30TH INTERNATIONAL SYMPOSIUM ON THE AUTONOMIC NERVOUS SYSTEM

Neurogenic orthostatic hypotension induced by tizanidine

Strategies to improve the quality of life in patients with hereditary transthyretin amyloidosis (hATTR) and autonomic neuropathy Abstract Purpose Hereditary transthyretin amyloidosis (hATTR) is a severe adult-onset progressive disease mainly involving the peripheral nervous system and the heart, with a prominent impact on the autonomic nervous system. This review summarizes the clinical aspects of autonomic dysfunction in hATTR, and their impact on quality of life as well as potential therapeutic options. Methods Literature review. Results Autonomic dysfunction, causing neurogenic orthostatic hypotension, gastroparesis, constipation, diarrhea, bladder dysfunction, and erectile dysfunction in males, has a major impact on the quality of life of patients with hATTR. Improvement of qualify of life in patients with hATTR implies periodic symptomatic screening and early management, taking into consideration comorbidities and medication side effects. The specific effect of the disease-modifying treatment on this aspect remains to be unraveled. Conclusions Management of autonomic dysfunction in patients with hAATR is feasible and can result in improved qualify of life. Novel disease-modifying treatments for hAATR may contribute to improve autonomic dysfunction, although specific studies are required.

Early sympathetic neural responses during a cold pressor test linked to pain perception Abstract Purpose There is considerable interindividual variability in the perception of pain. Given that pain management is a major public health problem, gaining insight into the underlying physiology of these perceptual differences is important. We tested the hypothesis that when interindividual variability in initial muscle sympathetic nerve activity (MSNA) responses to a cold pressor test (CPT) is identified, the divergent responses will be linked to differences in pain perception in healthy young men and women. Methods In the supine position, blood pressure (BP) and MSNA were measured at baseline and during a 2-min CPT. Immediately following the CPT, pain was rated (range 0–10). Results Two groups were established: positive responders (Pos, n = 12) and negative responders (Neg, n = 12) based on the initial (first 30 s) MSNA response profiles (Pos: 12 ± 9, Neg: −3 ± 3 bursts/min, P < 0.0001). MSNA response profiles throughout the CPT were different between groups (P < 0.0001). Peak MSNA increases were different (Pos: 27 ± 11, Neg: 9 ± 5 bursts/min, P < 0.0001) and corresponded with initial MSNA responses (R2 = 0.6881, P < 0.0001). Blood pressure responses were also different throughout the CPT (P < 0.0001). Most importantly, the perception of pain induced by the CPT was different between the two groups (Pos: 8 ± 1, Neg: 4 ± 1, P < 0.0001). Conclusions The results indicate that in healthy young men and women, there are divergent initial sympathetic neural responses to a given painful stimulus that are linked to the magnitude of pain perception. These findings highlight the distinctive sympathetic patterns that may contribute to the considerable interindividual variability in the perception of pain.

Correction to: ST‑segment changes during tilt table testing for postural tachycardia syndrome: correlation with exercise stress test results Unfortunately, the 3rd author name was incorrectly published in the original publication. The complete correct name is given below.

Cardiovascular autonomic responses in patients with Parkinson disease to pedunculopontine deep brain stimulation Abstract Purpose Dysautonomia can be a debilitating feature of Parkinson disease (PD). Pedunculopontine nucleus (PPN) stimulation may improve gait disorders in PD, and may also result in changes in autonomic performance. Methods To determine whether pedunculopontine nucleus stimulation improves cardiovascular responses to autonomic challenges of postural tilt and Valsalva manoeuver, eight patients with pedunculopontine nucleus deep brain stimulation were recruited to the study; two were excluded for technical reasons during testing. Participants underwent head up tilt and Valsalva manoeuver with stimulation turned ON and OFF. Continuous blood pressure and ECG waveforms were recorded during these tests. In a single patient, local field potential activity was recorded from the implanted electrode during tilt. Results The fall in systolic blood pressure after tilt was significantly smaller with stimulation ON (mean − 8.3% versus − 17.2%, p = 0.044). Valsalva ratio increased with stimulation from median 1.15 OFF to 1.20 ON (p = 0.028). Baroreflex sensitivity increased during Valsalva compared to rest with stimulation ON versus OFF (p = 0.028). The increase in baroreflex sensitivity correlated significantly with the mean depth of PPN stimulating electrode contacts. This accounted for 89% of its variance (r = 0.943, p = 0.005). Conclusion PPN stimulation can modulate the cardiovascular system in patients with PD. In this study, it reduced the postural fall in systolic blood pressure during head-up tilt and improved the cardiovascular response during Valsalva, presumably by altering the neural control of baroreflex activation.

Human papillomavirus (HPV) vaccine and autonomic disorders: a position statement from the American Autonomic Society Abstract Introduction Human papillomavirus (HPV) vaccination has been anecdotally connected to the development of dysautonomia, chronic fatigue, complex regional pain syndrome and postural tachycardia syndrome. Objectives To critically evaluate a potential connection between HPV vaccination and the above-noted conditions. Methods We reviewed the literature containing the biology of the virus, pathophysiology of infection, epidemiology of associated cancers, indications of HPV vaccination, safety surveillance data and published reports linking HPV vaccination to autonomic disorders. Results At this time, the American Autonomic Society finds that there are no data to support a causal relationship between HPV vaccination and CRPS, chronic fatigue, and postural tachycardia syndrome to other forms of dysautonomia. Conclusion Certain conditions are prevalent in the same populations that are vaccinated with the HPV vaccine (peri-pubertal males and females). This association, however, is an insufficient proof of causality.

Characteristics and natural history of autonomic involvement in hereditary ATTR amyloidosis: a systematic review Abstract Background Autonomic dysfunction is a hallmark feature of hereditary ATTR amyloidosis. The aim of this study was to summarize the characteristics and natural history of autonomic dysfunction in patients with hereditary ATTR amyloidosis. Methods A systematic review of the natural history and clinical trials of patients with ATTR amyloidosis was performed. Alternative surrogate markers of autonomic function were analyzed to understand the prevalence and outcome of autonomic dysfunction. Results Patients with early-onset disease displayed autonomic dysfunction more distinctively than those with late-onset disease. The nutritional status and some autonomic items in the quality-of-life questionnaires were used to assess the indirect progression of autonomic dysfunction in most studies. Gastrointestinal symptoms and orthostatic hypotension were resent earlier than urogenital complications. Once symptoms were present, their evolution was equivalent to the progression of the motor and sensory neuropathy impairment. Conclusion The development of autonomic dysfunction impacts morbidity, disease progression, and mortality in patients with hereditary ATTR amyloidosis.

Orthostatic hypotension in hereditary transthyretin amyloidosis: epidemiology, diagnosis and management Abstract Purpose Neurogenic orthostatic hypotension is a prominent and disabling manifestation of autonomic dysfunction in patients with hereditary transthyretin (TTR) amyloidosis affecting an estimated 40–60% of patients, and reducing their quality of life. We reviewed the epidemiology and pathophysiology of neurogenic orthostatic hypotension in patients with hereditary TTR amyloidosis, summarize non-pharmacologic and pharmacological treatment strategies and discuss the impact of novel disease-modifying treatments such as transthyretin stabilizers (diflunisal, tafamidis) and RNA interference agents (patisiran, inotersen). Methods Literature review. Results Orthostatic hypotension in patients with hereditary transthyretin amyloidosis can be a consequence of heart failure due to amyloid cardiomyopathy or volume depletion due to diarrhea or drug effects. When none of these circumstances are apparent, orthostatic hypotension is usually neurogenic, i.e., caused by impaired norepinephrine release from sympathetic postganglionic neurons, because of neuronal amyloid fibril deposition. Conclusions When recognized, neurogenic orthostatic hypotension can be treated. Discontinuation of potentially aggravating medications, patient education and non-pharmacologic approaches should be applied first. Droxidopa (Northera®), a synthetic norepinephrine precursor, has shown efficacy in controlled trials of neurogenic orthostatic hypotension in patients with hereditary TTR amyloidosis and is now approved in the US and Asia. Although they may be useful to ameliorate autonomic dysfunction in hereditary TTR amyloidosis, the impact of disease-modifying treatments on neurogenic orthostatic hypotension is still uninvestigated.

Diagnosis and treatment of gastrointestinal dysfunction in hereditary TTR amyloidosis Abstract Purpose To review the management of gastrointestinal symptoms in patients with hereditary transthyretin amyloidosis, discussing diagnostic evaluations, assessment of disease progression and therapeutic strategies that could be implemented in routine practice. Methods Literature review. Key search terms included “gastrointestinal symptoms”, “autonomic neuropathy”, “hereditary transthyretin amyloidosis” and “familial amyloid polyneuropathy”. Results Gastrointestinal disturbances are a common and serious manifestation of hereditary transthyretin amyloidosis, with significant effects on patients' quality of life and demonstrating a strong association with mortality. Gastrointestinal involvement is more often subclinical in the early stages of the disease, although in some patients gastric and/or bowel abnormalities may be the inaugural symptoms. In both cases, under-recognition, delayed investigation and suboptimal treatment frequently occur. A clear understanding of the mechanisms underlying gastrointestinal dysfunction in hereditary transthyretin amyloidosis is still lacking, but similar to diabetic enteropathy, multiple pathophysiological alterations seem to play a role. Conclusions Early detection and treatment of gastrointestinal disturbances is key to the successful treatment of this devastating disease. Gastroenterologists play a valuable role in both the diagnosis and the timely management of gastrointestinal symptoms in hereditary transthyretin amyloidosis and should, therefore, be part of a multidisciplinary and comprehensive approach to this disorder.