Inhibition of HIF-1α-AQP4 axis ameliorates brain edema and neurological functional deficits in a rat controlled cortical injury (CCI) model.

Traumatic brain injury (TBI) is an important cause of death in young adults and children. Till now, the treatment of TBI in the short- and long-term complications is still a challenge. Our previous evidence implied aquaporin 4 (AQP4) and hypoxia inducible factor-1α (HIF-1α) might be potential targets for TBI. In this study, we explored the roles of AQP4 and HIF-1α on brain edema formation, neuronal damage and neurological functional deficits after TBI using the controlled cortical injury (CCI) model. The adult male Sprague Dawley rats were randomly divided into sham and TBI group, the latter group was further divided into neutralized-AQP4 antibody group, 2-methoxyestradiol (2-ME2) group, and their corresponding control, IgG and isotonic saline groups, respectively. Brain edema was examined by water content. Hippocampal neuronal injury was assessed by neuron loss and neuronal skeleton related protein expressions. Spatial learning and memory deficits were evaluated by Morris water maze test and memory-related proteins were detected by western blot. Our data showed that increased AQP4 protein level was closely correlated with severity of brain edema after TBI. Compared with that in the control group, both blockage of AQP4 with neutralized-AQP4 antibody and inhibition of HIF-1α with 2-ME2 for one-time treatment within 30-60 min post TBI significantly ameliorated brain edema on the 1st day post-TBI, and markedly alleviated hippocampal neuron loss and spatial learning and memory deficits on the 21st day post-TBI. In summary, our preliminary study revealed the short-term and long-term benefits of targeting HIF-1α-AQP4 axis after TBI, which may provide new clues for the selection of potential therapeutic targets for TBI in clinical practice.

Neuroradiologic Features Associated With Severe Restriction of Functional Mobility in Children With Cerebral Palsy in North India.

BACKGROUND: Few studies have focused on magnetic resonance imaging (MRI) brain findings associated with functional mobility in cerebral palsy. OBJECTIVE: To determine association between MRI findings and Gross Motor Functional Classification System (GMFCS) levels in cerebral palsy. METHODS: Prospective-observational study conducted in Pediatric Neurology Clinic at a public teaching hospital, Northern India. First 3 new cases of cerebral palsy were enrolled on particular neuro-clinic day per week for 1 year. Functional mobility was classified according to GMFCS. Association between MRI findings, cerebral palsy type, and GMFCS levels were evaluated using χ2 test. RESULTS: A total of 138 cases (mean age 2.71 [SD = 1.91] years; male [64.5%]) were enrolled. Reported types of cerebral palsy were as follows: spastic quadriplegia (47.8%), spastic diplegia (28.35%), spastic hemiplegia (11.6%), extrapyramidal (6.5%), and ataxic/hypotonic (5.8%). GMFCS were classified into level 1 (13%), level 2 (7.2%), level 3 (4.3%), level 4 (10.9%), and level 5 (64.5%). Spastic quadriplegia and extrapyramidal cerebral palsy were significantly associated with higher (severe) levels (IV and V), whereas spastic diplegia and hemiplegia were significantly associated with lower (mild) levels (I-III) of GMFCS. MRI features of periventricular white matter injury, deep gray matter injury, basal ganglia and thalamic changes, and superficial gray matter injury were significantly associated with severe levels of GMFCS (V and IV). MRI was normal in 8 children (5 = mild category, 3 = severe category). CONCLUSION: Severe cerebral palsy is most often associated with spastic quadriplegia, extrapyramidal cerebral palsy, superficial gray matter lesions, deep gray matter lesions, and periventricular white matter injury. This information is useful for anticipating and addressing the needs of children with cerebral palsy and for prognostication.

Understanding and Managing Adolescents with Conversion and Functional Disorders.

A functional disorder is a constellation of bothersome physical symptoms that compromise regular function but for which there is no identifiable organic or psychiatric pathology. Functional disorders can present with various symptoms. Common forms of functional disorders include functional neurologic symptom disorder (also referred to as "conversion disorder"), functional gastrointestinal disorders, chronic pain syndromes, and chronic fatigue. One-third to one-half of outpatient consultations in many practices are due to functional disorders. Functional disorders must be distinguished from structural and psychiatric disorders but should not be considered diagnoses of exclusion. Recovery is facilitated by good relationships between patients and practitioners, with good explanations of the pathophysiology of functional disorders and effective encouragement and education of patients.

Effects of TPH2 gene variation and childhood trauma on the clinical and circuit-level phenotype of functional movement disorders.

BACKGROUND: Functional movement disorders (FMDs), part of the wide spectrum of functional neurological disorders (conversion disorders), are common and often associated with a poor prognosis. Nevertheless, little is known about their neurobiological underpinnings, particularly with regard to the contribution of genetic factors. Because FMD and stress-related disorders share a common core of biobehavioural manifestations, we investigated whether variants in stress-related genes also contributed, directly and interactively with childhood trauma, to the clinical and circuit-level phenotypes of FMD. METHODS: Sixty-nine patients with a 'clinically defined' diagnosis of FMD were genotyped for 18 single-nucleotide polymorphisms (SNPs) from 14 candidate genes. FMD clinical characteristics, psychiatric comorbidity and symptomatology, and childhood trauma exposure were assessed. Resting-state functional connectivity data were obtained in a subgroup of 38 patients with FMD and 38 age-matched and sex-matched healthy controls. Amygdala-frontal connectivity was analysed using a whole-brain seed-based approach. RESULTS: Among the SNPs analysed, a tryptophan hydroxylase 2 (TPH2) gene polymorphism-G703T-significantly predicted clinical and neurocircuitry manifestations of FMD. Relative to GG homozygotes, T carriers were characterised by earlier FMD age of onset and decreased connectivity between the right amygdala and the middle frontal gyrus. Furthermore, the TPH2 genotype showed a significant interaction with childhood trauma in predicting worse symptom severity. CONCLUSIONS: This is, to our knowledge, the first study showing that the TPH2 genotype may modulate FMD both directly and interactively with childhood trauma. Because both this polymorphism and early-life stress alter serotonin levels, our findings support a potential molecular mechanism modulating FMD phenotype.

Abdominal Pain Associated With Anorexia Nervosa and Median Arcuate Ligament Syndrome: A Rare Condition Shadowed by a Postoperative Conversion Disorder.

Median arcuate ligament syndrome (MALS) is an often discounted and vexing condition that may go unnoticed in a population of patients with complex comorbid conditions or those with poor psychiatric health. We report a unique case of a patient with anorexia nervosa in whom the successful operation for MALS was briefly complicated by a postoperative conversion disorder.

Stroke Mimics: Experience of a Moroccan Stroke Unit.

BACKGROUND: Stroke mimic is a medical condition presenting with acute neurological deficit and simulate real stroke. The objective of this study was to evaluate the frequency and the various etiologies of stroke mimics in our center. METHODS: We retrospectively reviewed the Thrombolysis Alert registry and we studied the frequency and characteristics of patients with stroke mimic. RESULTS: Among 673 patients who were admitted to the emergency department within 4.5 hours for sudden focal neurological deficit suggestive of acute stroke, 105 patients (15.6 %) had a stroke mimic. The mean age of patients with mimics and brain strokes were 66.3 and 64.8, respectively. The mean Onset-to-door time was 136.82 minutes and the mean door-to-imaging time was 32.63 minutes in stroke mimics. Seizure (28.5%) was the most common diagnosis of stroke mimics followed by conversion disorder (25.7%). CONCLUSIONS: Stroke mimic is frequent and heterogeneous entity that can be difficult to identify. Fortunately, most previous studies show no harmful effects when using thrombolysis in a stroke mimic.

What Does Neuroscience Tell Us About the Conversion Model of Functional Neurological Disorders?

A dualistic mind-body understanding of functional neurological disorders (FNDs), also known as conversion disorders, has led to the view that the cause of the symptom should be either psychological (psychogenic) or physical (neurogenic-"organic"). One of the most influential psychological approaches is the Freudian model of conversion, which suggests that FNDs arise from a defense process in which emotional stress is converted into physical symptoms. This conversion theory has been challenged in recent years, accompanied by a shift in emphasis toward neuropathophysiological models of FND and away from historical psychological concepts. In this review, the authors consider the contemporary relevance of the conversion model from the neuroscientific perspective to reconcile the role of both psychological and biological factors in FND. A narrative review of recent neuroscientific findings pertaining to the conversion model of FND, encompassing neuroimaging, cognitive psychology, biological markers, and epigenetic studies, was performed. Research on the role of psychological stressors is discussed. Neurobiological mechanisms of repression of traumatic memories and their translation into physical symptoms are then explored. Finally, the role of physical symptoms as a potential protective defense mechanism against social stressors is considered. The authors argue that the conversion concept is consistent with recent neuroscientific research findings, and the model allows psychological and neurobiological concepts to be reconciled within a single account of FND that begins to resolve the dualistic mind-body dichotomy.

Neurologists' experiences of participating in the CODES study-A multicentre randomised controlled trial comparing cognitive behavioural therapy vs standardised medical care for dissociative seizures.

PURPOSE: We investigated neurologists' experience of participating in the large CODES trial involving around 900 adults with dissociative seizures which subsequently evaluated the effectiveness of tailored cognitive behavioural therapy (CBT) plus standardised medical care versus standardised medical care alone in 368 patients with dissociative seizures. METHOD: We asked all neurologists referring patients with dissociative seizures to the CODES study to complete a 43-item online survey. This examined neurologists' (i) demographics, (ii) knowledge of dissociative seizures before and after their involvement in the CODES trial, (iii) clinical practice before, during and since their involvement, and (iv) their experience of the CODES trial. RESULTS: Forty-three (51%) neurologists completed the questionnaire. Only about half of neurologists could make referrals to psychological intervention specific for dissociative seizures before and after the trial. One-third of doctors reported having changed their referral practice following their involvement. The majority (>69%) agreed that patient satisfaction with different aspects of the trial was very high, and 83.7% thought that it was easy to recruit patients for the study. Over 90% agreed they would like the treatment pathway to continue. Respondents found different elements of the trial useful, in particular, the patient factsheet booklet (98%), diagnosis communication advice (93%) and the CBT package (93%). CONCLUSIONS: Neurologists participating in CODES generally found it easy to recruit patients and perceived patient satisfaction as very high. However, 46.5% of neurologists could not offer psychotherapy once the trial had finished, suggesting that problems with lack of access to psychological treatment for dissociative seizures persist.

Stress and functional neurological disorders: mechanistic insights.

At the interface between mind and body, psychiatry and neurology, functional neurological disorder (FND) remains poorly understood. Formerly dominant stress-related aetiological models have been increasingly challenged, in part due to cases without any history of past or recent trauma. In this perspective article, we review current evidence for such models, and how research into the role of traumatic stress in other disorders and the neurobiology of the stress response can inform our mechanistic understanding of FND. First, we discuss the association between stress and the onset or exacerbation of a variety of physical and mental health problems. Second, we review the role of hypothalamic-pituitary-adrenal axis dysfunction in the neurobiology of ill-health, alongside evidence for similar mechanisms in FND. Third, we advocate a stress-diathesis model, in which biological susceptibility interacts with early life adversity, where FND can be precipitated by traumatic events later in life and maintained by psychological responses. We hypothesise that greater biological susceptibility to FND is associated with less severe remote and recent stress, and that FND precipitated by more severe stress is associated with lower biological vulnerability. This would explain clinical experience of variable exposure to historical and recent traumatic stress among people with FND and requires empirical investigation. A testable, evidence-based stress-diathesis model can inform nuanced understanding of how biological and psychological factors interact at the individual level, with potential to inform personalised treatment pathways. Much-needed research to establish the aetiology of FND will enhance clinical care and communication, facilitate effective treatment and inform prevention strategies.

Clenched fist syndrome: a case report.

BACKGROUND: The clenched fist syndrome/psycho-flexed hand, first described in the early 1980s, has not yet entered the major psychiatric textbooks. Curiously, the phenomenon has been illuminated mainly in journals and textbooks on hand surgery. There is a need to examine, describe, and understand this syndrome from a psychiatric perspective. CASE PRESENTATION: We present a case we encountered in an intensive care unit. A 60-year-old white man with schizophrenia, cerebrovascular disease, diabetes mellitus type 2, and peripheral neuropathy, developed rather acutely bilateral clenched fists in the aftermath of a traumatic dislocated hip fracture that was operated on. He later died due to complications from the surgical procedure. CONCLUSIONS: While this was a complex case with some clinical uncertainty regarding the cause of our patient's symptoms, we conclude that psychological processes were central to the development of his clenched fists. The phenomenon of clenched fists and our case are discussed with reference to the accumulated literature on psychogenic hand disorders and the International Statistical Classification of Diseases and Related Health Problems, 10th version. The nosological status appears to be obscure. This case presentation is a first step in increasing the understanding of this syndrome from a psychiatric perspective.

The role of emotion dysregulation in Conversion Disorder.

INTRODUCTION: The role that emotion regulation plays in Conversion Disorders (CD) is not well known. This research deepens in this subject and describes the main differences between a group of conversion patients and a control group on different measures of emotion regulation and other clinical variables. METHODS: A case-control study was conducted including 43 patients suffering from CD and 42 healthy controls. Both groups went thought two psychiatric interviews and fulfilled 6 questionnaires assessing depression, anxiety, alexithymia, emotion dysregulation, affect intensity, psychoform and somatoform dissociation. RESULTS: Patients suffering from CD scored significantly higher on all the six questionnaires (p<0.001). Negative reactivity and negative intensity were also higher in patients (p<0.01), while cases and controls did not show any significant differences on positive affectivity and serenity. Anxiety, alexithymia and emotional dysregulation were the most relevant factors (OR=5.85/3.50/3.23 respectively). Anxiety and difficulties in emotion regulation were the most explicative variables for conversion in the regression analysis performed. Within the five factors assessing difficulties in emotion regulation, lack of emotional control and interference in goal directed behaviors were the most relevant. Positive and negative conversion where correlated to different emotional impairments. CONCLUSIONS: People suffering from CD show several emotional impairments when compared to healthy controls. Emotion dysregulation can be considered a relevant aspect in CD. The existence of specific emotional patterns for different conversion manifestations is suspected.

El papel de la desregulación emocional en el Trastorno Conversivo / The role of emotion dysregulation in Conversion Disorder

Introducción. El papel que juega la regulación de las emociones en la etiopatogénesis del Trastorno Conversivo (TC) es todavía poco conocido. Esta investigación pretende profundizar en este tema, buscando describir las diferencias principales que existen entre un grupo de pacientes con TC y un grupo control en lo que concierne a la forma de regular sus emociones así como a otras variables clínicas fundamentales. Métodos. Se ha realizado un estudio de tipo casos (n=43) y controles (n=42). Ambos grupos se sometieron a dos entrevistas psiquiátricas y completaron 6 cuestionarios autoadministrados evaluando la depresión, ansiedad, alexitimia, desregulación emocional, intensidad efectiva, así como la disociación psicomorfa y somatomorfa. Resultados. Los pacientes con TC puntuaron significativamente más alto en las seis variables estudiadas a través de los cuestionarios (p<0.001). La reactividad y la intensidad emocional negativas fueron mayores en el grupo de pacientes (p<0.01) mientras que ambos grupos puntuaron de manera similar en afectividad positiva y serenidad. La ansiedad, la alexitimia y la desregulación emocional fueron los factores de riesgo más importantes identificados (OR=5.85/3.50/3.23 respectivamente). La ansiedad y las dificultades en la regulación de las emociones fueron las variables que mejor explicaron la pertenencia al grupo de pacientes en los modelos de regresión logística calculados. Entre los 5 factores que midieron diferentes dificultades en la regulación emocional los más relevantes fueron la falta de control emocional y la interferencia en conductas orientadas a una meta. La sintomatología conversiva positiva y la sintomatología conversiva negativa se correlacionaron con distintos patrones de regulación emocional. Conclusiones. Los pacientes con TC sufrieron múltiples dificultades a la hora de regular sus emociones, comparados con el grupo control. La desregulación emocional puede ser considerada un factor de riesgo para padecer un TC. Se discute la posibilidad de que existan diferentes patrones de regulación emocional en pacientes con distintos tipos de sintomatología conversiva

Introduction. The role that emotion regulation plays in Conversion Disorders (CD) is not well known. This research deepens in this subject and describes the main differences between a group of conversion patients and a control group on different measures of emotion regulation and other clinical variables. Methods. A case-control study was conducted including 43 patients suffering from CD and 42 healthy controls. Both groups went thought two psychiatric interviews and fulfilled 6 questionnaires assessing depression, anxiety, alexithymia, emotion dysregulation, affect intensity, psychoform and somatoform dissociation. Results. Patients suffering from CD scored significantly higher on all the six questionnaires (p<0.001). Negative reactivity and negative intensity were also higher in patients (p<0.01) while cases and controls did not show any significant differences on positive affectivity and serenity. Anxiety, alexithymia and emotional dysregulation were the most relevant factors (OR=5.85/3.50/3.23 respectively). Anxiety and difficulties in emotion regulation were the most explicative variables for conversion in the regression analysis performed. Within the five factors assessing difficulties in emotion regulation, lack of emotional control and interference in goal directed behaviors were the most relevant. Positive and negative conversion where correlated to different emotional impairments. Conclusions. People suffering from CD show several emotional impairments when compared to healthy controls. Emotion dysregulation can be considered a relevant aspect in CD. The existence of specific emotional patterns for different conversion manifestations is suspected

An Overview of Psychogenic Non-Epileptic Seizures: Etiology, Diagnosis and Management.

The purpose of this review is to provide an update of the research regarding the etiology, diagnosis and management of psychogenic non-epileptic seizures (PNES). A literature search using Pubmed, Ovid MEDLINE and EMBASE database was performed from 2000 up to August 2017. We have evaluated the different factors leading to PNES as well as the diagnostic approach and management of this disorder which continue to be very difficult. The coexistence of epilepsy and PNES poses special challenges and requires the coordinated efforts of the family physicians, psychiatrists, psychologists and neurologists. Although this condition has an overall poor prognosis, a multidisciplinary approach in the diagnosis and management of this disorder would likely improve the outcomes. We have proposed a diagnostic and treatment algorithm for PNES and suggested a national registry of patients suffering from this condition. The registry would contain data regarding treatment and outcomes to aid in the understanding of this entity.

Postoperative Conversion Disorder Presenting as Inspiratory Stridor and Hemiparesis in a Pediatric Patient.

BACKGROUND Postoperative conversion disorder is rare and has been reported. The diagnosis is usually made after all major organic causes have been ruled out. CASE REPORT We describe a case of a 13-year-old female who presented in the post-anesthesia care unit with acute-onset inspiratory stridor and unresponsiveness to verbal or painful stimuli after receiving a general anesthetic for upper endoscopy. Later in the post-anesthesia care unit, she presented with acute-onset right hemiplegia and sensory loss. She was first evaluated for causes of her stridor and unresponsiveness. The evaluation revealed paradoxical vocal cord movement, and all laboratory test values were normal. For her hemiplegia and sensory loss, she was evaluated for stroke with head MRI and CT scans, which were normal. CONCLUSIONS After extensive workup and consideration of multiple etiologies for her presenting signs and symptoms, the most likely diagnosis was conversion disorder.

Understanding psychogenic nonepileptic seizures-Phenomenology, semiology and the Integrative Cognitive Model.

Psychogenic Nonepileptic Seizures (PNES) are one of the commonest differential diagnoses of epilepsy. This paper provides a narrative review of what has been learnt in the last 25 years regarding the visible manifestations, physiological features, subjective experiences and interactional aspects of PNES. We then explore how current insights into PNES semiology and phenomenology map onto the Integrative Cognitive Model (ICM), a new account of these phenomena that unifies previous approaches within a single explanatory framework. We discuss to what extent recent psychological and neurophysiological research is consistent with the ICM and indicate how the more detailed analysis of physiological data, connectivity analyses of EEG and functional or structural MRI data may provide greater insights into the biopsychosocial underpinnings of a disabling and under-researched disorder.

Stress, childhood trauma, and cognitive functions in functional neurologic disorders.

Conversion disorder (CD) has traditionally been ascribed to psychologic factors such as trauma, stress, or emotional conflict. Although reference to the psychologic origin of CD has been removed from the criteria list in DSM-5, many theories still incorporate CD as originating from adverse events. This chapter provides a critical review of the literature on stressful life events in CD and discusses current cognitive and neurobiologic models linking psychologic stressors with conversion symptomatology. In addition, we propose a neurobiologic stress model integrating those cognitive models with neuroendocrine stress research and propose that stress and stress-induced changes in hypothalamus-pituitary-adrenal (HPA) axis function may result in cognitive alterations, that in turn contribute to experiencing conversion symptoms. Experimental studies indeed suggest that basal as well as stress-induced changes in HPA axis responding lead to alterations in attentional processing in CD. Although those changes are stronger in traumatized patients, similar patterns have been observed in patients who do not report a history of traumatic events. We conclude that, whereas adverse events may play an important role in many cases of CD, a substantial proportion of patients do not report a history of traumatization or recent stressful events. Studies integrating effects of stress on cognitive functioning in CD are scarce. We propose that, instead of focusing research on defining etiologic events in terms of symptom-eliciting events, future research should work towards an integrated mechanistic account, assessing alterations in cognitive and biologic stress systems in an integrated manner in patients with CD. Such an account may not only serve early symptom detection, it might also provide a starting point for better-targeted interventions.

Conversion Disorder in an Appalachian Community.

OBJECTIVES: Conversion disorder (CD) is believed to be the manifestation of physical and/or neurological symptoms for primary gain without an identifiable organic cause. Although it is believed to be more common in rural areas, the literature examining this claim is sparse. To our knowledge, no study has been published evaluating the prevalence of CD in a rural Appalachian population. The aim of this study was to characterize and determine the prevalence of CD per Diagnostic and Statistical Manual of Mental Disorders, 5th Edition, criteria in a rural Appalachian psychiatric consultation service and to compare this population with control patients from the same service. METHODS: We performed a retrospective chart review of all patients diagnosed as having CD per Diagnostic and Statistical Manual of Mental Disorders, 5th Edition, criteria on a psychiatric consultation service at a rural Appalachian academic medical center during a 13-month time period. For each case, two consecutive control patients were selected from the same service and time span. RESULTS: There were 21 cases and 42 controls in this study, with a CD prevalence rate of 6.0% (N = 21/351). Sociodemographic, comorbidity, and recent symptomatology data were obtained. Compared with controls, cases were significantly younger and were more likely to have a history of sexual abuse, seizure disorder, antiepileptic use, neurologic referral, electroencephalogram, magnetic resonance imaging of the brain, and history of CD. We found it interesting that fewer cases reported alcohol and drug use. CONCLUSIONS: The observed prevalence of 6.0% does not support the historical theory that CD is more prevalent in rural or lower socioeconomic populations. Our data add to the characterization of the Appalachian CD population.