Psychiatric Comorbidities in Functional Neurological Disorders and Psychogenic Non-Epileptic Seizures: A Systematic Review and Policy Recommendations for Improving Assessment and Treatment

Introduction

The World Health Organisation – International Classification of Diseases (WHO ICD-11) classifies Functional Neurological Disorder (FND) and Psychogenic Non-Epileptic Seizures (PNES) in 6B60 as Dissociative Neurological Symptom Disorder characterized by the manifestation of motor, sensory, or cognitive symptoms that suggest an involuntary disruption in the typical coordination of motor, sensory, or cognitive functions.¹ These symptoms do not align with any known nervous system disease, mental or behavioral disorder, or other medical condition.¹ The symptoms are not present just during another dissociative illness and are not caused by the effects of a drug or medicine on the central nervous system, including withdrawal effects or a Sleep-Wake disorder.¹ Subclassifications include (1) visual disturbance (6B60.0) such as blindness, tunnel vision, diplopia, visual distortion, or hallucinations; (2) auditory disturbance (6B60.1) with loss of hearing or auditory hallucinations; (3) vertigo (6B60.2) or dizziness; (4) other sensory disturbance (6B60.3) such as numbness, tightness, tingling, burning pain, or other symptoms related to touch, smell, taste, balance, proprioception, kinaesthesia, or thermoception; (5) speech disturbance with dysphonia, aphonia or dysarthria; (6) paresis or weakness; (7) gait disturbance with difficulty in walking, including ataxia; (8) movement disorder such as chorea, myoclonus, tremor, dystonia, facial spasm, parkinsonism or dyskinesia; and (9) cognitive symptoms with impaired memory language and other cognitive areas; (10) other symptoms.¹

Psychogenic Non-epileptic Seizures (PNES) are episodes of altered movement, emotion, sensation, or experience similar to those due to epilepsy but which have purely emotional causes.² Some characteristics of PNES are the preserved memory for the events antecedent, during, and after the episodes with a duration of more than two minutes, with rapid recovery after the event, with no post-ictal confusion, and the patient asking what has happened.³

FND is a condition affecting many young people.³ It is estimated an incidence of 4–12/1000,000 population per year, with the motor FND affecting 4–5/100,000 per year and PNES 1.5–4.9/100,000 per year.³ The estimated prevalence for FND is 50/100,000 and for PNES 2–33/100,000 persons.³ Patients with FND make up 9% of neurology admissions, 16% of neurology clinic referrals, and 10–25% of patients referred to epilepsy specialist centers.⁴ In patients with PNES the annual cost of antiepileptic medication is about 160 dollars, and the cost for diagnostic tests up to a maximum of 1600 dollars.⁵ A systematic review of 16 studies in the USA reported that the cost of FNS is direct costs that represent resources used for health care (eg, cost of investigations or the time spent on assessment by a doctor) in contrast, indirect costs represent productivity losses arising from morbidity-related sickness absence (eg, loss of employment, benefits, or the cost of childcare while hospitalized).⁴ In the USA, the annual cost per person with FND is USD 46,000.⁶ In a study in Ireland, it was calculated that the annual cost of PNES per patient is about Euro 21,000 Euro, while the combined cost of diagnosis and psychological treatment is about Euro 9000.⁷

The literature proposes that FND and PNES could be comorbid with other psychiatric conditions. Due to the complexity of these diagnoses and the length of time it takes to assess and confirm them, it is vital that practitioners are aware of other comorbidities that might be the underlying triggers or presentations of FND and PNES. Therefore, the current review aimed to extract evidence of comorbid psychiatric conditions in FND and PNES and make policy recommendations.

Methods

Review Questions

Review Objectives

O2: To find any other factor associated with PNES and FND.

O3: To craft policies and recommendations reflecting the comorbidity theory.

Data Extraction

Literature Search

The study occurred from January 2024 to August 2024. PRISMA flowchart helped us extract salient literature and to condense our search findings (Figure 1).⁸ All articles selected were open access or we had access to them through the academic library database. All articles were in English and peer–reviewed. Exclusion criteria were articles not in English and studies where FND and PNES were not diagnosed although present. The databases used were PubMed, Scopus, Web of Science, Google Scholar, Google, PsychINFO, and Medline. The keywords were “psychogenic non$pileptic seizure*”, “functional neurological disorder*”, “comorbidit*”,’borderline personality disorder’, “emotionally unstable personality disorder”, “autism”, “PTSD”, “Post Traumatic Stress Disorder”, “FND”, and ‘PNES’. The Boolean connectives were “AND, OR”. When conflicts in the search existed between authors, the most senior helped choose relevant articles. We used Cochrane GRADE-Pro GDT framework (https://www.gradepro.org/) to summarize our findings and create the template for policy recommendations (Tables 1 and 2).^9–11 GRADE assessment allows the analysis of risk of biases or search results, extracts the outcomes and defines the grade of certainty in the results. The domains extractable by GRADE are (1) risk of bias both at the study level and outcome, (1) inconsistency here focused on clinical heterogeneity, (3) indirectness with the best evidence extractable by direct comparisons between treatments and conducted with a population and setting similar where the recommendation will be implemented, (4) imprecision, linked to the precision of the estimate of the population applicable from the sample, and (5) publication bias related to the likelihood that results have influenced the publishing outcomes.^9–12 Large effects ensue with robust research results, limited biases, and strong statistical relationships in the outcomes.¹² The PICO framework helped in the inclusion criteria (https://www.cochranelibrary.com/about-pico).

Table 1 Search Results from Database

Table 2 GRADE-Pro GDT Summary of Findings

Figure 1 PRISMA Flowchart. Adapted from Page MJ, McKenzie JE, Bossuyt PM, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021; 372. Creative Commons.8

Population

Persons of any age and gender attending general hospitals, neurology departments, clinics for epilepsy, and inpatient or outpatient psychiatric units with a diagnosis of FND and PNES.

Intervention

Standard clinical, neurological, and psychiatric assessments; use of targeted questionnaires; retrospective analysis of clinical records; ethnographic observations of units with persons with FND and PNES; EEG; patient’s history of presenting conditions.

Comparisons

Comparison of persons with FND and PNES with others with epilepsy or other neurological conditions. Comparisons of patients before and after the presentation of FND and PNES. Comparison with Epileptic Seizures (ES) and Other Neurological Disorders, Autism, PTSD, BPD Alexithymia, and other psychopathologies. Costs for FND and PNES diagnosis and treatment compared with other conditions.

Outcomes

Development of FND and PNES. Outcomes after targeted psychopharmacological and psychotherapeutic interventions. Response to treatment and carers’ support. Progression of symptoms after first assessment or intervention. Clinical outcomes after identification of FND and PNES.

Qualitative Critical Analysis

As emerging from the literature, extracting comorbidities in FND and PNES helps direct diagnoses and policies while reducing the risks of long-term needless assessments and therapies. The review found that PNES and FND might be comorbid with PTSD, autism, BPD, alexithymia, and mild learning disability.^{13–24,26–52} In specific, a history of childhood traumas or repeated sexual assaults, physical or emotional abuses, exposure to violence, and emotional neglect in children or adults might trigger PTSD, FND, and PNES.^{13–24,26–52}

The majority of patients with FND and PNES are young women.^{13–24,26–52} Persons with FND and PNES tend to have more frequent depression, dissociative disorders, alexithymia, PTSD, and anxiety compared to controls.^{13–24,26–52} In our experience in children, adolescents and adult psychiatric wards, PNES and FND can be copied and assume “epidemic” dissemination from more influential patients to others in the group.^34,35,39

Our ethnographic longitudinal study of PNES and FND in general adult psychiatric wards in the UK found that mostly affected were female patients, confirming what other authors found, and our diagnoses were BPD also comorbid to autism.^34,35,39 An empathic approach and placebo effect of provided medication were seen to resolve PNES crises.^34,35 For example, we found rapid resolution of crises, with low doses of anti–anxiety medications or anti–histamines, when we explained to these patients that these medications could help them or address their symptoms. In our population, FND usually presented with the sudden appearance of paralysis and wheelchair dependence in persons who were otherwise fit at the moment of self-referral at emergency departments.^34,35,39 The paralysis FND evolved in making these female patients bed-ridden in medical departments while and shortly after they developed double incontinence; no medical or neurological causes were found in all cases.^34,35,39

In our qualitative ethnographic research in general adult psychiatric wards and liaison psychiatry attached to emergency departments in the UK, and in men, FND was mostly comorbid with factitious disorder, and the neurological “shakes, foggy mind and memory problems” were allegedly related to a secondary gain in aiming for hospital admission.⁵³ The degree of evidence of our review findings was low to moderate due to the absence of randomized studies. Another limitation was the presence of different diagnostic criteria adopted in each study, which has made the comparison complex. In the assessment, several instruments were adopted, from visual EEG (vEEG) to structured interviews, psychiatric scales, retrospective analyses, and case reports. We also found that some studies reported only general symptoms such as “depression”, and “anxiety” while others tried to contextualize psychiatric symptoms into official psychopathological diagnoses.

Policy Recommendations

In this case, we used the GRADE-Pro GDT framework to complete the analysis of the comorbidity theory and make our policy recommendations (Figure 2)^9,11:

1. Is the problem a priority?^9,11 From the review, we hypothesize that there is moderate to high evidence that FND and PNES might be comorbid with autism, borderline personality disorder, alexithymia, PTSD, and mild learning disability. These could be a unique picture likely to occur in persons with a history of childhood and adulthood trauma.
2. How substantial are the desirable anticipated effects?^9,11 We hypothesize large desirable effects in endorsing the comorbidity theory. The selected research suggests a long-term presentation for a condition refractory to immediate pharmacological support. We scrutinized and shared the impression that the difficulty of diagnosis and patients’ resistance to accepting a “psychological explanation” of their condition can affect the recovery process.
3. How substantial are the undesirable anticipated effects?^9,11 We predict that these are small as there are no anticipated undesirable effects in endorsing the diagnosis of comorbidities of FND and PNES with autism, PTSD, alexithymia, and BPD.
4. What is the overall certainty of the evidence of effects?^9,11 When any research was conducted with a large sample, the effect of the evidence was moderate to large in favor of the comorbidity of FND and PNES. There was also a consensus on the existence of a history of former psychosocial traumas, childhood abuse, and earlier stressful events as triggers of FND and PNES.
5. Is there important uncertainty about or variability in how much people value the main outcomes?^9,11 We could not detect significant uncertainties in the outcomes of the selected research.
6. Does the balance between desirable and undesirable effects favor the comorbidity theory?^9,11 The extracted evidence from the literature favors the comparison and the assumption that FND and PNES have comorbid psychiatric conditions. There are no predicted undesirable effects in endorsing the theory that FND and PNES have comorbid BPD, autism, alexithymia, and PTSD. Favoring this assumption will improve the efficacy of psychological and psychiatric interventions.
7. Resources required.^9,11 We predicted a large saving as there is an expected gain in assessment and intervention if clinicians can consider psychiatric comorbidities in FND and PNES with a reduction of further diagnostic procedures and anti-seizure medication (unless used as mood stabilizers, as in BPD and PTSD). Endorsing these comorbidities will facilitate targeted and quick interventions supporting a combined psychological, psychotherapeutic, and neurological intervention.
8. What is the certainty of the evidence of resource requirements (cost)?^9,11 There is high evidence that undiagnosed psychiatric comorbidities in FND and PNES result in prolonged and expensive assessments and interventions. However, early diagnosis could reduce the costs of further unnecessary diagnostic procedures and medication while redirecting efforts and assets to explore the impact of the underlying comorbidities and causes.
9. Does the cost-effectiveness of the comorbidity theory favor it?^9,11 The confirmation of psychiatric comorbidities in PNES and FND favors multidisciplinary interventions, including psychiatric assessments and interventions.
10. What would be the impact on health equity?^9,11 Pursuing the comorbidity route and allowing a deeper understanding of the biopsychosocial model underlying the comorbidity theory will increase health equity. Furthermore, the history of childhood traumas, neglect, and violence should promote better policies for the protection of vulnerable children and persons.
11. Is the theory of comorbidity acceptable to key stakeholders?^9,11 There is the likelihood that once a diagnosis of psychiatric comorbidity of FND and PNES is posed, significant stakeholders will be able to understand the underlying mechanisms of their distress and undergo a targeted psychotherapeutic and psychological intervention to address the root causes of it (eg, PTSD and childhood trauma).
12. Is the comparison theory feasible to implement?^9,11 The intervention of supporting psychiatric comorbidity is possible to implement. However, constraints might be linked to the long and complex support needed for persons with FND and PNES. Nonetheless, a multidisciplinary team intervention (neurological, medical, and psychiatric) can be more successful once the comorbidity diagnosis is posed.

Figure 2 GRADEPro policy table. FND and PNES are considered clinical problems across several healthcare specialties. There are desirable effects in endorsing a comorbidity theory. We could not predict undesirable effects in confirming the comorbidity of FND and PNES with other psychiatric and neurodevelopmental conditions. From the literature collected and the lack of robust experimental data, the overall evidence for the comorbidity theory was usually moderate. We could not detect significant uncertainties or variabilities in the scrutinized evidence. The overall review would favor the intervention or conclusion about the comorbidity hypothesis, allowing substantial savings in assessing and treating FND and PNES. Cost-effectiveness is advantageous in the comorbidity model. Health equities will be improved, and persons with FND and PNES will receive adequate assessment and treatment. By endorsing the comorbidity model, patients with these conditions and their families will welcome this aspect, although some might still feel “misunderstood”. Using a comorbidity model is workable and is currently applied in several medical and psychiatric settings in the UK. (Adapted from GRADEpro GDT. GRADEpro Guideline Development Tool [Software]. McMaster University and Evidence Prime, 2024. Available from: https://www.gradepro.org).10

Discussion

The evidence supports the recommendations for endorsing the comorbidity theory for FND and PNES. The current review has highlighted the complexity of FND and PNES in the diagnosis and treatment. FND and PNES often face significant challenges in both diagnosis and social perception, primarily due to their complex and multifaceted nature.⁵⁴ Misdiagnosis is a frequent issue; patients are sometimes incorrectly labelled with psychiatric disorders or other neurological conditions because FND symptoms can closely mimic those of more well-known diseases.⁵⁵ This diagnostic ambiguity can lead to inappropriate treatments, exacerbating the patients’ conditions and prolonging their suffering.⁵⁶

The stigma surrounding FND further complicates the lives of those affected. Many people, including healthcare providers, may mistakenly believe that symptoms are “all in the head”, leading to dismissive attitudes and inadequate care.⁵⁶ This stigmatization not only affects individuals but also ripples through communities, fostering misunderstanding and isolation; as a result, patients may feel marginalized or reluctant to seek help, perpetuating a cycle of neglect and mistreatment.⁵⁷ Treatment for PNES and FND includes facilitating understanding and acceptance of the diagnosis, addressing predisposing, precipitating, and perpetuating factors within the biopsychosocial model while addressing psychiatric comorbidities.⁵⁸ Some advocated treatments include psychotherapy, physical therapy, occupational therapy, speech therapy, pharmacotherapy, hypnosis, and neuromodulation.⁵⁸

Another approach to treat PNES suggests a tripartite phase with (1) an initial stage where patients are helped to understand their diagnosis as they might question its accuracy, (2) the second phase of treatment includes psychotherapy and psychopharmacology also addressing psychiatric comorbidities, and (3) final phase is a long-term functional recovery.⁵⁸ There are hidden impacts of PNES on the community. PNES are often shrouded in misunderstanding and stigma, leading to significant repercussions for both individuals and the broader community.⁵⁹ The misdiagnosis of PNES as epilepsy is alarmingly common, primarily due to overlapping symptoms and a lack of awareness among healthcare professionals.⁶⁰

This misdiagnosis not only delays appropriate treatment but also exposes patients to unnecessary antiepileptic medications, which might have severe side effects⁶¹ unless these last are used as mood stabilizers in BPD and PTSD.³⁴ However, the withdrawal of anti-seizure medication in patients with PNES is more likely to occur if the treatment is started during the Epilepsy Monitor Unit and in the absence of structural brain lesions.⁶⁷ The societal stigma surrounding PNES exacerbates the issue. Individuals with PNES frequently face skepticism regarding the legitimacy of their condition, as it is perceived to be “invented”.⁶² Moreover, the lack of understanding within the community fosters a culture of silence and shame, preventing those affected from seeking help or discussing their experiences openly.⁶³ Major interventions include cognitive behavioural therapy, neurobehavioral therapy, group therapy, mindfulness-based therapy, hypnosis, eye movement desensitization and processing (EMDR), and EEG biofeedback.⁶⁴

In PNES patients, psychiatric comorbidities are common while only 5% of PNES patients have no mental condition or stressor; moreover, up to 80% of PNES patients have a history of trauma or abuse, and they may reveal this history during a rigorous and sympathetic stress assessment.⁶⁵ However, long-term outcome studies in PNES demonstrate that many patients remain symptomatic and have quality of life and functioning problems.⁶⁶

We propose an integrated theoretical psychopathological model to explain FND and PNES as extractable from the survey and corroborated by our clinical experience with persons with FND and PNES. We are inclined to endorse that childhood trauma, violence, and neglect, which can also appear late in childhood or adulthood and mostly in sensitive women, can represent the triggers for the development of the comorbidities in FND and PNES. This hypothesis also resonates with our biopsychosocial model postulating that neuroinflammation, consequent to childhood traumas, affects the corticolimbic system, which would make a person highly neuro-sensitive with direct loops going from emotions to the autonomic nervous system (Figure 3).⁶⁷

Figure 3 The biopsychosocial model of FND and PNES. Data from Lazzari et al.67

Conclusions

The current review has highlighted the complex relationships between FND, PNES, and other neurological and psychiatric conditions. The literature extracted seems to support the idea that FND and PNES emerge from a complex array of psychiatric comorbidities, are often difficult to diagnose, and require extensive assessment and interventions until a final diagnosis is posed. Also emerging from the scrutinized literature is the need for integrated and multidisciplinary investigations and treatments. The clinicians that usually come across FND and PNES are neurologists, psychiatrists and general medicine practitioners. They should make a full assessment to rule out any underlying organic cause. Once this process has terminated the psychiatric teams can start their intervention and follow–up together with the backup of other practitioners, including the patient’s family physicians. As we find that FND and PNES might have comorbid neurodiversity (autism, alexithymia and ADHD) and BPD, psychological interventions should accompany psychopharmacological treatment. We had good results with a combination of mood stabilizers, low doses of antidepressants, and low doses or antipsychotics.⁶⁸

One limitation of the review is the partial number of experimental studies with control groups extractable from the literature which has reduced the power of evidence to a maximum of moderate and many low. Another limitation is that some studies were based on retrospective analysis of cases or from the scrutiny of existing clinical data or interviews. Instead, when more objective investigations (eg vEEG) were used it was easier for the clinicians to confirm the diagnosis of PNES. In our experience, the diagnoses and understanding of triggers can benefit from ethnographic unobtrusive and prolonged observations of patients with FND and PNES in psychiatric and medical wards.

Another research indicates that baseline characteristics, including younger age at diagnosis, a brief duration of PNES before diagnosis, job status, prospective cohabitation, and less comorbid pathologies (such as migraine and anxiety), may serve as predictions for improvement in PNES.⁶⁹ In a cohort study, about 50% of patients reported a decrease and 33% a resolution of PNES after e median of 3.3 years from diagnosis.⁶⁹