The Diagnosis of Functional Seizures

Functional seizures (FS), also known as psychogenic nonepileptic seizures (PNES), are paroxysmal attacks that may resemble an epileptic seizure but are not caused by abnormal brain electric activity and have a psychologic etiology.¹

Although terminology has been evolving toward the term functional seizures, there is still debate within the field about what terminology is most appropriate. Other terms considered include nonepileptic seizures, which we consider too broad because that would include nonepileptic nonpsychogenic events (eg, syncope, migraines, transient ischemic attacks [TIAs], movement disorders, and sleep disorders); PNES; nonepileptic attacks, which is also overly broad; psychogenic nonepileptic attacks, psychogenic nonepileptic events, psychogenic seizures, and dissociative seizures.^2,3 A good argument can be made that the term seizures, in the English language, may imply an epileptic nature.⁴

FS are a specific subtype of a larger group of psychiatric conditions, previously defined in the American Psychiatric Association’s Diagnostic and Statistical Manual, 4th edition (DSM-IV) as somatoform disorders⁵ and in the 5th edition (DSM-5), as somatic symptom and related disorders. In the DSM-5, this category includes somatic symptom disorder, illness anxiety disorder, conversion disorder, and factitious disorder and other related conditions.⁶ “Attacks or seizures” is classified under conversion disorder (also termed functional neurologic symptom disorder [FND]) along with other neurologic symptoms. FS can also be considered dissociative.

Epidemiology & Prevalence

FS have an estimated prevalence rate of 2 to 33 per 100,000 annually;⁷ 25% of patients evaluated in an epilepsy center and 16% of those evaluated in neurology clinics have a diagnosis of FS and FND.⁸ Concurrent epilepsy occurs in 10% to 15% of persons with FS.⁹ There is higher prevalence of FS in women, and sexual trauma may be a mediating factor in the association between female sex/gender and FS. About 80% to 90% of people with FS have additional psychiatric diagnoses (eg, posttraumatic stress disorder [PTSD], anxiety, or depression).⁷

Etiology & Psychopathology

Contrary to what is commonly implied in the literature, FS are not a unique disorder, but rather are a specific subtype of the larger group of somatic symptom and related disorders or, previously, somatoform disorders. Thus, the etiology and psychopathology of FS are the same as the larger category where biopsychosocial factors play a major role.¹⁰ There is no established pathophysiology for FS, but sensorimotor, emotion regulation/processing, cognitive control, and multimodal integration brain systems are being studied.¹¹ Just like FS for neurology, every specialty has their share of psychogenic symptoms,^12,13 with similar psychopathology.

Causes & Consequences of Epilepsy Misdiagnosis

Misdiagnosis of epilepsy is common. Approximately 25% to 30% of persons diagnosed with epilepsy who do not respond to initial antiseizure medications (ASMs) have another diagnosis, most commonly FS, then syncope. Initial diagnosis typically depends on observations and descriptions of witnesses or even medical professionals who may not have a high enough index of suspicion. This trend of misdiagnosis results in unnecessary treatments, medication side effects, driving restrictions, and employment difficulties. It also brings psychologic and socioeconomic consequences and delays or prevents appropriate and adequate treatment of the correct diagnosis.¹⁴

In a UK study, the average medical cost per patient each year of misdiagnosis was £316, including the cost of inpatient admissions, inappropriate prescribing of ASMs, outpatient clinic visits, and care from general practitioners that averaged £138 million per year.¹⁵ In the US, more than $1.2 billion dollars per year are spent on FND, and there are increasing annual costs for emergency-department and inpatient care of persons with FND. This is comparable with other investigation-intensive and pharmacologically demanding neurologic disorders.¹⁶ These data indicate that the problem is global rather than specific to a particular region or health care system.

Diagnosing FS

The average diagnostic delay for FS is 7 to 10 years,¹⁴ which means patients carry an erroneous diagnosis of epilepsy, often considered drug-resistant, for a long period of time. This subjects the misdiagnosed individual not only to above-mentioned aspects of misdiagnosis, but also to carrying the lifestyle aspects of epilepsy diagnosis that can be difficult to reverse.

Differential Diagnosis

It is important to have a high degree of suspicion for nonepileptic events to avoid the misdiagnosis of epilepsy. Potential diagnoses other than FS for nonepileptic seizures comprise a large list (Box).¹⁷

History

Diagnosis of FS can be suspected based on the history, making accurate history from witnesses among the most important initial pieces of the puzzle. Some red flags that should raise suspicion for FS are: 1) psychiatric and psychologic history; however, psychiatric comorbidities are also frequent in intractable epilepsy; 2) involvement of multiple organ systems (review of systems), suggesting somatization; 3) events occurring in the presence of audience, with suggestion and exclusively while awake; 4) consistent unusual triggers (eg, stress, pain); and 5) attacks that are resistant to treatment with ASMs.¹⁷

Unfortunately, descriptions by witnesses have limitations and are notoriously unreliable.^18,19 There is also a tendency for health care professionals to use technical terms (eg, tonic-clonic or gaze deviation) for motor or eye movements based on descriptions alone, and those are frequently inaccurate. Recently, smartphone videos have been shown very useful,^20,21 with:

• 100% sensitivity and specificity for definite epileptic and nonepileptic episodes,
• 80% sensitivity and 100% specificity for probable epileptic episodes, and
• 100% sensitivity and 80% specificity for probable non-epileptic events.²⁰

Description of Events: Semiology

The sensitivities and specificities of some of the most common distinguishing features of FS and epileptic seizures are listed in Table 1.^13,22 Other features suggestive of FS include longer duration, slow or very gradual onset or termination, unusual precipitating factors, and opisthotonic posturing. Features suggestive of epileptic seizures are presence of an aura, behavioral arrest, automatisms, shorter duration, and stereotyped events.^22,23

Confirmation of FS With VideoEEG Monitoring

VideoEEG monitoring is based on the principle that FS lack ictal epileptiform discharges.²² To evaluate FS, the physician ideally should be able to look at the semiology of an event or events and analyze the EEG. VideoEEG monitoring allows simultaneous evaluation of these important aspects and is considered the gold standard for diagnosis of FS. Accuracy of diagnosis with FS, however, is unknown because of the lack of confirmatory tests. The best measure of accuracy and diagnostic reliability in this situation is the videoEEG interrater agreement, which was shown to be substantial for epileptic seizures but only be moderate for diagnosis of FS.²⁴

The general principles of videoEEG monitoring include the following. First, the presence of an ictal pattern (not normal variants or artifacts) during an event can confirm a diagnosis of epilepsy over FS. Secondly, the absence of an ictal pattern must be interpreted in the context of the semiology on the video, because some epileptic seizures may not have an ictal pattern visible on surface EEG. Third, induction techniques can provoke FS during EEG recording; and finally, monitoring heart rate during an event can be useful because the ictal heart rate is higher with a more rapid rate increase in epileptic seizures vs FS.²²

EEGs should be interpreted with caution because overreading EEGs is a well-known reason for misdiagnosis of epilepsy. Importantly, ictal EEG is not 100% sensitive because it can be negative in very limited focal (“simple partial” or “focal aware”) seizures and frontal lobe seizures²⁵ and can be obscured with muscle artifacts during excessive movements. Caution should be practiced while interpreting semiology and EEG in mild seizure-like activity or when there is more than 1 type of event. Overall, it is critical to take the entire clinical context into consideration.

There is some controversy about inductions (ie, activation procedures) being unethical, but we would argue that holding off on techniques that can help with accurate diagnosis may have worse consequences. Provocative techniques or inductions and suggestibility are helpful when clinical history and EEG are inconclusive. Ethical concerns are raised more with inductions that use a placebo, but other techniques (eg, verbal suggestion, hyperventilation, photic stimulation) are available.^26,27

Inpatient vs Ambulatory VideoEEG Monitoring. Traditionally, videoEEG monitoring has been performed in an inpatient setting to ensure that the patient’s typical event is captured on video and so that provocative techniques can be used. Recent data suggest that ambulatory videoEEG is a viable alternative to inpatient videoEEG for diagnosis of seizure-like episodes FS^28-32 and has a few advantages. Pros and cons of inpatient and ambulatory videoEEG are listed in Table 2.

Ambulatory videoEEG monitoring has become more widely available and may be particularly useful for some patients who do not have seizures in an observed setting. Outpatient ambulatory EEG allows patients to be in their typical environment where their usual triggers occur.²⁸ Other advantages of ambulatory videoEEG are convenience, faster access, and lower cost,³³ especially for nonurgent diagnostic evaluation of events.³⁴

Short-term (ie, 1-2 hour) outpatient videoEEG monitoring with induction may be useful, because FS usually manifest in the first few hours of videoEEG monitoring, but is of higher yield when combined with induction techniques. This can obviate the need for prolonged inpatient monitoring,^35,36 but does not allow for large sampling to identify any interictal epileptiform discharges.

Other Diagnostic Tests

Blood Serum Tests. Prolactin increases that are twice the normal relative or absolute levels in blood serum drawn 10 to 120 minutes after an event can be used to differentiate generalized tonic-clonic or complex-partial seizures from FS. Prolactin or creatine kinase (CK) levels, however, are not nearly as reliable as videoEEG and only have a role when videoEEG is not available. Other tests, such as peripheral white blood cell count, neuron specific enolase, diurnal cortisol levels, and brain-derived neurotrophic factor are under investigation.³⁷

Neuroimaging. Brain imaging helps to identify the cause of localization-related epilepsy but does not in itself help conclude if episodes are functional. Events can still be functional in the presence of imaging abnormalities. Studies on the use of neuroimaging to diagnose FS, including CT, structural MRI (sMRI), resting state functional MRI (rsfMRI), functional MRI (fMRI), single photon emission CT (SPECT), diffusion tensor imaging (DTI), subtraction ictal SPECT (SISOM), and fluorodeoxyglucose–positron emission tomography (FDG-PET) have been inconclusive.³⁸

Conclusion

FS are a common entity, which is usually misdiagnosed as epilepsy. It is important to note that FS are a subtype of somatic symptom and related disorders. Therefore, just like any disorder with a psychiatric basis, FS deserve recognition as a psychiatric diagnosis to ensure that patients receive appropriate management. FS can be suspected based on history but should be confirmed with video-EEG monitoring, which also helps in ruling out coexisting epilepsy. Hence, a neurologic evaluation is necessary in reaching the diagnosis, so that the individual can be treated effectively by mental health professionals.