Joint Hypermobility, Autonomic Dysfunction, Gastrointestinal Dysfunction, and Autoimmune Markers: Clinical Associations and Response to Intravenous Immunoglobulin Therapy.

INTRODUCTION: We examined autoimmunity markers (AIM) and autonomic dysfunction in patients with chronic neurogastroenterological symptoms and their relationship to joint hypermobility/hypermobility spectrum disorder (JH/HSD). METHODS: AIM positivity was defined as a diagnosis of known autoimmune/autoinflammatory disorder with at least 1 positive seromarker of autoimmunity or at least 2 positive seromarkers by themselves. Three cohorts were studied: (i) retrospective (n = 300), (ii) prospective validation cohort (n = 133), and (iii) treatment cohort (n = 40), administered open-label intravenous immunoglobulin (IVIG). RESULTS: AIM positivity was found in 40% and 29% of the retrospective and prospective cohorts, the majority of whom (71% and 69%, respectively) had autoinflammatory disorder. Significantly more patients with AIM had elevations of C-reactive protein (31% vs 15%, P < 0.001) along with an increased proportion of cardiovascular autonomic dysfunction (48% vs 29%; P < 0.001), small fiber neuropathy (20% vs 9%; P = 0.002), and HLADQ8 positivity (24% vs 13%, P = 0.01). Patients with JH/HSD were more likely to have AIM (43% vs 15%, P = 0.001) along with more severe autonomic and gastrointestinal (GI) symptom scores. IVIG treatment was associated with robust improvement in pain, GI, and autonomic symptoms, but adverse events were experienced by 62% of patients. DISCUSSION: Autoimmune markers and autonomic dysfunction are common in patients with unexplained GI symptoms, especially in those with JH/HSD. Many patients seem to respond to IVIG treatment, but this needs to be confirmed by controlled trials. These results highlight the need for vigilance for autoimmune and autonomic factors and JH/HSD in patients with neurogastroenterological disorders. Clinicaltrials.gov , NCT04859829.

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.

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.

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.

Compound muscle action potential duration in critical illness neuromyopathy.

INTRODUCTION: We sought to determine the specificity of compound muscle action potential (CMAP) durations and amplitudes in a large critical illness neuromyopathy (CINM) cohort relative to controls with other neuromuscular conditions. METHODS: Fifty-eight patients with CINM who had been seen over a 17-year period were retrospectively studied. Electrodiagnostic findings of the CINM cohort were compared with patients with axonal peripheral neuropathy and myopathy due to other causes. RESULTS: Mean CMAP durations were prolonged, and mean CMAP amplitudes were severely reduced both proximally and distally in all nerves studied in the CINM cohort relative to the control groups. The specificity of prolonged CMAP durations for CINM approached 100% if they were encountered in more than 1 nerve. DISCUSSION: Prolonged, low-amplitude CMAPs occur more frequently and with greater severity in CINM patients than in neuromuscular controls with myopathy and axonal neuropathy and are highly specific for the diagnosis of CINM. Muscle Nerve 57: 395-400, 2018.

Clinical, physiological and pathological characterisation of the sensory predominant peripheral neuropathy in copper deficiency.

INTRODUCTION: Myelopathy is considered the most common neurological complication of copper deficiency. Concurrent peripheral neuropathy has been recognised in association with copper deficiency but has not been well characterised. OBJECTIVES: To characterise the clinical, physiological and pathological features of copper-deficient peripheral neuropathy. METHODS: Patients with simultaneous copper deficiency (<0.78 µg/mL) and peripheral neuropathy seen at the Mayo Clinic from 1985 to 2005 were identified. RESULTS: 34 patients were identified (median age 55 years, range 36-78) including 24 women and 10 men. Myelopathy was found in 21 patients. Median serum copper level was 0.11 µg/mL (range 0-0.58). The most frequent clinical and electrophysiological pattern of neuropathy was a sensory predominant length-dependent peripheral neuropathy (71%). Somatosensory evoked potentials demonstrated central slowing supporting myelopathy (96%). Quantitative sensory testing demonstrated both small and large fibre involvement (100%). Autonomic reflex screens (77%) and thermoregulatory sweat test (67%) confirmed sudomotor dysfunction. 14 cutaneous nerve biopsies revealed loss of myelinated nerve fibres (86%), increased regenerative clusters (50%), increased rates of axonal degeneration (91%) and increased numbers of empty nerve strands (73%). 71% of biopsies demonstrated epineurial perivascular inflammation. CONCLUSIONS: An axonal, length-dependent sensory predominant peripheral neuropathy causing sensory ataxia is characteristic of copper deficiency usually co-occurring with myelopathy. Neurophysiological testing confirms involvement of large, greater than small fibres. The pathological findings suggest axonal degeneration and repair. Inflammatory infiltrates are common but are small and of doubtful pathological significance.

Immunoresponsive postinfectious autonomic neuropathy.

A 36-year-old healthy woman developed a postinfectious autonomic neuropathy with adrenergic failure and symptoms of orthostatic intolerance. Treatment with immunomodulating therapy, including corticosteroids and immunoglobulin, resulted in marked improvement in clinical symptoms and findings on autonomic testing.

Autonomic dysfunction in adult-onset alexander disease: a case report and review of the literature.

BACKGROUND: Alexander disease (AxD) is an astrogliopathy, resulting from a mutation in the glial fibrillary astrocytic protein gene. Different clinical subtypes have been described, including infantile, juvenile, and adult onset, based upon the age at which symptoms begin. Patients with the adult-onset form, develop a progressive, spastic paraparesis, palatal myoclonus, ataxia, and bulbar weakness. Autonomic nervous system (ANS) dysfunction has been reported as a potential manifestation of adult-onset AxD, but has not been well characterized. OBJECTIVE: We report a case of adult-onset AxD with symptomatic orthostatic hypotension (OH) and heat intolerance that underwent formal autonomic testing. In addition, a comprehensive literature search was conducted to review the frequency and pattern of autonomic dysfunction in this patient population. RESULTS: A 51-year-old patient was diagnosed with AxD at the age of 47, following an 8-year history of vertigo, intermittent diplopia, and sleep disturbance. The patient developed symptoms of OH, erectile dysfunction, and heat intolerance soon after his diagnosis. Autonomic testing demonstrated OH on tilt-table testing (47 mmHg decrease in BP with 18 BPM heart rate increment) with absent late phase II and IV responses during the Valsalva maneuver, severe cardiovagal impairment, and preserved postganglionic sympathetic sudomotor function. These findings were interpreted as being consistent with central autonomic failure. The most common autonomic symptoms reported in other AxD cases include constipation, urinary incontinence, and sphincter dysfunction. To our knowledge, this is the first report of formal autonomic testing in AxD. CONCLUSION: Signs and symptoms of ANS impairment can occur in patients with AxD, and can include orthostatic hypotension and bowel/bladder dysfunction. Autonomic testing in our patient suggests impairment in central autonomic pathways.

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.

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.

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.

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.

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.

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.