YEBEH-04278; No of Pages 6 Epilepsy & Behavior xxx (2015) xxx–xxx
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Review
Epidemiology of psychogenic nonepileptic seizures Ali A. Asadi-Pooya a,b,⁎, Michael R. Sperling a a b
Jefferson Comprehensive Epilepsy Center, Department of Neurology, Thomas Jefferson University, Philadelphia, USA Neurosciences Research Center, Shiraz Medical School, Shiraz University of Medical Sciences, Shiraz, Iran
a r t i c l e
i n f o
Article history: Received 8 December 2014 Revised 3 March 2015 Accepted 4 March 2015 Available online xxxx Keywords: Definition Epidemiology Psychogenic nonepileptic seizures
a b s t r a c t We critically review the existing literature about the epidemiology (i.e., diagnosis, occurrence, age, gender, comorbidity with epilepsy, associated factors, prognosis, mortality, and cost) of psychogenic nonepileptic seizures (PNES) and provide suggestions for future research. Psychogenic nonepileptic seizures are commonly diagnosed at epilepsy centers. The diagnosis of PNES relies on a multidisciplinary evaluation and is usually based on different combinations of data. Recording a seizure, while under video-EEG monitoring, is the most reliable diagnostic test. However, not all patients present with seizures while under video-EEG monitoring. Furthermore, not all epileptic seizures produce visible changes in the scalp EEG. The incidence of PNES was estimated to be 1.4–4.9/100,000/ year in three previous studies, and the prevalence was calculated to be between 2 to 33 per 100,000 in one study, making it a significant neuropsychiatric condition. However, there remains a scarcity of data about the epidemiology of PNES, and extant studies that assessed the epidemiological characteristics of PNES have significant limitations. For example, inconsistencies with regard to the age of patients studied and lack of standardization of the diagnostic criteria are some of the significant limitations among studies. In conclusion, PNES merit further epidemiological and pathophysiological investigation. A more precise definition and clear guidance on standards for the diagnosis might influence the direction of future research. Well-designed prospective population-based studies to clarify the epidemiology of PNES in various parts of the world, including an evaluation of the predisposing, precipitating, and perpetuating factors in cross-cultural comparisons is required. © 2015 Elsevier Inc. All rights reserved.
1. Introduction Psychogenic nonepileptic seizures (PNES) are relatively common occurrences in epilepsy centers [1,2]. The International League Against Epilepsy (ILAE) has identified PNES as one of the 10 key neuropsychiatric issues associated with epilepsy [3]. High-quality epidemiological data significantly influence health care and research [4]. In this paper, we critically review the current literature about the definition, ascertainment criteria, occurrence, and clinical characteristics of PNES (i.e., age, gender, comorbidity with epilepsy, associated factors, prognosis, mortality, and cost) and provide suggestions for future research. 2. Diagnosis Psychogenic nonepileptic seizures consist of paroxysmal changes in responsiveness, movements, or behavior that superficially resemble epileptic seizures but lack a neurobiological origin similar to epileptic seizures and are not associated with electrophysiological epileptic changes [5–7]. This condition has been a subject of enduring interest to both neurology and psychiatry experts. The terminologies used to describe this ⁎ Corresponding author at: Jefferson Comprehensive Epilepsy Center, Department of Neurology, Thomas Jefferson University, Philadelphia, USA. Tel.: +1 816 694 0498. E-mail address: [email protected] (A.A. Asadi-Pooya).
condition reflect the prevailing etiological assumptions of their times; hysterical seizures, conversion seizures or disorder, functional seizures, functional neurological symptom disorder, pseudoseizures, psychogenic seizures, and finally, psychogenic nonepileptic seizures (PNES) are some of the terms used to describe this disorder. Interestingly, PNES is a condition made unique by having largely been defined in terms of what it is not, rather than what it is. Having achieved the exclusion of an epileptic or movement disorder does little to define the variables that might affect management of affected patients. Even the newest criteria in the diagnostic and statistical manual of mental disorders, fifth edition (DSM-5), for conversion disorder with attacks or seizures, in which the emphasis is “incompatibility” with a known neurological disorder, does little to help define PNES clearly and explicitly [8]. Epilepsy and PNES have a variety of differing symptoms and signs; however, none of them is pathognomonic of PNES. Thus, sometimes clinical differentiation of PNES from epileptic seizures proves to be difficult. Video-EEG monitoring with ictal recording is considered the optimal test for the diagnosis of PNES, and a definitive diagnosis is made when typical seizures lack accompanying EEG abnormalities. However, there are patients with epilepsy (e.g., frontal lobe epilepsy) and abnormal movements during their epileptic seizures, with no visible change in their scalp EEGs [9]. Therefore, misdiagnosis is common, and symptoms may be attributed to more than one condition in a single patient,
http://dx.doi.org/10.1016/j.yebeh.2015.03.015 1525-5050/© 2015 Elsevier Inc. All rights reserved.
Please cite this article as: Asadi-Pooya AA, Sperling MR, Epidemiology of psychogenic nonepileptic seizures, Epilepsy Behav (2015), http:// dx.doi.org/10.1016/j.yebeh.2015.03.015
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or different physicians may offer different diagnoses to the same patient. In one previous study of 350 adult patients with uncontrolled seizures, who were taking antiepileptic drugs (AEDs), 9% were proved to have PNES [10]. In another similar study of 198 children, this figure was 1.5% [11]. The term psychogenic movement disorders (PMD) has been applied to disorders that manifest with physical symptoms, specifically abnormal movements (e.g., tremor), which cannot be attributed to any known underlying neurological disorders [12]. However, the distinction between PNES and PMDs is not always easy. One retrospective study of comparison of psychogenic movement disorders and psychogenic nonepileptic seizures revealed more similarities than differences between these two conditions [13]. Both groups were overwhelmingly female, with high rates of chronic pain disorders, depression, fatigue, subjective cognitive complaints, and abuse. Over half were unemployed or disabled. Despite the presence of known risk factors for somatization, both were characterized by prolonged time to diagnosis during which multiple neurologic evaluations, trials of medications, and other unnecessary interventions were performed [13]. However, there is a wide degree of opinion about these findings, and there are articles suggesting differences. In the latter study, significant differences were observed between these two conditions, including age, rates of childhood abuse, and anxiety disorder diagnosis [13]. In one study, the authors found no differences between the psychiatric profiles, health-related quality of life, or self-efficacy for self-management of disease among patients with PNES and patients with PMDs despite their different physical manifestations [14]. In another study, the authors observed that patients with motor conversion disorder had IQ levels in the average range and intact general cognitive functioning, suggesting possible mechanistic differences from patients with PNES [15]. Generally speaking, the precision of the epidemiological data about a disease depends on the methods used to find affected patient. The diagnosis of PNES may be based on different combinations of data. The combination of patient history, witness reports, clinician observations ictal and interictal electroencephalography (EEG), and ictal video is used for diagnostic determination. Four categories of diagnostic levels of certainty for PNES have been suggested based on common scenarios and the combination of data (Table 1) [16]. However, there are important caveats even in this proposed scheme. For example, patients may have both epilepsy and PNES and may have an incorrect diagnosis. The presumed gold standard test [i.e., video-electroencephalography (video-EEG)] for the diagnosis of PNES but may have either false positive (e.g., in the case of some frontal lobe epilepsies) or false negative (not all patients have a seizure while under video-EEG monitoring) results. In a systematic review of sensitivity and specificity of procedures for the differential diagnosis of epileptic and nonepileptic seizures, no procedure with both high sensitivity and specificity and adequately replicated findings emerged [17]. However, this review suggested that video-EEG monitoring has as yet no reliable equivalent among the range of procedures and observations which have been investigated. The range of symptoms presented in PNES suggests that a multimethod approach may be required [17].
3. Occurrence Psychogenic nonepileptic seizures are relatively common. It has been reported that from 5 to 10% of outpatients in epilepsy clinics and 20 to 40% of inpatients in epilepsy monitoring units have PNES [1,2, 18]. This observation has been made in both developed and developing countries. However, most reports derive from tertiary referral centers, and the findings from these centers cannot be applied to the whole population. Population-based studies are scarce from developed countries and nonexistent from developing countries. In one populationbased prospective study from Scotland, the authors identified first presentations of PNES from a population of 367,566 over 3 years. Psychogenic nonepileptic seizures were diagnosed in 68 people, in 54 of whom the diagnosis was confirmed by video-EEG recording, indicating an incidence of 4.9/100,000/year [19]. However, this study had some limitations. Primarily, referrals were accepted from the age of 13 years upward, despite the fact that PNES can present at earlier ages (see below). Besides, in 14 patients, the diagnosis of PNES was not confirmed. In another study, the incidence of PNES was estimated to be 1.4/100,000/year in Iceland [20]. This study had similar limitations; only patients 15 years of age or above at the time of the investigation were included. The method of case ascertainment and exclusion of nonsevere cases limited the value of this study. In a retrospective study of patients referred to a specialist center, the incidence of PNES in Hamilton County, Ohio, USA between 1995 and 1998 was determined. The mean incidence of PNES was 3.03/100,000/year [21]. However, this was a retrospective study and required evaluation at a referral center, which limits the validity of the findings. The authors themselves stated that “Our study may have underestimated the true incidence of PNES, as our diagnostic criteria required video and EEG monitoring for diagnosis. Some patients may have been diagnosed with PNES based on routine EEG or in other centers, and were not included in our study” [21]. Prevalence data of PNES are even scarcer. There is just one study in the literature, in which the authors tried to provide an estimate based on a calculation. They used the following data as the basis of their calculation. A prevalence of epilepsy of 0.5–1%; a proportion of intractable epilepsy of 20–30%; a percentage of these referred to epilepsy centers of 20–50%; and a percentage of patients referred to epilepsy centers that are PNES of 10–20%. They concluded that the prevalence of PNES is somewhere between 1/50,000 and 1/3000 or between 2 and 33 per 100,000, making it a significant neuropsychiatric condition [22]. This calculation is reasonable, but the accuracy of the estimate is unknown. 4. Age Psychogenic nonepileptic seizures tend to begin in adolescence and young adulthood, although the seizures can begin at any age [23–33]. There are reports about PNES in young children (as young as 5 years of age) [23,24], and some studies reported PNES in the elderly (even above 70 years of age) [23,25,32]. Age at onset in most patients appears
Table 1 Overview of proposed diagnostic levels of certainty for psychogenic nonepileptic seizures (PNES). Adapted from LaFrance WC, Baker GA, Duncan R, Goldstein LH, and Reuber M. Minimum requirements for the diagnosis of psychogenic nonepileptic seizures: a staged approach. A report from the International League Against Epilepsy Nonepileptic Seizures Task Force. Epilepsia 2013; 54(11): 2005–2018. Diagnostic level
History
Witnessed event
Electroencephalography (EEG)
Possible Probable
+ +
No epileptiform activity in routine or sleep-deprived interictal EEG No epileptiform activity in routine or sleep-deprived interictal EEG
Clinically established
+
By witness or self-report/description By clinician, who reviewed video recording, or in person, showing semiology typical of PNES By clinician experienced in diagnosis of seizure disorders, showing semiology typical of PNES (on video or in person), while not on EEG
Documented
+
By clinician experienced in diagnosis of seizure disorders, showing semiology typical of PNES, while on video-EEG
No epileptiform activity in routine or ambulatory ictal EEG during a typical ictus/event in which the semiology would make ictal epileptiform EEG activity expectable during equivalent epileptic seizures No epileptiform activity immediately before, during, or after ictus captured on ictal video-EEG with typical PNES semiology
Key: +, history characteristics consistent with PNES.
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to be in young adulthood, but there is often a significant delay to have a confirmed diagnosis, and patients often receive unnecessary treatments (e.g., antiepileptic drugs) for years before a correct diagnosis is made (Table 2). In one study, the authors dichotomized the patients into two groups: (1) those with age at onset below 18 years (juvenile) and (2) those with age at onset from 18–55 years (adult). Age at onset of PNES did not correlate with clinical manifestations, although factors potentially predisposing to PNES were quite different in patients with juvenile-onset PNES compared with those with adult-onset PNES. History of being abused, academic failure, epilepsy, or family history of epilepsy were more frequently observed in patients with juvenile-onset PNES, while medical comorbidities were more frequent among patients with adult-onset PNES [23]. In another study, the authors compared patients with onset of PNES after 55 years of age (n = 26) with those with onset at earlier ages (n = 241). They observed that patients with late-onset PNES were more likely to be male and to have severe physical health problems, while they were less likely to report antecedent sexual abuse [25].
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criteria but similar semiologic criteria should be used for the diagnosis of probable PNES in the outpatient clinic in men and women [33]. 6. Comorbid epilepsy The proportion of patients with PNES who also have epilepsy has been reported to vary from 5% to 50% [18,22,26,38–40]. Criteria for concomitant diagnosis of epilepsy have not been consistent in literature reports. Having interictal spikes, as most studies defined their epilepsy cases, does not necessarily mean that epilepsy is also present. Interictal epileptiform abnormalities have been reported in nonepileptic conditions [41] and in healthy people [42]. Demographic and clinical characteristics of patients with both PNES and coexisting epilepsy are similar to those of patients with only PNES [43]. It has been speculated that epilepsy may contribute to the risk of developing PNES not only through biologic mechanisms but also because the experience or observation of epileptic seizures may provide an opportunity for model learning [44]. 7. Associated factors
5. Gender There is a predominance of female gender among patients with PNES [33–37]. The female:male ratio in one study from China was reported to be 1 [35], but studies from five continents generally note PNES to be far more common in females (Table 2). Lesser examined the sex distribution in 21 studies and found descriptions of 734 women and 250 men who had PNES (female:male ratio = 2.94) [36]. However, most studies are not specifically designed to determine the demographic characteristics of patients with PNES. Psychogenic nonepileptic seizures are not only less common in men but also more challenging to diagnose in men than in women and more difficult to confirm with video-EEG monitoring in men compared to women [34]. However, no specific or consistent difference in the underlying psychopathology between men and women with PNES has been reported. In one study (129 women and 59 men), there were no significant demographic differences between women and men with PNES. Likewise, seizure characteristics and semiology were similar in both genders [37]. Another study also tried to determine if gender-specific differences exist in PNES predictors and PNES semiology. The authors retrospectively investigated 59 women and 27 men. They found significantly lower rates of reported physical and sexual abuse, lower rates of previous psychiatric diagnoses, and lower rates of chronic pain in male patients. However, they found no difference in PNES semiology between men and women. They concluded that distinct risk factor Table 2 Demographic characteristics of patients with PNES.a
North America (New Hampshire, USA) North America (Arizona, USA) South America (Brazil) South America (Argentina) Europe (Scotland) Europe (UK) Asia (Iran) Asia (India) Africa (South Africa) Australia
Mean age at onset (years)
Mean time to confirmed diagnosis (years)
33.4
6.51
NS 27.85 NS 30.9 31.55 23.2 21.8 NS 32.7
Female/male (ratio)
Reference
59/27 (2.18)
[33]
NS
142/42 (3.38)
[34]
7.89 11.18 0.6 7.1 5.5 7.4 NS 5.6
78/24 (3.25) 27/8 (3.37) 44/10 (4.4) 117/43 (2.72) 141/70 (2.01) 44/38 (1.15) 17/5 (3.4) 156/65 (2.4)
[26] [27] [19] [28] [1] [29] [30] [31]
PNES: psychogenic nonepileptic seizures; NS: not specified. a Most of these studies were not specifically designed to determine the demographic characteristics of patients with PNES.
Psychogenic nonepileptic seizures occur in a heterogeneous patient population. No single mechanism or contributing factor has been identified that is necessary and sufficient to explain PNES in all patients [44]. The most commonly reported PNES-associated factors are shown in Table 3 [2,45–52]. The relationship between childhood sexual abuse and PNES has received particular attention in the literature. In a study comparing childhood abuse in patients who had PNES (71 patients) with those who had epilepsy (140 patients), significantly higher rates of both sexual abuse (24.0% versus 7.1%) and physical abuse (15.5% versus 2.9%) were found in those who had PNES (P b 0.001) [52]. In a recent comparison of patients with PNES only (324 patients) with those who had epilepsy only (281 patients), history of abuse (physical or sexual) was more frequent among those with PNES [odds ratio: 3.35 (1.23–9.10); P = 0.018] [53]. However, there are discrepancies and inconsistencies among studies with regard to the interaction between childhood sexual or physical abuse and PNES depending on the study and depending on the design. In one study from Iran, the authors observed that history of childhood abuse (12.8%), physical abuse (11.8%), and sexual abuse (8.1%) was not as common in patients with PNES compared with Western patients [2,52]. There could be real differences between the latter series and the others. In other words, the observed differences might be clinically important and highlight the issue that other psychopathological mechanisms may explain development of PNES in a Muslim culture. However, these differences could have cultural or religious reasons, as extramarital sex is forbidden by law and religion in Iran and people might deny being physically or sexually abused due to family considerations [2]. The wide variety of methods used for assessment of abuse (sexual and physical) and lack of control populations in most of the published studies make it difficult to establish a cause and effect relationship between PNES and abuse. Another commonly reported PNES-associated factor is traumatic brain injury. In one study of 92 patients with PNES, 41 (44.6%) had a history of traumatic brain injury (TBI). Patients with TBI had more mood disorder diagnoses, were more likely to receive disability, and had lower global functioning compared with non-TBI patients with PNES after adjusting for age and sex. Patients with TBI and PNES had significantly increased odds for having major depression, behavioral impulsivity, posttraumatic stress disorder diagnosis, and a trauma/abuse history. The authors concluded that TBI is a significant risk factor in patients with PNES, being associated with increased psychiatric diagnostic comorbidity, symptom severity, poorer functioning, and increased disability [47]. In another study of 157 patients with video-EEG-confirmed PNES, 37 (24%) had the onset of their seizures attributed to a head injury [50]. Further exploration of the interaction between PNES and TBI could help with development of new treatment strategies, as
Please cite this article as: Asadi-Pooya AA, Sperling MR, Epidemiology of psychogenic nonepileptic seizures, Epilepsy Behav (2015), http:// dx.doi.org/10.1016/j.yebeh.2015.03.015
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Table 3 The most commonly reported psychogenic nonepileptic seizures associated factors. Associated factor
Observed rate (% of patients)
Reference
Sexual abuse
8.1 24 32.5 36.3 67 15.5 24.6 26 67 24 32 44.6 8.3 23.2
1 52 46 45 48 52 1 46 48 50 49 47 46 1
Physical abuse/neglect
Traumatic brain injury
Medical comorbidities (health-related trauma)
new pharmacologic and rehabilitative options become available [47]. We should emphasize that an agreed upon distinction between PNES-associated factors and comorbidities is not apparent in the literature, and a complete discussion of psychiatric comorbidities (e.g., depression and anxiety) is too broad to be covered in this review. In most patients with PNES, several potential interacting factors may be identified [44]. Reuber concluded that predisposing factors (e.g., abuse and neglect) increase vulnerability to the development of PNES. Precipitating factors may occur over days to months before the onset of seizures and seem to cause PNES to start, but these are far from universal. Factors that have been described as precipitating PNES include rape, injury, death of or separation from family members or friends, job loss, accidents, giving birth, surgical procedures, natural disasters (e.g., earthquakes), relationship difficulties, and legal action [44]. In older people, medical comorbidity is a common identifiable precipitant [23,37,44]. Finally, perpetuating factors (e.g., isolation, anger, anxiety, depression, misdiagnosis, and mistreatment) make it harder for patients to regain control of seizures or can aggravate the problem once seizures have started. Even if one factor seems to play a predominant role in a particular patient, other factors are likely to have contributed and should not be ignored [44]. These factors have been studied in Western countries and discussed in comprehensive reviews by other authors [2,7,44,51]. Finally, brain dysfunction is also associated with PNES. The neurobiology of PNES is still poorly understood. Obviously, PNES lack a neurobiological origin similar to epileptic seizures, but emerging evidence suggests that there is a neurobiological basis for these events. An association of PNES with brain dysfunction appears to be likely based on recent evidence of functional and structural brain connectivity abnormalities and also functional neuroimaging findings [54–57]. Psychogenic nonepileptic seizures could be the result of neurobiological dysfunctions of specific brain networks. 8. Prognosis Definitive diagnosis of PNES can lead to appropriate therapy and even cessation of the events [58]. In one study, seizure frequency during inpatient video-EEG monitoring was examined before and after the diagnosis of PNES was presented to 22 patients. A control group of 10 patients with epilepsy were also followed from prediagnosis to postdiagnosis. The number of nonepileptic seizures (in patients with PNES) or epileptic seizures (in those with epilepsy) within the 24-hour period prior to diagnosis was compared with the number of events that occurred within the 24-hour period after presentation of the diagnosis. The findings indicated that patients with PNES had a significant decrease in the frequency of events after diagnosis, while those with epilepsy showed no change in event frequency after diagnosis. Eighteen of the 22 patients with PNES had no further events during an acute follow-up period [58]. However,
in a previous review, the authors concluded that communicating to the patient that the seizures are not epileptic may stop PNES in the shortterm but does little to improve associated psychological morbidity, distress, or health-related quality of life. Without dedicated further treatments, PNES are likely to restart in the majority of patients [59]. Unfortunately, longer-term studies suggest that many patients with PNES will continue to experience seizures despite neurological and psychotherapeutic care [60]. Clinical and personality factors should be used to provide an individualized prognosis in patients with PNES. In one study, 164 adult patients with PNES were investigated, for a mean of 11.9 years after manifestation and 4.1 years after diagnosis of PNES. The responses showed that 71.2% of the patients continued to have seizures and that 56.4% were dependent on social security. Outcome was better in patients with greater educational attainment, younger onset and diagnosis, attacks with less dramatic features, fewer additional somatoform complaints, and lower dissociation scores [60]. In a systematic review published in 2011, the authors concluded that the prognosis of PNES in adults is poor. From their reviewed data, fewer than 4 in 10 newly diagnosed adults could be expected to become seizure-free within 5 years after diagnosis. In children, the proportion of patients achieving seizure remission appeared to be around 70%, which indicates a more favorable result [61]. 9. Mortality Scattered evidence suggests that PNES are associated with increased mortality. In one study, the authors obtained death certificate information in a cohort of 260 patients who presented with PNES between 1999 and 2004 from West of Scotland Regional Epilepsy Service, Southern General Hospital, Glasgow, UK. The follow-up period averaged 7.92 years, during which 17 patients died. Twelve out of the 17 patients who died were under the age of 75 years, giving a premature mortality rate of 0.58% per year compared with a Scottish mortality rate for the 40- to 75-year age group of 0.41%, per year. These results suggest that a diagnosis of PNES may be associated with a modest increase in mortality [62]. However, serious physical illness is prevalent in patients with PNES with an onset of their attacks after the age of 55 years. The development of physical illness (especially, where this has been frightening to the patient) may be an important triggering factor for PNES, at least in a subset of patients [25]. This means that the medical comorbidities could be responsible for increased mortality seen in patients with PNES and not necessarily the itself (i.e., PNES). Besides, in the Scottish study mentioned above, patients came from a population that was deprived relative to the general Scottish population; the authors concluded that some excess mortality might be expected secondary to socioeconomic factors [62]. On the other hand, in one study of 43 patients with PNES, 23% reported suicide attempts [63]. This may also contribute to the increased mortality among patients with PNES. 10. Health-care costs Psychogenic nonepileptic seizures place a heavy demand on emergency and nonemergency health-care services [64]. It has been observed that most patients who have PNES diagnosed with video-EEG monitoring experience substantial subsequent reductions in healthcare utilization and costs [64–66]. In one study, it was reported that in patients with a new diagnosis of PNES documented, prediagnosis medical costs exceeded $15,000 per patient and loss of work costs exceeded $22,000 per patient [67]. In another study in 2013, overall costs dropped from the 12-month period preceding PNES diagnosis (mean costs: $4567) to the 12-month period following PNES diagnosis (mean costs: $2783). This equated to a cost reduction of nearly $1800 per person [66]. In another study in 1998, there was an 84% average reduction in total seizure-related medical charges in the six months following PNES diagnosis. Average diagnostic testing charges declined by 76%, average medication charges decreased by 69%, outpatient clinic visits
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declined by 80%, and emergency room visits declined by 97% [65]. In a more recent study, the authors performed a 1-year prospective audit of use of PNES-related health-care items in patients with newly diagnosed PNES from PNES onset to diagnosis and from diagnosis to six months postdiagnosis. Before diagnosis, twenty-eight patients were responsible for 14 general practitioner home visits, 31 ambulance calls, 34 emergency department visits, 21 hospital admissions, 2 standard EEGs, 28 short video-EEG recordings, and 5 ambulatory EEG recordings. In the 6 months following diagnosis, there were 2 emergency department visits (94.1% reduction), no hospital admissions (100% reduction), 2 ambulance calls (93.5% reduction), no general practitioner visits (100% reduction), and no EEGs (100% reduction) [65]. Overall, the burden of PNES is significant, particularly if it remains undiagnosed. Early diagnosis of PNES may save money and reduce the service utilization burden for patients and the health-care system [66]. 11. Future directions Psychogenic nonepileptic seizures merit further epidemiological and pathophysiological investigation. A more precise and informative definition might influence the direction of future research. Developing clear guidance on standards for the diagnosis of PNES and well-designed prospective population-based studies to clarify the epidemiology of PNES in various parts of the world are necessary (considering the limited number of high-quality studies). The most appropriate way(s) to differentiate PNES from epileptic seizures and the true comorbidity rate of epilepsy and PNES (when it exists) need to be further investigated. Studying the predisposing, precipitating, and perpetuating factors of PNES in crosscultural comparisons are required. Finally, large-scale longitudinal prospective population-based studies in developed and developing countries are necessary to investigate the mortality rate among patients with PNES at various age groups. These studies should consider possible confounding factors, including suicidal behaviors, socioeconomic factors, and medical comorbidities. Acknowledgment This was a nonfunded study. Conflict of interest Ali A. Asadi-Pooya, M.D.: Honoraria from Cobel Daru. Michael R. Sperling, M.D.: Consulting: UCB Pharma; Research: contracts with Thomas Jefferson University, Eisai, UCB Pharma, Sunovion, SK Life Sciences, Marinus, Lundbeck, Medtronics, Visualase, Acorda, UpsherSmith, and Brain Sentinel. References [1] Asadi-Pooya AA, Emami Y, Emami M. Psychogenic non-epileptic seizures in Iran. Seizure 2014;23(3):175–7. [2] Alsaadi TM, Marquez AV. Psychogenic non-epileptic seizures. Am Fam Physician 2005;72:849–56. [3] Kerr MP, Mensah S, Besag F, et al. International consensus clinical practice statements for the treatment of neuropsychiatric conditions associated with epilepsy. Epilepsia 2011;52:2133–8. [4] Wiebe S. Epidemiology of temporal lobe epilepsy. Can J Neurol Sci 2000;27(Suppl. 1): S6–S10. [5] O'Sullivan SS, Spillane JE, McMahon EM, et al. Clinical characteristics and outcome of patients diagnosed with psychogenic non-epileptic seizures: a 5-year review. Epilepsy Behav 2007;11:77–84. [6] Hubsch C, Baumann C, Hingray C, et al. Clinical classification of psychogenic nonepileptic seizures based on video-EEG analysis and automatic clustering. J Neurol Neurosurg Psychiatry 2011;82:955–60. [7] Bodde NM, Brooks JL, Baker GA, et al. Psychogenic non-epileptic seizures-definition, etiology, treatment and prognostic issues: a critical review. Seizure 2009;18:543–53. [8] http://emedicine.medscape.com/article/1184694-overview. [9] Ricciardi L, Edwards MJ. Treatment of functional (psychogenic) movement disorders. Neurotherapeutics 2014;11(1):201–7.
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Contents lists available at ScienceDirect
Epilepsy & Behavior journal homepage: www.elsevier.com/locate/yebeh
Review
Epidemiology of psychogenic nonepileptic seizures Ali A. Asadi-Pooya a,b,⁎, Michael R. Sperling a a b
Jefferson Comprehensive Epilepsy Center, Department of Neurology, Thomas Jefferson University, Philadelphia, USA Neurosciences Research Center, Shiraz Medical School, Shiraz University of Medical Sciences, Shiraz, Iran
a r t i c l e
i n f o
Article history: Received 8 December 2014 Revised 3 March 2015 Accepted 4 March 2015 Available online xxxx Keywords: Definition Epidemiology Psychogenic nonepileptic seizures
a b s t r a c t We critically review the existing literature about the epidemiology (i.e., diagnosis, occurrence, age, gender, comorbidity with epilepsy, associated factors, prognosis, mortality, and cost) of psychogenic nonepileptic seizures (PNES) and provide suggestions for future research. Psychogenic nonepileptic seizures are commonly diagnosed at epilepsy centers. The diagnosis of PNES relies on a multidisciplinary evaluation and is usually based on different combinations of data. Recording a seizure, while under video-EEG monitoring, is the most reliable diagnostic test. However, not all patients present with seizures while under video-EEG monitoring. Furthermore, not all epileptic seizures produce visible changes in the scalp EEG. The incidence of PNES was estimated to be 1.4–4.9/100,000/ year in three previous studies, and the prevalence was calculated to be between 2 to 33 per 100,000 in one study, making it a significant neuropsychiatric condition. However, there remains a scarcity of data about the epidemiology of PNES, and extant studies that assessed the epidemiological characteristics of PNES have significant limitations. For example, inconsistencies with regard to the age of patients studied and lack of standardization of the diagnostic criteria are some of the significant limitations among studies. In conclusion, PNES merit further epidemiological and pathophysiological investigation. A more precise definition and clear guidance on standards for the diagnosis might influence the direction of future research. Well-designed prospective population-based studies to clarify the epidemiology of PNES in various parts of the world, including an evaluation of the predisposing, precipitating, and perpetuating factors in cross-cultural comparisons is required. © 2015 Elsevier Inc. All rights reserved.
1. Introduction Psychogenic nonepileptic seizures (PNES) are relatively common occurrences in epilepsy centers [1,2]. The International League Against Epilepsy (ILAE) has identified PNES as one of the 10 key neuropsychiatric issues associated with epilepsy [3]. High-quality epidemiological data significantly influence health care and research [4]. In this paper, we critically review the current literature about the definition, ascertainment criteria, occurrence, and clinical characteristics of PNES (i.e., age, gender, comorbidity with epilepsy, associated factors, prognosis, mortality, and cost) and provide suggestions for future research. 2. Diagnosis Psychogenic nonepileptic seizures consist of paroxysmal changes in responsiveness, movements, or behavior that superficially resemble epileptic seizures but lack a neurobiological origin similar to epileptic seizures and are not associated with electrophysiological epileptic changes [5–7]. This condition has been a subject of enduring interest to both neurology and psychiatry experts. The terminologies used to describe this ⁎ Corresponding author at: Jefferson Comprehensive Epilepsy Center, Department of Neurology, Thomas Jefferson University, Philadelphia, USA. Tel.: +1 816 694 0498. E-mail address: [email protected] (A.A. Asadi-Pooya).
condition reflect the prevailing etiological assumptions of their times; hysterical seizures, conversion seizures or disorder, functional seizures, functional neurological symptom disorder, pseudoseizures, psychogenic seizures, and finally, psychogenic nonepileptic seizures (PNES) are some of the terms used to describe this disorder. Interestingly, PNES is a condition made unique by having largely been defined in terms of what it is not, rather than what it is. Having achieved the exclusion of an epileptic or movement disorder does little to define the variables that might affect management of affected patients. Even the newest criteria in the diagnostic and statistical manual of mental disorders, fifth edition (DSM-5), for conversion disorder with attacks or seizures, in which the emphasis is “incompatibility” with a known neurological disorder, does little to help define PNES clearly and explicitly [8]. Epilepsy and PNES have a variety of differing symptoms and signs; however, none of them is pathognomonic of PNES. Thus, sometimes clinical differentiation of PNES from epileptic seizures proves to be difficult. Video-EEG monitoring with ictal recording is considered the optimal test for the diagnosis of PNES, and a definitive diagnosis is made when typical seizures lack accompanying EEG abnormalities. However, there are patients with epilepsy (e.g., frontal lobe epilepsy) and abnormal movements during their epileptic seizures, with no visible change in their scalp EEGs [9]. Therefore, misdiagnosis is common, and symptoms may be attributed to more than one condition in a single patient,
http://dx.doi.org/10.1016/j.yebeh.2015.03.015 1525-5050/© 2015 Elsevier Inc. All rights reserved.
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or different physicians may offer different diagnoses to the same patient. In one previous study of 350 adult patients with uncontrolled seizures, who were taking antiepileptic drugs (AEDs), 9% were proved to have PNES [10]. In another similar study of 198 children, this figure was 1.5% [11]. The term psychogenic movement disorders (PMD) has been applied to disorders that manifest with physical symptoms, specifically abnormal movements (e.g., tremor), which cannot be attributed to any known underlying neurological disorders [12]. However, the distinction between PNES and PMDs is not always easy. One retrospective study of comparison of psychogenic movement disorders and psychogenic nonepileptic seizures revealed more similarities than differences between these two conditions [13]. Both groups were overwhelmingly female, with high rates of chronic pain disorders, depression, fatigue, subjective cognitive complaints, and abuse. Over half were unemployed or disabled. Despite the presence of known risk factors for somatization, both were characterized by prolonged time to diagnosis during which multiple neurologic evaluations, trials of medications, and other unnecessary interventions were performed [13]. However, there is a wide degree of opinion about these findings, and there are articles suggesting differences. In the latter study, significant differences were observed between these two conditions, including age, rates of childhood abuse, and anxiety disorder diagnosis [13]. In one study, the authors found no differences between the psychiatric profiles, health-related quality of life, or self-efficacy for self-management of disease among patients with PNES and patients with PMDs despite their different physical manifestations [14]. In another study, the authors observed that patients with motor conversion disorder had IQ levels in the average range and intact general cognitive functioning, suggesting possible mechanistic differences from patients with PNES [15]. Generally speaking, the precision of the epidemiological data about a disease depends on the methods used to find affected patient. The diagnosis of PNES may be based on different combinations of data. The combination of patient history, witness reports, clinician observations ictal and interictal electroencephalography (EEG), and ictal video is used for diagnostic determination. Four categories of diagnostic levels of certainty for PNES have been suggested based on common scenarios and the combination of data (Table 1) [16]. However, there are important caveats even in this proposed scheme. For example, patients may have both epilepsy and PNES and may have an incorrect diagnosis. The presumed gold standard test [i.e., video-electroencephalography (video-EEG)] for the diagnosis of PNES but may have either false positive (e.g., in the case of some frontal lobe epilepsies) or false negative (not all patients have a seizure while under video-EEG monitoring) results. In a systematic review of sensitivity and specificity of procedures for the differential diagnosis of epileptic and nonepileptic seizures, no procedure with both high sensitivity and specificity and adequately replicated findings emerged [17]. However, this review suggested that video-EEG monitoring has as yet no reliable equivalent among the range of procedures and observations which have been investigated. The range of symptoms presented in PNES suggests that a multimethod approach may be required [17].
3. Occurrence Psychogenic nonepileptic seizures are relatively common. It has been reported that from 5 to 10% of outpatients in epilepsy clinics and 20 to 40% of inpatients in epilepsy monitoring units have PNES [1,2, 18]. This observation has been made in both developed and developing countries. However, most reports derive from tertiary referral centers, and the findings from these centers cannot be applied to the whole population. Population-based studies are scarce from developed countries and nonexistent from developing countries. In one populationbased prospective study from Scotland, the authors identified first presentations of PNES from a population of 367,566 over 3 years. Psychogenic nonepileptic seizures were diagnosed in 68 people, in 54 of whom the diagnosis was confirmed by video-EEG recording, indicating an incidence of 4.9/100,000/year [19]. However, this study had some limitations. Primarily, referrals were accepted from the age of 13 years upward, despite the fact that PNES can present at earlier ages (see below). Besides, in 14 patients, the diagnosis of PNES was not confirmed. In another study, the incidence of PNES was estimated to be 1.4/100,000/year in Iceland [20]. This study had similar limitations; only patients 15 years of age or above at the time of the investigation were included. The method of case ascertainment and exclusion of nonsevere cases limited the value of this study. In a retrospective study of patients referred to a specialist center, the incidence of PNES in Hamilton County, Ohio, USA between 1995 and 1998 was determined. The mean incidence of PNES was 3.03/100,000/year [21]. However, this was a retrospective study and required evaluation at a referral center, which limits the validity of the findings. The authors themselves stated that “Our study may have underestimated the true incidence of PNES, as our diagnostic criteria required video and EEG monitoring for diagnosis. Some patients may have been diagnosed with PNES based on routine EEG or in other centers, and were not included in our study” [21]. Prevalence data of PNES are even scarcer. There is just one study in the literature, in which the authors tried to provide an estimate based on a calculation. They used the following data as the basis of their calculation. A prevalence of epilepsy of 0.5–1%; a proportion of intractable epilepsy of 20–30%; a percentage of these referred to epilepsy centers of 20–50%; and a percentage of patients referred to epilepsy centers that are PNES of 10–20%. They concluded that the prevalence of PNES is somewhere between 1/50,000 and 1/3000 or between 2 and 33 per 100,000, making it a significant neuropsychiatric condition [22]. This calculation is reasonable, but the accuracy of the estimate is unknown. 4. Age Psychogenic nonepileptic seizures tend to begin in adolescence and young adulthood, although the seizures can begin at any age [23–33]. There are reports about PNES in young children (as young as 5 years of age) [23,24], and some studies reported PNES in the elderly (even above 70 years of age) [23,25,32]. Age at onset in most patients appears
Table 1 Overview of proposed diagnostic levels of certainty for psychogenic nonepileptic seizures (PNES). Adapted from LaFrance WC, Baker GA, Duncan R, Goldstein LH, and Reuber M. Minimum requirements for the diagnosis of psychogenic nonepileptic seizures: a staged approach. A report from the International League Against Epilepsy Nonepileptic Seizures Task Force. Epilepsia 2013; 54(11): 2005–2018. Diagnostic level
History
Witnessed event
Electroencephalography (EEG)
Possible Probable
+ +
No epileptiform activity in routine or sleep-deprived interictal EEG No epileptiform activity in routine or sleep-deprived interictal EEG
Clinically established
+
By witness or self-report/description By clinician, who reviewed video recording, or in person, showing semiology typical of PNES By clinician experienced in diagnosis of seizure disorders, showing semiology typical of PNES (on video or in person), while not on EEG
Documented
+
By clinician experienced in diagnosis of seizure disorders, showing semiology typical of PNES, while on video-EEG
No epileptiform activity in routine or ambulatory ictal EEG during a typical ictus/event in which the semiology would make ictal epileptiform EEG activity expectable during equivalent epileptic seizures No epileptiform activity immediately before, during, or after ictus captured on ictal video-EEG with typical PNES semiology
Key: +, history characteristics consistent with PNES.
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to be in young adulthood, but there is often a significant delay to have a confirmed diagnosis, and patients often receive unnecessary treatments (e.g., antiepileptic drugs) for years before a correct diagnosis is made (Table 2). In one study, the authors dichotomized the patients into two groups: (1) those with age at onset below 18 years (juvenile) and (2) those with age at onset from 18–55 years (adult). Age at onset of PNES did not correlate with clinical manifestations, although factors potentially predisposing to PNES were quite different in patients with juvenile-onset PNES compared with those with adult-onset PNES. History of being abused, academic failure, epilepsy, or family history of epilepsy were more frequently observed in patients with juvenile-onset PNES, while medical comorbidities were more frequent among patients with adult-onset PNES [23]. In another study, the authors compared patients with onset of PNES after 55 years of age (n = 26) with those with onset at earlier ages (n = 241). They observed that patients with late-onset PNES were more likely to be male and to have severe physical health problems, while they were less likely to report antecedent sexual abuse [25].
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criteria but similar semiologic criteria should be used for the diagnosis of probable PNES in the outpatient clinic in men and women [33]. 6. Comorbid epilepsy The proportion of patients with PNES who also have epilepsy has been reported to vary from 5% to 50% [18,22,26,38–40]. Criteria for concomitant diagnosis of epilepsy have not been consistent in literature reports. Having interictal spikes, as most studies defined their epilepsy cases, does not necessarily mean that epilepsy is also present. Interictal epileptiform abnormalities have been reported in nonepileptic conditions [41] and in healthy people [42]. Demographic and clinical characteristics of patients with both PNES and coexisting epilepsy are similar to those of patients with only PNES [43]. It has been speculated that epilepsy may contribute to the risk of developing PNES not only through biologic mechanisms but also because the experience or observation of epileptic seizures may provide an opportunity for model learning [44]. 7. Associated factors
5. Gender There is a predominance of female gender among patients with PNES [33–37]. The female:male ratio in one study from China was reported to be 1 [35], but studies from five continents generally note PNES to be far more common in females (Table 2). Lesser examined the sex distribution in 21 studies and found descriptions of 734 women and 250 men who had PNES (female:male ratio = 2.94) [36]. However, most studies are not specifically designed to determine the demographic characteristics of patients with PNES. Psychogenic nonepileptic seizures are not only less common in men but also more challenging to diagnose in men than in women and more difficult to confirm with video-EEG monitoring in men compared to women [34]. However, no specific or consistent difference in the underlying psychopathology between men and women with PNES has been reported. In one study (129 women and 59 men), there were no significant demographic differences between women and men with PNES. Likewise, seizure characteristics and semiology were similar in both genders [37]. Another study also tried to determine if gender-specific differences exist in PNES predictors and PNES semiology. The authors retrospectively investigated 59 women and 27 men. They found significantly lower rates of reported physical and sexual abuse, lower rates of previous psychiatric diagnoses, and lower rates of chronic pain in male patients. However, they found no difference in PNES semiology between men and women. They concluded that distinct risk factor Table 2 Demographic characteristics of patients with PNES.a
North America (New Hampshire, USA) North America (Arizona, USA) South America (Brazil) South America (Argentina) Europe (Scotland) Europe (UK) Asia (Iran) Asia (India) Africa (South Africa) Australia
Mean age at onset (years)
Mean time to confirmed diagnosis (years)
33.4
6.51
NS 27.85 NS 30.9 31.55 23.2 21.8 NS 32.7
Female/male (ratio)
Reference
59/27 (2.18)
[33]
NS
142/42 (3.38)
[34]
7.89 11.18 0.6 7.1 5.5 7.4 NS 5.6
78/24 (3.25) 27/8 (3.37) 44/10 (4.4) 117/43 (2.72) 141/70 (2.01) 44/38 (1.15) 17/5 (3.4) 156/65 (2.4)
[26] [27] [19] [28] [1] [29] [30] [31]
PNES: psychogenic nonepileptic seizures; NS: not specified. a Most of these studies were not specifically designed to determine the demographic characteristics of patients with PNES.
Psychogenic nonepileptic seizures occur in a heterogeneous patient population. No single mechanism or contributing factor has been identified that is necessary and sufficient to explain PNES in all patients [44]. The most commonly reported PNES-associated factors are shown in Table 3 [2,45–52]. The relationship between childhood sexual abuse and PNES has received particular attention in the literature. In a study comparing childhood abuse in patients who had PNES (71 patients) with those who had epilepsy (140 patients), significantly higher rates of both sexual abuse (24.0% versus 7.1%) and physical abuse (15.5% versus 2.9%) were found in those who had PNES (P b 0.001) [52]. In a recent comparison of patients with PNES only (324 patients) with those who had epilepsy only (281 patients), history of abuse (physical or sexual) was more frequent among those with PNES [odds ratio: 3.35 (1.23–9.10); P = 0.018] [53]. However, there are discrepancies and inconsistencies among studies with regard to the interaction between childhood sexual or physical abuse and PNES depending on the study and depending on the design. In one study from Iran, the authors observed that history of childhood abuse (12.8%), physical abuse (11.8%), and sexual abuse (8.1%) was not as common in patients with PNES compared with Western patients [2,52]. There could be real differences between the latter series and the others. In other words, the observed differences might be clinically important and highlight the issue that other psychopathological mechanisms may explain development of PNES in a Muslim culture. However, these differences could have cultural or religious reasons, as extramarital sex is forbidden by law and religion in Iran and people might deny being physically or sexually abused due to family considerations [2]. The wide variety of methods used for assessment of abuse (sexual and physical) and lack of control populations in most of the published studies make it difficult to establish a cause and effect relationship between PNES and abuse. Another commonly reported PNES-associated factor is traumatic brain injury. In one study of 92 patients with PNES, 41 (44.6%) had a history of traumatic brain injury (TBI). Patients with TBI had more mood disorder diagnoses, were more likely to receive disability, and had lower global functioning compared with non-TBI patients with PNES after adjusting for age and sex. Patients with TBI and PNES had significantly increased odds for having major depression, behavioral impulsivity, posttraumatic stress disorder diagnosis, and a trauma/abuse history. The authors concluded that TBI is a significant risk factor in patients with PNES, being associated with increased psychiatric diagnostic comorbidity, symptom severity, poorer functioning, and increased disability [47]. In another study of 157 patients with video-EEG-confirmed PNES, 37 (24%) had the onset of their seizures attributed to a head injury [50]. Further exploration of the interaction between PNES and TBI could help with development of new treatment strategies, as
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Table 3 The most commonly reported psychogenic nonepileptic seizures associated factors. Associated factor
Observed rate (% of patients)
Reference
Sexual abuse
8.1 24 32.5 36.3 67 15.5 24.6 26 67 24 32 44.6 8.3 23.2
1 52 46 45 48 52 1 46 48 50 49 47 46 1
Physical abuse/neglect
Traumatic brain injury
Medical comorbidities (health-related trauma)
new pharmacologic and rehabilitative options become available [47]. We should emphasize that an agreed upon distinction between PNES-associated factors and comorbidities is not apparent in the literature, and a complete discussion of psychiatric comorbidities (e.g., depression and anxiety) is too broad to be covered in this review. In most patients with PNES, several potential interacting factors may be identified [44]. Reuber concluded that predisposing factors (e.g., abuse and neglect) increase vulnerability to the development of PNES. Precipitating factors may occur over days to months before the onset of seizures and seem to cause PNES to start, but these are far from universal. Factors that have been described as precipitating PNES include rape, injury, death of or separation from family members or friends, job loss, accidents, giving birth, surgical procedures, natural disasters (e.g., earthquakes), relationship difficulties, and legal action [44]. In older people, medical comorbidity is a common identifiable precipitant [23,37,44]. Finally, perpetuating factors (e.g., isolation, anger, anxiety, depression, misdiagnosis, and mistreatment) make it harder for patients to regain control of seizures or can aggravate the problem once seizures have started. Even if one factor seems to play a predominant role in a particular patient, other factors are likely to have contributed and should not be ignored [44]. These factors have been studied in Western countries and discussed in comprehensive reviews by other authors [2,7,44,51]. Finally, brain dysfunction is also associated with PNES. The neurobiology of PNES is still poorly understood. Obviously, PNES lack a neurobiological origin similar to epileptic seizures, but emerging evidence suggests that there is a neurobiological basis for these events. An association of PNES with brain dysfunction appears to be likely based on recent evidence of functional and structural brain connectivity abnormalities and also functional neuroimaging findings [54–57]. Psychogenic nonepileptic seizures could be the result of neurobiological dysfunctions of specific brain networks. 8. Prognosis Definitive diagnosis of PNES can lead to appropriate therapy and even cessation of the events [58]. In one study, seizure frequency during inpatient video-EEG monitoring was examined before and after the diagnosis of PNES was presented to 22 patients. A control group of 10 patients with epilepsy were also followed from prediagnosis to postdiagnosis. The number of nonepileptic seizures (in patients with PNES) or epileptic seizures (in those with epilepsy) within the 24-hour period prior to diagnosis was compared with the number of events that occurred within the 24-hour period after presentation of the diagnosis. The findings indicated that patients with PNES had a significant decrease in the frequency of events after diagnosis, while those with epilepsy showed no change in event frequency after diagnosis. Eighteen of the 22 patients with PNES had no further events during an acute follow-up period [58]. However,
in a previous review, the authors concluded that communicating to the patient that the seizures are not epileptic may stop PNES in the shortterm but does little to improve associated psychological morbidity, distress, or health-related quality of life. Without dedicated further treatments, PNES are likely to restart in the majority of patients [59]. Unfortunately, longer-term studies suggest that many patients with PNES will continue to experience seizures despite neurological and psychotherapeutic care [60]. Clinical and personality factors should be used to provide an individualized prognosis in patients with PNES. In one study, 164 adult patients with PNES were investigated, for a mean of 11.9 years after manifestation and 4.1 years after diagnosis of PNES. The responses showed that 71.2% of the patients continued to have seizures and that 56.4% were dependent on social security. Outcome was better in patients with greater educational attainment, younger onset and diagnosis, attacks with less dramatic features, fewer additional somatoform complaints, and lower dissociation scores [60]. In a systematic review published in 2011, the authors concluded that the prognosis of PNES in adults is poor. From their reviewed data, fewer than 4 in 10 newly diagnosed adults could be expected to become seizure-free within 5 years after diagnosis. In children, the proportion of patients achieving seizure remission appeared to be around 70%, which indicates a more favorable result [61]. 9. Mortality Scattered evidence suggests that PNES are associated with increased mortality. In one study, the authors obtained death certificate information in a cohort of 260 patients who presented with PNES between 1999 and 2004 from West of Scotland Regional Epilepsy Service, Southern General Hospital, Glasgow, UK. The follow-up period averaged 7.92 years, during which 17 patients died. Twelve out of the 17 patients who died were under the age of 75 years, giving a premature mortality rate of 0.58% per year compared with a Scottish mortality rate for the 40- to 75-year age group of 0.41%, per year. These results suggest that a diagnosis of PNES may be associated with a modest increase in mortality [62]. However, serious physical illness is prevalent in patients with PNES with an onset of their attacks after the age of 55 years. The development of physical illness (especially, where this has been frightening to the patient) may be an important triggering factor for PNES, at least in a subset of patients [25]. This means that the medical comorbidities could be responsible for increased mortality seen in patients with PNES and not necessarily the itself (i.e., PNES). Besides, in the Scottish study mentioned above, patients came from a population that was deprived relative to the general Scottish population; the authors concluded that some excess mortality might be expected secondary to socioeconomic factors [62]. On the other hand, in one study of 43 patients with PNES, 23% reported suicide attempts [63]. This may also contribute to the increased mortality among patients with PNES. 10. Health-care costs Psychogenic nonepileptic seizures place a heavy demand on emergency and nonemergency health-care services [64]. It has been observed that most patients who have PNES diagnosed with video-EEG monitoring experience substantial subsequent reductions in healthcare utilization and costs [64–66]. In one study, it was reported that in patients with a new diagnosis of PNES documented, prediagnosis medical costs exceeded $15,000 per patient and loss of work costs exceeded $22,000 per patient [67]. In another study in 2013, overall costs dropped from the 12-month period preceding PNES diagnosis (mean costs: $4567) to the 12-month period following PNES diagnosis (mean costs: $2783). This equated to a cost reduction of nearly $1800 per person [66]. In another study in 1998, there was an 84% average reduction in total seizure-related medical charges in the six months following PNES diagnosis. Average diagnostic testing charges declined by 76%, average medication charges decreased by 69%, outpatient clinic visits
Please cite this article as: Asadi-Pooya AA, Sperling MR, Epidemiology of psychogenic nonepileptic seizures, Epilepsy Behav (2015), http:// dx.doi.org/10.1016/j.yebeh.2015.03.015
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declined by 80%, and emergency room visits declined by 97% [65]. In a more recent study, the authors performed a 1-year prospective audit of use of PNES-related health-care items in patients with newly diagnosed PNES from PNES onset to diagnosis and from diagnosis to six months postdiagnosis. Before diagnosis, twenty-eight patients were responsible for 14 general practitioner home visits, 31 ambulance calls, 34 emergency department visits, 21 hospital admissions, 2 standard EEGs, 28 short video-EEG recordings, and 5 ambulatory EEG recordings. In the 6 months following diagnosis, there were 2 emergency department visits (94.1% reduction), no hospital admissions (100% reduction), 2 ambulance calls (93.5% reduction), no general practitioner visits (100% reduction), and no EEGs (100% reduction) [65]. Overall, the burden of PNES is significant, particularly if it remains undiagnosed. Early diagnosis of PNES may save money and reduce the service utilization burden for patients and the health-care system [66]. 11. Future directions Psychogenic nonepileptic seizures merit further epidemiological and pathophysiological investigation. A more precise and informative definition might influence the direction of future research. Developing clear guidance on standards for the diagnosis of PNES and well-designed prospective population-based studies to clarify the epidemiology of PNES in various parts of the world are necessary (considering the limited number of high-quality studies). The most appropriate way(s) to differentiate PNES from epileptic seizures and the true comorbidity rate of epilepsy and PNES (when it exists) need to be further investigated. Studying the predisposing, precipitating, and perpetuating factors of PNES in crosscultural comparisons are required. Finally, large-scale longitudinal prospective population-based studies in developed and developing countries are necessary to investigate the mortality rate among patients with PNES at various age groups. These studies should consider possible confounding factors, including suicidal behaviors, socioeconomic factors, and medical comorbidities. Acknowledgment This was a nonfunded study. Conflict of interest Ali A. Asadi-Pooya, M.D.: Honoraria from Cobel Daru. Michael R. Sperling, M.D.: Consulting: UCB Pharma; Research: contracts with Thomas Jefferson University, Eisai, UCB Pharma, Sunovion, SK Life Sciences, Marinus, Lundbeck, Medtronics, Visualase, Acorda, UpsherSmith, and Brain Sentinel. References [1] Asadi-Pooya AA, Emami Y, Emami M. Psychogenic non-epileptic seizures in Iran. Seizure 2014;23(3):175–7. [2] Alsaadi TM, Marquez AV. Psychogenic non-epileptic seizures. Am Fam Physician 2005;72:849–56. [3] Kerr MP, Mensah S, Besag F, et al. International consensus clinical practice statements for the treatment of neuropsychiatric conditions associated with epilepsy. Epilepsia 2011;52:2133–8. [4] Wiebe S. Epidemiology of temporal lobe epilepsy. Can J Neurol Sci 2000;27(Suppl. 1): S6–S10. [5] O'Sullivan SS, Spillane JE, McMahon EM, et al. Clinical characteristics and outcome of patients diagnosed with psychogenic non-epileptic seizures: a 5-year review. Epilepsy Behav 2007;11:77–84. [6] Hubsch C, Baumann C, Hingray C, et al. Clinical classification of psychogenic nonepileptic seizures based on video-EEG analysis and automatic clustering. J Neurol Neurosurg Psychiatry 2011;82:955–60. [7] Bodde NM, Brooks JL, Baker GA, et al. Psychogenic non-epileptic seizures-definition, etiology, treatment and prognostic issues: a critical review. Seizure 2009;18:543–53. [8] http://emedicine.medscape.com/article/1184694-overview. [9] Ricciardi L, Edwards MJ. Treatment of functional (psychogenic) movement disorders. Neurotherapeutics 2014;11(1):201–7.
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