Psychogenic Non-Epileptic Seizures: An Update on Diagnosis and Management

Abstract

Psychogenic non-epileptic seizures (PNES) are functional neurological disorders that mimic epileptic seizures. Over the past decades, relevant advancements have been made in the diagnosis, neurobiological understanding and management of PNES. This chapter is a review about epidemiology, comorbidities, biomarkers, neurobiology and treatment of PNES. The author discusses in particular the diagnosis of PNES that is based on clinical history, semiology, presence of witness and instrumental features. Neuroimaging studies suggest that PNES may occur in a context of anatomical alterations that regulate sensorimotor functions, emotional processing, cognitive control and multimodal integration of brain functions. The gold standard of PNES instrumental assessment remains video electroencephalography, showing the absence of epileptiform activity during the event and the absence of slow activity after the event. Several studies and clinical trials have demonstrated the importance of psychological treatments and in particular cognitive behavioral therapy. Further future studies are necessary to investigate about similarities and differences between psychogenic non-epileptic seizures, real epileptic seizures and other psychosomatic disorders. We also need studies for more appropriate psychotherapies and treatment guidelines.

1. Introduction

Functional neurological disorders (FND) are common neurobehavioral conditions at the interface between neurology and psychiatry. Psychogenic non-epileptic seizures (or PNES) are a subtype of functional neurological disorder that consists of sudden and involuntary paroxysmal events characterized by disturbance in motor, autonomic, sensory, cognitive and emotional functions associated with alterations of consciousness and behavior. PNES frequently resemble epileptic seizures (ES) but are not associated with epileptic changes in cortical activity as demonstrated by EEG registrations [1].

Jean-Martin Charcot was one of the first neurologists to introduce PNES and other somatic symptoms in the medical literature as “hysteria.” Subsequently, other researchers such as Sigmund Freud or Pierre Janet postulated psychological theories to explain this neurological condition [2]. In 1964, Liske and Foster created the term pseudo-seizures to refer to paroxysmal events similar to epileptic seizures but without EEG changes of epilepsy [3]. Over time, PNES received several names such as psychogenic seizures, pseudo-seizures, non-epileptic seizures, psychogenic non-epileptic attacks and psychogenic pseudo-seizures. Recently, other researchers have proposed to mention this condition as functional seizures [4] or dissociative seizures [5]. However, the most widely widespread term in current scientific literature is “psychogenic non-epileptic seizures” [6].

According to a modern vision, the conceptualization of PNES integrates both brain and mind [7].

Patients with PNES are often misdiagnosed for epilepsy and consequently treated with unnecessary antiepileptic drugs, emergency treatments and even hospital admissions.

Nowadays, notable advances have been made in the diagnosis and treatment of patients with PNES. Epidemiology studies have demonstrated that the treatment of patients with PNES needs a comprehensive multidisciplinary approach. Advances in clinical neuroscience are starting to better understand etiology, neurobiology, pathophysiological mechanisms and biomarkers of PNES. This coud facilitate the diagnosis and treatment. This chapter is a review about PNES focusing in particular on diagnostic criteria, semiological features that distinguish PNES from epileptic seizures and evidence-based treatment interventions.

2. Epidemiology

Psychogenic non-epileptic seizures is a neurobehavioral condition that occurs worldwide with a prevalence of approximately 1.5% per 100,000 inhabitants per year [8]. However, epidemiological data on PNES are limited and sparse. A study conducted in Iceland estimated the incidence of PNES as 1.4 per 100.000, with symptoms commonly emerging from 20 to 40 years [9]. Studies conducted in the USA have demonstrated that up to 20% of civilians and up to 25% of veterans diagnosed as epileptic, on the contrary, have PNES [10]. Therefore, PNES is common as other neurological diseases such as Parkinson’s disease or multiple sclerosis [11]. Epidemiological investigations conducted in Ohio have estimated prevalence of PNES up to 33/100,000 individuals [9], while prospective studies conducted on 367,566 individuals followed for 3 years found an incidence rate of 4.9/100,000 per year [12].

Regarding gender differences, PNES individuals are typically women in approximately 80% of cases, with a mean age of onset of 31 years ± 15 years. Prevalence is higher in women, probably due to social and neurobiological differences [13].

The majority of PNES patients are unemployed, 43% received a prior diagnosis with depression or anxiety, and 57% had at least one medically unexplained symptom [14]. Even if PNES can be detected at any age and can have many stereotypes, younger women with high levels of mental health and a history of past abuse are more likely to be among the patient group. The coincidence of PNES with epileptic seizures is about 10% [15]. Epilepsy may also increase the risk of PNES through biological mechanisms and by experiencing epileptic seizures [16].

3. Comorbidities and risk factors

Adult patients with PNES have various comorbid medical, neurological and psychiatric conditions that contribute to prognosis and treatment responses. A two-year retrospective review on 158 patients with PNES demonstrated that they were more likely to report a history of other medical conditions and in particular somatic syndromes such as chronic fatigue syndrome, fibromyalgia, chronic pain and irritable bowel syndrome [17]. These patients also often suffer from chronic, intermittent medical conditions such as asthma and migraine [17]. When compared with ES with the use of medical questionnaires, PNES patients frequently report a history of traumatic brain injury or have comorbidity with intellectual disabilities [15].

Psychiatric disorders that may be found in comorbidity with PNES are affective disorders [18], anxiety, depression, eating disorders [19] and other somatoform disorders [7], but also personality disorders, in particular clusters B and C of personality disorders [20].

Another psychiatric disorder often associated with PNES is post-traumatic stress disorder (PTSD). In fact, three-fourths of individuals with PNES report traumatic experiences including physical abuses (in about 25% of cases) or sexual abuses (in about 30% of cases) [21]. Patients with a history of sexual abuses exhibit an earlier event onset, more severe convulsions, emotional disorders and other post-traumatic symptoms [22]. Patients with eating disorders often have a history of prior trauma and subsequent PTSD and related psychiatric comorbidities [19]. Individuals with prior traumas are more likely to have comorbid psychiatric conditions and dissociative symptoms [23]. Studies on the association between PNES and PTSD have been conducted in retrospective reviews of veterans with PNES and 37 veterans with ES. These studies have demonstrated that PTSD symptoms preceded the diagnosis of PNES in 58% of patients and that PTSD comorbidity was able to differentiate between PNES and ES [10]. Veterans with PNES showed more non-motor or hypomotor PNES events [24].

Patients with PNES have abnormal neuropsychiatric and personality profiles. Depressive symptoms are associated with PNES even if depression scores on psychometric questionnaires do not differentiate between PNES and ES [25].

Patients with PNES can also have dissociative symptoms such as fragmentation of internal experience of the outside world (derealization) or fragmentation of perception of body schema (depersonalization) linked to somatic symptoms and depression [26]. Alexithimia that consists in the reduced ability to express and recognize emotions, has also been observed in PNES patients. However, it is not clear if alexithimia scores can differentiate between PNES and ES [27].

Studies based on cluster analysis suggest that patients with PNES could have different subtypes of psychopathologies. For example, in a cohort study of 43 PNES subjects, 11 individuals were categorized as having high levels of psychopathologic disorders with somatization, alexithimia and impairment in emotional regulation, while 32 individuals were categorized as having high levels of somatization disorders and depression, but relatively normal emotion expression [28].

Personality of subjects with PNES has been studied with psychiatric instruments such as Minnesota Multiphasic Personality Inventory (MMPI-2) or Personality Assessment Inventory (PAI). In a cohort of 75 patients with PNES and 109 patients with ES, Personality Assessment Inventory showed significant high scores in somatic, conversion, anxious, depression and suicidal symptoms [29]. Instead, Minnesota Multiphasic Personality Inventory showed a “conversion V pattern” with elevation in hypochondria and hysteria in depression subscales [30]. Regression analysis suggests that the use of health scales and conversion scales of PAI and hysteria subscale of MMPI2 could be useful to distinct between PNES and ES patients [31].

Neuropsychological studies have not demonstrated different cognitive profile of PNES patients when compared to ES patients. However, PNES subjects frequently complain cognitive symptoms including concentration difficulties and memory disorders. Cognitive studies have demonstrated that PNES patients potentially overestimate their cognitive deficits. In neuropsychological assessment, they have generally worse performance in tests that consist in word finding and some specific language tests such as Boston Naming Test [32]. Other studies have demonstrated that patients with PNES show some impairment in tests that explore attention, executive functions, spatial working memory [33] or difficulty in switching attention from emotion-related task demands [34]. A study conducted on patients with PNES and a story of prior trauma and patients with PNES without prior trauma showed that patients with PNES and PTSD had lower performances in neuropsychological tests exploring verbal memory performances than the group of patients without PTSD [35].

Numerous studies identified potential risk factors, precipitant factors and perpetuating factors for PNES. As already mentioned, predisposing factors for PNES are generally traumatic experiences such as physical or sexual abuses since they increase the vulnerability of the subjects [16]. Precipitating factors that trigger PNES attacks are generally stressor situations such as death or separation events (such as death of a friend or a family member, and job loss), natural disasters or relationship difficulties, since they occur before the onset of the attacks [36]. Perpetuating factors of PNES are psychological comorbidities such as mood disorders (anxiety, depression), anger and mistreatments [16].

4. Neurological diagnosis of PNES

When a medical doctor tries to reach the diagnosis of a PNES, it is important to consider that about 10% of patients with psychogenic non-epileptic seizures have also epilepsy [37]. PNES must be distinguished from other disorders such as sleep disorders, migraine, syncope, movement disorders and transient ischemic attacks that are mediated by other pathophysiological mechanisms [13].

Approaches for diagnosis of PNES include clinical history, symptom provocation, observation and EEG analysis [36]. Characteristic historical features and semiologic signs [38] that help to distinguish PNES from epileptic attacks are listed in Table 1.

Historical features	PNES	Epileptic seizures
Associated psychiatric disorders	One or multiple	Generally absent
Prior sexual or physical abuses	In about 30% of cases	Absent
Intellectual disability	Frequent	In encephalopathies
Emergency department visits	Multiple	Occasional
Seizure frequency	High	Variable
Injury from seizures	Absent	Occasional
Response to antiepileptic	Absent	Up to 70% of cases
Experience with epilepsy	Frequent in family	In genetic forms
Setting of seizures	Generally in the presence of others	Variable
Semiological features	PNES	Epileptic seizures
Emotional triggers	Present	Absent
Onset of the event	Gradual	Sudden
Duration of the event	Long duration	Short duration
Progression	Fluctuating course	Physiological course
Symptomatology	Variable	Stereotyped
Ictal crying	Usually present	Usually absent
Movements during the event	Asynchronous	Synchronous
Breathing during the event	Normal	Stertorous
Eyes closure during the event	Forced	Not forced
Anxiety during the attack	Present	Absent
Autonomic signs	Common	Infrequent
Kind of tongue biting	Not on the side	On the side
Post-ictal confusion	Absent	Present
Memory of the event	Present	Absent

Table 1.

Main historical and semiologic differences between psychogenic non-epileptic seizures (PNES) and epileptic seizures (ES).

Clinical signs evaluated to distinguish between PNES and seizures consist in motor, somatic and other signs. Motor signs have been reported in controlled studies where a video-EEG was used to diagnose the events. Examples of motor signs that can help to differentiate PNES from seizures are long duration of the event, a fluctuating course, the presence of asynchronous movements, pelvic thrusting, side-to-side head movements, ictal eye closure at onset, ictal crying and post-ictal recall of information. However, there are no pathognomonic signs that totally rule out epileptic seizures [39]. For example, non-synchronic hypermotor symptoms that were considered typical of PNES are not specific since they could be seen in epileptic seizures originated in frontal lobe or in generalized tonic-clonic seizures [40]. Moreover, between 8 and 31% of patients with PNES have suffered injuries during seizures such as tongue biting, bumps and falls [41]. Urinary incontinence [42] and appearance of seizures during sleep [43] have been also described in patients with PNES even if they are more frequent in epilepsy. On the other hand, post-ictal confusion supports the diagnosis of epileptic seizures. Post-ictal stertorous breathing supports diagnosis of epileptic seizure, but only in cases of convulsive events. In events that resemble syncope, a sudden collapse to the ground with eyes closed for more than 2 minutes is characteristic of psychogenic non-epileptic events. Other useful clinical signs proposed for diagnosis of PNES are: ictal stuttering [44] and the bringing of an inappropriate toy animal during video-EEG monitoring (known as teddy bear sign) which has a specificity of 100% but a sensitivity between 5.2 and 9% [45].

Somatic signs of anxiety during the attacks are more frequent in PNES compared to epileptic seizures and can help in the diagnosis [46]. The presence during or after a panic attack at least 4 of the 13 symptoms of anxiety reported in DSM-4 TR has a sensitivity of 83% and specificity of 65% [47]. These symptoms include: (1) palpitations or pounding heart, (2) sweating, (3) trembling or shaking, (4) sensation of shortness, (5) feeling of choking, (6) chest pain, (7) nausea or abdominal distress, (8) dizziness, (9) derealization or depersonalization, (10) fear of losing control, (11) fear of dying, (12) paresthesia and (13) chills or hot flushes [48]. Other relatively common signs that support the diagnosis of a PNES are: gradual onset, the presence of non-stereotyped movements, thrashing movements, opisthotonos and tongue biting [49].

Patients with PNES can have impaired state of conscience such as lack of responsiveness, psychic symptoms, aura that may resemble generalized absence seizures or temporal seizures with automatisms [50]. Other types of PNES such as psychogenic atonic seizures or presyncopes may show behavioral arrest, immobility, psychic aura, unusual somatic sensations, dissociation states (derealization and depersonalization) and hallucinations (auditory, visual and olfactory) resembling seizures with impaired state of conscience [51]. In patients with PNES, autonomic manifestations are also common such as tachycardia, incontinence, flushing and sweating [46]. Specific triggers such as flashing lights could provoke attacks of PNES, while intermittent light stimulation is observed in some forms of photo-inducted epileptic syndromes [46]. Other elements are characteristic of PNES; for example, patients with PNES are more likely to have attacks in the presence of others or in medical settings [38] or can talk about the attacks since have memory of the event [52].

Even if clinical signs are useful for the diagnosis of PNES, instrumental features are useful [53].

One of the most important instrumental examinations that differentiates PNES from real seizures is based on the use of standard electroencephalography. Typical events of PNES are characterized by lack of electrographic changes [54], while an EEG with epileptic anomalies followed by slow abnormalities and sleep supports the diagnosis of epileptic seizures.

Gold standard for the diagnosis of PNES is video-EEG monitoring and recording of positive EEG features during the episodes [55]. Video-EEG consists in the continuous monitoring of patient’s behavior during the paroxysmal episodes, while electrical brain activity is simultaneously recorded through the surface electrodes of the EEG [56]. Video-EEG monitoring is a highly specific and sensitive technique with a diagnostic yield of 50 to 60 percent. Video-EEG could not be available and some patients may have low event frequencies so that admission for long-term EEG monitoring is impractical. The absence of video-EEG recording can result in false-positive diagnosis [57]. A perspective study has shown that epileptic seizures are misdiagnosed as PNES more likely than the opposite with a frequency of 57 vs. 12% [58]. Furthermore, epileptic seizures of fronto-mesial origin are often misdiagnosed as PNES since semiology can mimic a pseudo-seizure and EEG often fails to identify ictal patterns [43].

Recently, using a combination of history, witness description and clinical signs, and EEG findings, the International League Against Epilepsy (ILAE) Commission on Neuropsychobiology Non-Epileptic Seizure Task Force has published a consensus guideline on the minimal criteria to diagnosis of PNES. According to ILAE, “Documented PNES” criteria consists in clinical history in favor of PNES and confirmation with video-EEG demonstrating the absence of epileptiform activity. Lower levels of certainly depend on availability of diagnostic components (see Table 2).

Diagnostic level	History	Witness event	EEG finding
Possible PNES	+	Self-reported and/or witness description	Absence of epileptiform activity in routine EEG or sleep-deprived interictal EEG
Probable PNES	+	Physicians witnessed the event or reviewed a video showing typical semiological findings of PNES	Absence of epileptiform activity in routine EEG or sleep-deprived interictal EEG
Clinically established PNES	+	Clinical experienced in epilepsy reviewed the video or witnessed an event showing semiology, while not on EEG typical of PNES	Absence of epileptiform activity in routine EEG or sleep-deprived EEG registered during an equivalent epileptic seizure
Documented PNES	+	Clinical experienced in diagnosis of epilepsy reviewed the video or witnessed an event showing semiology typical of PNES	Absence of epileptiform activity in EEG registered immediately before, during and after the event captured by video-EEG

Table 2.

Diagnostic levels of PNES according to ILAE.

Given the need to clarify a diagnosis of PNES, whenever possible, the use of provocation EEG techniques including hyperventilation and photic stimulation may be effective procedures [59]. Standard induction protocols may aid diagnostic evaluation. Surface electromyography recordings could also help to differentiate PNES from convulsive epileptic seizures events [60].

5. Psychiatric diagnosis of PNES

There are different psychiatric categories that represent the so-called PNES.

According to the Diagnostic and Statistical Manual of Mental Disorders, version 4 Text Revision (DSM-4 TR), PNES with motor disorders are mainly represented by the category of somatoform disorders [48]. According to this classification, somatoform disorders are subdivided into four categories: conversion disorders with motor symptoms, conversion disorders with sensory symptoms, conversion disorders with seizures and conversion disorders with mixed presentation. However, when an impairment of conscience is evident, PNES could be better represented by the category of dissociative disorders.

The Diagnostic and Statistical Manual of Mental Disorders, version 5 (DSM-5) has replaced conversion and dissociative categories in functional neurological disorders, which encompasses all types of PNES [61]. According to this classification, PNES disorders would be considered as functional rather than structural disturbances of central nervous system.

According to the 10th version of the International Classification of Diseases (ICD-10), conversion disorders include the categories of conversion hysteria, conversion reaction, hysterical psychosis and dissociative seizures [62]. Therefore, ICD-10 considers PNES within mental and behavioral disorders that are somatoform and dissociative disorders. Dissociative disorders are characterized by alteration of normal integration between memories of the past, awareness of own identity and sensation of loss of control of body movements.

According to the 11th version of the International Classification of Diseases (ICD-11), dissociative disorders are considered in a separate way by somatic symptoms in the chapter about mental, behavioral and neurodevelopmental disorders. The ICD-11 classifies conversion disorders as neurotic, somatoform and stress-related disorders [63].

6. Rating scales for PNES

Cianci et al. in 2011 developed a rating scale for psychogenic non-epileptic seizures PNES [64] (See Table 3).

Scale for motor phenomena				Scale for associated features
Motor phenomena	Presence	Severity	Duration	Associated features	Presence
Tonic tremor; Clonic tremor; Hypermotor/agitation; Atonic/akinetic; Automatisms	0 = absent; 1 = present	0 = none; 1 = minimal; 2 = mild; 3 = moderate; 4 = severe	0 = none; 1 = <25% of the time; 2 = 25–50% of the time; 3 = 50–75% of the time; 4= > 75% of the time	Incontinence; Tongue biting; Drooling; Eye closure; Hyperventilation; Lament/crying	0 = absent; 1 = present

Table 3.

Rating scale for PNES.

For this purpose, 60 PNES patients were included in the study. These patients had EEG without ictal or interictal epileptiform activity and no post-ictal slowing. The rating scale showed a high sensitivity, specificity and inter-rater reliability that ranged from 0.69 to 1 in case of the presence or absence of motor signs and associated features [65]. In a study that compared this scale to the Clinical Global Impression (CGI), a non-specific scale, researchers demonstrated a strong correlation (with a Spearman correlation score of 0.69) between the mean CGI score and the total PNES score. The limitations of the PNES scale are such as the ability to evaluate the severity of the event or clearly define the associated events that support the diagnosis of PNES. Finally, this scale gives more importance to motor phenomena rather than the assessment of consciousness.

Further studies are necessary to clarify the relationship between PNES, cognitive deficits and anxiety and mood symptoms to understand in particular if these deficits occur independently.

7. Biomarkers

Since EEG is not available in many centers, researches have studied various substances as potential biomarkers for differentiation between PNES and epileptic seizures.

According to many studies, serum creatine phosphokinase (CPK) levels should be able to differentiate epileptic seizures from PNES with a sensitivity of 75% and a specificity of 85.5% [66, 67]. In different studies, serum creatine phosphokinase correlates positively with occurrence of real seizures, while none of patients with PNES show elevation in serum levels of CPK [68].

Some pituitary hormones such as prolactin (PRL), thyrotropin-releasing hormone (TRH) and growth hormone (GH) have resulted increased in serum following epileptic seizures but not in PNES [68, 69]. For example, a study demonstrated that 10-20 minutes following an ictal event, prolactin levels were ​​approximately doubled in the serum of epileptic patients but not in PNES patients [70, 71, 72].

Results related to cortisol level are controversial. Some authors have demonstrated pre-ictal decrease and post-ictal increase of cortisol in epileptic patients and no changes in PNES patients [73]. Other studies showed basal hypercorticolism in PNES patients and a positive correlation with both levels of vigilance, traumatic history [74] and attentional difficulties in an emotional Stroop task [75]. Some authors speculated that PNES patients have hyperactivation of hypothalamic-pituitary axis (HPA axis); then, adrenocorticotropic hormone (ACTH) is hyper-secreted into blood stream and induces release of cortisol. In fact, as mentioned previously, nearly 50% of PNES patients have psychological disorders related to trauma or post-traumatic stress disorders [76]. Therefore, stress response would induce activation of sympathetic nervous system (SNS) and hypothalamic-pituitary axis resulting in increased cortisol levels. The activation of SNS and HPA axis could also led to health consequences such as growth disorders or autoimmune diseases [77]. Other changes in potential biomarkers have been attributed to stress problems in PNES patients such as high levels of testosterone and lower levels of oxytocina in women with a history of chronic stress or childhood abuse [78]. Instead, estradiol level is lower in women with stressful conditions [79].

Other hormonal biomarkers have been studied as diagnostic tools for PNES such as nesfatin, ghrelin and brain-derived neurotrophic factors (BDNF) [80]. Serum and salivary levels of nesfatin were found to be high in post-ictal epileptic seizures compared to PNES [81]. Instead, post-ictal serum ghrelin levels were lower in patients who had epileptic seizures if compared to ones who had PNES [82]. Brain-derived neurotrophic factors are neurotrophins implicated in neurogenesis and synaptic reorganization. BDNF have resulted reduced in a sample of PNES patients compared to healthy controls [83] or in patients with depressive disorders [84]. However, post-ictal levels of BDNF resulted similar in ES and PNES patients; therefore, BDNF is not a biomarker specific in differentiating seizure types. This happens since BDNF levels are probably related to stress than to seizure type [76].

Neuropeptide Y (NPY), an inhibitory neuromodulator of the brain that could control propagation of limbic seizures, has been studied in epileptic and PNES patients. The presence of stress disorders could help to reduce the levels of NPY and determine the onset of PNES symptoms. In fact, different studies have demonstrated lower level of NPY in PNES patients in comparison with healthy subjects [85].

Finally, PNES patients have post-ictal higher levels of a natriuretic peptide hormone called C-type natriuretic peptide (CNP) that is a hormone produced by nervous system cells as well as by endothelial cells and bone cells [86]. Authors hypothesized that the difference is due to increased blood-brain barrier permeability, synaptic stabilization and altered microcirculation [87].

8. Neurobiology and pathophysiology of PNES

Structural neuroimaging studies have started to understand neurobiology of PNES [7]. Techniques based on the use of functional magnetic resonance imaging (f-MRI) and positron emission tomography (PET) have tried to investigate neural functional connectivity anomalies in PNES [88, 89]. On the bases of these studies, researchers have demonstrated that PNES patients have an increased functional connectivity between motor regions localized in precentral sulcus and regions involved in emotional processing localized in anterior cingulate cortex or regions involved in frontal function (such as executive functions) localized in inferior frontal gyrus and parietal cortex [90]. Instead, other studies have found functional connectivity dissociation between the precentral sulcus and the posterior insula [89]. Several neuroanatomical studies have demonstrated functional connectivity alterations in networks implicated in executive and attentional functions, emotional control and sensorimotor functions [91]. Other research that had the purpose to study functional connectivity patterns in PNES patients compared to healthy subjects demonstrated increased functional connectivity between left ventral anterior insula, left post-central gyrus and bilateral supplementary motor area [92]. Functional connectivity between the bilateral supplementary motor areas positively correlated with the frequency of psychogenic seizures [93]. Functional connectivity between supplementary motor areas and anterior cingulate cortex also positively correlated with the frequency of psychogenic seizures [92]. A PET study that compared cerebral metabolism between healthy subjects and patients with PNES demonstrated that patients with psychogenic non-epileptic seizures had hypometabolism in bilateral anterior cingulate cortex and right inferior parietal lobule [88].

Neuroimaging studies based on the use of quantitative structural MRI and voxel-based morphometry (VBM) have demonstrated that patients with PNES have anterior cingulate cortex, supplementary motor areas and pre- and post-central gyrus atrophy [94]. Other studies showed reduction in the thickness of the cortex in insular and orbitofrontal regions in PNES patients [95].

A diffusion tensor tractography (DTT) study that compared PNES patients to healthy subjects demonstrated in PNES patients a right asymmetry of the uncinated fasciculus, which is a tract that connects medial prefrontal cortex with medial temporal regions [96].

All these anatomical and functional neuroimaging studies suggest that PNES patients have a context of cerebral alterations that concern interactions across brain areas designated to sensorimotor functions, cognitive control, emotion processing and multimodal integration. Further research is necessary to confirm these findings and better understand neural circuit alterations and cerebral network dysfunctions. Researchers should also study better neurofunctional circuit alterations in specific psychiatric functional patter or semiological frameworks such as convulsive vs. atonic events.

Autonomic nervous system studies and electrophysiological studies are also contributing to understand pathophysiology of non-epileptic psychogenic seizures. For example, a study based on EEG analyses conducted in a cohort or 18 PNES patients and 18 health control subjects, demonstrated a reduction of functional connectivity between basal ganglia and cortical regions and a reduction of interhemispheric connectivity across paralimbic areas [97]. Some autonomic investigations have demonstrated an increase in sympathetic tone ictally in epileptic seizures rather than non-epileptic psychogenic seizures [98], while other studies have documented pre-ictal and post-ictal autonomic changes between the two groups [99].

9. Treatment of PNES

PNES is a condition that causes social stigma for both patients and their families. The understanding of the factors determining the psychogenic non-epileptic seizures is important to predict the patient’s response to the diagnosis and subsequent therapies.

To the present days, significant progresses have been made in the management of PNES [71]. The management of PNES can be divided in four phases. The first phase (diagnostic phase) aims to communicate the diagnosis of PNES to the patients who are often confused and irritated. The second phase (engagement phase) consists in making the patients aware of the diagnosis and make them actively participating to the treatments. The third phase (acute intervention phase) aims to reduce the frequency of seizures, improve psychiatric comorbidities and improve quality of life. The fourth phase (long-term intervention) aims to manage in the long-term PNES patients. A pioneering study conducted in 1998 demonstrated that a clear explanation of PNES diagnosis, combined with immediate psychological treatment, markedly reduces the use of medical services [100]. How the diagnosis is communicated is very important since a correct information to the patient and his family about non-epileptic origin of the seizures can remit the symptoms in some patients [101] or can have consequences on the evolution of the seizures [102]. After the diagnosis of PNES, the treating neurologist gradually discontinues antiepileptic medications and simultaneously starts other specific treatments.

The best strategies of treatment for PNES are psychotherapies, psychotropic medications or other psychiatric interventions based on evidence that PNES patients have a huge variety of psychological and psychiatric disorders [103]. Clinicians have proposed a wide variety of psychotherapeutically interventions that include cognitive behavioral approaches, psychodynamic interpersonal therapy, mindfulness-based therapies, psychoeducational therapy, group and family therapies, psychodynamic therapies, supportive psychotherapy and hypnosis [18].

Cognitive behavioral therapy (CBT) is one of the most useful approaches to a wide range of clinical and psychological factors. Cognitive behavioral therapy has a proven effectiveness for treatment of anxiety and depression, frequently associated with development and maintenance of PNES [104]. In a randomized trial of 12 weeks conducted on 66 patients with PNES, CBT associated with standard medical care showed a statistically significant reduction in seizure frequency at the end of the treatment sessions [105]. Goldstein proposed a 12-session model focused on cognitive, emotional and behavioral aspects of PNES [105]. According to this model, the treatment consists in five stages. The first stage consists in commitment to treatment and rational explanation. The second stage is teaching techniques for controlling pseudo-seizures. The third stage is exposing techniques to reduce avoidance. The fourth stage is the management of emotions and cognition related to seizures. The last stage is relapse prevention [105].

Howlet and Reuber have developed a brief psychodynamic interpersonal therapy (PDIT) for the treatment of patients with PNES (Howlet and [106]). They proposed an empathetic approach aimed to improve copying stiles and promote patient collaboration. Treatment consists of an initial two-hour semi-structured interview followed by 19 therapy sessions with intervals of 1 or 2 weeks. A study conducted on 108 patients with PNES treated with this model demonstrated that between 12 and 60 months after the end of the therapy, 40% of patients presented a 50% reduction of pseudo-seizures and 25% of patients were seizure free [107].

Mindfulness-based therapies (MBT) try to promote self-regulation of attention, adopt an attitude of curiosity and accept own experience at each moment. According to Baslet, MBT program is organized in five modules that include psychoeducation, mindfulness for everyday life, stress management strategies, emotion management and relapse prevention [107]. In PNES patients, MDT determined reduction in the seizure frequency and improvement in quality of life.

Acceptance commitment therapy (ACT) is a hybrid psychotherapy with components derived from both cognitive behavior therapy and mindfulness-based therapy [108]. ACT has demonstrated efficacy in the treatment of depression, post-traumatic stress disorder, dissociative conditions and experimentally in psychogenic seizures [109]. It focuses on enhancing individual psychological flexibility using techniques that changes patient’s relationship with his own emotions. In a study conducted on a small group of patients, ACT showed clinically significant improvement in psychological flexibility and reduction in seizure episodes [110].

Approaches based on psychoeducational programs (PEP) have been demonstrated to be important in the management of patients with PNES. The basis of this treatment consists in making the patient aware of his condition through the use of educational modules aimed to explain psychogenic origin of seizures and treating the associated aspects. PEP are mainly designed in a group format. One of the first PEP was proposed by Zaroff in USA in 2004 who reported improvement in post-traumatic symptoms, dissociation and perceived quality of life [111]. A randomized controlled trial conducted by Chen on PNES patients showed that psychoeducational intervention improves psychosocial functioning and reduces access to emergency rooms, visits and hospitalizations, but if it does not reduce frequency and intensity of PNES [112]. Other studies based on psychoeducational treatment that included among the interventions explanation regarding mind-body relationship, distraction exercises and relaxation have determined also a significant decrease in the frequency of PNES [113].

Some researchers have proposed group and family therapies (GFT) in patients with PNES since their families are more conflictive than those of epileptic patients [114]. These therapies have demonstrated improvement in psychological well-being but variable results regarding the reduction of seizures [115].

Psychodynamic therapies (PDT) are based on the psychoanalytic concept of trauma using principles of Anna Freud’s psychology and object relations theory. A study conducted by de Olivera Santos applying psychodynamic therapy reported a 30% of seizure-freedom in patients with PNES [116].

Other studies have reported that prolonged exposure therapy (PET) reduces the number of PNES and improves post-traumatic symptomatology for patients diagnosed with PNES and PTSD [117]. For example, a study conducted on 16 patients diagnosed with PNES and PTSD, after 12–15 weekly sessions they had a significant reduction in seizure frequency and PTSD symptoms and maintained these improvements for a long period [118].

In recent years, eye movement desensitization and reprocessing (EMDR) has also been proposed in the treatment pf patients diagnosed with PNES and post-traumatic stress disorders [119]. However, it has not shown effective results when used as first line of treatment and it is more useful if associated with a battery of treatments [106].

In addition to psychotherapeutically interventions, when depression or post-traumatic stress disorders are present in comorbidity, some antidepressant drugs are effective as pharmacological treatment. Serotonin reuptake inhibitors (SSRI) are the antidepressants with more effective results. For example, a double-blind, randomized, placebo-controlled study conducted over 12 weeks showed that sertraline treatment determined a reduction of 45% of seizure frequency; instead, placebo treatment determined an increase of 8% of seizure frequency [120]. A multicenter randomized clinical trial conducted in 2014 compared four types of treatment: only sertraline with a flexible dose, only cognitive behavioral psychotherapy, association of sertraline with CBT and standard medical care [121]. This study demonstrated that the two groups that received psychotherapy exhibited a significant reduction in seizures: 51% in the group treated only with cognitive behavioral psychotherapy and 59% in the group treated with association of sertraline with CBT. The group of patients treated with standard medical care did not show a significant reduction in the frequency of seizures. The group treated only with cognitive behavioral psychotherapy showed improvement in many psychological disorders such as anxiety, depression and global functioning. These findings support that in patients with non-epileptic seizures, it is possible to control the seizures with an approach based on use of psychotherapies and in particular cognitive behavioral therapy [122].

Long-term benefits of therapies have been examined in randomized controlled clinical trials that take in consideration pharmacologic and psychotherapy options of intervention [123].

Outcomes of PNES subjects are improved when the assessment of these patients is based on accurate diagnosis, effective communication with the patient and correct management [124]. A retrospective study of 260 consecutive PNES patients measuring outcome at six and 12 months after diagnosis demonstrated that 18% showed an increase in seizures, 38% were seizures free and the majority of patients continued to have seizures [125]. Patients with psychiatric disorders such as anxiety or depression had less chances to become seizure free. In addition to psychiatric and psychosocial disorders, patients with PNES and a story of traumatic brain injury have worse outcomes other than increased depression, impulsivity, behavioral disorders and lower global functioning [72].

10. Conclusions

Psychogenic non-epileptic seizures are functional neurologic disorders with high prevalence. In recent years, relevant advancement has been made in diagnosis and the management of this neuropsychiatric condition. Accurate diagnosis and management of PNES need a multidisciplinary collaborative approach among neurologists, psychiatrists and other specialists. In addition to an accurate medical history, research for clinical signs and video-EEG, different biomarkers could help the diagnosis of PNES. Examples of biomarkers useful for differentiating PNES from epileptic seizures are hyper-cortisolism, delayed creatine phosphokinase, lower post-ictal levels of nesfatin and elevated post-ictal levels of ghrelin. Neuroimaging studies are helping clinicians to clarify neurobiology of PNES and reduce the stigma associated with this condition. Although there is a general agreement that psychogenic non-epileptic seizures can be treated with psychotherapies, the effectiveness of the most psychotherapeutic methods has not been adequately investigated. Future investigations will be useful to identify new biomarkers and psychopathological mechanism for an appropriate diagnosis and treatment of PNES.

Conflict of interest

The author declares no conflict of interest.