Breathing control training for functional seizures: A multi-site, open-label pilot study.

There are no well-validated treatments for functional seizures. While specialist psychotherapy is usually recommended, the evidence for its benefit is qualified, and it can be difficult to obtain. Given the association between hyperventilation and functional seizures we explored an alternative modality, breathing control training, in a multi-site open label pilot trial. Participants with functional seizures over the age of 16 received an hour of breathing training from a respiratory physiotherapist, with a half-hour booster session a month later. Seizure frequency and Nijmegen scores (a measure of hyperventilation) were reported at baseline and follow-up, 3-4 months later. Eighteen subjects were recruited, and 10 completed follow-up. Seven of these 10 had improved seizure frequency, and 3 did not (Wilcoxon signed rank test, p = 0.09), with seizure frequency correlating with Nijmegen score (Spearman's rank correlation = 0.75, p = 0.034). The intervention was well tolerated, with no adverse events reported. These preliminary results support a potentially new approach to treating functional seizures that should prove cost-effective and acceptable, though require confirmation by a randomised controlled trial.

Efficacy of Cognitive-Behavioral Therapy Targeting Severe Fatigue Following Coronavirus Disease 2019: Results of a Randomized Controlled Trial.

BACKGROUND: Severe fatigue following coronavirus disease 2019 (COVID-19) is prevalent and debilitating. This study investigated the efficacy of cognitive-behavioral therapy (CBT) for severe fatigue following COVID-19. METHODS: A multicenter, 2-arm randomized controlled trial was conducted in the Netherlands with patients being severely fatigued 3-12 months following COVID-19. Patients (N = 114) were randomly assigned (1:1) to CBT or care as usual (CAU). CBT, targeting perpetuating factors of fatigue, was provided for 17 weeks. The primary outcome was the overall mean difference between CBT and CAU on the fatigue severity subscale of the Checklist Individual Strength, directly post-CBT or CAU (T1), and after 6 months (T2). Secondary outcomes were differences in proportions of patients meeting criteria for severe and/or chronic fatigue, differences in physical and social functioning, somatic symptoms, and problems concentrating between CBT and CAU. RESULTS: Patients were mainly nonhospitalized and self-referred. Patients who received CBT were significantly less severely fatigued across follow-up assessments than patients receiving CAU (-8.8 [95% confidence interval {CI}, -11.9 to -5.8]); P < .001), representing a medium Cohen's d effect size (0.69). The between-group difference in fatigue severity was present at T1 (-9.3 [95% CI, -13.3 to -5.3]) and T2 (-8.4 [95% CI, -13.1 to -3.7]). All secondary outcomes favored CBT. Eight adverse events were recorded during CBT, and 20 during CAU. No serious adverse events were recorded. CONCLUSIONS: Among patients, who were mainly nonhospitalized and self-referred, CBT was effective in reducing fatigue. The positive effect was sustained at 6-month follow-up. CLINICAL TRIALS REGISTRATION: Netherlands Trial Register NL8947.

Improving the treatment of functional seizures through a public specialist outpatient clinic.

OBJECTIVES: We performed an audit of the first 12 months of clinical operations to assess the feasibility of a newly established public outpatient clinic for the assessment and treatment of functional (psychogenic nonepileptic) seizures (FS). METHOD: Clinical notes for the first 12 months of the FSclinic weresystematicallyreviewed with data compiled onreferral pathways, clinic attendance, clinical features, treatments, and outcomes. RESULTS: Of eighty-two new FS patients referred to the clinic, over 90% attended. Patients were diagnosed with FS after comprehensive epileptological and neuropsychiatric review, mostly with typical seizure-like episodes captured during video-EEG monitoring, and most accepted the diagnosis. Most had FS at least weekly, with little sense of control and significant impairment. The majority of individuals had significant psychiatric and medical comorbidity. Predisposing, precipitating, and perpetuating factors were readily identified in >90% of cases. Of 52 patients with follow-up data within12 months, 88% were either stable or improved in terms of the control of their FS. CONCLUSION: The Alfred functional seizure clinic model, the first dedicated public outpatient clinic for FS in Australia, provides a feasible and potentially effective treatment pathway for this underserved and disabled patient group.

Effect of estradiol on cognition in men undergoing androgen deprivation therapy: A randomized placebo-controlled trial.

OBJECTIVE: Roles for estradiol in modulating cognition in men remain uncertain. We assessed the isolated effects of estradiol on cognition in men in the absence of testosterone. DESIGN: Randomized trial of transdermal estradiol 0.9 mg daily, or matched placebo, for 6 months, hypothesizing that estradiol would improve verbal learning, verbal memory, and spatial problem solving over time. PATIENTS: Men receiving androgen deprivation therapy (ADT) for prostate cancer. MEASUREMENTS: Cognition was assessed by a tablet-based cognitive battery (Cogstate) at baseline, Month 1, Month 3, and Month 6. Anxiety and depression symptoms were assessed using the Hospital Anxiety and Depression Scale. RESULTS: Seventy-eight participants were randomized. Baseline mean scores were 21.0 (standard deviation [SD] 4.1) for the International Shopping List test (ISL), assessing verbal learning and memory (higher scores better), and 60.4 (SD 19.5) for the Groton Maze Learning test (GML), assessing spatial problem solving (lower scores better). There was no significant difference in performance over time for the estradiol group versus the placebo group for the ISL, mean adjusted difference (MAD) 0.7 (95% confidence interval [CI] -1.2 to 2.5), p = .36, or the GML, MAD -3.2 (95% CI -12.0 to 5.6), p = 0.53. There was no significant difference between groups over time in performance in any other cognitive domain, or on depression or anxiety scores. CONCLUSIONS: We found no major effects of estradiol on cognition in men with castrate testosterone concentrations. Although the cognitive effects of ADT are debated, this study suggests that any such effects are unlikely to be prevented by the administration of estradiol.

The relationship between types of life events and the onset of functional neurological (conversion) disorder in adults: a systematic review and meta-analysis.

Adverse life events precede the onset of functional neurological disorder (FND, also known as conversion disorder) more commonly than other neuropsychiatric conditions, but their aetiological role is unclear. We conducted a systematic review and quantitative analysis of the type, timing and number of life events preceding the onset of FND in adults, and a meta-analysis of the proportions of types of events in controlled studies. Fifty-one studies of different designs, covering 4247 patients, were eligible for inclusion. There was no clear majority of any type of preceding event. Family problems were the most common category of events, followed by relationship problems. Females were more likely to experience preceding family/relationship problems than males, who reported more work problems. Family problems were the commonest type of preceding event in studies in developing countries, whereas family and health problems were equally common in developed countries. Abuse was associated with early symptom onset, while patients with later onset were more likely to report family problems. The median number of events was one, and the events occurred closer to onset than in controls. Meta-analysis found that family, relationship and work events were all relatively more common in patients than pathological controls, as were events where symptoms might provide a solution to the stressor. In conclusion, although a range of events precede the onset of FND, they do not appear to do so uniformly. This may support a different aetiological role for stressors than in other disorders, although the support is indirect and the quality generally low.

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.

Characterising DSCATT: A case series of Australian patients with debilitating symptom complexes attributed to ticks.

OBJECTIVES(S): To characterise the clinical profile, aetiology and treatment responsiveness of 'Australian Lyme', or Debilitating Symptom Complexes Attributed to Ticks. METHODS: Single-centre retrospective case analysis of patients referred to the Infectious Diseases Unit at Austin Health - a tertiary health service in Heidelberg, Australia - between 2014 and 2020 for investigation and treatment of suspected Debilitating Symptom Complexes Attributed to Ticks. Patients were included if they had debilitating symptoms suggested by either themselves or the referring clinician as being attributed to ticks. RESULTS: Twenty-nine Debilitating Symptom Complexes Attributed to Ticks cases were included in the analysis. Other than Lyme disease (83%), the most common prior medical diagnoses were Epstein-Barr virus (38%), chronic fatigue syndrome (28%) and fibromyalgia (24%). Prior histories of anxiety (48%) and depression (41%) were common. The most frequently reported symptoms included fatigue (83%), headache (72%) and arthralgia (69%). National Association of Testing Authorities/Royal College of Pathologists of Australasia-accredited serology was not diagnostic of acute infective causes, including Lyme disease, in any patient. Of 25 cases with available data, 23 (92%) had previously been prescribed antimicrobials, with 53% reporting benefit from them. The most common diagnoses made by our hospital were chronic fatigue syndrome (31%), migraines (28%) and fibromyalgia (21%). Only one patient's symptoms were not accounted for by other diagnoses. CONCLUSION: This is the first case series of patients with Debilitating Symptom Complexes Attributed to Ticks. They had high rates of other medically unexplained syndromes, and no evidence of acute Lyme disease, or any common organic disease process. Debilitating Symptom Complexes Attributed to Ticks remains medically unexplained, and may therefore be due to an as yet unidentified cause, or may be considered a medically unexplained syndrome similar to conditions such as chronic fatigue syndrome.

Clinical differences between patients with psychogenic nonepileptic seizures and functional motor disorder.

OBJECTIVES: Why a patient might present with psychogenic nonepileptic seizures (PNES) as opposed to another functional neurological symptom is unknown. A recent review suggested that patients with PNES and functional motor disorders (FMD) differ on demographic and clinical factors of potential aetiological and mechanistic significance, arguing they might represent different disorders, though direct comparisons are limited. We sought to determine whether these factors differed in patients presenting with FMD and PNES at our clinic, as well as whether preceding medical complaints would differ between the two, particularly those affecting the limbs or head. METHODS: A retrospective chart review of all presentations with FMD or PNES patients to a functional neurology clinic, collecting demographic and clinical data, including medical and surgical history. RESULTS: Fifty-six patients with FMD and 52 with PNES were included. Significantly more patients with FMD had functional somatic syndromes (46% vs 27%, p = 0.036) and preceding medical events that affected their limbs than patients with PNES (34% vs 14%, p = 0.013); significantly more patients with PNES had dissociative symptoms (31% vs 4%, p < 0.001) and lifetime suicidal ideation (56% vs 32%, p = 0.013). SIGNIFICANCE: These results highlight the substantial comorbidities affecting FMD and PNES, but find clinical differences between the two groups that may be of aetiological or mechanistic significance.

How Positive Are Conversion Disorder Diagnoses?: Patterns of Referral to a Functional Neurology Clinic.

ABSTRACT: The Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) diagnostic criteria for conversion disorder have replaced the criterion of evidence of a "psychogenic" etiology with a criterion that patients must be "positively" diagnosed on the basis of their neurological assessment. We retrospectively studied referrals to a specialist functional neurology clinic to see how commonly the new criteria were met since DSM-5's introduction. Positive signs were reported in a quarter of referrals (26.5%), which was associated with diagnosticians' confidence (p = 0.001) and with the clinic confirming the diagnosis (p = 0.01). Our clinic found positive signs in 28.6% of the referrals. In 13 (13.3%) patients, the new criterion was not met. In conclusion, positive signs are diagnostically helpful but are only reported in a minority of assessments. A significant group of those currently believed to have conversion disorder would not meet the revised diagnostic criteria based on this.

The relationship between psychosocial trauma type and conversion (functional neurological) disorder symptoms: a cross-sectional study.

OBJECTIVE: Psychosocial trauma was associated with developing conversion disorder (also known as functional neurological disorder) before Freud, though why a particular symptom should arise is unknown. We aimed to determine if there was a relationship between trauma type and symptom. METHODS: We retrospectively reviewed the medical records of patients attending Australia's first functional neurology clinic, including referral, clinic letters and a clinic questionnaire. RESULTS: There were 106 females, 43 males and five transgender patients. Sensory (51%), motor (47%) and seizures (39%) were the commonest functional symptoms. Most patients (92%) reported stressors associated with symptom onset. Multiple trauma/symptom type associations were found: patients with in-law problems experienced more cognitive symptoms (p = .036), for example, while expressive speech problems more commonly followed relationship difficulties (p = .021). CONCLUSION: Associations were found between type of traumatic events and type of symptoms in conversion disorder. This will require verification in a larger sample.

Systematic review of psychotherapy for adults with functional neurological disorder.

Functional neurological disorder (FND) is a common and disabling disorder that is often considered difficult to treat, particularly in adults. Psychological therapies are often recommended for FND. Outcome research on psychological therapies for FND has grown in recent years but has not been systematically evaluated since 2005. This study aims to build on that by systematically reviewing the evidence-base for individual outpatient cognitive behavioural and psychodynamic psychotherapies for FND. Medical databases were systematically searched for prospective studies of individual outpatient psychotherapy for FND with at least five adult participants. Studies were assessed for methodological quality using a standardised assessment tool. Results were synthesised, and effect sizes calculated for illustrative purposes. The search strategy identified 131 relevant studies, of which 19 were eligible for inclusion: 12 examining cognitive behavioural therapy (CBT) and 7 investigating psychodynamic therapy (PDT). Eleven were pre-post studies and eight were randomised controlled trials. Most studies recruited a single symptom-based subtype rather than all presentations of FND. Effect sizes, where calculable, showed generally medium-sized benefits for physical symptoms, mental health, well-being, function and resource use for both CBT and PDT. Outcomes were broadly comparable across the two therapy types, although a lack of high-quality controlled trials of PDT is a significant limitation, as is the lack of long-term follow-up data in the majority of identified CBT trials. In conclusion, both CBT and PDT appear to potentially offer some benefit for FND, although better quality studies are needed.

Outcome measurement in functional neurological disorder: a systematic review and recommendations.

OBJECTIVES: We aimed to identify existing outcome measures for functional neurological disorder (FND), to inform the development of recommendations and to guide future research on FND outcomes. METHODS: A systematic review was conducted to identify existing FND-specific outcome measures and the most common measurement domains and measures in previous treatment studies. Searches of Embase, MEDLINE and PsycINFO were conducted between January 1965 and June 2019. The findings were discussed during two international meetings of the FND-Core Outcome Measures group. RESULTS: Five FND-specific measures were identified-three clinician-rated and two patient-rated-but their measurement properties have not been rigorously evaluated. No single measure was identified for use across the range of FND symptoms in adults. Across randomised controlled trials (k=40) and observational treatment studies (k=40), outcome measures most often assessed core FND symptom change. Other domains measured commonly were additional physical and psychological symptoms, life impact (ie, quality of life, disability and general functioning) and health economics/cost-utility (eg, healthcare resource use and quality-adjusted life years). CONCLUSIONS: There are few well-validated FND-specific outcome measures. Thus, at present, we recommend that existing outcome measures, known to be reliable, valid and responsive in FND or closely related populations, are used to capture key outcome domains. Increased consistency in outcome measurement will facilitate comparison of treatment effects across FND symptom types and treatment modalities. Future work needs to more rigorously validate outcome measures used in this population.

Enlarged hippocampal fissure in psychosis of epilepsy.

Psychosis of epilepsy (POE) can be a devastating condition, and its neurobiological basis remains unclear. In a previous study, we identified reduced posterior hippocampal volumes in patients with POE. The hippocampus can be further subdivided into anatomically and functionally distinct subfields that, along with the hippocampal fissure, have been shown to be selectively affected in other psychotic disorders and are not captured by gross measures of hippocampal volume. Therefore, in this study, we compared the volume of selected hippocampal subfields and the hippocampal fissure in 31 patients with POE with 31 patients with epilepsy without psychosis. Cortical reconstruction, volumetric segmentation, and calculation of hippocampal subfields and the hippocampal fissure were performed using FreeSurfer. The group with POE had larger hippocampal fissures bilaterally compared with controls with epilepsy, which was significant on the right. There were no significant differences in the volumes of the hippocampal subfields between the two groups. Our findings suggest abnormal development of the hippocampus in POE. They support and expand the neurodevelopmental model of psychosis, which holds that early life stressors lead to abnormal neurodevelopmental processes, which underpin the onset of psychosis in later life. In line with this model, the findings of the present study suggest that enlarged hippocampal fissures may be a biomarker of abnormal neurodevelopment and risk for psychosis in patients with epilepsy.

A multi-centre, double-blind, 12-week, randomized, placebo-controlled trial to assess the efficacy of adjunctive N-Acetylcysteine for treatment-resistant PTSD: a study protocol.

BACKGROUND: Most patients with Posttraumatic Stress Disorder (PTSD) suffer residual symptoms following first-line treatment. Oxidative stress has been implicated in the pathophysiology of PTSD. N-acetylcysteine (NAC) is a precursor of the brain's primary antioxidant, glutathione, and may diminish oxidative cellular damage. An 8-week pilot study of NAC in veterans with PTSD found that symptoms were significantly reduced in the NAC group compared to placebo. This study aims to confirm these findings with a larger sample in a double-blind, placebo-controlled trial to further explore the efficacy of NAC as an adjunctive therapy in treatment-resistant PTSD. METHODS: A multicentre, randomised, double-blind, placebo-controlled trial for adult patients who still meet criteria for PTSD following first-line treatment. The intervention comprises either NAC as a fixed dose regime of 2.7 g/day (900 mg three times daily) administered orally for 12 weeks, or placebo. Standard care for PTSD will continue in addition, including other pharmacotherapies. Detailed clinical data will be collected at randomisation and weeks 4, 8, 12, 16, and 64 post-randomisation, with self-report measures completed weekly from baseline to 16 weeks and at 64 weeks post-randomisation. Blood-based biomarkers will be collected at baseline and 12 weeks to assess the mechanism of effect. The primary outcome measure will be change in Clinician-Administered PTSD Scale for DSM-5 at 12 weeks compared with baseline. Secondary outcomes will be change in quality of life, depression, anxiety, substance use and craving, and somatic symptoms. With 126 completed participants (63 per arm), the study is powered at 80% to detect a true difference in the primary outcome measure using a two-tailed analysis with alpha = 0.05, beta = 0.2. DISCUSSION: This is the first multicentre, double blind, randomised, placebo-controlled trial of adjunctive NAC for treatment-resistant PTSD. NAC has an established safety profile, is readily available and easy to administer, and has a favourable tolerability profile, therefore making it an attractive adjunctive therapy. Inclusion of blood analyses to assess potential target engagement biomarkers of oxidative stress and neuroinflammation may help gauge the biological mechanisms of effect of NAC. TRIAL REGISTRATION: ACTRN12618001784202, retrospectively registered 31/10/2018, URL: http://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=376004 .

Preictal autonomic dynamics in psychogenic nonepileptic seizures.

OBJECTIVES: Psychogenic nonepileptic seizures (PNES) resemble seizures but are psychological in origin. The etiology of PNES remains poorly understood, yet several theories argue for the importance of autonomic dysregulation in its pathophysiology. We therefore conducted a retrospective study to investigate autonomic dynamics leading up to a seizure to inform their mechanistic relevance. METHODS: One hundred one patients with PNES and 45 patients with epileptic seizure (ES) were analyzed for preictal heart rate (HR) and respiratory rate (RR) at baseline and at minute intervals from 5 min to onset. RESULTS: Patients with PNES showed rising HR (p < 0.001, repeated-measures analysis of variance (ANOVA)) and rising RR (p = 0.012, repeated-measures ANOVA) from baseline to the onset of their seizures. Patients with ES did not exhibit significant preictal HR or RR increase. Patients with PNES had nonsignificantly higher preictal HR and RR than patients with ES. SIGNIFICANCE: Patients with PNES exhibit increasing autonomic arousal prior to seizure events unlike patients with epilepsy. This may reflect increasing levels of preictal anxiety, and future studies could study patients' subjective experiences of the preictal period, and more definitive measures of ventilation to see if this supported a model of PNES as "panic without panic".

Are psychogenic non-epileptic seizures just another symptom of conversion disorder?

BACKGROUND: Psychogenic non-epileptic seizures (PNES) are classified with other functional neurological symptoms as 'Conversion Disorder', but there are reasons to wonder whether this symptomatology constitutes a distinct entity. METHODS: We reviewed the literature comparing PNES with other functional neurological symptoms. RESULTS: We find eight studies that directly examined this question. Though all but one found significant differences-notably in presenting age, trauma history, and dissociation-they were divided on whether these differences represented an important distinction. CONCLUSION: We argue that the aetiological and mechanistic distinctions they support, particularly when bolstered by additional data, give reason to sustain a separation between these conditions.

White matter deficits in schizophrenia are global and don't progress with age.

INTRODUCTION: Diffusion tensor imaging has revealed differences in all examined white matter tracts in schizophrenia, with a range of explanations for why this may be. The distribution and timing of differences may help explain their origin; however, results are usually dependent on the analytical method. We therefore sought to examine the extent of differences and their relationship with age using two different methods. METHODS: A combined voxel-based whole-brain study and a tract-based spatial-statistics study of 104 patients with schizophrenia and 200 matched healthy controls, aged between 17 and 63 years. RESULTS: Fractional anisotropy was reduced throughout the brain in both analyses. The relationship of fractional anisotropy with age differed between patients and controls, with controls showing the gentle fractional anisotropy decline widely noted but patients showing an essentially flat relationship: younger patients had lower fractional anisotropy than controls, but the difference disappeared with age. Mean diffusivity was widely increased in patients. CONCLUSION: Reduction in fractional anisotropy and increase in mean diffusivity would be consistent with global disruption in myelination; the relationship with age would suggest this is present already at the onset of their illness, but does not progress.

Misidentification of mental health symptoms in presence of organic diseases and delirium during psychiatric liaison consulting.

OBJECTIVE: To identify predictors of misidentification of organic mental disorders and delirium in patients undergoing psychiatric liaison consultation. METHODS: Data were collected at Santa Casa de São Paulo between July of 2009 and March of 2013. We included in our analysis all inpatients for whom the requesting service judged that a psychiatric consultation was required for a possible mental health condition. Outcomes of interest were the instances of misidentification where a condition was initially deemed to be of a psychiatric nature, whereas the final diagnosis by the liaison psychiatric team was of an organic disease or delirium. Our predictors were the clinical specialty of the requesting service, requester and patient characteristics. A series of generalised linear models were used to evaluate misidentification risks. RESULTS: A total of 947 subjects met our inclusion criteria, 14.6% having a final liaison diagnosis of organic mental disorder and 8.1% of delirium. Older patients were significantly associated with increased risk of misidentification for both organic conditions (OR 3.01 - 95% CI 2.01, 4.5) and delirium (OR 3.92 - 2.4, 6.39). CONCLUSIONS: Educational interventions in general hospitals focused on preventing psychiatric misdiagnosis should target in-hospital services where patients tend to be older.