Differentiating Frontal Lobe Epilepsy from Psychogenic Nonepileptic Seizures

There are three major categories of seizures: 1) Epileptic seizures (ES), 2) Psychogenic Nonepileptic Seizures (PNES), 3) Physiologic nonepileptic events (NEEs). PNES/NESS are can be difficult to distinguish from ES.

Primary Category
Epilepsy
P-Category
Secondary Category
Behavioural Neurology
S-Category

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
 

Further Reading

  • Tinuper, P., Bisulli, F., Cross, J. H., Hesdorffer, D., Kahane, P., Nobili, L., Provini, F., Scheffer, I. E., Tassi, L., Vignatelli, L., Bassetti, C., Cirignotta, F., Derry, C., Gambardella, A., Guerrini, R., Halasz, P., Licchetta, L., Mahowald, M., Manni, R., Marini, C., … Ottman, R. (2016). Definition and diagnostic criteria of sleep-related hypermotor epilepsy. Neurology, 86(19), 1834–1842. https://doi.org/10.1212/WNL.0000000000002666
  • Gasparini, S., Ferlazzo, E., Beghi, E., Tripepi, G., Labate, A., Mumoli, L., Leonardi, C. G., Cianci, V., Latella, M. A., Gambardella, A., & Aguglia, U. (2013). Family history and frontal lobe seizures predict long-term remission in newly diagnosed cryptogenic focal epilepsy. Epilepsy research, 107(1-2), 101–108. https://doi.org/10.1016/j.eplepsyres.2013.07.004
  • Rini, J., & Ochoa, J. (2020). Pharyngeal dysesthesias as aura in epilepsy localized to the non-dominant frontal operculum misdiagnosed as non-epileptic seizures. Neurocase, 26(4), 227–230. https://doi.org/10.1080/13554794.2020.1789177

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  • Beleza, P., & Pinho, J. (2011). Frontal lobe epilepsy. Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia, 18(5), 593–600. https://doi.org/10.1016/j.jocn.2010.08.018
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Anas Zahid MBBS

Written by

Anas Zahid MBBS

ECFMG certified, Match 2023 applicant

Muhammad Hasnain Haider MBBS

Contributing Author at AINeuroCare Academy, US residency aspirant

Ayaz Khawaja MD

Written by

Ayaz Khawaja MD

Assistant Professor with Department of Neurology at Wayne State University, Neurohospitalist and consultant at Harper University Hospital and Karmanos Cancer Institute, and as a Neurohospitalist, consultant and Neurointensivist at Detroit Receiving Hospital.

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