Continuing Education Activity

Nonepileptic episodic events can be vexing for the patient, and they present considerable diagnostic and therapeutic challenges to neurologists, psychiatrists, and other healthcare practitioners. Broadly construed, nonepileptic episodic events are paroxysmal occurrences arising from a physiologic or psychogenic cause, resulting in alterations in behavior, experience, sensation, or movement.  Nonepileptic episodic events closely resemble so-called epileptic seizures. However, they are not caused by the excessive synchronous cortical electroencephalographic activity that defines epileptic seizures, nor are they associated with concomitant epileptiform abnormalities on electroencephalogram. Both physiologic and psychogenic origins are subsumed under the general term nonepileptic episodic events. The term "psychogenic nonepileptic seizures" (PNES) reinforces the idea that events are not epileptic seizures and may instead be of psychogenic origin. At the same time, PNES signals to the knowledgeable practitioner that the evaluation and management will be different than for similar-appearing events that do have "epileptic" origins. PNES and epilepsy can coexist.

In most cases, the skills of an epilepsy specialist with access to an epilepsy monitoring unit will be needed to confirm the PNES diagnosis. Diagnostic confirmation is necessary to avoid misdiagnosis and unnecessary treatments, some of which risk nontrivial harm. This activity reviews the differences between epileptic seizures and PNES and outlines an approach to prompt diagnostic confirmation and implementation of appropriate treatment strategies. This activity further highlights the role of the interprofessional team in caring for patients with PNES.

Objectives:

• Differentiate elements of the history and the ictus that suggest psychogenic nonepileptic seizures versus those suggesting epilepsy.

• Identify the necessary elements of history, physical examination, and testing that must be present to substantiate a diagnosis of psychogenic nonepileptic seizures.

• Select the correct treatment strategies for psychogenic nonepileptic seizures and differentiate them from the usual treatment for epilepsy.

• Apply interprofessional team strategies for improving care coordination and patient education to advance the treatment of psychogenic nonepileptic seizures and improve patient outcomes.

Introduction

Psychogenic nonepileptic seizures (PNES) are relatively common but poorly understood and often misdiagnosed as epilepsy, which can lead to unnecessary procedures and treatments along with the possibility of failure to engage patients in necessary behavioral health care. Despite a superficial resemblance to epilepsy, in PNES, the underlying cause has long been considered to be psychological. However, increasingly integrated theories of causation invoking genetics, environmental factors, temperament, and early childhood experiences are being proposed.[1][2][3][4][5] Rarely is a nonepileptic event intentional, in which case it could be due to factitious disorder or malingering, but by definition, PNES themselves are never intentional.

"Pseudoseizure" is a now-outmoded term for paroxysmal events that appear to be epileptic seizures but do not arise from the abnormal excessive synchronous cortical activity that defines an epileptic seizure. Patients and healthcare practitioners alike are prone to misinterpret "pseudoseizure" as indicating that the patient is "faking" or otherwise feigning the events when, in fact, the events are involuntary behavioral responses to underlying psychological triggers or stresses. Other terms used in the past that should now be avoided are hysterical seizures, functional seizures, stress seizures, and others. 

Distinguishing PNES from epileptic seizures may be difficult at the bedside, even for experienced clinicians.[6][7] Indeed, some researchers have characterized PNES as occupying a no-man's land at the intersection between Neurology and Psychiatry.[8] Diagnostic delay of years with PNES is common.[9] Video electroencephalography (video-EEG) of a typical event showing the absence of epileptiform activity during the spell in the setting of a compatible history is the gold standard for diagnosis.[10] Between 20% and 40% of patients referred to epilepsy monitoring units for difficult-to-control seizures are ultimately found to have PNES. A recently reported pediatric series examined 15 years of video-EEG monitoring and found that the final diagnosis was PNES in nearly 20% of monitored individuals; eventual discontinuation of antiseizure medication (ASM) on the grounds of initial misdiagnosis was necessary for nearly 25%.[11] 

Correct diagnosis is imperative for the successful treatment of PNES. Still, misdiagnosis is common, especially among primary care and emergency physicians, nearly two-thirds of whom reported their belief that video-EEG is not needed for diagnostic confirmation in a recent study.[1] A comprehensive history and examination are vital steps toward a correct diagnosis. Consultation with neurology is nearly always beneficial; admission to an epilepsy monitoring unit for video-EEG analysis is almost always required. Referral to a comprehensive epilepsy center may be helpful in challenging cases. 

The diagnosis of PNES needs to be conveyed to the patient effectively and empathically; doing otherwise carries a non-trivial risk of prompting confusion, anger, or resentment, any or all of which can then exacerbate PNES symptomatology. Diagnostic disclosure is particularly delicate if a given patient was previously diagnosed with epilepsy, and patients with a history of trauma or abuse can easily be re-traumatized by a clumsily rendered diagnosis. Above all, the clinician must acknowledge and underscore that help is available for the patient's symptoms, that these symptoms are real, and that symptoms represent a source of distress to the patient, family, and friends. 

Treatment of PNES may be complex, but it is clear that ASMs are of no benefit, and they may cause harm.ASMs should be discontinued unless they are in use to manage concomitant epilepsy, chronic pain, or mood disorders; continuation of ASMs after the PNES diagnosis has been made is associated with poor outcomes.[12] Psychotherapy is effective and can improve seizure frequency, overall psychosocial functioning, and health-related quality of life. 

Etiology

In PNES, symptoms are traditionally considered to be a manifestation of underlying psychological distress coupled with unresolved emotions. Considerable heterogeneity governs the presentation of PNES, which has created obstacles in advancing a universal etiologic model, although recently integrative cognitive models have been proposed.[13]

Certain factors are generally accepted as increasing the risk of PNES, such as trauma or other acute stressors. A non-inclusive list of comorbid disorders conveying increased risk encompasses functional or dissociative disorders, post-traumatic stress disorder, mood and personality disorders, concomitant epilepsy, mild head injury, problems with thinking or sleep, migraine headaches, pain disorders, and even asthma.[14]

The most common underlying psychiatric mechanism has traditionally been that of conversion disorder. However, this relatively simple explanation is now being challenged by theories positing the existence of a complex and multifactorial network etiology incorporating biological, psychological, and social elements.[13] A conversion disorder, by definition, implies that the individual is not aware of the underlying psychological stressor and is not consciously feigning events. The Diagnostic and Statistical Manual of Mental Disorders (fifth edition) classifies PNES as a form of conversion disorder [DMS-5-TR]. In contrast, the 11th revision of the International Classification of Diseases (ICD-11) considers PNES a dissociative disorder. The International League Against Epilepsy (ILAE) states that PNES is one of the 10 most critical neuropsychiatric conditions related to epilepsy.[8]

A diagnosis of PNES should under no circumstance be made based on a single (or even a combination of) several suggestive elements of history or seizure semiology. How the various risk factors summate to produce spells is poorly understood.[15] Different psychological stressors have been reported as precipitating or initiating events for the emergence of PNES. These include parental conflicts and divorce for children, ongoing physical and especially sexual abuse, bereavement, and job or financial loss.[16] 

A paroxysmal nonepileptic episodic event can also occur secondary to physiological causes, which can be neurological or non-neurologic. Common neurological physiologic antecedents include migraine, nonepileptic myoclonus, cerebrovascular ischemia or stroke, and parasomnia; non-neurological antecedents include metabolic derangement, cardiac arrhythmias, and syncope (the latter especially when accompanied by the tonic or clonic movements of "convulsive" syncope). 

Epidemiology

A recent systematic review estimated the US incidence of PNES to be 3.1 per 100,000, with a corresponding prevalence of 108.5 per 100,000.[1][17] In ambulatory epilepsy clinics, 5 to 10% of patients have PNES rather than epilepsy; between 20% to 40% of inpatients on epilepsy monitoring units have PNES.[8] In a recent study of generalized convulsive status epilepticus, 10% of patients thought to have benzodiazepine-refractory generalized convulsive status epilepticus who were given additional antiepileptic drugs after adjudicated review were found to have PNES.[18]

Female sex, psychiatric comorbidities (eg, depression, anxiety, posttraumatic stress disorder), and a history of sexual abuse during childhood are all recognized risk factors for the development of PNES. In addition, trauma, brain injury, surgical procedures, and learning disabilities have been suggested as possible risk factors.[8]

Pathophysiology

The underlying pathophysiology of PNES is poorly understood. An emerging consensus posits that PNES is a network disorder wherein genetics, emotional dysregulation, abnormal sensorimotor processing, and stress responses combine to produce symptoms.[19]

Some evidence from functional and structural neuroimaging studies has revealed abnormalities in the limbic system, including prefrontal, cingulate, and insular cortices, hippocampal and parahippocampal gyri, and the amygdala.[20]

History and Physical

Psychogenic nonepileptic seizures may be difficult to distinguish from epileptic seizures solely by history and observation. The importance of an early and accurate diagnosis cannot be understated, as individuals with PNES commonly experience lengthy delays in diagnosis along with off-target treatment with ASMs and other interventions that can include intubation. 

Table. Characteristics of Ictal Semiology That May Aid in Differentiating PNES From an Epileptic Seizure

References for Table.[8][13]

In one recent meta-analysis, only ictal eye closure and asynchronous limb movements were reported to exhibit a moderate to large effect on the post-test probability of PNES. There is no single pathognomonic sign or symptom that can reliably distinguish PNES from an epileptic seizure.[21][1][21]

Aura, a type of focal-onset seizure that often precedes a generalized tonic-clonic epileptic seizure (especially those with temporal lobe onset), can also occur in PNES, making aura a poor discriminating feature between the two conditions. In one recent prospective registry study, researchers found that the aura manifestation was similar in PNES and epileptic seizures; in PNES, headache and dizziness/vertigo were most frequently reported, suggesting that they can be considered "in favor" of PNES but not diagnostic of it.[22]

In PNES, events have been associated with light triggers, emotional stressors, pre-ictal and post-ictal headache, post-ictal muscle soreness, and ictal sensory symptoms, whereas in epileptic seizures, missing scheduled ASMs is one of the most commonly occurring seizure triggers.[23]

Well-documented exceptions to these observations are important to understand. For example, pelvic thrusting, bicycling movements, and abnormal posturing occur frequently in frontal lobe epilepsy, often with nocturnal onset.[24][25]

With the current near-ubiquity of cell phone cameras, an event's witness may offer a video recording. Analysis of these recordings by expert review has been found to have additive value for diagnosing nonepileptic seizures.[26]

Evaluation

The pattern of a generalized convulsive seizure is typically abrupt onset of brief tonic posturing followed by synchronized clonic extremity movements, alteration of consciousness, and a postictal confusion phase. Exceptions do occur, particularly in patients with focal impaired awareness seizures (previously known as complex partial seizures) starting in frontal or temporal areas. At times, unusual motor patterns occur with focal impaired awareness seizures or persistent confusional states with minor motor automatisms. If hospital policies permit and appropriate patient consent (or assent) is in place, capturing events with video may be helpful in later analysis. 

Though sometimes used to "wake up" a patient thought to be having feigned unresponsiveness or nonepileptic spells, noxious stimuli such as ammonia capsules or painful stimuli (eg, sternal rub) should be avoided.

Correct diagnosis is essential for the successful treatment of PNES. Patients with PNES are frequently misdiagnosed as having epilepsy and often have been prescribed multiple ASMs. Consultation with neurology is recommended for all but the most obvious situations. In all cases, a comprehensive history of a PNES-consistent event coupled with video EEG monitoring during a typical event is considered the gold standard for diagnosing PNES.[1][27] Video-EEG monitoring facilitates simultaneous video and electrographic documentation of the events of interest. In an apparently unconscious patient, an alpha rhythm on EEG indicates underlying alertness. The lack of epileptiform correlation on the EEG suggests that the captured event is nonepileptic, although caution is recommended given that not all epileptic seizures can be captured by scalp electrodes.[1] Additional investigation may be necessary to distinguish PNES from a precipitating physiologic event.[7] Recently, short-term video EEG has been found helpful in diagnosing PNES.[28]

Laboratory testing is generally of limited utility in the evaluation of PNES. Serum prolactin levels have long been noted to increase immediately after a generalized convulsive seizure but not after PNES. Prolactin levels peak 10–20 minutes after the event and return to normal within an hour, and though discussed extensively in the literature, they are of limited pragmatic value. Episodes of convulsive syncope can also elevate prolactin. Prolactin levels do not help distinguish PNES from focal impaired awareness seizures or focal seizures with retained awareness.[29] A normal prolactin level does not confirm PNES.[30] Prolactin is useless in distinguishing PNES from physiological nonepileptic events, although it can be elevated in cases of convulsive syncope.[31] False positives can occur in individuals taking dopamine agonists or with breast stimulation; false negatives can occur in frontal lobe epilepsy and even in status epilepticus.[13]

Lactic acidosis commonly follows a generalized convulsion. However, elevated lactate levels are not specific for convulsions of epileptic origin; elevations also occurred in volunteers simulating generalized seizures.[32] A normal lactate level with high prolactin can indicate convulsive syncope.[31] White blood cell counts, neurotrophic factors, cortisol, and creatine kinase show limited discriminative utility but are not routinely used. Elevated creatine kinase levels have been observed after generalized convulsive status epilepticus but not psychogenic nonepileptic status epilepticus and may have some utility in distinguishing psychogenic status epilepticus from generalized convulsive status epilepticus.[33]

Neuroimaging is standard in the workup of an initial seizure, no matter its etiology, but interpretive caution is required as, here, too, there is no pathognomonic signature that can discriminate between PNES and epileptic seizures. One recent study compared three groups: individuals with PNES, individuals with major depressive disorder (MDD), and healthy control subjects. Individuals with PNES displayed selective cortical thinning over the medial orbitofrontal cortex, whereas individuals with MDD had wider regions of thinning. Somatoform dissociation was the only psychopathological assessment significantly different in PNES and MDD.[34]

Neuropsychological testing can provide helpful adjunctive information, but it should not be relied upon to diagnose PNES. After a comprehensive clinical assessment and video-EEG have been undertaken, neuropsychological testing can guide future ancillary testing; its best use is likely integration of results into a treatment plan that targets the patient's personality structure and cognitive strengths and weaknesses. Recent research into personality structure and psychiatric co-morbidities in PNES reveals that patients with PNES more often have isolated cluster B symptomatology compared to those with epileptic seizures; structured personality inventories demonstrate a statistically significant increased prevalence of borderline and depressive personality disorders in PNES.[35]

Treatment / Management

The first and arguably most important step in treating PNES is how the diagnosis is presented to the patient. The need for an empathetic approach that stresses the "real" nature of the events (thus avoiding the "it's all in your head" stigma) and underscores that effective treatment is available cannot be underestimated. Opinions differ on whether the term "seizure" or "event" is preferred. Unless concomitant epilepsy is present, there is no need for ASMs, and this point must be underscored at the time of diagnostic disclosure. If the diagnosis of PNES is secure, ASMs should be withdrawn.[36][37] A respectful approach and the reassurance that supportive therapy will most likely decrease or even eliminate the frequency of spells should be outlined. 

The best treatment for PNES is unknown, and the approach often requires individualization. Comorbid psychiatric conditions, such as PSTD and mood disorders, require treatment in their own right. 

Supportive care should be initiated immediately after the diagnostic disclosure. Some patients will resist the diagnosis and will seek alternative opinions. It should be stressed that returning regularly for follow-up can be beneficial for long-term care outcomes. The neurologist who makes the diagnosis should remain involved in subsequent care to minimize feelings of abandonment that can undermine overall treatment engagement. 

There is consensus that cognitive behavioral therapy (CBT) is the most effective treatment of PNES. A multicenter randomized clinical trial reported reductions in seizure frequency of more than 50% with CBT alone and nearly 60% reduction when CBT was combined with an antidepressant (sertraline). The trial also noted considerable improvements in overall quality of life, mood, and global functioning.[13]

Differential Diagnosis

Psychogenic nonepileptic seizures are essentially a diagnosis of exclusion. Any paroxysmal event may simulate a seizure or PNES, such as syncope, arrhythmia, functional movement disorders, and other spells. Once other paroxysmal events have been excluded, distinguishing PNES from epileptic seizures nonetheless remains a significant challenge, even for experienced practitioners. The differential diagnosis for PNES includes:

• convulsive syncope
• sleep disorders, especially arousals and parasomnias
• functional movement disorders
• factitious disorder
• malingering

Prognosis

The prognosis of patients with PNES is not clear. With correct identification of spells and diagnosis of PNES, treatment of any psychiatric comorbidities along with psychotherapy may decrease the frequency of spells. Cognitive-behavioral therapy-informed psychotherapy does seem to be efficacious. Patient acceptance of the diagnosis of PNES is thought to improve outcomes.[10] However, patients with PNES nonetheless face more than double the mortality risk of the general population; in PNES, mortality rates are comparable to those of patients with drug-resistant epilepsy, and as many as 20% of deaths in individuals with PNES were due to suicide.[38] Furthermore, PNES is associated with poor quality of life, excessive unemployment, and disability.[16] 

Complications

Potential complications of erroneously treating generalized status epilepticus include adverse reactions to medications. One study found that with the misdiagnosis of PNES as convulsive status epilepticus, massive doses of ASMs were administered until impaired consciousness or respiratory failure occurred.[39] Unneeded endotracheal intubations with iatrogenic complications have also been reported.[40][41]

Consultations

Consultation with neurology, preferably an epileptologist with access to an EMU, is virtually mandatory in all but the most apparent presentations of PNES. Primary care practitioners, social workers, psychiatrists, and especially psychotherapists skilled in CBT and other potentially helpful therapies form the backbone of the multidisciplinary care team and should become involved immediately after diagnosis. Psychotherapeutic approaches, like novel integrative psychotherapy, eye movement desensitisation therapy, or mindfulness-based therapy, require further exploration in large clinical trials.

Deterrence and Patient Education

As discussed previously, the correct diagnosis of PNES is necessary to facilitate appropriate interventions. Patient and family education about the psychiatric etiology of the spells and withdrawal of antiepileptic medications is beneficial in decreasing the frequency of spells. Patients should be counseled about the importance of attending follow-up appointments with both neurology and the behavioral health team to maximize the likelihood of reducing seizure frequency and improving overall quality of life.

Pearls and Other Issues

Key facts to keep in mind regarding PNES:

• It is critical to realize that patients suffering from PNES present with involuntary events. Patients often feel accused by the medical team of "faking" their events. In cases of the latter, malingering would be the preferred diagnosis. 
• There is no single pathognomonic sign or symptom that is capable of reliably differentiating PNES from epileptic seizures. 
• In the overwhelming majority of cases, a PNES diagnosis requires the capture of typical events while undergoing monitoring in an epilepsy unit. In PNES, there will be no electrographic correlation of the "ictus." 
• A multidisciplinary team approach with cognitive behavioral therapy as the primary treatment helps the patients the most. 

Enhancing Healthcare Team Outcomes

PNES are paroxysmal events resembling epileptic seizures but without abnormal electrical activity in the brain. Recognizing PNES requires clinicians to differentiate between physiological and psychological origins. Diagnosing PNES involves video-EEG monitoring and psychological evaluation. Clinicians must approach patients empathetically, acknowledging the psychosocial aspects contributing to PNES. Management encompasses psychological interventions, such as cognitive-behavioral therapy, addressing underlying stressors. Patient education and collaboration with mental health professionals are crucial. This summary emphasizes the importance of a holistic approach, combining neurological and psychological perspectives, to effectively diagnose, treat, and support individuals with PNES.

An interprofessional team of healthcare professionals is needed for the ideal treatment of PNES. This team will include emergency medicine and primary care clinicians, specialists (neurologists, psychiatrists, psychotherapists), nursing staff, pharmacists, and supportive mental health professionals, all collaborating across disciplinary boundaries to achieve optimal patient outcomes. Team members should be consistent in communication with the patient and family members. Neurologic evaluation and referral to appropriate psychiatric or counseling resources is an ideal course.