Non-pharmacological and drug treatment of autonomic dysfunction in multiple system atrophy: current status and future directions.

Multiple system atrophy (MSA) is a sporadic, fatal, and rapidly progressive neurodegenerative disease of unknown etiology that is clinically characterized by autonomic failure, parkinsonism, cerebellar ataxia, and pyramidal signs in any combination. Early onset and extensive autonomic dysfunction, including cardiovascular dysfunction characterized by orthostatic hypotension (OH) and supine hypertension, urinary dysfunction characterized by overactive bladder and incomplete bladder emptying, sexual dysfunction characterized by sexual desire deficiency and erectile dysfunction, and gastrointestinal dysfunction characterized by delayed gastric emptying and constipation, are the main features of MSA. Autonomic dysfunction greatly reduces quality of life and increases mortality. Therefore, early diagnosis and intervention are urgently needed to benefit MSA patients. In this review, we aim to discuss the systematic treatment of autonomic dysfunction in MSA, and focus on the current methods, starting from non-pharmacological methods, such as patient education, psychotherapy, diet change, surgery, and neuromodulation, to various drug treatments targeting autonomic nerve and its projection fibers. In addition, we also draw attention to the interactions among various treatments, and introduce novel methods proposed in recent years, such as gene therapy, stem cell therapy, and neural prosthesis implantation. Furthermore, we elaborate on the specific targets and mechanisms of action of various drugs. We would like to call for large-scale research to determine the efficacy of these methods in the future. Finally, we point out that studies on the pathogenesis of MSA and pathophysiological mechanisms of various autonomic dysfunction would also contribute to the development of new promising treatments and concepts.

Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD): a collaborative review of the current understanding.

PURPOSE: To provide an overview of the discovery, presentation, and management of Rapid-onset Obesity with Hypothalamic dysfunction, Hypoventilation, and Autonomic Dysregulation (ROHHAD). To discuss a search for causative etiology spanning multiple disciplines and continents. METHODS: The literature (1965-2022) on the diagnosis, management, pathophysiology, and potential etiology of ROHHAD was methodically reviewed. The experience of several academic centers with expertise in ROHHAD is presented, along with a detailed discussion of scientific discovery in the search for a cause. RESULTS: ROHHAD is an ultra-rare syndrome with fewer than 200 known cases. Although variations occur, the acronym ROHHAD is intended to alert physicians to the usual sequence or unfolding of the phenotypic presentation, including the full phenotype. Nearly 60 years after its first description, more is known about the pathophysiology of ROHHAD, but the etiology remains enigmatic. The search for a genetic mutation common to patients with ROHHAD has not, to date, demonstrated a disease-defining gene. Similarly, a search for the autoimmune basis of ROHHAD has not resulted in a definitive answer. This review summarizes current knowledge and potential future directions. CONCLUSION: ROHHAD is a poorly understood, complex, and potentially devastating disorder. The search for its cause intertwines with the search for causes of obesity and autonomic dysregulation. The care for the patient with ROHHAD necessitates collaborative international efforts to advance our knowledge and, thereby, treatment, to decrease the disease burden and eventually to stop, and/or reverse the unfolding of the phenotype.

Updates on the Diagnosis and Treatment of Peripheral Autonomic Neuropathies.

PURPOSE OF REVIEW: Autonomic neuropathies are a complex group of disorders and result in diverse clinical manifestations that affect the cardiovascular, gastrointestinal, urogenital, and sudomotor systems. We focus this review on the diagnosis and treatment of peripheral autonomic neuropathies. We summarize the diagnostic tools and current treatment options that will help the clinician care for individuals with peripheral autonomic neuropathies. RECENT FINDINGS: Autonomic neuropathies occur often in conjunction with somatic neuropathies but they can also occur in isolation. The autonomic reflex screen is a validated tool to assess sympathetic postganglionic sudomotor, cardiovascular sympathetic noradrenergic, and cardiac parasympathetic (i.e., cardiovagal) function. Initial laboratory evaluation for autonomic neuropathies includes fasting glucose or oral glucose tolerance test, thyroid function tests, kidney function tests, vitamin-B12, serum, and urine protein electrophoresis with immunofixation. Other laboratory tests should be guided by the clinical context. Reduced intraepidermal nerve density on skin biopsy is a finding, not a diagnosis. Skin biopsy can be helpful in selected individuals for the diagnosis of disorders affecting small nerve fibers; however, we strongly discourage the use of skin biopsy without clinical-physiological correlation. Ambulatory blood pressure monitoring may lead to early identification of patients with cardiovascular autonomic neuropathy in the primary care setting. Disease-modifying therapies should be used when available in combination with nonpharmacological management and symptomatic pharmacologic therapies. Autonomic function testing can guide the therapeutic decisions and document improvement with treatment. A systematic approach guided by the autonomic history and standardized autonomic function testing may help clinicians when identifying and/or counseling patients with autonomic neuropathies. Treatment should be individualized and disease-modifying therapies should be used when available.

Cardiac failure in a child with tuberculous meningitis as a complication of Paroxysmal sympathetic hyperactivity.

BACKGROUND: Paroxysmal sympathetic hyperactivity (PSH) is a disorder due to the loss of regulation of autonomic activity. The most common condition predisposing to the development of PSH is traumatic brain injury (TBI), followed by anoxic brain injury, stroke, tumors, and infections. Awareness about the condition and early recognition is important to avoid life threatening complications. CASE: We report a 4-year-old child with tuberculous meningitis with symptoms of PSH who developed cardiac failure. PSH episodes were treated with beta blocker, benzodiazepine, morphine, dexmedetomidine, baclofen, and tizanidine. Three weeks after readmission PSH episodes decreased and the patient was transferred to the general ward. CONCLUSIONS: PSH assessment tool has benefits such as monitoring the patient, evaluating response to treatment and early diagnosing PSH patients.

Paroxysmal Sympathetic Hyperactivity in Patients Victims of Traumatic Brain Injury: Literature Review

The present literature review aims to present the physiology of paroxysmal sympathetic hyperactivity (PSH) as well as its clinical course, conceptualizing them, and establishing its diagnosis and treatment. Paroxysmal sympathetic hyperactivity is a rare syndrome, which often presents after an acute traumatic brain injury. Characterized by a hyperactivity of the sympathetic nervous system, when diagnosed in its pure form, its symptomatologic presentation is through tachycardia, tachypnea, hyperthermia, hypertension, dystonia, and sialorrhea. The treatment of PSH is basically pharmacological, using central nervous system suppressors; however, the nonmedication approach is closely associated with a reduction in external stimuli, such as visual and auditory stimuli. Mismanagement can lead to the development of serious cardiovascular and diencephalic complications, and the need for neurosurgeons and neurointensivists to know about PSH is evident in order to provide a fast and accurate treatment of this syndrome.

Weight management in youth with rapid-onset obesity with hypothalamic dysregulation, hypoventilation, autonomic dysregulation, and neural crest tumor (ROHHAD-NET): literature search and case report.

OBJECTIVES: Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, autonomic dysregulation, and neural endocrine tumor (ROHHAD-NET) syndrome is a youth-onset constellation of symptoms including rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation. Despite growing understanding of the clinical classification of this syndrome there is limited investigation into treatment of the rapid-onset obesity which can be progressive and life-limiting. The purpose of this case report is to describe the clinical timeline and treatment of severe obesity in a patient with of ROHHAD-NET and propose recommendations for the treatment of associated obesity. CASE PRESENTATION: We present the case of a 10-year-old female with a clinical presentation consistent with ROHHAD-NET who achieved clinically meaningful weight loss with a combination of lifestyle modification and anti-obesity pharmacotherapies. We report on the use of three separate pharmacological agents and ultimately the referral for bariatric surgery. CONCLUSIONS: Given that early-onset obesity and hypoventilation are life-limiting components of this condition, early recognition and treatment are essential to improve health outcomes.

[Paroxysmal sympathetic hyperactivity]. / ABC om Paroxysmal sympatisk hyperaktivitet.

Paroxysmal sympathetic hyperactivity (PSH) is a condition mainly described in patients after traumatic brain injury and it is also known under the terms "autonomic storm" and "dysautonomia". It affects between 8-10% of patients after traumatic brain injury and can also affect patients after other neurological diseases, such as anoxic brain injury, stroke, tumors or infections. PSH manifests with six main symptoms: tachycardia, tachypnea, hypertension, hyperthermia, hyperhidrosis and increased muscle tonus. It is of outmost importance to exclude other causes for the symptoms and there are diagnostic criteria established to identify and diagnose PSH. The treatment is pharmacological and non-pharmacological and often multimodal. PSH is probably underdiagnosed and increased awareness is needed.

A practical approach to peripheral autonomic neuropathies.

PURPOSE OF REVIEW: The review focuses on the practical evaluation and management of patients with autonomic neuropathies. RECENT FINDINGS: Autonomic neuropathies are complex disorders and result in diverse clinical manifestations that affect the cardiovascular, gastrointestinal, urogenital, and sudomotor systems. The autonomic medical history is key when seeing a patient with suspected autonomic neuropathy. The history guides the clinical evaluation, laboratory testing, and autonomic testing in patients with autonomic neuropathies. The treatment of autonomic neuropathies is based on the combination of disease-modifying therapies, symptomatic pharmacologic therapies, and nonpharmacological management. Response to treatment can be assessed with quantitative autonomic biomarkers. SUMMARY: Treatment of autonomic neuropathies should be individualized, guided by disease state, medications' mechanism of action and adverse event profile as well as cost. Genetic discoveries and pathologic understanding lead to the development of disease-modifying therapies as seen in familial amyloid polyneuropathy.

Paroxysmal Sympathetic Hyperactivity in Severe Anti-N-Methyl-d-Aspartate Receptor Encephalitis: A Single Center Retrospective Observational Study.

Background: Paroxysmal sympathetic hyperactivity (PSH) is a disorder with excessive sympathetic activity commonly recognized in patients with acquired brain injury. Autonomic instability is frequent in anti-N-methyl-d-aspartate receptor encephalitis (anti-NMDARE). However, PSH in anti-NMDARE has gained little attention. Methods: We retrospectively reviewed 24 patients diagnosed with severe anti-NMDARE in the neuro-intensive care unit (NICU) between 2014 and 2019. Patients were assessed with the PSH assessment measure (PSH-AM) scale, and categorized into "PSH+" group and "PSH-" group. The clinical characteristics, hospital mortality, and functional outcome by modified Rankin Scale (mRS) score at six months after discharge were compared between the two groups. Among patients with PSH+, the clinical features and pharmacotherapy of PSH were summarized and compared. Results: Twenty-four patients were included in the study. Twelve of them (50%) were categorized as PSH+ based on PSH-AM scores. There were no significant differences in the demographic characteristic, GCS scores upon admission, incidence of status epilepticus, teratoma occurrence, hospital mortality, and 6-month mRS between PSH+ and PSH- groups. Patients with PSH+ had increased length of NICU stay, hospital stay and duration of mechanical ventilation. The most prominent clinical features of PSH in severe anti-NMDARE were tachycardia and hyperthermia, while posturing was the relatively mildest clinical feature. Propranolol and clonazepam were more commonly used than gabapentin in pharmacotherapy of PSH in severe anti-NMDARE. Conclusions: The incidence of PSH in severe anti-NMDARE patients was as high as 50%. Patients with PSH demonstrated prolonged NICU stay, hospital stay and increased duration of mechanical ventilation, while no effect on hospital mortality and functional outcome. Clinicians should be aware of the distinctive characteristics and treatment options of PSH in severe anti-NMDARE.

Autonomic neuropathies.

Autonomic neuropathies represent a complex group of disorders that preferentially target autonomic fibers and can be classified as either acute/subacute or chronic in onset. Acute-onset autonomic neuropathies manifest with such conditions as paraneoplastic syndromes, Guillain-Barre syndrome, Sjögren syndrome, infection, or toxins/chemotherapy. When the presentation is acute, immune-mediated, and without a secondary cause, autoimmune autonomic ganglionopathy is likely, and should be considered for immunotherapy. Of the chronic-onset forms, diabetes is the most widespread and disabling, with autonomic impairment portending increased mortality and cardiac wall remodeling risk. Acquired light chain (AL) and transthyretin (TTR) amyloidosis represent two other key etiologies, with TTR amyloidosis now amenable to newly-approved gene-modifying therapies. The COMPASS-31 questionnaire is a validated outcome measure that can be used to monitor autonomic severity and track treatment response. Symptomatic treatments targeting orthostatic hypotension, among other symptoms, should be individualized and complement disease-modifying therapy, when possible.

Cardiac autonomic dysfunction in survivors of childhood acute lymphoblastic leukemia: The St. Jude Lifetime Cohort Study.

BACKGROUND: Cardiac autonomic dysfunction (CAD) is possible following treatment for childhood cancer. The aims of our analyses were to compare the prevalence of CAD between adult survivors of childhood acute lymphoblastic leukemia and controls, compare exercise response among survivors with and without CAD, and identify treatment-related risk factors for CAD. PROCEDURE: Participants were treated for childhood acute lymphoblastic leukemia at St. Jude Children's Research Hospital between 1980 and 2003 (N = 338). A comparison group matched for race/ethnicity, age, and sex was also recruited (N = 325). Resting heart rate (HR) was assessed via electrocardiogram, and heart rate recovery (HRR) and exercise capacity were evaluated with submaximal cardiopulmonary exercise testing. RESULTS: CAD was present in 33.7% of survivors and 27.6% of controls (P = 0.09). Although mean resting HR did not differ between survivors and controls (74 ± 12 vs 72 ± 12 beats per minute (bpm), P = 0.07), survivors had lower mean HRR than controls (22 ± 9 vs 25 ± 10 bpm; P < 0.001). Survivors with CAD had lower peak exercise tolerance (25.7 ± 6.5 vs 21.2 ± 4.9 mL/kg/min, P < 0.001) than those without. Survivors treated with cyclophosphamide in combination with vincristine ≥38 mg/m2 and/or glucocorticoids ≥10 000 mg/m2 were 1.56 (95% CI 1.09-2.24) times more likely to have CAD than those without this treatment. Obese survivors were 1.78 (95% CI: 1.31-2.40) times more likely to have CAD than nonobese survivors (P < 0.001). CONCLUSION: CAD was present in over one third of survivors and was associated with lower exercise capacity. Obese survivors and those exposed to cyclophosphamide with high doses of vincristine and/or corticosteroids were at greatest risk.

A 12-month lifestyle intervention does not improve cardiac autonomic function in patients with chronic kidney disease.

OBJECTIVES: Patients with chronic kidney disease (CKD) are at a high risk of future autonomic dysfunction and cardiovascular disease. The aim of this study was to examine the effects of a 12-month lifestyle intervention (LI) involving regular aerobic exercise on cardiac autonomic function in CKD patients. DESIGN: Pooled exploratory analysis. METHODS: 113 eligible patients with stage 3-4 CKD (eGFR 25-60 ml/min/1.75m2) participated in a LI program, including an 8-week individualised gym-based exercise program followed by a 10-month home-based program. The control (CON) group underwent standard nephrological care. The following parameters were assessed prior to and following the 12-month study period: cardiorespiratory fitness (VO2peak) from a graded exercise test; cardiac autonomic function from time, frequency, and non-linear measures of heart rate variability (HRV), heart rate (HR) recovery following peak exercise, and chronotropic competence during exercise. RESULTS: Compared to the CON group, the LI group significantly increased VO2peak (CON = -1.0 vs. LI = +1.8 ml/kg/min, p < 0.01) while there was no significant improvement in any HRV measure (p = 0.85), HR recovery (p = 0.38) or chronotropic competence (p = 0.28). Changes in relative VO2peak were significantly associated with changes in a non-linear HRV measure, α1 (p < 0.01), independent of age and eGFR (r2 = 0.196, p = 0.03). CONCLUSIONS: Despite the significant increase in cardiorespiratory fitness for the LI group, there were no changes in cardiac autonomic function. However, α1 may be a sensitive measure to assess VO2peak changes in this clinical cohort. Further research is required to investigate the role of different modalities of exercise training to enhance cardiac autonomic function in patients with CKD.

Music, heart rate variability, and symptom clusters: a comparative study.

PURPOSE: This study aimed to explore the possible range of change of a single-session music intervention (SMI) on symptom clusters and neurological reactivity for women with breast cancer undergoing chemotherapy. METHODS: A parallel and randomized, controlled study with repeated measures design was used. A total of 100 women with breast cancer were randomly assigned to the SMI or a control group. The outcome measurements of symptom cluster were collected using the Multidimensional Fatigue Symptom Inventory, Pittsburgh Sleep Quality Index, the Hospital Anxiety and Depression Scale, and the neurological reactivity with heart rate variability at four time points: before commencement of the intervention (T0), immediately afterward (T1), 1 week later (T2), and 3 weeks after the intervention (T3). RESULTS: Of the 50 women in each group, 46 in the SMI and 48 in the control group completed the post-test at T3. Multivariate analysis of variance indicated that the SMI group had a medium effect in change of symptom clusters compared to the control group at T2. Moreover, after adjusting for baseline between normal and higher levels of sympathetic tone activity, significant differences existed in fatigue and depression at T2 and sleep disturbance at T3. CONCLUSIONS: A single-session music intervention can be effectively used to reduce symptom clusters for women with breast cancer. Targeting those who have a higher level of sympathetic tone activity is recommended.

Impact of supportive therapy modalities on heart rate variability in cancer patients - a systematic review.

Purpose: To systematically review literature for interventional studies and their impact on autonomic dysfunction assessed by heart rate variability in cancer patients.Methods: Research was conducted using the databases Medline/Pubmed, Scopus, and Web of science from their inception to October 2017. Original articles with an interventional design that reported changes in at least one heart rate variability parameter as outcome parameter were included and described.Results: Ten studies were identified as eligible for subsequent analysis. The main application field in oncological therapy setting was music therapy intervention, Traditional Chinese Medicine related treatments, exercise interventions, relaxation, and myofascial release techniques. Breast cancer was the most frequently described single cancer entity. Heart rate variability recording was performed with standard electrocardiography devices or wearable heart rate monitors, within a time range between 5 and 20 min and a sampling rate varying from 200 to 1000 Hz. No adverse events were reported in all studies.Conclusions: Supportive therapy modalities may have the potential to enhance vegetative functioning. In this context, heart rate variability analysis appears to be an easily applicable and safe method to evaluate cancer related autonomic dysfunction. More large prospective multicentre randomised controlled trials are needed.Implication for rehabilitationMost cancer patients face autonomic dysfunction due to the disease itself the applied treatments or combination of both.HRV measurement is an easy and safe method to asses autonomic dysfunction.Supportive treatments targeting on an elevation of the vagal tone and autonomic balance in general might have beneficial effects for cancer patients.

Autonomic dysfunction: Diagnosis and management.

The autonomic nervous system is designed to maintain physiologic homeostasis. Its widespread connections make it vulnerable to disruption by many disease processes including primary etiologies such as Parkinson's disease, multiple system atrophy, dementia with Lewy bodies, and pure autonomic failure and secondary etiologies such as diabetes mellitus, amyloidosis, and immune-mediated illnesses. The result is numerous symptoms involving the cardiovascular, gastrointestinal, and urogenital systems. Patients with autonomic dysfunction (AUD) often have peripheral and/or cardiac denervation leading to impairment of the baroreflex, which is known to play a major role in determining hemodynamic outcome during orthostatic stress and low cardiac output states. Heart rate and plasma norepinephrine responses to orthostatic stress are helpful in diagnosing impairment of the baroreflex in patients with orthostatic hypotension (OH) and suspected AUD. Similarly, cardiac sympathetic denervation diagnosed with MIBG scintigraphy or 18F-DA PET scanning has also been shown to be helpful in distinguishing preganglionic from postganglionic involvement and in diagnosing early stages of neurodegenerative diseases. In this chapter, we review the causes of AUD, the pathophysiology and resulting cardiovascular manifestations with emphasis on the diagnosis and treatment of OH.

Anti-Hypothalamus and Anti-Pituitary Auto-antibodies in ROHHAD Syndrome: Additional Evidence Supporting an Autoimmune Etiopathogenesis.

BACKGROUND: Rapid-onset Obesity with Hypothalamic dysfunction, Hypoventilation and Autonomic Dysregulation (ROHHAD) is a very rare and complex pediatric syndrome characterized by altered hypothalamic thermal regulation, pain threshold, and respiratory control, hyperphagia with rapid weight gain and, often, hypothalamic-pituitary dysfunction. Its etiopathogenesis remains undetermined. We investigated the presence of alterations to target genes and hypothalamic-pituitary autoimmunity in a patient with -ROHHAD syndrome. METHODS: A 3-year-old girl presenting with obesity after rapid weight gain was diagnosed with ROHHAD syndrome based on clinical features and abnormal biochemical and functional testing results. Because of worsening of rapid symptoms and demonstration of oligoclonal bands on cerebrospinal fluid (CSF) analysis, she was treated with plasmapheresis, methylprednisolone, anti-CD20 monoclonal antibodies, and azathioprine. Despite initial partial clinical improvement, the patient soon died of cardiorespiratory arrest. Post-mortem, whole exome sequencing, high-resolution comparative genomic hybridization array, and optimized indirect immunofluorescence (IIF) analysis were performed on blood and CSF. RESULTS: No putative causative genomic variants compatible with dominant or recessive inheritance nor clinically significant structural rearrangement were detected. IIF on serum and CSF demonstrated the presence of anti-pituitary and anti-hypothalamus autoantibodies. CONCLUSIONS: These findings support the involvement of autoimmunity in ROHHAD syndrome. However, response to immunosuppressive treatment was only transient and the patient died. Further cases are required to define the complex disease pathogenesis.

Modulation of Autonomic Function by Physical Exercise in Patients with Fibromyalgia Syndrome: A Systematic Review.

OBJECTIVE: To evaluate the effects of physical exercise on autonomic dysfunction in patients with fibromyalgia syndrome (FM). LITERATURE SURVEY AND METHODOLOGY: A systematic review of experimental studies published until December 2017 that analyzed the effect of physical exercise on autonomic dysfunction in patients with FM was performed using the PubMed, Pedro, Scopus, ScienceDirect, and Web of Science databases. SYNTHESIS: A total of 1105 articles were identified, 12 of which were included in the final analysis. The most analyzed exercise modalities were aerobic and resistance exercises. Overall, the studies demonstrated that aerobic exercise performed twice a week with moderate to high intensity was effective in reducing autonomic dysfunction by increasing heart rate variability. Resistance training was associated with reduced symptoms of anxiety and depression as well as increased muscle strength; however, it did not reduce autonomic dysfunction in these patients in the short or long term. CONCLUSIONS: Preliminary evidence suggests that aerobic exercise reduces autonomic dysfunction in patients with FM, whereas resistance training reduces psychological symptoms such as anxiety and depression. LEVEL OF EVIDENCE: I.

Update on the Impact, Diagnosis and Management of Cardiovascular Autonomic Neuropathy in Diabetes: What Is Defined, What Is New, and What Is Unmet.

The burden of diabetic cardiovascular autonomic neuropathy (CAN) is expected to increase due to the diabetes epidemic and its early and widespread appearance. CAN has a definite prognostic role for mortality and cardiovascular morbidity. Putative mechanisms for this are tachycardia, QT interval prolongation, orthostatic hypotension, reverse dipping, and impaired heart rate variability, while emerging mechanisms like inflammation support the pervasiveness of autonomic dysfunction. Efforts to overcome CAN under-diagnosis are on the table: by promoting screening for symptoms and signs; by simplifying cardiovascular reflex tests; and by selecting the candidates for screening. CAN assessment allows for treatment of its manifestations, cardiovascular risk stratification, and tailoring therapeutic targets. Risk factors for CAN are mainly glycaemic control in type 1 diabetes mellitus (T1DM) and, in addition, hypertension, dyslipidaemia, and obesity in type 2 diabetes mellitus (T2DM), while preliminary data regard glycaemic variability, vitamin B12 and D changes, oxidative stress, inflammation, and genetic biomarkers. Glycaemic control prevents CAN in T1DM, whereas multifactorial intervention might be effective in T2DM. Lifestyle intervention improves autonomic function mostly in pre-diabetes. While there is no conclusive evidence for a disease-modifying therapy, treatment of CAN manifestations is available. The modulation of autonomic function by SGLT2i represents a promising research field with possible clinical relevance.