Differentiating Frontal Lobe Epilepsy from Psychogenic Nonepileptic Seizures

Primary Category

Epilepsy

P-Category

Secondary Category

Behavioural Neurology

S-Category

Authors:

Anas Zahid MBBS,
Muhammad Hasnain Haider MBBS,
Ayaz Khawaja MD

Introduction

💡

Three major categories of seizures

Epileptic seizures (ES)

Psychogenic Nonepileptic Seizures (PNES)

Physiologic nonepileptic events (NEEs)

Nonepileptic seizures can be difficult to distinguish from ES

Both types show alterations in behavior, consciousness, sensation, and perception

Erroneous diagnosis of epilepsy is common

Often the result of a weak history and a weak (“over-read”) EEG
Clinicians may perceive missing an epilepsy diagnosis as riskier than over-diagnosing it
May result in unnecessary treatments and side effects patient
May result in stigma and consequences on the personal and professional life of the patient associated with an epilepsy diagnosis

Most patients who are misdiagnosed are eventually found to have PNES

These are time-limited, paroxysmal changes in movements, sensations, behaviors, or consciousness that are not associated with epileptiform activity
Not due to any paroxysmal neurophysiological change within the brain, or any other organic cause
The semiological patterns of PNES are similar across ethnicities and cultures
The neuropathophysiology remains unclear
Hypersensitive-hyperexcitable limbic-frontal circuitry has been proposed as a possible etiology

Seizures in Frontal lobe epilepsy (FLE) may mimic PNES semiology while ictal characteristics of PNES may resemble epileptic seizures (ES)

Seizures originating within the frontal lobe can spread to other cortical areas while seizures originating outside the frontal lobe might spread to it
This can result in atypical clinical manifestations of frontal lobe epilepsy, which may lead to the incorrect diagnosis as a nonepileptic seizure
Differentiating PNES from FLE can be challenging, especially by history alone

FLE is further classiﬁed as:

Dorsolateral frontal
Mesial frontal
Basal

The average delay in diagnosing PNES is 7 to 10 years

This suggests that treating neurologists do not have a high enough index of suspicion
One of the main reasons is that PNES is limited to a negative process and is consequently characterized as a "nondisease" (not epilepsy)

Video electroencephalography (vEEG) is the gold standard for PNES diagnosis

Helpful adjuncts to the video EEG to confirm the diagnosis include:

Physical signs
Patient characteristics
Neuropsychological testing

Video EEG has vast inter-rater reliability (IRR) for epilepsy and moderate IRR for PNES

Treatment begins with the neurologists who share the findings of the video EEG monitoring

Neurologists, psychiatrists, and psychologists must work together to diagnose comorbidities and effectively treat this difficult population

Anti Seizure Medications (ASMs)

In most patients with PNES, clinicians should be able to withdraw unneeded ASMs on the basis of history and simple investigations (such as interictal EEG recordings and brain MRI)

However, initial observation in an inpatient setting may be needed in cases where the concern for epilepsy is higher, but a definitive diagnosis of epilepsy cannot be established by alternate methods
PNES and Epilepsy can co-exist

Significant proportion of epilepsy patients also have non-epileptic spells
Need to consider when deciding to withdraw ASMs

A long period of clinical monitoring may be needed. Initially recommended more close follow-ups
Removal of ASMs carries risk and that risk needs to be discussed with patient and family

Background factors

Background factors are of limited use to differentiate PNES from epilepsy on an individual level

Many patients with chronic epilepsy exhibit many personality and behavioral irregularities also found in PNES patients

Nevertheless, neuropsychological test results, personality inventories and psychiatric assessment can provide important diagnostic information in select patients

PNES tend to present in patients in their 20s and 30s

Depression and drug and alcohol abuse may be more frequent in patients with PNES

Approximately 70% of patients with PNES have other psychogenic disorders

Up to 70% of patients report antecedent trauma, which is of a sexual nature in up to 40%
Early childhood stress has been strongly linked to psychosomatic disorders, including conversion disorders like PNES
Current or previous mental health and psychosocial problems are common, though far from universal

Factors such as antecedent sexual abuse may not become known until after the diagnosis has been made

Epilepsy patients may have concomitant PNES:

Up to 5-10% of outpatient epilepsy patients have PNES
Up to 20-40% of inpatient epilepsy patients have PNES

As much as 30% of PNES patients with intellectual disability (ID) have additional ES

Up to half of of patients with PNES report a precipitating event that may also be associated with epilepsy

Events: Patterns & Trigger

Higher event frequency in patients with PNES than those with epilepsy

The triggering of events by stressful or difficult situations should suggest PNES

A diverse range of unchanging non-stereotyped attacks or those uncontrollable by AEDs may suggest a nonepileptic disorder

Attacks for which the patient has consulted a number of different physicians may suggest a non-epileptic disorder

PNES as a disorder may be triggered by surgery (including epilepsy surgery) and physical trauma

Events: Semiology

Semiologically, there are similarities and difference between ES and PNES

Individual elements of seizure semiology are not reliable to distinguish the diagnoses

Eye witness reports of semiology characteristics may not be reliable

Each separate semiology should be differentiated and classified as there can be combination of both FLE and PNES in the same patient

Complete semiology needs to evaluated rather than one feature that can mislead the diagnosis

Features highlighted in the following table 1 may be of help in distinguishing FLE and PNES

🎯

Similarities in semiology features of frontal lobe epilepsy and psychogenic nonepileptic seizures

Ictal crying may be present

Tongue biting may be present

Auras may be present

Behavioral disturbances in the postictal phase of ES may superficially resemble PNES

Seizures clustering may occur

Lack of prolonged post-ictal phase

Unilateral or asymmetrical tonic attacks may be present

History of urinary incontinence and injury may be present

A history of psychiatric disorder, ictal pelvic thrusting, body rocking, side-to-side head movements, or rapid postictal recovery may be present

Table 1: Differences in semiological features FLE vs PNES:

Semiologic Feature	Frontal Lobe Epileptic Seizures	Psychogenic Nonepileptic Seizures
Typical/Common seizure semiology	Unilateral clonic seizures Tonic asymmetric seizures Hypermotor seizures	Convulsive or Thrashing Swoon, Catatonic or Pseudosyncope
Duration of event	Shorter	Longer (>10 min strongly suggestive)
Nocturnal occurrence and turning to a prone position during the seizure	Present in Frontal Lobe Partial Seizures	Absent
Consciousness during event	Remains unclouded during tonic seizures, at least at the onset of seizures	May be clouded
Seizure motor activity frequency and amplitude	Frequency declines gradually over the course of the ictus while amplitude increases	Frequency remains unchanged throughout while amplitude is variable
Vocalization	Occurs at the beginning, is primitive, and has no emotional expression	Occurs during or after seizures, and may be complex, with affective content
Eye movements	Lateral deviation of the eyes can often be seen (Indicative of activation of the contralateral frontal eye field)	May exhibit geotropic eye movements (eyes deviate downward to the side that the head is turned)
Eye closure during the seizure	Less specific finding	More specific finding
Duration of eyelid closure	Shorter duration (~2 seconds)	Longer duration (20 seconds)
Noisy or stertorous breathing	Can be seen after ictus (this finding does not apply to partial seizures, however)	Not seen
Ictal crying	Much less common Shorter in duration Not intermittent	Much more common Longer in duration May be intermittent
Character of the injury due to the seizure	Lacerations	Excoriations on long bone surfaces, such as the arm, leg, or cheek
Pattern of tongue biting	Lateral tongue biting more common	Biting the tip of the tongue is more common
Whole body trembling	Tend to follow a stereotyped evolution	May vary in direction and rhythm
Different types of convulsive attacks at presentation	Less likely	More Likely
"Dialeptic” or “absence”-like events (alteration in consciousness)	Rare	More likely
Relation to sleep	Occurs in sleep	Occurs while awake or during pseudosleep (patient is awake with eyes closed)
Motor manifestations	Early	Gradual onset (and termination)
Opisthotonic posturing	Absent	Present
Signs of emotional distress	Less likely	More likely
Change in intensity of symptoms with attention	Not likely	Aggravation of psychogenic symptoms when attended to along with attenuation of the symptoms with distraction may be present
Findings not fitting any recognized pattern of epilepsy	Not present	Usually present
Ictal grasping	Can occur	Rare
Likelihood to bring in certain belongings with them into the Seizure Monitoring Unit, for example stuffed toy animals	Less likely	More likely

Electroencephalographic Findings

☝

Video electroencephalography (EEG) remains the gold standard for PNES diagnosis

Of note, Typical and atypical events need to be captured on vEEG to officially diagnose

The diagnosis of PNES is best confirmed by:

Recording events simultaneously on video and EEG
Finding an absence of ictal EEG changes (and the presence of normal awake EEG rhythms) before, during, and after the event
Without video EEG, neurologists’ ability to differentiate ES from NES by history alone has a specificity of 50%

A vEEG diagnosis with PNES-consistent semiology must be made in the context of clinical data

Psychogenic events do not occur out of physiologic sleep
Events that arise out of EEG-verified sleep are related to neurologic disorders (ES or parasomnias)

The concurrent recording of ECG during vEEG is essential

Ictal heart rate is higher and the ictal heart rate increase is more rapid in epilepsy than in PNES
Unlike that seen in ES, the heart rate increase in PNES is usually commensurate with the physical activity involved in the seizure

The majority of patients with PNES will produce an event within the first few hours of vEEG recording

Use of suggestion techniques may improve rate of seizure capture
These techniques include:

Simple verbal suggestion
Injection of saline
Hypnosis
Hyperventilation
Intermittent light stimulation
Injection of magnesium sulphate
Placement of a placebo skin patch

Suggestion increases both sensitivity and specificity of video-EEG monitoring
It may produce an event ‘on demand’ rather than having to wait for it to occur spontaneously
Only events typical of those experienced by the patient should be considered as positive indicators in favor of a PNES diagnosis

However, the absence of EEG change in and of itself is not always diagnostic of PNES

For example, if the recorded events are clinically compatible with:

Simple partial ES (i.e., consist of very localized motor movements, or a subjective experience only)
Hypermotor FLE

Consider physiologic nonepileptic events, such as syncope, for episodes that occur during waking
Parasomnias for episodes that occur in sleep

Few patients have PNES and additional epilepsy

Prevalence of epileptiform EEG abnormality will be low enough to make false positives a concern
In these patients, the exclusion of epilepsy primarily depends on clinical monitoring
Use of subdural grid electrodes that extensively cover the frontal areas may be able to localize dorsolateral FLE seizure onset zone in >90% of patients

Ambulatory EEG is being increasingly used

In the past, ambulatory EEG was not accompanied by video but that has changed with modern equipment
Compared with inpatient EEG video, the advantages of ambulatory EEG are:

The patient is in his or her regular environment where the episodes in question normally occur
The cost is lower
There is less or no wait time

One downside is that it does not allow for medication reduction

Interictal EEG findings

Interictal EEG data should be interpreted with great care

It is not capable of making or excluding a diagnosis of PNES

Nor is it capable of excluding epilepsy, as its false-negative rate is significant

High speciﬁcity of interictal EEG when interictal epileptiform discharges are detected

No longer true if artifacts or benign variants are overread as epileptiform

Important to distinguish between specific and non specific EEG abnormalities

An example of nonspecific EEG abnormalities is non-focal slowing
Examples of specific EEG changes include:

Spikes
Sharp waves
Spike-wave
Sharp/slow wave

Interictal discharges in frontal lobe seizures can be:

Bilateral synchronous
Multifocal
Lateralized to temporal lobe
Normal

Interictal epileptiform discharges (IED) occur in 60% to 80% of FLE

Interictal EEG in patients with mesial FLE generally shows either:

Abundance of non-lateralized epileptiform activity
No epileptiform activity

Seizures originating from dorsolateral frontal cortex are more likely to have concordant interictal epileptiform discharges than mesial frontal seizure foci
Bilateral frontal synchronous discharges are characteristic, but not speciﬁc, of mesial FLE

Interictal rhythmical midline theta (RMT) is common (50% of FLE patients)

Has localizing value in patients with FLE

But must be distinguished from normal variants occurring with drowsiness and mental activation tasks

RMT may be a neurophysiological marker for mesial frontal lobe abnormality

💡

A normal interictal EEG does not exclude epilepsy or confirm PNES. Similarly, an abnormal interictal EEG does not confirm epilepsy or exclude PNES

Limitations and pitfalls of EEG / video EEG

Continuous Video EEG is not available in some locations

Events cannot be recorded in certain patients

Frequent muscle artifacts in motor seizures

A large portion of the frontal lobe cortex is ‘‘hidden’’ to scalp electrodes

Ictal EEG may be negative in simple partial ES and in some complex partial ES, especially those of frontal lobe onset

In patients with extratemporal epileptic foci (medial or orbital surface of the frontal lobe, parietal lobe) interictal EEG’s can be normal or non-epileptiform
Absence of any ictal or immediate postictal EEG slowing has been reported in patients with mesial FLE
Only 25% of mesial FLE seizures correctly localize or lateralize on EEG
75% of mesial FLE seizures had non-lateralized patterns
Only discharges involving large areas of cortex (~7 cm 2 ), and in relatively close proximity to the recording electrodes can be correctly localized

Discharges arising from the basal frontal surface and buried cortex, such as amygdala, hippocampus, insula, and interhemispheric regions, may not be accessible to scalp electrodes

A negative EEG can only be interpreted in the context of the semiology of the event in question.

Both the video and EEG must be available

Video EEG cannot offer the same degree of a definitive diagnosis for PNES as, for example, a biopsy can for a brain tumor

Closest test to a biopsy for PNES would be intracranial monitoring
Associated risk and morbidity associated with intracranial monitoring (craniotomy and grid or depth electrode placement) not low enough to just justify its use for PNES diagnosis

Outpatient ambulatory EEG with caregivers' video recording seldom captures the beginning of the event

False Positives in EEG

Having a report of a prior abnormal EEG in cases of PNES is a common problem

When reviewed, most will turn out to show normal variants that were overinterpreted as epileptiform

A wrong diagnosis can result in a lifelong “label” that is repeated in the medical records and is difﬁcult to undo

Consequences on employment, insurance, and the like
Particularly illustrated by an epilepsy diagnosis

False diagnosis of seizures may be entirely based on the (over-read) EEG

Commonly, for episodic nonspecific symptoms such as:

Light-headedness
Dizziness
Numbness

Essential to obtain and review the tracing previously read as epileptiform,

No amount of normal subsequent EEGs will cancel the previous “abnormal” one
Can be difﬁcult

Previous records are not always available or accessible
Not all digital EEG systems are compatible

Adjunct diagnostic measures

Only ictal EEG can be used to differentiate PNES from ES definitively at the individual level

However, a number of neurophysiologic, neurohumoral, and neuropsychological tests allow discrimination at the population level

After conducting a thorough history, mental status, and neurologic examination, these instruments can be used to assist in the diagnosis of PNES

They are summarized in the subsequent sections below

Neurophysiologic Measures

More advanced neurophysiologic techniques such as high-density EEG and magnetoencephalography [MEG] can detect more functional disturbances

For example, pre-frontal hyposynchronization, suggestive of a regional neural dysfunction in PNES patients

Neurohumoral Measures

Serum prolactin (PRL) drawn within 30 minutes of the ictus onset is helpful for differentiating generalized tonic-clonic (GTC) epileptic seizures and complex partial epileptic seizures (CPS) from PNES

Strong confirmation of a diagnosis of ES when an increased PRL is found in patients with GTC- or CPS-like events suspected of being PNES

However, PRL is of limited usefulness for differentiating FLE of any semiology from PNES

Neuroimaging

Neuroimaging findings are of modest differential diagnostic value at present

Structural neuroimaging abnormalities neither confirm nor exclude ES or PNES

A frontal lobe lesion on MRI is highly suggestive of FLPS

Functional imaging is not useful for the diagnosis of PNES versus FLE.

A negative ictal single-photon emission computed tomography (SPECT) scan does not imply a diagnosis of PNES
Nor does an abnormal scan mean epilepsy is present
Ictal single photon emission CT and positron emission tomography are able to localize FLE in about one-third of patients only

Structural and functional imaging studies in patients with PNES have documented changes in

Cortical and cerebellar regions at group level
Functional connectivity between emotional, cognitive, and motor regions
Between structural and functional connectivity network coupling

There may be differences in the locations of brain MRI abnormalities in patients with epileptic seizures (more frequently temporal) versus PNES (more frequently multifocal)

Neuropsychological Measures

Neuropsychological tests do not distinguish ES from PNES at the individual level

Patients with ES and PNES perform roughly the same on neuropsychological (NP) measures but worse than healthy controls

For cognitive measures, patients with ES and PNES show no significant differences on tests of intelligence, learning, and memory but score lower than healthy control subjects

Temper tantrums and rage attacks usually indicate Frontal Lobe Partial Seizures (FLPS)

Depression and drug and alcohol abuse may be more frequent in patients with PNES

On psycho-motor measures, patients with PNES show reduced motor speed and grip strength, compared with healthy controls

Patients with PNES score lower than patients with ES on some motivational measures

Personality testing shows increases in hypochondria, hysteria, and depression scores in PNES

Mean scores on the psychophysiologic distress scale for the PNES and the ES/PNES groups were found to be higher than the mean scores of the ES control group

Individuals with PNES consider their families to be more dysfunctional

Particularly in regard to communication
Family members of patients with PNES reported difficulties defining roles

Individuals with PNES score higher on symptom checklists (a measure of somatic complaints) compared with other patients with seizures

Pain disorders are also common in patients with PNES

Among patients in epilepsy clinics, a diagnosis of fibromyalgia or chronic pain has an 85% positive predictive value for PNES

Patients with PNES have several psychiatric diagnosis comorbidities including

Depression
Anxiety
Posttraumatic stress disorder
Personality disorders

The simultaneous presence of depression, a history of abuse, and a personality disorder may portend a worse prognosis for patients with PNES

Overall, neuropsychological measures are not useful to make a diagnosis of PNES (vs epilepsy), because they are neither sensitive nor specific

Psychological testing may be a useful adjunct once the diagnosis of PNES has been made

Characterize the psychopathology and mechanisms underlying the symptoms
Clarify the psychiatric diagnosis (eg, somatoform disorder, dissociation)

Other Diagnostic Techniques

Hypnosis

Reported as diagnostically (and therapeutically) useful by highly trained individuals with extensive experience with PNES

Unclear at present how readily applicable or how accurate diagnoses would be if the procedure was carried out by less experienced practitioners

Conversation analysis (CA)

Not much is known about the reliability of “history-taking”

How patients describe their subjective seizure experience to the doctor can help with the differential diagnosis of epilepsy and PNES

Patients with epilepsy:

Readily focus on subjective seizure symptoms
Tend to give detailed accounts of these symptoms

Characterized by extensive formulation effort (including reformulations, re-starts, neologisms, pauses)

Patients with PNES:

Tend to focus on the situations in which seizures have occurred or the consequences of their seizures
Subjective seizure symptoms may be listed but are not described in detail

When trying to direct the patient’s attention to particularly memorable seizures (e.g., the first, last, or worst seizure), patients with PNES commonly resist e.g.:

not providing further information
rapid generalization of the description to their events in general

Patients with epilepsy readily provide more information about their subjective seizure symptoms in these particular seizures.

Patients with epilepsy tended to describe their seizures as acting independently (and often as doing something to the patient)

Those with PNES preferred metaphors depicting their seizures as a place or space they traveled through or to which they were confined

Patients with PNES catastrophize their seizure experiences compared to patients with ES

Patients with ES tend to normalize their seizure experiences when talking to a doctor

Remains to be seen which features can help with the differential diagnosis of patients who present with first seizures, and which (if any) features clinicians can identify “online,” as they are talking to patients

Post Hoc Confirmation of PNES

Remission of events after communication of the diagnosis, or after psychological intervention, occurs in a subset of patients with PNES

In up to 30% of patients, possibly more when events are of recent onset, PNES cease immediately after the patient has been provided with an explanation of their condition

A significantly large proportion of patients relapse if appropriate treatment is not provided
Nonetheless, such a response could be documented when the diagnosis of PNES is being considered
This response could augment other diagnostic data
Should be mindful that some epilepsies also take a variable course with periods of higher and lower seizure frequency

Diagnostic Uncertainty

Clinicians should always be mindful that the diagnoses may be wrong and routinely question and review diagnoses

It has been shown that experts are more likely to admit to diagnostic uncertainty than non-specialists.

Treatment of PNES

Mainstay of treatment for PNES is mental health therapy after referral to mental health professionals

Proper communication of diagnosis to patient is a significant portion of the therapeutic process

Moreover, the clinician should help the patient, in an individualized manner

adapt to their diagnosis
start using the mental health services as they need

Neurologists continue to be a part of treatment:

Safely decrease doses and eventually discontinue ASMs
Treat any other neurological conditions present
Make sure no improper treatment is being administered

Acutely, treatment with Cognitive Behavioral Therapy (CBT), with or without Selective Serotonin Reuptake Inhibitors, is most beneficial

Long-term interventions may be needed:

long-term psychotherapy
case management
continuing management of other psychiatric conditions

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