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.

Neurometabolic alterations in children and adolescents with functional neurological disorder.

OBJECTIVES: In vivo magnetic resonance spectroscopy (MRS) was used to investigate neurometabolic homeostasis in children with functional neurological disorder (FND) in three regions of interest: supplementary motor area (SMA), anterior default mode network (aDMN), and posterior default mode network (dDMN). Metabolites assessed included N-acetyl aspartate (NAA), a marker of neuron function; myo-inositol (mI), a glial-cell marker; choline (Cho), a membrane marker; glutamate plus glutamine (Glx), a marker of excitatory neurotransmission; γ-aminobutyric acid (GABA), a marker of inhibitor neurotransmission; and creatine (Cr), an energy marker. The relationship between excitatory (glutamate and glutamine) and inhibitory (GABA) neurotransmitter (E/I) balance was also examined. METHODS: MRS data were acquired for 32 children with mixed FND (25 girls, 7 boys, aged 10.00 to 16.08 years) and 41 healthy controls of similar age using both short echo point-resolved spectroscopy (PRESS) and Mescher-Garwood point-resolved spectroscopy (MEGAPRESS) sequences in the three regions of interest. RESULTS: In the SMA, children with FND had lower NAA/Cr, mI/Cr (trend level), and GABA/Cr ratios. In the aDMN, no group differences in metabolite ratios were found. In the pDMN, children with FND had lower NAA/Cr and mI/Cr (trend level) ratios. While no group differences in E/I balance were found (FND vs. controls), E/I balance in the aDMN was lower in children with functional seizures-a subgroup within the FND group. Pearson correlations found that increased arousal (indexed by higher heart rate) was associated with lower mI/Cr in the SMA and pDMN. CONCLUSIONS: Our findings of multiple differences in neurometabolites in children with FND suggest dysfunction on multiple levels of the biological system: the neuron (lower NAA), the glial cell (lower mI), and inhibitory neurotransmission (lower GABA), as well as dysfunction in energy regulation in the subgroup with functional seizures.

Illness-Promoting Psychological Processes in Children and Adolescents with Functional Neurological Disorder.

Previous studies suggest that subjective distress in children with functional neurological disorder (FND) is associated with stress-system dysregulation and modulates aberrant changes in neural networks. The current study documents illness-promoting psychological processes in 76 children with FND (60 girls and 16 boys, aged 10.00-17.08 years) admitted to the Mind-Body Program. The children completed a comprehensive family assessment and self-report measures, and they worked with the clinical team to identify psychological processes during their inpatient admission. A total of 47 healthy controls (35 girls and 12 boys, aged 8.58-17.92 years) also completed self-report measures, but were not assessed for illness-promoting psychological processes. Children with FND (vs. controls) reported higher levels of subjective distress (total DASS score, t(104.24) = 12.18; p ˂ 0.001) and more adverse childhood experiences across their lifespans (total ELSQ score, t(88.57) = 9.38; p ˂ 0.001). Illness-promoting psychological processes were identified in all children with FND. Most common were the following: chronic worries about schoolwork, friendships, or parental wellbeing (n = 64; 84.2%); attention to symptoms (n = 61; 80.3%); feeling sad (n = 58; 76.3%); experiencing a low sense of control (helplessness) in relation to symptoms (n = 44; 57.9%); pushing difficult thoughts out of mind (n = 44; 57.9%); self-critical rumination (n = 42; 55.3%); negative/catastrophic-symptom expectations (n = 40; 52.6%); avoidance of activities (n = 38; 50%); intrusive thoughts/feelings/memories associated with adverse events (n = 38, 50%); and pushing difficult feelings out of mind (n = 37; 48.7%). In children with FND-disabled enough to be admitted for inpatient treatment-illness-promoting psychological processes are part of the clinical presentation. They contribute to the child's ongoing sense of subjective distress, and if not addressed can maintain the illness process. A range of clinical interventions used to address illness-promoting psychological processes are discussed, along with illustrative vignettes.

Setting up Functional Neurological Disorder Treatment Services: Questions and Answers.

Functional neurologic disorder (FND) is commonly encountered across outpatient and inpatient medical settings. Given the potential for a high burden of disability in some patients and mounting evidence for the efficacy of FND-specific multidisciplinary treatment services, expanding clinical services for this population is a necessity. In this perspective article, we discuss considerations for creating FND services, including the types of services that exist, how to start, how to identify appropriate referrals, and how to develop and monitor individualized treatment plans. In addition, we discuss how this effort can be done sustainably - balancing patient needs with limited healthcare resources.

Evidence-Based Mind-Body Interventions for Children and Adolescents with Functional Neurological Disorder.

LEARNING OBJECTIVES: • Develop and implement treatment plans for children and adolescents with functional neurological disorder (FND)• Outline a plan to increase awareness and standardize the care for patients with FND using evidence-based interventions. ABSTRACT: Functional neurological disorder (FND) in children and adolescents involves the biological embedding of lived experience in the body and brain. This embedding culminates in stress-system activation or dysregulation and in aberrant changes in neural network function. In pediatric neurology clinics, FND represents up to one-fifth of patients. Current research shows good outcomes with prompt diagnosis and treatment using a biopsychosocial, stepped-care approach. At present, however-and worldwide-FND services are scarce, the result of long-standing stigma and ingrained belief that patients with FND do not suffer from a real ("organic") disorder and that they therefore do not require, or even deserve, treatment. Since 1994, the Mind-Body Program for children and adolescents with FND at The Children's Hospital at Westmead in Sydney, Australia-run by a consultation-liaison team-has delivered inpatient care to hundreds of patients with FND and outpatient care to hundreds of others. For less-disabled patients, the program enables community-based clinicians to implement biopsychosocial interventions locally by providing a positive diagnosis (by a neurologist or pediatrician), a biopsychosocial assessment and formulation (by clinicians from the consultation-liaison team), a physical therapy assessment, and clinical support (from the consultation-liaison team and the physiotherapist). In this Perspective we describe the elements of a biopsychosocial mind-body program intervention capable of providing, as needed, effective treatment to children and adolescents with FND. Our aim is to communicate to clinicians and institutions around the world what is needed to establish effective community treatment programs, as well as hospital inpatient and outpatient interventions, in their own health care settings.

Developmental Pathway Choices of Young People Presenting to a Gender Service with Gender Distress: A Prospective Follow-Up Study.

This prospective case-cohort study examines the developmental pathway choices of 79 young people (13.25-23.75 years old; 33 biological males and 46 biological females) referred to a tertiary care hospital's Department of Psychological Medicine (December 2013-November 2018, at ages 8.42-15.92 years) for diagnostic assessment for gender dysphoria (GD) and for potential gender-affirming medical interventions. All of the young people had attended a screening medical assessment (including puberty staging) by paediatricians. The Psychological Medicine assessment (individual and family) yielded a formal DSM-5 diagnosis of GD in 66 of the young people. Of the 13 not meeting DSM-5 criteria, two obtained a GD diagnosis at a later time. This yielded 68 young people (68/79; 86.1%) with formal diagnoses of GD who were potentially eligible for gender-affirming medical interventions and 11 young people (11/79; 13.9%) who were not. Follow-up took place between November 2022 and January 2023. Within the GD subgroup (n = 68) (with two lost to follow-up), six had desisted (desistance rate of 9.1%; 6/66), and 60 had persisted on a GD (transgender) pathway (persistence rate of 90.9%; 60/66). Within the cohort as a whole (with two lost to follow-up), the overall persistence rate was 77.9% (60/77), and overall desistance rate for gender-related distress was 22.1% (17/77). Ongoing mental health concerns were reported by 44/50 (88.0%), and educational/occupational outcomes varied widely. The study highlights the importance of careful screening, comprehensive biopsychosocial (including family) assessment, and holistic therapeutic support. Even in highly screened samples of children and adolescents seeking a GD diagnosis and gender-affirming medical care, outcome pathways follow a diverse range of possibilities.

Cortisol and α-amylase awakening response in children and adolescents with functional neurological (conversion) disorder.

OBJECTIVE: Stress system dysregulation is considered to have an important role in the aetiology of paediatric functional neurological (conversion) disorder. This study examined salivary cortisol and α-amylase awakening responses in children with functional neurological disorder to determine activation patterns of the hypothalamic-pituitary-adrenal axis and sympathetic system. A healthy cortisol awakening response involves a robust increase in cortisol within 30 minutes of awakening. Alpha-amylase awakening response is variable in children. METHODS: Cortisol and α-amylase were measured in saliva from 32 patients with functional neurological disorder (26 girls and 6 boys, aged 11.3-16.1 years) and 31 healthy controls (23 girls and 8 boys, aged 8.6-17.7 years). Saliva samples were collected using a Salivette sampling device at two time points - upon awakening and 30 minutes after awakening. RESULTS: Patients with functional neurological disorder showed a decrease in cortisol awakening response (-4 nmol.min/L) and controls showed an increase (107 nmol.min/L), t(55) = -.4.6, p < 0.001. Within the functional neurological disorder group, 57% showed an attenuated cortisol awakening response and 43% showed an obliterated/reversed cortisol awakening response: Cortisol awakening response was negatively correlated with adverse childhood experiences, r(58) = -0.6, p = 0.002, and subjective distress (total Depression Anxiety and Stress Scales score), r(58) = -0.4, p = 0.050. In controls, cortisol awakening response showed no correlation with adverse childhood experiences and a positive correlation with subjective distress, r(56) = 0.4, p = 0.023. Total cortisol remained similar between the functional neurological disorder and control group. No significant differences were observed between the functional neurological disorder and control group in any of the α-amylase analyses. DISCUSSION: The results suggest dysregulation of the hypothalamic-pituitary-adrenal axis in children with functional neurological disorder. Hypothalamic-pituitary-adrenal dysregulation in children with functional neurological disorder may contribute to comorbid symptoms of fatigue, sleep disturbance and subjective loss of well-being because circadian rhythms and energy metabolism are disrupted. Hypothalamic-pituitary-adrenal dysregulation - and changes in glucocorticoid (cortisol) signalling at the molecular level - may also contribute to increased vulnerability for functional neurological disorder symptoms because of epigenetically mediated changes to neural networks implicated in functional neurological disorder.

The spectrum of functional tic-like behaviours: Data from an international registry.

BACKGROUND AND PURPOSE: Between 2019 and 2022, there was a marked rise in adolescents/young adults seeking urgent help for functional tic-like behaviours (FTLBs). Given the global scale of this phenomenon, we aimed to pool cases from different institutions in an international registry to better characterize this spectrum and facilitate future longitudinal observation. METHODS: An international collaborative group from 10 tertiary referral centres for tic disorders collected retrospective data on FTLB patients who sought specialists' attention between the last quarter of 2019 and June 2022. An audit procedure was used for collection of data, which comprised demographics, course of presentation and duration, precipitating and predisposing factors, phenomenology, comorbidities, and pharmacological treatment outcome. RESULTS: During the study period, we collected data on 294 patients with FTLBs, 97% of whom were adolescents and young adults and 87% of whom were female. FTLBs were found to have a peak of severity within 1 month in 70% of patients, with spontaneous remissions in 20%, and a very high frequency of complex movements (85%) and vocalizations (81%). Less than one-fifth of patients had pre-existing primary tic disorder, 66% had comorbid anxiety disorders, 28% comorbid depressive disorders, 24% autism spectrum disorder and 23% attention deficit/hyperactivity disorder. Almost 60% explicitly reported exposure to tic-related social media content. The vast majority of pharmacologically treated patients did not report benefit with tic-suppressing medications. CONCLUSIONS: Our data from the largest multicentre registry of FTLBs to date confirm substantial clinical differences from primary tic disorders. Social modelling was the most relevant contributing factor during the pandemic. Future longitudinal analyses from this database may help understand treatment approaches and responsiveness.

COVID-19 Vaccination in Young People with Functional Neurological Disorder: A Case-Control Study.

BACKGROUND: The emergence of acute-onset functional neurological symptoms, the focus of this study, is one of three stress responses related to immunisation. This case-control study documents the experience of 61 young people with past or current functional neurological disorder (FND) in relation to the COVID-19 vaccination program in Australia. METHODS: Information about the young person's/parent's choice and response pertaining to COVID-19 vaccination was collected as part of routine clinical care or FND research program follow-up. RESULTS: 61 young people treated for FND (47 females, mean age = 16.22 years) and 46 healthy controls (34 females, mean age = 16.37 years) were included in the study. Vaccination rates were high: 58/61 (95.1%) in the FND group and 45/46 (97.8%) in the control group. In the FND group, 2 young people (2/61, 3.3%) presented with new-onset FND following COVID-19 vaccination; two young people with resolved FND reported an FND relapse (2/36, 5.56%); and two young people with unresolved FND (2/20, 10.0%) reported an FND exacerbation. In the control group no FND symptoms were reported. CONCLUSIONS: Acute-onset FND symptoms following COVID-19 vaccination are uncommon in the general population. In young people prone to FND, COVID-19 vaccination can sometimes trigger new-onset FND, FND relapse, or FND exacerbation.

Altered resting-state neural networks in children and adolescents with functional neurological disorder.

OBJECTIVES: Previous studies with adults suggest that aberrant communication between neural networks underpins functional neurological disorder (FND). The current study adopts a data-driven approach to investigate the extent that functional resting-state networks are disrupted in a pediatric mixed-FND cohort. METHODS: 31 children with mixed FND and 33 age- and sex-matched healthy controls completed resting-state fMRI scans. Whole-brain independent component analysis (pFWE < 0.05) was then used to identify group differences in resting-state connectivity. Self-report measures included the Depression, Anxiety and Stress Scale (DASS-21) and Early Life Stress Questionnaire (ELSQ). Resting-state heart rate (HR) and cortisol-awakening response (CAR) were available in a subset. RESULTS: Children with FND showed wide-ranging connectivity changes in eight independent components corresponding to eight resting-state neural networks: language networks (IC6 and IC1), visual network, frontoparietal network, salience network, dorsal attention network, cerebellar network, and sensorimotor network. Children whose clinical presentation included functional seizures (vs children with other FND symptoms) showed greater connectivity decreases in the frontoparietal and dorsal attentional networks. Subjective distress (total DASS score), autonomic arousal (indexed by HR), and HPA dysregulation (attenuated/reversed CAR) contributed to changes in neural network connectivity. Children with FND (vs controls) reported more subjective distress (total DASS score) and more adverse childhood experiences (ACEs) across their lifespan. CONCLUSIONS: Children with FND demonstrate changes in resting-state connectivity. Identified network alterations underpin a broad range of functions typically disrupted in children with FND. This study complements the adult literature by suggesting that FND in children and adolescents emerges in the context of their lived experience and that it reflects aberrant communication across neural networks.

The Role of Physiotherapy in the Management of Functional Neurological Disorder in Children and Adolescents.

Children and adolescents with functional neurological (conversion) disorder (FND) present with symptoms of impaired motor and sensory function. FND involves complex interactions between the brain, mind, body, and lived experience of the child. The gold standard for treatment is therefore a holistic, biopsychosocial approach with multimodal interventions delivered by a multidisciplinary team. In this narrative review we examine the role of physiotherapy in managing FND in children. We searched Embase, Medline, PsycINFO, and PubMed (back to 2000) for relevant physiotherapy articles and also manually searched their reference lists. Two review articles and ten observational studies were identified. Data were extracted concerning the type of study, therapies involved, outcome measures, and comorbid mental health outcomes. FND symptoms resolved in 85% to 95% of the patients, and about two-thirds returned to full-time school after completing the multidisciplinary intervention. Ongoing mental health concerns at follow-up were associated with poorer functional outcomes. Key themes included the following: use of psychological interventions embedded in the physiotherapy intervention; integration of play, music, and dance; role of physical exercise in modulating physiological, neural, and endocrine systems; need for FND-specific outcome measures; ethical issues pertaining to randomized trials; and need to develop alternate study methodologies for assessing combined treatments. Clinical vignettes were included to highlight a range of physiotherapy interventions. In conclusion, the emerging literature suggests that physiotherapy for children with FND is a useful intervention for improving motor dysfunction and for addressing other concurrent issues such as physical deconditioning, neuroprotection, chronic pain, disturbed sleep, anxiety and depression, and resilience building.

Treatment Approaches for Functional Neurological Disorders in Children.

Purpose of Review: Functional neurological disorder (FND) is a multi-network brain disorder that encompasses a broad range of neurological symptoms. FND is common in pediatric practice. It places substantial strains on children, families, and health care systems. Treatment begins at assessment, which requires the following: the medical task of making the diagnosis, the interpersonal task of engaging the child and family so that they feel heard and respected, the communication task of communicating and explaining the diagnosis, and the logistical task of organizing treatment. Recent Findings: Over the past decade, three treatment approaches-Retraining and Control Therapy (ReACT), other cognitive-behavioral therapies, and multidisciplinary rehabilitation-have been evaluated in the USA, Canada, and Australia. Of children treated in such programs, 63 - 95% showed full resolution of FND symptoms. The common thread across the programs is their biopsychosocial approach-consideration of biological, psychological, relational, and school-related factors that contribute to the child's clinical presentation. Summary: Current research strongly supports a biopsychosocial approach to pediatric FND and provides a foundation for a stepped approach to treatment. Stepped care is initially tailored to the needs of the individual child (and family) based on the pattern and severity of FND presentation. The level of care and type of intervention may then be adjusted to consider the child's response, over time, to treatment or treatment combinations. Future research is needed to confirm effective treatment targets, to inform the development of stepped care, and to improve methodologies that can assess the efficacy of stepped-care interventions.

Rapid onset functional tic-like behaviours in children and adolescents during COVID-19: Clinical features, assessment and biopsychosocial treatment approach.

AIM: To report the prevalence and clinical characteristics of children with rapid onset functional tic-like behaviours during the COVID-19 pandemic. METHODS: Single centre, retrospective cohort study of children (<18 years) referred to the tic clinic from January 2018 to July 2021. We calculate the prevalence of newly diagnosed functional tics, and compare the clinical features to chronic tic disorder/Tourette syndrome (CTD/TS). RESULTS: A total of 185 new patients were referred to the tic clinic between 2018 and 2021. There was a significant increase in the percentage of functional tics in 2020 and 2021 (2% in 2018, 5.6% in 2019, 10.6% in 2020 and 36% in 2021). Differences between functional tics (n = 22) and CTD/TS (n = 163) include female predominance (100 vs. 28%, P < 0.0001), later age of onset (mean age 13.8 vs. 6.8 years, P < 0.0001) and higher rates of anxiety/depression (95 vs. 41%, P < 0.0001). The functional tic group were more likely to present with coprolalia-like behaviours (77 vs. 10%, P < 0.0001), complex phrases (45 vs. 0.6%, P < 0.0001), copropraxia (45 vs. 2%, P < 0.0001), self-injury (50 vs. 4%, P < 0.0001), hospitalisation/emergency visits (36 vs. 2%, P < 0.0001) and school absenteeism (56 vs. 7%, P < 0.0001). A total of 18.2% of patients with functional tics reported preceding exposure to social media content involving tics. CONCLUSIONS: There is an increase in adolescent females presenting with rapid onset functional tic-like behaviours during the COVID-19 pandemic. We highlight differences in clinical features between the functional tic group and CTD/TS to aid diagnosis and management in the community. Based on our findings, we propose a mixed model of neuropsychiatric vulnerability and social media contagion in this group of adolescents with functional tics.

The co-occurrence of neurodevelopmental disorders in gender dysphoria: Characteristics within a paediatric treatment-seeking cohort and factors that predict distress pertaining to gender.

Gender dysphoria, characterised by distress associated with an incongruence between an individual's assigned and experienced gender, is encountered in 1%-2% of children and adolescents. Recent findings suggest neurodevelopmental disorders (NDDs), including Autism, are frequently reported among youth with Gender Dysphoria. This study aims to explore the frequency of NDDs in children and adolescents presenting to a hospital-based gender service, and to investigate the contribution of autistic traits and general psychological distress to distress pertaining to gender. Sixty-four participants (mean age = 12.91 years) with Gender Dysphoria were recruited to this study. Self- and caregiver-report questionnaires were used to evaluate psychological distress, autistic traits, and distress pertaining to gender. Relative to the rest of the participants, the 13 (20.31%) with a co-occurring NDD diagnosis reported elevated autistic traits (p < .001). They did not differ in terms of psychological distress or distress pertaining to gender. A hierarchical linear regression revealed autistic traits alone did not contribute to the variability in distress pertaining to gender, whereas general psychological distress accounted for 9.9% of the variability in distress pertaining to gender (p = .012). The current findings indicate that NDD diagnoses are common in children and adolescents with Gender Dysphoria who attend hospital-based services. Psychological distress, rather than autistic traits, contributes more variability in distress pertaining to gender. Taken together, these findings indicate the need to consider NDDs in treatment plans but also to focus on the important relationship between psychological distress and Gender Dysphoria.

The regulation of driving with non-epileptic seizures must be made clearer.

Patients with epilepsy have their authorisation to drive restricted under detailed guidelines, but the rules for those with non-epileptic seizures are far less clear. We surveyed specialist clinicians in Australia and found little agreement as to whether such guidelines existed for non-epileptic seizures or what they might be. A number of possible interpretations of the Australian fitness to drive guidelines are explored, and these are often vague in themselves, as well as uncertain in their scope. This means clinicians making momentous driving decisions for their patients with non-epileptic seizures are doubly challenged, first in interpreting what guidelines exist, and second in what they mean. The International League Against Epilepsy proposed specific guidelines for driving with non-epileptic seizures, which reflect the range of presentations of non-epileptic seizures in a decision-making algorithm. We believe a specific algorithm such as this is essential in removing one level of uncertainty and responsibility for clinicians, and restoring equity for patients with non-epileptic seizures.

How to do things with words: Two seminars on the naming of functional (psychogenic, non-epileptic, dissociative, conversion, ) seizures.

Amongst the most important conditions in the differential diagnosis of epilepsy is the one that manifests as paroxysms of altered behaviour, awareness, sensation or sense of bodily control in ways that often resemble epileptic seizures, but without the abnormal excessive or synchronous electrical activity in the brain that defines these. Despite this importance, there remains little agreement - and frequent debate - on what to call this condition, known inter alia as psychogenic non-epileptic seizures (PNES), dissociative seizures (DS), functional seizures (FS), non-epileptic attack disorder (NEAD), pseudoseizures, conversion disorder with seizures, and by many other labels besides. This choice of terminology is not merely academic - it affects patients' response to and understanding of their diagnosis, and their ability to navigate health care systems.This paper summarises two recent discussions hosted by the American Epilepsy Society and Functional Neurological Disorders Society on the naming of this condition. These discussions are conceptualised as the initial step of an exploration of whether it might be possible to build consensus for a new diagnostic label.

Changing the culture of care for children and adolescents with functional neurological disorder.

As members of a multidisciplinary team of professionals who treat children and adolescents with functional neurological (conversion) disorder (FND), we highlight the pressing need to develop an FND-informed culture of care that takes into account recent advances in our understanding of this group of patients. Stories of clinical encounters in health care settings from around the world-told by children and adolescents with FND, their parents, and health professionals-portray an outdated culture of care characterized by iatrogenic stigma, erosion of empathy and compassion within the clinician-patient relationship, and a lack of understanding of FND and its complex neurobiology. After a brief exploration of the outdated culture, we share our counterstories: how we and our colleagues have worked, and continue to work, to create an FND-informed culture in the health systems where we practice. We discuss the therapeutic use of child-friendly language. We also discuss a range of structural, educational, and process interventions that can be used to promote FND-informed beliefs and attitudes, FND-informed clinician-patient encounters, and FND-informed referral processes, treatment pathways, and therapeutic interventions.