Altered Autonomic Functions and Gut Microbiome in Individuals with Autism Spectrum Disorder (ASD): Implications for Assisting ASD Screening and Diagnosis.

Autism spectrum disorder (ASD) is a complex neurological and developmental disorder, and a growing body of literature suggests the presence of autonomic nervous system (ANS) dysfunction in individuals with ASD. ANS is part of the "gut brain axis", which consists of an intricate interplay between the gut microbiome, mucosal immune system, enteric nervous system, ANS, and central processes receiving input from the vagus nerve. Measurements of the gut microbiome and the autonomic indices can serve as non-invasive markers of the status of the gut-brain axis in ASD. To our knowledge, no previous studies have explored the relationship between ANS and gut microbiome in individuals with ASD. Furthermore, while previous studies investigated the use of autonomic indices and gut microbiome independently as markers of ASD-related comorbidities, such as anxiety, cardiovascular issues, and gastrointestinal dysfunction, the use of combined autonomic indices and gut microbiome factors to classify ASD and control subjects has not been explored. In this study, we characterized autonomic function of a group of individuals with ASD in comparison to their paired, first-degree relative controls. Second, we explored the ASD gut-brain-axis through the relationship between gut microbiome markers and autonomic indices, as well as the correlation between the gut-brain-axis and clinical presentation of ASD. Lastly, this study explores the predictive capability of gut-brain-axis biomarkers (including autonomic and microbiome indices) in subtyping ASD cases, serving as a starting point to investigate the possibility of assisting in ASD screening and diagnosis that still heavily relies on psychological testing, which may be based on highly subjective standards.

Improved Behavior and Neuropsychological Function in Children With ROHHAD After High-Dose Cyclophosphamide.

Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD) is a rare, generally progressive, and potentially fatal syndrome of unclear etiology. The syndrome is characterized by normal development followed by a sudden, rapid hyperphagic weight gain beginning during the preschool period, hypothalamic dysfunction, and central hypoventilation, and is often accompanied by personality changes and developmental regression, leading to substantial morbidity and mortality. We describe 2 children who had symptomatic and neuropsychological improvement after high-dose cyclophosphamide treatment. Our experience supports an autoimmune pathogenesis and provides the first neuropsychological profile of patients with rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation.

A longitudinal study of a family with adult-onset autosomal dominant leukodystrophy: Clinical, autonomic and neuropsychological findings.

BACKGROUND AND PURPOSE: Adult-onset autosomal dominant leukodystrophy (ADLD) is a rare progressive neurological disorder caused by Lamin B1 duplication (LMNB1). Our aim was to investigate longitudinally the pattern of the autonomic dysfunction and the degree of neuropsychological involvement. METHODS: Three related ADLD patients and one asymptomatic carrier of LMNB1 duplication underwent a standardized evaluation of autonomic nervous system, including cardiovascular reflexes, pharmacological testing, microneurography, skin biopsy, Metaiodobenzylguanidine scintigraphy and a complete neuropsychological battery. RESULTS: An early neurogenic orthostatic hypotension was detected in all patients and confirmed by a low rise in noradrenaline levels on Tilt Test. However infusion of noradrenaline resulted in normal blood pressure rise as well as the infusion of clonidine. At the insulin tolerance test the increase in adrenaline resulted pathological in two out three patients. Microneurography failed to detect muscle sympathetic nerve activity bursts. Skin biopsy revealed a poor adrenergic innervation, while cardiac sympathetic nerves were normal. None of ADLD patients showed a global cognitive deficit but a selective impairment in the executive functions. CONCLUSION: Autonomic disorder in ADLD involves selectively the postganglionic sympathetic system including the sympatho-adrenal response. Cognitive involvement consisting in an early impairment of executive tasks that might precede brain MR abnormalities.

Evaluating exposure to abuse and violence in neurological patients.

OBJECTIVE: The relationship between abuse and violence and the care of neurological patients is an important topic not often addressed, and studies suggest that most neurologists do not routinely screen patients for abuse. In this pilot study, our aim was to demonstrate a simple and effective strategy for screening patients for exposure to abuse. METHODS: A total of 103 consecutive patients reporting to an academic neurology clinic specializing in autonomic and movement disorders were screened for a history of abuse and violence. A set of 6 questions were included in the standard patient intake questionnaire. The questions were then repeated verbally during the physician history taking. All patients were provided with information on available local resources for abuse counseling during the visit. Retrospective chart review analysis was performed to determine the prevalence of history of abuse in the population, the most common type of abuse suffered, and the number of individuals reporting current abuse. RESULTS: Twenty-two of the 103 patients (21%) screened for abuse reported exposure to abuse or violence. Two patients with ongoing issues with abuse were identified. The most commonly reported abuse was being a witness to violence (65%), followed by physical abuse (41%), sexual and emotional abuse (36% each), and financial abuse (23%). The neurological disorders most frequently observed in these patients were chronic pain, neuropathy, autonomic dysfunction, headache, and Parkinson disease. CONCLUSIONS: Patients with neurological disorders may have been exposed to abuse and violence. It is important to recognize these issues and address them routinely in the neurological evaluation. A simple, effective way to accomplish screening in the outpatient setting is through the use of an intake questionnaire combined with verbal clarification.

Prevalence, frequency and problem rating of hot flushes persist in older postmenopausal women: impact of age, body mass index, hysterectomy, hormone therapy use, lifestyle and mood in a cross-sectional cohort study of 10,418 British women aged 54-65.

OBJECTIVE: Hot flushes and night sweats (HFs/NSs) are the main menopausal symptoms, but few studies have been adequately powered to examine the dimensions or predictors of experiencing HFs/NSs. We report on these variables in a large UK cohort of postmenopausal women. DESIGN: Cross-sectional cohort study. SETTING: UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) cohort. POPULATION: A cohort of 202,638 postmenopausal women, aged 50-74 years, without oophorectomy, recruited to UKCTOCS between 2001 and 2005. METHODS: Women completed a follow-up questionnaire, and those aged 54-65 years were mailed a survey in July 2008. MAIN OUTCOME MEASURES: Hot flush prevalence and hot flush rating scale. RESULTS: Of the 15,000 women mailed, 10,418 returned completed questionnaires; 90% had previously had HFs/NSs. Despite being on average 10 years postmenopausal, 54% experienced HFs/NSs (frequency of 33 per week with mean problem rating 4/10) that persisted across the age range. Past hysterectomy (OR 1.50, 95% CI 1.19-1.86), ever having smoked (OR 1.27, 95% CI 1.11-1.46) and alcohol consumption (current units) (OR 1.05, 95% CI 1.01-1.09) predicted ever having had HFs/NSs. Anxiety (OR 3.09, 95% CI 2.57-3.72), hysterectomy (OR 2.74, 95% CI 2.32-3.25), depressed mood (OR 1.57, 95% CI 1.24-1.99), years since last menstrual period (OR 0.95, 95% CI 0.94-0.96) and education (above and below 18 years) (OR 0.98, 95% CI 0.97-0.99) predicted the current prevalence of HFs/NSs. Few predictors of frequency were identified, but problem rating was associated with depressed mood, hysterectomy, skirt size increase and frequency of HFs/NSs. Past hormone therapy users who had discontinued treatment were more likely to have HFs/NSs that were more frequent and problematic. CONCLUSIONS: To date, this is the largest UK study of the experience of HFs/NSs amongst older postmenopausal women. HFs/NSs are more prevalent in this age band than has previously been assumed. These findings and the associations of smoking, hysterectomy, anxiety, depressed mood and hormone therapy use with the experience of HFs/NSs have implications for prevention and symptom management.

[Anti-NMDA receptor encephalitis: a neurological and psychiatric emergency]. / Anti-NMDA-Rezeptor-Enzephalitis: Ein neurologisch-psychiatrischer Notfall.

Anti-NMDA receptor encephalitis is a severe autoimmune disease, first described in 2007.  Since then a number of cases have been published, suggesting that to date the disease is a considerably underdiagnosed entity. The clinical picture develops over a relatively long period of time and is initially characterised by psychiatric symptoms such as decreased levels of consciousness and hallucinations as well as paranoid behaviour. In the course of the disease neurological symptoms occur, in particular, seizures, autonomic dysfunction and dyskinesias. Due to the young age of many patients, the symptoms are often mistaken as to result from drug-induced psychosis. Anti-NMDA receptor Encephalitis was first described in young women with teratomas. In the past few years the disorder has also been reported in men and children and without any detectable neoplasia. The diagnosis is based on the characteristic clinical picture and supportive findings in MRI, EEG and the cerebrospinal fluid. Hereby, highly specific autoantibodies directed against the NR1 subunit of the NMDA-type glutamate receptors in the CSF (or serum) play an important role and should be sought specifically in any case of an "encephalitis of unknown cause". The prognosis of the disease is favourable, even when autonomic disorders entail ventilation and/or prolonged intensive care treatment is necessary. Nonetheless, the clinical outcome is highly dependent on an early diagnosis and immunotherapy without delay. In the case of a malignancy, tumour removal is also crucial. Taken together, an interdisciplinary approach including neurologists, psychiatrists, oncologists and gynaecologists is essential in order to detect and effectively treat this disorder.

Does self-regulation and autonomic regulation have an influence on survival in breast and colon carcinoma patients? results of a prospective outcome study.

BACKGROUND: Cancer Related Fatigue (CRF) and circadian rhythm have a great impact on the quality of life (HRQL) of patients with breast (BC) and colon cancer (CRC). Other patient related outcomes in oncology are measured by new instruments focusing on adaptive characteristics such as sense of coherence or self-regulation, which could be more appropriate as a prognostic tool than classical HRQL. The aim of this study was to assess the association of autonomic regulation (aR) and self-regulation (SR) with survival. METHODS: 146 cancer patients and 120 healthy controls took part in an initial evaluation in 2000/2001. At a median follow up of 5.9 years later, 62 of 95 BC, 17 of 51 CRC patients, and 85 of 117 healthy controls took part in the follow-up study. 41 participants had died. For the follow-up evaluation, participants were requested to complete the standardized aR and SR questionnaires. RESULTS: On average, cancer patients had survived for 10.1 years with the disease. Using a Cox proportional hazard regression with stepwise variables such as age, diagnosis group, Charlson co-morbidity index, body mass index (BMI)) aR and SR. SR were identified as independent parameters with potential prognostic relevance on survival While aR did not significantly influence survival, SR showed a positive and independent impact on survival (OR = 0.589; 95%-CI: 0.354 - 0.979). This positive effect persisted significantly in the sensitivity analysis of the subgroup of tumour patients and in the subscale 'Achieve satisfaction and well-being' and by tendency in the UICC stages nested for the different diagnoses groups. CONCLUSIONS: Self-regulation might be an independent prognostic factor for the survival of breast and colon carcinoma patients and merits further prospective studies.

Analysis of potential predictors of depression among coronary heart disease risk factors including heart rate variability, markers of inflammation, and endothelial function.

AIMS: We investigated the relationship between autonomic nervous system balance, systemic immune activation, endothelial dysfunction, and depression in patients free of coronary heart disease (CHD) with increased CHD risk. METHODS AND RESULTS: Depression status (Beck Depression Inventory, BDI), selected CHD risk factors, inflammation markers, measures of heart rate variability (HRV), and indices of endothelial function (flow-mediated dilation, FMD) were evaluated in 415 subjects free of CHD, diabetes mellitus, and other life-threatening conditions, with at least two CHD risk factors among the following: older age, male gender, current smoking, hypertension, and dislipidaemia. Overall, 51.7% of the participants were males, aged 57.6 +/- 8.8 years on average (minimum 30, maximum 70). Almost half were hypertensive, 43.9% were dyslipidemic, 30.4% current smokers, and 23.1% showed a depressive symptomatology (BDI > or = 10). Logistic regression showed that, as compared with non-depressed individuals and after adjustment for age, gender, and hypertension, depressive subjects were significantly more likely to be smokers, to have higher total cholesterol, higher C-reactive protein, and Interleukin-6. In addition, depressed subjects were more likely to have altered HRV and their FMD was severely impaired (adjusted odds ratio of 1% increase = 0.72; 95% CI: 0.61-0.86). CONCLUSION: Our data indicate an independent association between depression and impaired HRV, systemic inflammatory, and endothelial function. These mechanisms play a role not only in the complication of advanced forms of disease, but also promote and/or accelerate the early disease and connect depression and CHD.

Autonomic activation and pain in response to low-grade mental stress in fibromyalgia and shoulder/neck pain patients.

OBJECTIVE: Psychosocial stress is a risk factor for musculoskeletal pain, but how stress affects musculoskeletal pain is poorly understood. We wanted to examine the relationship between low-grade autonomic activation and stress-related pain in patients with fibromyalgia and localised chronic shoulder/neck pain. METHODS: Twenty-three female patients with fibromyalgia, 29 female patients with chronic shoulder-neck pain, and 35 healthy women performed a stressful task lasting 60min. With a blinded study design, we recorded continuous blood pressure, heart rate, finger skin blood flow and respiration frequency before (10min), during (60min) and after (30min) the stressful task. The physiological responses were compared with subjective reports of pain. RESULTS: The increase in diastolic blood pressure and heart rate in response to the stressful task were smaller in fibromyalgia patients compared with the healthy controls. Furthermore, fibromyalgia patients had reduced finger skin blood flow at the end of the stressful task compared to healthy controls. We also found an inverse relationship between the heart rate response and development and recovery of the stress-related pain in fibromyalgia patients. CONCLUSION: We found abnormal cardiovascular responses to a 60min long stressful task in fibromyalgia patients. Furthermore, we found a negative association between the heart rate response and the pain which developed during the stressful task in the fibromyalgia group, possibly a result of reduced stress-induced analgesia for fibromyalgia patients.

Cerebrospinal fluid corticotropin-releasing factor concentration is associated with pain but not fatigue symptoms in patients with fibromyalgia.

Previous studies have identified stress system dysregulation in fibromyalgia (FM) patients; such dysregulation may be involved in the generation and/or maintenance of pain and other symptoms. Corticotropin-releasing factor (CRF) is the principal known central nervous system mediator of the stress response; however, to date no studies have examined cerebrospinal fluid (CSF) CRF levels in patients with FM. The relationship between CSF CRF level, heart rate variability (HRV), and pain, fatigue, and depressive symptoms was examined in patients with FM. Among participants (n=26), CSF CRF levels were associated with sensory pain symptoms (r=0.574, p=0.003) and affective pain symptoms (r=0.497, p=0.011), but not fatigue symptoms. Increased HRV was also strongly associated with increased CSF CRF and FM pain. In multivariate analyses adjusting for age, sex, and depressive symptoms, the association between CSF CRF and sensory pain symptoms (t=2.54, p=0.027) persisted. Women with FM who reported a history of physical or sexual abuse had lower CSF CRF levels than women who did not report such a history. CSF CRF levels are associated with both pain symptoms and variation in autonomic function in FM. Differences in CSF CRF levels among women with and without a self-reported history of physical or sexual abuse suggest that subgroups of FM patients may exist with different neurobiological characteristics. Further studies are needed to better understand the nature of the association between CSF CRF and pain symptoms in FM.

Arc de cercle and dysautonomia from anoxic injury.

Autonomic dysregulation and catatonic posturing are well described following acute cerebral injury. Others have referred to this as diencephalic seizures, sympathetic storms, midbrain dysregulatory syndrome, and, most recently, paroxysmal autonomic instability with dystonia. Some of these syndromes can evolve into malignant catatonia requiring electroconvulsive therapy. Here we report a case of hanging associated anoxic brain injury resulting in severe dysautonomia and an extreme opisthotonus (arc de cercle).

Drug treatment of non-motor symptoms in Parkinson's disease.

Non-motor symptoms may considerably reduce parkinsonian quality of life, particularly in advanced stages of the disease. Autonomic features, such as seborrhoea, hyperhidrosis, orthostatic hypotension, excessive salivation, bladder dysfunction and GI disturbances, and neuropsychiatric symptoms, such as depression, sleep disorders, psychosis and dementia, appear in the course of Parkinson's disease. Pharmacotherapy of these non-motor symptoms complicates long-term antiparkinsonian combination drug therapy due to possible drug interactions, side effects and changes in metabolism. Moreover, antiparkinsonian compounds themselves contribute to the onset of these non-motor symptoms to a considerable extent. This complicates differentiation between the disease process itself and drug-related effects, thus influencing therapeutic options, which are often limited because of comorbidity and polypharmacy. Therefore, standardised recommendations are questionable, since drug tolerability and response differ between patients. Nevertheless, this review tries to provide a survey of possible therapeutic options for the treatment of the symptoms of Parkinson's disease other the dopamine-sensitive motor features.

Neuroleptic malignant syndrome after neuroleptic discontinuation.

1. Neuroleptic withdrawal can cause autonomic and behavioral symptoms (nausea, vomiting, diarrhea, diaphoresis, myalgia, anxiety, restlessness) and movement disorders (withdrawal emergent parkinsonism, withdrawal dyskinesia, covert dyskinesia). 2. Neuroleptic malignant syndrome (NMS) is a rare but extremely severe adverse reaction to neuroleptic drugs characterized by extrapyramidal and autonomic symptoms, altered level of consciousness and abnormal laboratory findings. 3. Withdrawal neuroleptic malignant syndrome, though an even rarer condition (only 7 cases reported to date), should alert to consider the possibility that abrupt neuroleptic discontinuation can be complicated by NMS. 4. The pathophysiology of withdrawal medical symptoms may be related to a cholinergic rebound; withdrawal neuroleptic malignant syndrome may be attributed to an "imbalance" in the dopaminergic system. 5. The authors report two cases of NMS precipitated by the abrupt withdrawal of neuroleptic drugs.

Clinical physiological study of the therapeutic effects of phenytoin in acute alcohol withdrawal and the asthenic-autonomic syndrome in patients with chronic alcoholism.

The effects of diphenylhydantoin [phenytoin (PHT)] on both the acute withdrawal syndrome (AWS) and the asthenic-autonomic syndrome associated with chronic alcoholism were evaluated in a single-blind, controlled, clinical, and comprehensive multiparameter psychophysiological and neurophysiological study. Twenty-four patients were treated with PHT (100 mg, PO, tid) and our standard detoxification therapy (intravenous fluids and vitamins as an antihistamine and a vasodilator; cognitive psychotherapy; and occupational therapy) and their progress was compared to that of 12 patients receiving only our standard detoxification therapy. The use of PHT and standard detoxification therapy resulted in an amelioration or cessation of the main symptoms of acute alcohol withdrawal within a mean of 3 +/- 1 days. Vital fear, psychomotor excitation, sense of shortness of breath, pronounced chill-like state, and pronounced perspiration disappeared within 3 days. In the control group, the same improvements were found in a mean of 11 +/- 3 days. After the acute withdrawal period, PHT (50-100 mg, bid-tid) was continued in all 24 patients of the PHT group to evaluate its effects on the asthenic-autonomic syndrome. PHT's most marked therapeutic effects (improvements in mood, aggression, ability to react appropriately to surroundings, attention, active vigilance, and autonomic parameters) were seen in eight patients with the sympathetic-adrenal type of autonomic disorders. Dynamic EEG and infraslow physiological processes showed confirmatory improvement. A reduction in alcohol craving and longer alcohol-free remission times were also seen. Although there were some benefits in the 16 patients with the parasympathetic type of autonomic disorders, they were smaller and less stable. There were no beneficial effects of PHT or standard therapy in a group of five young patients with a malignant, rapidly progressive form of alcoholism. We conclude that PHT is useful in acute alcohol withdrawal and in the treatment of the asthenic-autonomic syndrome (during the rehabilitative phase) in patients with sympathetic type of autonomic disorder. Further clinical evaluation and use of PHT in alcohol withdrawal and rehabilitation are indicated.

Primary central nervous system lymphoma presenting as autonomic dysfunction.

We describe a patient with primary central nervous system lymphoma (PCNSL) who presented with symptoms of subacute onset of dysautonomia. Autonomic testing indicated a peripheral autonomic neuropathy while magnetic resonance imaging revealed brainstem involvement. We propose that this patient's autonomic dysfunction could be the result of a paraneoplastic syndrome and PCNSL should be considered in the differential diagnosis of dysautonomia.

[Mental and somato-autonomic disorders from long-term exposure to low doses of radiation]. / Psikhicheskie i somatovegetativnye rasstroistva pri dlitel'nom vozdeistvii malykh doz radiatsii.

The paper presents the results of psychopathological and clinical examinations of the subjects exposed to low-dose radiation consequent to the Chernobyl accident. Relevant psychic disorders are specified. A close correlation was found between some psychopathological syndromes and somatovegetative disturbances.

[Autonomic disorders in the clinical picture of gastric and duodenal peptic ulcer and their acupuncture reflexotherapy]. / Vegetativnye rasstroistva v klinike iazvennoi bolezni zheludka i refleksoterapii.

Patients with peptic ulcer demonstrate diverse psychovegetative disorders that complicate the course of the somatic disease. Depending on the intensity of psychovegetative disorders the following syndromes were distinguished: astheno-neurotic, astheno-hypochondriac, astheno-depressive and psycho-vegetative with organic microsymptomatology. The use of laser puncture in multimodality therapy of peptic ulcer patients favours correction of vegetative disorders and normalization of regenerative processes occurring in the gastroduodenal system.

Some neurovegetative correlates of Minnesota Multiphasic Personality Inventory (MMPI)

In 57 patients with psicovegetative disorders and abnormal MMPI, abnormality in MMPI scales indicating hypochondriasis, hysteria, gender deviant, paranoia, psychastenia, schizophrenia, hypomania or introversion was accompanied by increased plasma catecholamine levels and/or responses to hypoglycemia or by an increased cardiovascular reactivity. A high depression scale was associated with lower plasma catecholamine levels. Blunted plasma growth hormone responses to hypoglycemia were found in abnormal hypomania scale, and augmented responses of plasma cortisol in abnormal hysteria or schizophrenia scales. Paranoia and hypomania traits correlated with absence of morning-evening differences in blood cortisol levels. Electrodermal responses compatible with increased sympathetic activity correlated with high hysteria, gender, paranoia, schizophrenia or hypomania MMPI scales. This study indicates that most psychopathological traits in MMPI are accompanied by humoral and/or electrophysiological signs of abnormality of the autonomic nervous system