Semi-supervised exercise training program more effective for individuals with postural orthostatic tachycardia syndrome in randomized controlled trial.

PURPOSE: Exercise like any medication requires the correct dose; to be effective the appropriate frequency, duration, and intensity are necessary. This study aimed to assess if a semi-supervised exercise training (ET) program would be more effective at improving aerobic fitness (VO2PEAK), exercise tolerance, and symptoms in individuals with postural orthostatic tachycardia syndrome (POTS) compared to the standard of care (SOC). METHODS: Subjects were randomized to either the ET or SOC groups (n 26 vs. 23; age 33 ± 11 vs. 37 ± 10 years; VO2PEAK 66 ± 15 vs. 62 ± 15% predicted, ET vs. SOC respectively, p > 0.05). Composite Autonomic Symptom Score (COMPASS 31), 10 min stand test, and cardiopulmonary exercise test were performed at baseline and following 12 weeks. The ET group received an exercise consultation and eight semi-supervised in-person or virtual exercise sessions. RESULTS: The ET group demonstrated a greater improvement in VO2PEAK, higher or longer tolerance for baseline peak workload, and more often had a delayed symptom onset with exercise than the SOC group (ΔVO2PEAK 3.4 vs. - 0.2 mL/min/kg, p < 0.0001, ΔWorkload 19 ± 17 vs. 0 ± 10 W; Workload time 63 ± 29 vs. 22 ± 30 s; onset-delay 80% vs. 30%, p < 0.05). Individuals in the ET group reported a significant improvement in orthostatic intolerance domain score (p = 0.02), but there was not a significant difference in the improvement in total COMPASS score (- 11.38 vs. - 6.49, p = 0.09). CONCLUSION: Exercise training was more effective with greater improvements in aerobic fitness, orthostatic symptoms, and exercise tolerance for individuals with POTS when intensity and progression were personalized and delivered with minimal supervision compared to the SOC.

Standardized Autonomic Testing in Patients With Probable Radiation-Induced Afferent Baroreflex Failure.

Injury of the afferent limb of the baroreflex from neck radiation causes radiation-induced afferent baroreflex failure (R-ABF). Identification and management of R-ABF is challenging. We aimed to investigate the pattern of autonomic dysfunction on standardized autonomic testing in patients with probable R-ABF. We retrospectively analyzed all autonomic reflex screens performed at Mayo Clinic in Rochester, MN, between 2000 and 2020 in patients with probable R-ABF. Additional tests reviewed included ambulatory blood pressure monitoring, plasma norepinephrine, and thermoregulatory sweat test. We identified 90 patients with probable R-ABF. Median total composite autonomic severity score (range, 0-10) was 7 (interquartile range, 6-7). Cardiovascular adrenergic impairment was seen in 85 patients (94.4%), increased blood pressure recovery time after Valsalva maneuver in 71 patients (78.9%; median 17.4 seconds), and orthostatic hypotension in 68 patients (75.6%). Cardiovagal impairment was demonstrated by abnormal heart rate responses to deep breathing (79.5%), Valsalva ratio (87.2%), and vagal baroreflex sensitivity (57.9%). Plasma norepinephrine was elevated and rose appropriately upon standing (722-1207 pg/mL). Ambulatory blood pressure monitoring revealed hypertension, postural hypotension, hypertensive surges, tachycardia, and absence of nocturnal dipping. Blood pressure lability correlated with impaired vagal baroreflex function. Postganglionic sympathetic sudomotor function was normal in most cases; the most frequent thermoregulatory sweat test finding was focal neck anhidrosis (78.9%). Standardized autonomic testing in R-ABF demonstrates cardiovascular adrenergic impairment with orthostatic hypotension, blood pressure lability, and elevated plasma norepinephrine. Cardiovagal impairment is common, while sudomotor deficits are limited to direct radiation effects.

It Is in the Eye of the Beholder: Ocular Ultrasound Enhanced Monitoring of Neurotoxicity after CAR-T Cell Therapy.

Usually used in emergency settings, bedside sonographic measurement of optic nerve sheath diameter can aid in diagnosing elevated intracranial pressure. We report a case of a 26-year-old male hospitalized for CAR T-cell therapy with Axicabtagene Ciloleucel for treatment of relapsed diffuse large B-cell lymphoma, who developed progressive symptoms of immune effector cell-associated neurotoxicity syndrome. Fundoscopic examination suggested the presence of blurred optic disc margins. Bedside ocular ultrasound revealed wide optic nerve sheath diameters and bulging optic discs bilaterally. The patient had a ventriculostomy placed for monitoring and received treatment with steroids and mannitol, as well as tocilizumab. After 7 days in the ICU, the patient recovered with no evidence of long-term neurological deficits.

Postural orthostatic tachycardia syndrome (POTS): Priorities for POTS care and research from a 2019 National Institutes of Health Expert Consensus Meeting - Part 2.

The National Institutes of Health hosted a workshop in 2019 to build consensus around the current state of understanding of the pathophysiology of postural orthostatic tachycardia syndrome (POTS) and to identify knowledge gaps that must be addressed to enhance clinical care of POTS patients through research. This second (of two) articles summarizes current knowledge gaps, and outlines the clinical and research priorities for POTS. POTS is a complex, multi-system, chronic disorder of the autonomic nervous system characterized by orthostatic intolerance and orthostatic tachycardia without hypotension. Patients often experience a host of other related disabling symptoms. The functional and economic impacts of this disorder are significant. The pathophysiology remains incompletely understood. Beyond the significant gaps in understanding the disorder itself, there is a paucity of evidence to guide treatment which can contribute to suboptimal care for this patient population. The vast majority of physicians have minimal to no familiarity or training in the assessment and management of POTS. Funding for POTS research remains very low relative to the size of the patient population and impact of the syndrome. In addition to efforts to improve awareness and physician education, an investment in research infrastructure including the development of standardized disease-specific evaluation tools and outcome measures is needed to facilitate effective collaborative research. A national POTS research consortium could facilitate well-controlled multidisciplinary clinical research studies and therapeutic trials. These priorities will require a substantial increase in the number of research investigators and the amount of research funding in this area.

Vasculitis Presenting as Autonomic Failure.

INTRODUCTION: Granulomatosis with polyangiitis (GPA) is a vasculitic process that can cause neurological dysfunction in addition to characteristic sinus and pulmonary manifestations. This case report highlights the spectrum of nervous system manifestations and includes rarely reported autonomic and pituitary involvement. CASE REPORT: A 62-year-old woman presented with orthostatic intolerance, tachycardia, dry mouth, and temperature sensitivity; subsequent autonomic reflex study demonstrated widespread postganglionic sympathetic sudomotor, cardiovagal, and cardiovascular adrenergic impairment reflective of autonomic neuropathy and overall autonomic failure. Additional progressive symptoms included dysarthria, dysphagia, bilateral hearing loss, voice hoarseness, and right-sided facial numbness with multiple cranial neuropathies identified on neurological examination. The diagnosis of central diabetes insipidus was also confirmed. Pachymeningitis was present on brain magnetic resonance imaging. Pathologic review of the dural biopsy specimen revealed necrotizing granulomatous vasculitis consistent with GPA. She was treated with intravenous methylprednisolone and rituximab. Over the next 2 months, she had near-complete resolution of her symptoms with normalization on repeat autonomic testing. CONCLUSIONS: This is a unique GPA case presenting with autonomic failure and pituitary dysfunction with conclusive objective findings of autonomic dysfunction. Autonomic dysfunction and other disease manifestations were responsive to immunosuppressive therapy.

Postural orthostatic tachycardia syndrome (POTS): State of the science and clinical care from a 2019 National Institutes of Health Expert Consensus Meeting - Part 1.

Postural orthostatic tachycardia syndrome (POTS) is a chronic and often disabling disorder characterized by orthostatic intolerance with excessive heart rate increase without hypotension during upright posture. Patients often experience a constellation of other typical symptoms including fatigue, exercise intolerance and gastrointestinal distress. A typical patient with POTS is a female of child-bearing age, who often first displays symptoms in adolescence. The onset of POTS may be precipitated by immunological stressors such as a viral infection. A variety of pathophysiologies are involved in the abnormal postural tachycardia response; however, the pathophysiology of the syndrome is incompletely understood and undoubtedly multifaceted. Clinicians and researchers focused on POTS convened at the National Institutes of Health in July 2019 to discuss the current state of understanding of the pathophysiology of POTS and to identify priorities for POTS research. This article, the first of two articles summarizing the information discussed at this meeting, summarizes the current understanding of this disorder and best practices for clinical care. The evaluation of a patient with suspected POTS should seek to establish the diagnosis, identify co-morbid conditions, and exclude conditions that could cause or mimic the syndrome. Once diagnosed, management typically begins with patient education and non-pharmacologic treatment options. Various medications are often used to address specific symptoms, but there are currently no FDA-approved medications for the treatment of POTS, and evidence for many of the medications used to treat POTS is not robust.

Natural History of Afferent Baroreflex Failure in Adults.

OBJECTIVE: To describe the natural history of afferent baroreflex failure (ABF) based on systematic review of clinical and laboratory data in patients with a diagnosis of ABF at Mayo Clinic Rochester. METHODS: We performed a retrospective chart review of all patients who underwent standardized autonomic reflex testing between 2000 and 2020 and had confirmation of the diagnosis of ABF by an autonomic disorders specialist. Patients were identified using a data repository of medical records. Variables included demographic, all-cause mortality, medications, ABF manifestations, comorbidities, and laboratory (autonomic testing, blood pressure monitoring, echocardiogram, brain imaging, plasma catecholamines, serum sodium level, and kidney function tests). RESULTS: A total of 104 patients with ABF were identified. Head and neck radiation was the most common etiology (86.5%), followed by neck surgery (5.8%) and other causes (7.7%). The most common findings were hypertension (87.5%), fluctuating blood pressure (78.8%), orthostatic hypotension (91.3%), syncope (58.6%), headache (22.1%), and tachycardia (20.2%). Patients commonly received antihypertensives (66.3%), pressor agents (41.3%), or a combination of both (19.2%). The median latency from completion of radiation to ABF was longer compared to the latency in the surgery group (p < 0.0001). Comorbidities, including complications from neck radiation, were frequently seen and all-cause mortality was 39.4% over a 20-year period. CONCLUSIONS: ABF should be suspected in patients with prior head and neck cancer treated by radiation or surgery who present with labile hypertension and orthostatic hypotension. Management may require both antihypertensive and pressor medications. The morbidity and mortality in ABF are high.

COVID-19 Dysautonomia.

Objective: To report a case series of dysautonomia associated with COVID-19 infection. Methods: This is a retrospective review of patients evaluated in the autonomic clinic at our institution with suspected signs and symptoms of dysautonomia who underwent formal evaluation, including autonomic testing. Results: Six patients were identified with signs and symptoms suggestive of dysautonomia who underwent autonomic testing. All patients had symptoms typical of COVID-19 infection, though none were hospitalized for these or other symptoms. All patients reported symptoms of postural lightheadedness and near-syncope, fatigue, and activity intolerance. Five patients reported the onset of autonomic symptoms concomitant with other COVID-19 symptoms, with the other patient reporting symptom onset 6 weeks following initial COVID-19 symptoms. Autonomic testing demonstrated an excessive postural tachycardia in 4 patients, a hypertensive response with head-up tilt in 3 patients, orthostatic hypotension in 1 patient, and sudomotor impairment in 1 of the patients with excessive postural tachycardia. Conclusions: We present clinical features and results of autonomic testing in 6 patients with a history COVID-19 infection. While all patients reported typical features of orthostatic intolerance, fatigue, and activity intolerance, the results of autonomic testing were heterogenous, with orthostatic hypotension in 1 patient, excessive postural tachycardia typical of postural tachycardia syndrome in 4 patients, and postural hypertension in 3 patients.

Tumor Necrosis Factor-Alpha Signaling May Contribute to Chronic West Nile Virus Post-infectious Proinflammatory State.

Background: West Nile virus (WNV) causes a spectrum of human disease ranging from a febrile illness (WNV fever) to severe neuroinvasive disease (meningitis, encephalitis, acute flaccid paralysis). Since WNV gained entry into North America in 1999, clinicians caring for WNV survivors have observed persistent neurological symptoms occurring long-after the production of neutralizing antibodies and clearance of the virus. Accordingly, alternative pathogeneses other than direct viral invasion have been hypothesized to explain these post-infectious symptoms. The dominant hypothesis is that antiviral inflammatory responses triggered initially to clear WNV may persist to promote a post-infectious proinflammatory state. Methods: In 4 serologically-confirmed WNV patients with persistent post-infectious symptoms (3 WNV fever, 1 neuroinvasive disease), we ordered a comprehensive cytokine panel at weeks 8, 10, 12, and 36 months post-onset of illness, respectively, to better understand the pathophysiology of the protracted symptoms. Results: All patients had abnormally elevated tumor necrosis factor alpha (TNF-α), a major molecule triggering antiviral cytokines and chronic inflammation in many human autoimmune diseases, but heretofore not reported to be upregulated in human WNV infection. Three patients also had elevations of other proinflammatory proteins. Major symptoms included fatigue, arthralgias, myalgias, generalized or multifocal pain or weakness, imbalance, headaches, cognitive problems, and symptoms of dysautonomia. Conclusion: The findings provide support for an extended post-infectious proinflammatory state that may contribute to chronic inflammation and long-term morbidity in some WNV survivors and further suggest that TNF-α may play a pathogenic role in initiating this inflammatory environment. Clinical trials may be warranted to determine if TNF-α inhibitors or other immunosuppressive agents can improve patient outcomes.

Rheumatoid Meningitis: Clinical Characteristics, Diagnostic Evaluation, and Treatment.

BACKGROUND AND PURPOSE: Due to the potential for high mortality and neurologic complications of rheumatoid meningitis (RM), awaiting biopsy confirmation may delay vital treatment intervention. Our aim was to describe the clinical presentations of RM in our population and determine whether meningeal biopsy impacted diagnosis, treatment, and outcomes. METHODS: A retrospective chart review was completed for patients at Mayo Clinic with a diagnosis of RM within the last 28 years. Those with identified alternative inflammatory, infectious, or neoplastic causes of pachymeningitis or leptomeningitis were excluded. RESULTS: Fourteen patients meeting inclusion/exclusion criteria were identified. All patients were positive for rheumatoid factor or cyclic citrullinated peptide. All patients had magnetic resonance imaging abnormalities characterized by pachymeningeal and/or leptomeningeal enhancement. Of the 10 patients who underwent biopsy, nonspecific findings were seen in 74%. All patients except one were treated with corticosteroids with subsequent symptomatic improvement. Radiographic improvement or resolution was seen in 10 (83%) of 12. Patients improved with corticosteroid treatment, including those who were diagnosed with RM on clinical basis without undergoing a biopsy as well. CONCLUSIONS: This retrospective review displays the myriad of clinical presentations of RM. It also suggests that with appropriate exclusion of infectious, neoplastic, and other autoimmune etiologies, biopsy may not be necessary to initiate treatment.

Nonconvulsive status epilepticus secondary to acute porphyria crisis.

Both variegate and acute intermittent porphyria can manifest with various neurological symptoms. Although acute symptomatic seizures have been previously described, they are typically tonic-clonic and focal impaired awareness seizures. Convulsive status epilepticus and epilepsia partialis continua are rare and have been described on a case report basis. To our knowledge, there are no previously reported cases describing non-convulsive status epilepticus (NCSE) with electroencephalogram (EEG) documentation in the setting of acute porphyria crisis. We report a unique presentation of NCSE, which resolved after administering levetiracetam in a patient with variegate porphyria, without a known seizure disorder.

The spectrum of acute cardiopulmonary events associated with multiple sclerosis exacerbations.

Diverse acute neurological injuries may cause acute cardiopulmonary events including neurogenic pulmonary edema (NPE) and neurogenic stunned myocardium (NSM). The mechanism is probably mediated by sympathetic nervous system activation. Focal central nervous system (CNS) lesions, such as demyelinating lesions in multiple sclerosis (MS), may also cause cardiopulmonary disturbances. We aim to review the acute cardiopulmonary events associated with MS relapses. We performed a literature search using PubMed, and selected case reports of acute cardiac and/or pulmonary events related to MS exacerbations. We grouped these events into three categories: 1) NPE with normal cardiac function; 2) NSM and Takotsubo cardiomyopathy (TTC); 3) coexisting myocardial dysfunction and pulmonary edema. In some cases, cardiac and pulmonary symptoms preceded the onset of neurological symptoms. The majority of cases were associated with acute demyelinating lesions located in the medulla. Acute brainstem MS relapses, with demyelinating lesions affecting the medulla, may cause acute cardiac and pulmonary events presumably secondary to sympathetic hyperstimulation. Specific regions in the medulla that regulate cardiac function, systemic blood pressure and pulmonary hydrostatic pressure seem to be responsible for these events.

Immunoresponsive Autonomic Neuropathy in Sjögren Syndrome-Case Series and Literature Review.

BACKGROUND: Sjögren syndrome (SS) is one of the most common autoimmune disorders that classically affects exocrine glands, resulting in keratoconjunctivitis sicca and xerostomia, and frequently is associated with other systemic symptoms. SS appears to have a particular predilection for involving the autonomic nervous system. STUDY QUESTION: Does immunotherapy improve signs and symptoms of autonomic nervous system impairment in SS? STUDY DESIGN: This is a retrospective review of patients seen in the autonomic clinic at our institution who underwent an evaluation for a suspected autonomic disorder that ultimately was attributed to SS. SS patients who were treated with immunotherapy and completed autonomic testing before and after treatment were included in this review. RESULTS: A total of 4 patients were identified who were treated for SS-related autonomic dysfunction with immunotherapy and underwent repeat autonomic testing after treatment. Marked clinical and functional improvement was seen after treatment with intravenous immunoglobulin in all patients and adjunctive rituximab therapy in 1 patient. The clinical improvement with immunotherapy in these patients correlated with markedly improved findings on autonomic testing in all. MEASURES AND OUTCOMES: Clinical symptoms and results of autonomic testing prior to and following immunotherapy were assessed. CONCLUSIONS: Autonomic signs and symptoms in SS are potentially immunoresponsive, but immunotherapy in these patients may require repeated, ongoing, or adjunctive therapy for optimal and sustained improvement.

Factors Associated With Use of Nonoral Nutrition and Hydration Support in Adult Patients With Postural Tachycardia Syndrome.

BACKGROUND: Patients with postural tachycardia syndrome (POTS) often have gastrointestinal (GI) symptoms. Occasionally, these symptoms can be so severe that nonoral nutrition/hydration support (NONHS), including intravenous fluids (IVFs), enteral nutrition (EN), and parenteral nutrition (PN), becomes necessary. METHODS: This is a retrospective cohort study of adult patients diagnosed with POTS at the Mayo Clinic Arizona from January 2010 to January 2017 with a minimum of 6 months of follow up. Demographic information, symptomatology, medications, GI testing, autonomic and autoantibody testing, and healthcare utilization data were abstracted from the electronic medical record. RESULTS: Three-hundred thirty-two patients with POTS were included, of which 32 required NONHS. Patients receiving NONHS were more likely to be female; have lower body mass index; have GI symptoms including nausea, vomiting, diarrhea, and constipation; have abdominal pain; use opiates; have delayed gastric emptying; see more specialists; and be seen in an emergency room or be hospitalized for symptoms. Of these patients, 21 (66%) required IVF, 19 (59%) required EN, and 9 (28%) required PN. Six (19%) patients required all 3 NONHS modalities at some point during their follow-up period. CONCLUSIONS: NONHS may be required in a subset of patients with POTS. Those receiving NONHS have more severe symptoms and abnormal GI motility and autonomic testing and exhibit greater healthcare utilization. Management of these patients is complex and challenging and requires a multidisciplinary approach. Further prospective studies are needed to identify optimal management strategies.

Postural Tachycardia Syndrome (POTS) and the GI Tract: A Primer for the Gastroenterologist.

Postural tachycardia syndrome (POTS) is one of the most common causes of orthostatic intolerance and is being increasingly recognized in clinical practice. Gastrointestinal (GI) symptoms are reported commonly in patients with POTS and pose a considerable management challenge, making it imperative that gastroenterologists be aware of this condition and its GI comorbidities. Although the evidence presented herein does not prove causation, it does support an association between GI symptoms, GI dysmotility, and POTS. At present, the evaluation and treatment of GI symptoms in patients with POTS remains largely empirical. General measures to treat POTS may lead to improvement in both GI and non-GI symptoms. GI symptoms refractory to these measures should prompt further diagnostic evaluation of gastrointestinal dysmotility and appropriate dietary and pharmacologic management. This review focuses its attention on the involvement of the GI tract in POTS including a discussion of GI symptoms and conditions associated with POTS, followed by an analysis of abnormalities in gut physiology described in POTS, and concluding with an overview of management and suggestions for research directions.

Rheumatoid Meningitis: A Case Review.

INTRODUCTION: Rheumatoid meningitis (RM) is a rare complication of rheumatoid arthritis (RA) and has a high mortality rate. It can present as a first diagnosis of RA, in long-standing disease, or in active or well-controlled disease. Neurological manifestations vary widely. CASE REPORT: A patient with a 30-year history of RA, well controlled with methotrexate therapy, presented with new-onset seizures. Magnetic resonance imaging showed leptomeningeal and pachymeningeal enhancement. A de novo workup resulted in diagnosis of RM. CONCLUSIONS: Cerebrospinal fluid findings for RM are nonspecific, typically lymphocytic pleocytosis; however, they can be neutrophilic, as in this case. Magnetic resonance imaging findings consist of leptomeningeal and pachymeningeal enhancement but can also involve the parenchyma. The diagnosis is typically confirmed with meningeal biopsy. Treatment involves high-dose corticosteroids or immunomodulatory therapy, or both. Long-term follow-up with radiologic surveillance typically ranges from improvement to resolution.

Disorders of the Cauda Equina.

PURPOSE OF REVIEW: Conditions that affect the cauda equina are a diverse group of disorders that require timely recognition and management. This article reviews cauda equina anatomy, the diagnostic approach to disorders of the cauda equina, features of cauda equina syndrome, and diskogenic and nondiskogenic disorders of the cauda equina. RECENT FINDINGS: Establishing clinical criteria for cauda equina syndrome has been a focus of a number of reviews, although the clinician must maintain a low threshold for emergent imaging in cases of suspected cauda equina syndrome because of the suboptimal reliability of various signs and symptoms in identifying this condition clinically. The timing of surgical intervention for compressive causes of cauda equina dysfunction remains a point of contention, although urgent decompression remains standard practice. A recent review that focused on outcomes in patients with cauda equina compression who underwent surgical decompression identified significant residual deficits in patients despite appropriate and timely intervention. Autoimmune conditions targeting the cauda equina have been increasingly recognized, including chronic immune sensory polyradiculopathy and chronic immune sensorimotor polyradiculopathy. SUMMARY: Disorders that affect the cauda equina require thoughtful and timely clinical examination and diagnostic testing to establish a definitive cause and an appropriate treatment approach.

Evaluation of postural tachycardia syndrome (POTS).

The diagnostic evaluation of a patient with suspected postural tachycardia syndrome (POTS) requires a thoughtful diagnostic approach utilizing a careful clinical history and examination, laboratory, and autonomic testing. This article outlines the importance of a thorough history in identifying mechanism of symptom onset, clinical features, associated clinical conditions or disorders, and factors that may result in symptom exacerbation. The clinical examination involves an assessment of pupillary responses, an evaluation for sudomotor and vasomotor signs, and an assessment for joint hypermobility. Laboratory testing helps to exclude mimics of autonomic dysfunction, recognize conditions that may exacerbate symptoms, and to identify conditions that may cause or be associated with autonomic nervous system disease. The purpose of autonomic testing is to confirm a POTS diagnosis, exclude other causes of orthostatic intolerance, and may provide for characterization of POTS into neuropathic and hyperadrenergic subtypes. Other diagnostic studies, such as epidermal skin punch biopsy, exercise testing, radiographic studies, sleep studies, gastrointestinal motility studies, and urodynamic studies should be considered when clinically appropriate.