'Positive' inter-ictal clinical signs of functional neurological disorders are found in patients with functional dissociative seizures.

BACKGROUND AND PURPOSE: Prior studies highlighted the high diagnostic specificity (ranging from 92% to 100%) of clinical signs observed in functional neurological disorders (FNDs). However, these signs are rarely looked for by epileptologists when trying to distinguish between functional dissociative seizure (FDS) and epileptic seizure. The aim of this study was to determine the prevalence of inter-ictal clinical signs of FND in a cohort of patients with probable FDS. The secondary objective was to compare the prevalence of inter-ictal FND clinical signs in FDS patients with age- and gender-matched epileptic patients without FDS. METHODS: Patients diagnosed with FDS seen at two tertiary care centres and epileptic outpatients were included in the study. Each patient underwent a physical examination, searching for inter-ictal clinical signs of FND. RESULTS: In the FDS group, 79% of patients presented at least one sign of FND, compared to 16.6% of patients with epilepsy (p < 0.001). Moreover, 66.6% of FDS patients presented three or more FND signs, whereas only 4.1% of epileptic patients did (p < 0.001). The median number of FND clinical signs in the FDS group was four (SD 1.7; 5.5). Using the threshold of three signs or more, the specificity of detecting three or more FND signs was 83.3%, with a sensitivity of 79.2%. CONCLUSION: Inter-ictal clinical signs of FND are present in patients with FDS and should be looked for during neurological examination.

Could motor blocks be a therapeutic option for treatment-resistant functional dystonia? A case series of three patients.

The diagnosis of functional dystonia is challenging because it is difficult to distinguish functional dystonia from other types of dystonia. After diagnostic explanation, multidisciplinary care is recommended, but some patients are resistant to treatments. We used motor blocks in three patients with severe resistant functional dystonia of the upper limbs to test (i) whether joint contracture was present and (ii) whether motor blocks have a therapeutic effect on functional dystonia. Patient 1 showed a good and sustained therapeutic response, Patient 2 experienced a resolution of the dystonic posture that lasted for 10 days, and Patient 3 experienced no effect. Motor blocks may be a useful therapeutic option in chronic treatment-resistant functional dystonia. The treatment effect might be achieved through the experience of normal positioning and functioning of the limb.

Death of a loved one: A potential risk factor for onset of functional seizures.

Functional seizures (FS) are a symptom of Functional Neurological Disorder (FND), the second most common neurological diagnosis made worldwide. Childhood trauma is associated with the development of FS, but more research is needed to truly understand the effects of trauma on FS onset. A sample of 256 responses by adults with FS to the Childhood Traumatic Events Scale were analyzed using a Cox proportional hazard model. When investigating each unique childhood traumatic exposure and its associated self-reported severity together, experiencing death of a loved one and experiencing violence were significantly associated with FS onset, suggesting reduced time from trauma exposure to first FS. Death of a loved one in childhood is often overlooked as an influential risk factor for future development of serious mental illnesses such as FS. In this study we show death of a loved one in childhood should be considered as an influential traumatic experience and recommend FND researchers examine its prevalence in patient histories and the potential effects on attachment-related processes and clinical treatment formulations. We recommend future studies incorporate loss of a loved one during childhood (before age 18) in both quantitative and qualitative assessments of persons with FND.

The Financial Burden of Functional Neurological Disorders.

PURPOSE OF REVIEW: Functional neurological disorder (FND) is a common and severely debilitating condition lacking clinical ownership, existing between neurology and psychiatry. This article reports the findings of recent research investigating the economic costs of FND diagnosis and management. We define what the costs are, why they exist, and suggest actionable steps to reduce them. RECENT FINDINGS: The financial burden of FND exists across the globe characterized by high healthcare utilization resulting in exorbitant direct and indirect costs for the patient, healthcare system, and society. Inadequate medical education and stigmatization of the disorder prolong the time to diagnosis, during which cyclical utilization of inpatient and emergency department services drive up costs. Despite being cost-effective, lack of accessible treatment compounds the issue, leaving patients without a reliable exit. Recent findings support an increased awareness and the need for a cultural shift to overcome the financial burden associated with this underserved population.

Principles for delivering improved care of people with functional seizures: Closing the treatment gap.

Patients diagnosed with functional (psychogenic nonepileptic) seizures have similar or greater levels of disability, morbidity and mortality than people with epilepsy, but there are far fewer treatment services. In contrast to epilepsy, the current understanding of pathophysiological mechanisms and the development of evidence-based treatments for functional seizures is rudimentary. This leads to high direct healthcare costs and high indirect costs to the patient, family and wider society. There are many patient, clinician and system-level barriers to improving outcomes for functional seizures. At a patient level, these include the heterogeneity of symptoms, diagnostic uncertainty, family factors and difficulty in perceiving psychological aspects of illness and potential benefits of treatment. Clinician-level barriers include sub-specialism, poor knowledge, skills and attitudes and stigma. System-level barriers include the siloed nature of healthcare, the high prevalence of functional seizures and funding models relying on individual medical practitioners. Through the examination of international examples and expert recommendations, several themes emerge that may address some of these barriers. These include (1) stepped care with low-level, brief generalised interventions, proceeding to higher level, extended and individualised treatments; (2) active triage of complexity, acuity and treatment readiness; (3) integrated interdisciplinary teams that individualise formulation, triage, and treatment planning and (4) shared care with primary, emergency and community providers and secondary consultation. Consideration of the application of these principles to the Australian and New Zealand context is proposed as a significant opportunity to meet an urgent need.

Are there differences in clinical presentation, radiologic findings, and outcomes in female patients with cavernous malformation?

BACKGROUND: Little data exist regarding sex differences in cavernous malformations (CM) patients. METHODS: From an ongoing, prospective registry of consenting adults with CM, we assessed the differences between male and female patients in regard to age at presentation, type of presentation, radiologic characteristics and prospective, symptomatic hemorrhage and or focal neurologic deficit (FND) risk and functional outcome. Cox proportional-hazard ratios and 95% confidence intervals with P values < 0.05 were considered significant in the outcome analysis. Familial form CM female patients were compared to sporadic form. RESULTS: As of 1/1/2023, our cohort comprised 386 people (58.0% female) after excluding radiation-induced CM. There were no demographic or clinical presentation differences between male and female patients. Radiological features did not differ between sexes, except that female, sporadic patients were more likely to have an associated developmental venous anomaly (DVA) (43.2% male vs. 56.2% female; p = 0.03). Overall, there was no difference in prospective symptomatic hemorrhage or functional outcome between sexes. Female sex was a predictor of symptomatic hemorrhage or FND in sporadic patients with ruptured CM (39.6% males versus 65.7% females; p = 0.02). The latter was not due to presence or absence of DVA. Familial CM females were more likely to have a spinal cord CM (15.2% familial female vs. 3.9% sporadic female; p = 0.001) and had a longer time to recurrent hemorrhage than sporadic female (2.2 years sporadic vs. 8.2 years familial; p = 0.0006). CONCLUSION: Minimal differences in clinical, radiologic, and outcomes were found in male versus female patients and familial versus sporadic females in the overall CM patient group. The finding that sporadic form female patients with history of prior hemorrhage had increased rates of prospective hemorrhage or FND compared to male patients raise the question whether to "lump" or "split" ruptured versus unruptured CM patients when analyzing risk factors for prospective hemorrhage in natural history studies.

Compassion-Focused Therapy for an Older Adult with Motor Functional Neurological Disorder: A Case Study.

OBJECTIVES: Motor functional neurological disorder (mFND) is a condition where individuals may experience difficulties such as tremors, gait impairments, and paralysis which are not explained by identified structural damage to the brain. Studies on chronic conditions have suggested that psychological interventions such as compassion-focused therapy (CFT) may be effective in improving well-being in people with mFND. However, no evidence is currently available on psychotherapy for older people with mFND. METHODS: A 12-session CFT intervention was delivered to an 81-year-old British male with mFND. Standardized measures were administered at baseline and post-intervention. RESULTS: At post-intervention, a 30% decrease in perceived psychological impact of mFND was found, along with clinically significant changes in anxiety and depression. Good levels of feasibility and acceptability were also observed. CONCLUSIONS: To our knowledge, this is the first evidence of the feasibility, acceptability, and potential effectiveness of CFT for psychological difficulties linked with mFND, as well as the first evidence for any psychotherapy with an older adult with mFND. CLINICAL IMPLICATIONS: CFT shows the potential to be effective, feasible, and acceptable for treating difficulties linked with mFND in older people. However, further high-quality investigations based on experimental designs are needed to build on the present preliminary findings.

Costs of adult functional neurological disorders at a tertiary hospital in central South Africa.

Background: Functional neurological disorders (FND) lead to increased care requirements and costs, negatively impacting healthcare budgets. Healthcare expenditure in FND has escalated beyond other neurologic disorders during the past decade. Objectives: To assess inpatient costs in adults admitted to the neurology ward at Universitas Academic Hospital (UAH) in central South Africa. Methods: A retrospective observational study with a comparative component was conducted on patients admitted during 2018 and 2019. All FND cases (n = 29) and a systematic sample of other neurological disorders were included in the comparison group (n = 29). Data were obtained from the Meditech billing system and clinical records. Results: FND patients accounted for 5.5% of 530 admissions in the neurology ward during the study period. No significant differences regarding daily median cost, age categories, gender or medical comorbidity were observed between FND and the comparison group. However, the length of stay was significantly shorter for the FND patients (median of four versus eight days), translating to approximately half the total costs of patients admitted for other neurological disorders. Conclusion: The daily median cost was similar for FND and other neurology-related admissions. The lower overall inpatient costs for FND patients were only related to significantly shorter durations of stay, which may reflect new diagnostic approaches resulting from changes in the Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5) diagnostic criteria. The prevalence of FND was similar to those reported in previous studies conducted at neurology clinics. Contribution: The study contributes towards better understanding the prevalence and cost of FND in local neurology inpatient care settings.

International online survey of 1048 individuals with functional neurological disorder.

BACKGROUND AND PURPOSE: Functional neurological disorder (FND) is common, and symptoms can be severe. There have been no international large-scale studies of patient experiences of FND. METHODS: A patient questionnaire was created to assess FND patient characteristics, symptom comorbidities and illness perceptions. Respondents were recruited internationally through an open access questionnaire via social media and patient groups over a month-long period. RESULTS: In total, 1048 respondents from 16 countries participated. Mean age was 42 years (86% female). Median FND symptom duration was 5 years, and median time from first symptom to diagnosis was 2 years. Mean number of current symptoms (core FND and associated) was 9.9. Many respondents had associated symptoms, for example fatigue (93%), memory difficulties (80%) and headache (70%). Self-reported psychiatric comorbidities were relatively common (depression, 43%; anxiety, 51%; panic, 20%; and post-traumatic stress disorder, 22%). Most respondents reported that FND had multiple causes, including physical and psychological. CONCLUSIONS: This large survey adds further evidence that people with FND typically have high levels of multiple symptom comorbidity with resultant distress. It also supports the notion that associated physical symptoms are of particular clinical significance in FND patients. Dualistic ideas of FND were not supported by respondents, who generally preferred to conceptualize the disorder as one at the interface of mind and brain. The need for a broad approach to this poorly served patient group is highlighted. Potential selection and response biases due to distribution of the survey online, mostly via FND patient groups, are a key limitation.

FNDC3B 3'-UTR shortening escapes from microRNA-mediated gene repression and promotes nasopharyngeal carcinoma progression.

Alternative polyadenylation (APA), which induces shortening of the 3'-UTR, is emerging as an important feature in cancer development and progression. Nevertheless, the effects and mechanisms of APA-induced 3'-UTR shortening in nasopharyngeal carcinoma (NPC) remain largely unclear. Fibronectin type III domain containing 3B (FNDC3B) tended to use proximal polyadenylation site and produce shorter 3'-UTR according to our previous sequencing study. Herein, we found that FNDC3B with shorter 3'-UTR could escape from miRNA-mediated gene repression, and caused its increased expression in NPC. Knocking down of FNDC3B inhibited NPC cell proliferation, migration, invasion, and metastasis in vitro and in vivo. Overexpression of FNDC3B, especially those with shorter 3'-UTR, promoted NPC progression. Furthermore, the mechanism study revealed that FNDC3B could bind to and stabilize myosin heavy chain 9 (MYH9) to activate the Wnt/ß-catenin signaling pathway. In addition, MYH9 could reverse the inhibitory effects of FNDC3B knockdown in NPC. Altogether, our results suggested that the 3'-UTR shortening of FNDC3B mRNA mediated its overexpression in NPC and promoted NPC progression by targeting MYH9. This newly identified FNDC3B-MYH9-Wnt/ß-catenin axis could represent potential targets for individualized treatment in NPC.

Transient Receptor Potential Vanilloid 6 (TRPV6) Proteins Control the Extracellular Matrix Structure of the Placental Labyrinth.

Calcium-selective transient receptor potential Vanilloid 6 (TRPV6) channels are expressed in fetal labyrinth trophoblasts as part of the feto-maternal barrier, necessary for sufficient calcium supply, embryo growth, and bone development during pregnancy. Recently, we have shown a less- compact labyrinth morphology of Trpv6-deficient placentae, and reduced Ca2+ uptake of primary trophoblasts upon functional deletion of TRPV6. Trpv6-/- trophoblasts show a distinct calcium-dependent phenotype. Deep proteomic profiling of wt and Trpv6-/- primary trophoblasts using label-free quantitative mass spectrometry leads to the identification of 2778 proteins. Among those, a group of proteases, including high-temperature requirement A serine peptidase 1 (HTRA1) and different granzymes are more abundantly expressed in Trpv6-/- trophoblast lysates, whereas the extracellular matrix protein fibronectin and the fibronectin-domain-containing protein 3A (FND3A) were markedly reduced. Trpv6-/-placenta lysates contain a higher intrinsic proteolytic activity increasing fibronectin degradation. Our results show that the extracellular matrix formation of the placental labyrinth depends on TRPV6; its deletion in trophoblasts correlates with the increased expression of proteases controlling the extracellular matrix in the labyrinth during pregnancy.

Aristaless-Like Homeobox protein 1 (ALX1) variant associated with craniofacial structure and frontonasal dysplasia in Burmese cats.

Frontonasal dysplasia (FND) can have severe presentations that are medically and socially debilitating. Several genes are implicated in FND conditions, including Aristaless-Like Homeobox 1 (ALX1), which is associated with FND3. Breeds of cats are selected and bred for extremes in craniofacial morphologies. In particular, a lineage of Burmese cats with severe brachycephyla is extremely popular and is termed Contemporary Burmese. Genetic studies demonstrated that the brachycephyla of the Contemporary Burmese is a simple co-dominant trait, however, the homozygous cats have a severe craniofacial defect that is incompatible with life. The craniofacial defect of the Burmese was genetically analyzed over a 20 year period, using various genetic analysis techniques. Family-based linkage analysis localized the trait to cat chromosome B4. Genome-wide association studies and other genetic analyses of SNP data refined a critical region. Sequence analysis identified a 12bp in frame deletion in ALX1, c.496delCTCTCAGGACTG, which is 100% concordant with the craniofacial defect and not found in cats not related to the Contemporary Burmese.

Electron spin resonance of nitrogen-vacancy defects embedded in single nanodiamonds in an ABEL trap.

Room temperature optically detected magnetic resonance of a single quantum object with nanoscale position control is an outstanding challenge in many areas, particularly in the life sciences. We introduce a novel approach to control the nitrogen-vacancy (NV) centers hosted in a single fluorescent nanodiamond (FND) for which an anti-Brownian electrokinetic trap (ABEL) performs the position control and an integrated radiofrequency (RF) circuit provides enhanced magnetic flux density for ensemble spin-state control simultaneously. We demonstrate static magnetic field sensing in platforms compatible with ABEL trap. With the advances in the synthesis and functionalization of stable arbitrarily small FNDs, we foresee the use of our device for the trapping and manipulation of single molecular-sized FNDs in aqueous solution.

The Current State of Pediatric Functional Neurological Disorder Treatment in the United States.

BACKGROUND: Pediatric functional neurological disorders (FNDs) are common but grossly under-researched. This survey study aims to define the current landscape of pediatric FND treatment in the United States, identifying treatment programs, care team composition, treatment approaches, and aftercare management. METHODS: The Functional Neurological Disorder Society (FNDS) Pediatric Special Interest Group (SIG), a diverse set of clinician and caregiver stakeholders, collected information on available treatment programs in the United States via survey. Current programs were identified through the FNDS Pediatric SIG and FND Hope's provider registry. RESULTS: Thirty-nine care team members from 24 health care centers yielded 31 unique FND treatment settings. Centers existed in 16 states, concentrated in the Midwest and Southern regions. Outpatient settings (62%) were more prevalent than inpatient. A psychologist (PhD/PsyD) was the most common clinician (52%) with dedicated time to treat FNDs. Most settings accepted ages six to 21 (55%) and treated all FND symptoms (77%). A spectrum of treatment approaches was endorsed with the most common being cognitive behavioral therapy (77%) and personalized approaches (58%). A biopsychosocial approach was evident, with most settings reporting active involvement with school (97%) and caregivers (94%). Most settings (74%) encouraged treatment re-engagement when needed with no strict time limits. All respondents provided aftercare recommendations or referrals. CONCLUSIONS: Pediatric FND treatment is available across the United States, but there is high variability in care team membership, treatment approach, and aftercare management. Future research is necessary to develop effective and sustainable treatment to improve access for this population.

Corrigendum: Sensory nerve action potential in patients with functional neurological disorders with sensory manifestations.

[This corrects the article DOI: 10.3389/fneur.2023.1259887.].

Recent advances in understanding the neurobiology of pediatric functional neurological disorder.

INTRODUCTION: Functional neurological disorder (FND) is a neuropsychiatric disorder that manifests in a broad array of functional motor, sensory, or cognitive symptoms, which arise from complex interactions between brain, mind, body, and context. Children with FND make up 10%-20% of presentations to neurology services in children's hospitals and up to 20% of adolescents admitted to hospital for the management of intractable seizures. AREAS COVERED: The current review focuses on the neurobiology of pediatric FND. The authors present an overview of the small but growing body of research pertaining to the biological, emotion-processing, cognitive, mental health, physical health, and social system levels. EXPERT OPINION: Emerging research suggests that pediatric FND is underpinned by aberrant changes within and between neuron-glial (brain) networks, with a variety of factors - on multiple system levels - contributing to brain network changes. In pediatric practice, adverse childhood experiences (ACEs) are commonly reported, and activation or dysregulation of stress-system components is a frequent finding. Our growing understanding of the neurobiology of pediatric FND has yielded important flow-on effects for assessing and diagnosing FND, for developing targeted treatment interventions, and for improving the treatment outcomes of children and adolescents with FND.

The clinical management of functional neurological disorder: A scoping review of the literature.

OBJECTIVE: To date, there have been no reviews bringing together evidence on the clinical management of functional neurological disorder (FND) and patients', caregivers', and healthcare workers' experiences. This review provides an overview of the literature focused on the clinical management of FND. METHODS: Four databases were searched, and a consultation exercise was conducted to retrieve relevant records dated from September 2010 to September 2020. Articles documenting diagnostic methods, treatments or interventions, or the experiences and perspectives of patients and healthcare workers in the clinical management of FND were included. RESULTS: In total, 2756 records were retrieved, with 162 included in this review. The diagnostic methods reported predominantly included positive clinical signs, v-EEG and EEG. Psychological treatments and medication were the most reported treatments. Mixed findings of the effectiveness of CBT were found. Haloperidol, physiotherapy and scripted diagnosis were found to be effective in reducing FND symptoms. Several facilitators and barriers for patients accessing treatment for FND were reported. CONCLUSION: The literature describing the clinical management for FND has increased considerably in recent times. A wide variety of diagnostic tools and treatments and interventions were found, with more focus being placed on tests that confirm a diagnosis than 'rule-out' tests. The main treatment type found in this review was medication. This review revealed that there is a lack of high-quality evidence and reflects the need for official clinical guidelines for FND, providing healthcare workers and patients the support needed to navigate the process to diagnose and manage FND.

Functional neurological disorder: Clinical manifestations and comorbidities; an online survey.

Functional Neurological Disorder (FND) is common and is often accompanied by multiple comorbid symptoms and conditions. There have been no large-scale studies exploring the change of its clinical manifestations and comorbidities. We used an online survey to assess FND patient characteristics, changes to fatigue, sleep and pain and comorbid symptoms and diagnoses, as well as treatment strategies. The survey was shared via the charities FND Action and FND Hope. 527 participants were included in the analysis. Most (97.3%) reported experiencing more than one core FND symptom. Many respondents reported associated pain (78.1%), fatigue (78.0%) and sleep disturbances (46.7%) before FND diagnosis which often increased thereafter. Rates of obesity were higher (36.9%) than in the general population. Obesity was associated with increased pain, fatigue and sleep difficulties. There was frequent weight gain after diagnosis. 50.0% of participants reported having other diagnoses prior to FND, while in 43.3% new comorbidities arise after FND diagnosis. Many respondents reported being dissatisfied with their care, expressing a wish for further follow-up from mental health (32.7%) and/or neurological services (44.3%). This large online survey further supports the phenotypic complexity of FND. High rates of pain, fatigue and sleep disturbance exist before diagnosis but monitoring for change is worthwhile. Our study identified major gaps in service provision; we highlight the importance of an open mind regarding change in symptoms; this could aid the early identification and management of co-morbidities, including obesity and migraine, which possibly have a negative impact on FND.

The neurobiology of functional neurological disorders characterised by impaired awareness.

We review the neurobiology of Functional Neurological Disorders (FND), i.e., neurological disorders not explained by currently identifiable histopathological processes, in order to focus on those characterised by impaired awareness (functionally impaired awareness disorders, FIAD), and especially, on the paradigmatic case of Resignation Syndrome (RS). We thus provide an improved more integrated theory of FIAD, able to guide both research priorities and the diagnostic formulation of FIAD. We systematically address the diverse spectrum of clinical presentations of FND with impaired awareness, and offer a new framework for understanding FIAD. We find that unraveling the historical development of neurobiological theory of FIAD is of paramount importance for its current understanding. Then, we integrate contemporary clinical material in order to contextualise the neurobiology of FIAD within social, cultural, and psychological perspectives. We thus review neuro-computational insights in FND in general, to arrive at a more coherent account of FIAD. FIAD may be based on maladaptive predictive coding, shaped by stress, attention, uncertainty, and, ultimately, neurally encoded beliefs and their updates. We also critically appraise arguments in support of and against such Bayesian models. Finally, we discuss implications of our theoretical account and provide pointers towards an improved clinical diagnostic formulation of FIAD. We suggest directions for future research towards a more unified theory on which future interventions and management strategies could be based, as effective treatments and clinical trial evidence remain limited.

Sensory nerve action potential in patients with functional neurological disorders with sensory manifestations.

Introduction: Functional neurological disorder (FND) has various clinical manifestations. Even though diagnostic criteria for FND have been proposed, FND characteristics with sensory manifestations have not been elucidated. Therefore, we aimed to investigate the association between sensory nerve action potential (SNAP) amplitudes and FND with sensory manifestations. Methods: We included 76 outpatients with FND with sensory manifestations whose nerve conduction studies were performed retrospectively. Additionally, we defined 121 patients with other neurological diseases who did not have peripheral neuropathy as disease controls. The SNAP amplitudes were compared between the two groups. We also explored the relationship between SNAP amplitudes and FND-specific clinical symptoms in patients with FND. Results: No differences were observed in SNAP amplitudes adjusted for age between patients with FND who had sensory manifestations and disease control patients. Additionally, no differences were observed between patients with FND who had and did not have FND-specific clinical symptoms. Conclusion: The SNAP amplitude in patients with FND who had sensory manifestations was equivalent to that in controls.