of our primary outcome variable should be viewed in this context.
Overall, however, outcomes in terms of spells were encouraging, with 50% in the IW group and 27% in the DW being spell free 18 months after diagnosis, with a nonsignificant difference in favor of the IW group. This compares favorably with series in the literature, including one published trial of cognitive behavioral therapy (Ettinger et al., 1999; Reuber et al., 2003a; Goldstein et al., 2004). Our patients received a great deal of attention during the trial (see below), which may have improved the overall outcome, particularly as our patient population often feels rejected and misunderstood by physicians (Mokleby et al., 2002).
Our secondary outcomes provide clearer indication of a positive effect of AED withdrawal. The use of emergency services for PNEAs dropped to zero in IW and DW groups, as did the use of rescue medication, but they did so earlier in the IW group, and in the case of rescue medication the difference between IW and DW groups was significant. This is consistent with our previous study, which showed a drop in use of emergency services at diagnosis that was largely independent of the result in terms of continuing to have spells (McKenzie et al., 2009), and with the study of Martin et al. (1998) who found that video-EEG monitoring and the subsequent delivery of diagnosis substantially reduced medical costs by 6 months and reduced the use of emergency rooms.
Reduction in demand for emergency health care suggests a change in attitude toward the spells themselves, possibly on the part of relatives and carers, if not patients. Health care contacts may act to perpetuate psychogenic disorders (Page & Wessely, 2003), and a reduction may, therefore, be beneficial in the long term as well as reducing the impact of the disorder in the short term. These issues require further study.
There exists a concern that patients who cease having PNEAs will go on to develop new psychogenic symptoms. Our data are reassuring in this regard, with only a small minority of patients developing new symptoms during the study, all of which resolved by study completion. This was also reflected in the IPQ, with a reduction of the number of symptoms reported throughout the study. It was also encouraging that use of emergency services for reasons other than PNEAs dropped, suggesting that patients did not simply replace PNEA with other emergency symptomatology.
Occupational status is poor in patients with PNEAs, and existing evidence suggests that it remains so even in patients whose spells resolve (Reuber & Elger, 2003). A small minority of patients may cease to be dependent (McKenzie et al., 2009), and our relatively short-term data are consistent with this.
All of our patients were on AEDs known to have mood-stabilizing effects (Ettinger & Argoff, 2007). One possible outcome of withdrawal would, therefore, be exacerbation of anxiety and depression. The HADS scores, however, remained stable throughout the study, with no differences between groups. As might be expected, SEALS scores did suggest that the IW group was significantly less tired than the DW group at 9 months, but provided no other evidence of a benefit in “well-being” as a result of AED withdrawal.
One of the theories behind the study was that removing medication would enhance the message that PNEAs are not a result of a neurologic condition and change patients’ illness attribution. Consistent with this, patients’ perceptions that their attacks were due to stress or mental state increased steadily in the IW group, becoming significantly higher at the end of the study reflecting a greater internal locus of control. For the rest of the IPQ results it is difficult to draw conclusions because of the potential for multiple testing effects. In any event, we found no evidence of deterioration.
Trials in this area are known to be difficult (LaFrance et al., 2007), and this trial posed a number of practical problems. Our final recruitment was smaller than we anticipated. This was mainly because of the increasing (and otherwise welcome) tendency for neurologists in the region to refer before prescribing AEDs, but partly because of our stringent diagnostic criteria (both for PNEAs and for excluding coexisting epilepsy). Because of difficulties recording spells, poor patient motivation, and other factors, the diagnostic process may be prolonged in some patients with PNEAs, and we underestimated the effect of this on recruitment. One third of patients declined participation.
The ethical implications of leaving subjects with PNEA on AEDs for 9 months was an issue discussed extensively by the research team and the research ethics committee. We considered that, although it is intuitive that patients with PNEA (only) should not be prescribed AEDs, in practice a large proportion of patients are left on medication (Ettinger et al., 1999; Reuber et al., 2003; O’Sullivan et al., 2007, Hall-Patch et al., 2010), to the point that it could be said to constitute “treatment as usual” for many physicians. Furthermore, there is no published evidence that withdrawing AEDs improves outcome, or that maintaining them worsens it. The trial was approved by our research ethics committee on this basis. Ethical constraints may also have had a negative impact on the results of the trial. In our daily practice, we positively emphasize the importance of withdrawing AEDs as a crucial step to a complete recovery. In the context of informed consent for the trial, it was not possible to be so one-sided, thus potentially diluting the psychological impact of withdrawal.
Our drop-out rate was low, but the numbers conceal the great effort it took to achieve this. Patients with PNEAs are poor attenders, and repeated reminders and much flexibility on the part of the research fellow were required to ensure that data were acquired.
Anticipating some of the above difficulties, we chose to carry out a pilot study. To expose the potential difficulties of a definitive exercise, we elected to stick as rigorously as possible to standard trial methodology. Unsurprisingly, we concluded that a definitive trial would have to sacrifice rigor for power and practicality in order to be successful.
This trial has not definitively answered the question of whether AED withdrawal has in itself a therapeutic effect on PNEAs. However, as an exploratory exercise, the results have provided a suggestion that there may be a positive effect, and have provided clearer evidence of a positive effect on use of emergency services and rescue medication, as well as on locus of control, as reflected by a shift in illness attribution. As such, our results may encourage the practice of AED withdrawal in appropriate patients.
Finally, and as a by-product of this work, we hope to inform other researches considering a trial in this area on the challenges likely to be encountered in the PNEA population.