Looking forward The opportunities for further clinical research into autonomic medicine are too numerous to list. However, by pointing to a number of strategic areas, I hope to stimulate thought and catalyze ideas for potential research projects: • Well-designed epidemiologic studies are needed to assess the prevalence of common autonomic disorders such as postural tachycardia syndrome (POTS). These should include objective data regarding symptom burden, economic burden, distribution across ethnicity and gender, longterm treatment outcomes, and recovery rate over time. • There is an urgent need for the development of effective disease-modifying drugs for devastating autonomic disorders such as multiple system atrophy. Novel therapeutic approaches await discovery. The designs of prior negative trials nevertheless provide useful methodological frameworks once new candidate drugs are available to be tested. • Among the non-motor manifestations of alpha-synucleinopathies, autonomic dysfunction increasingly has been recognized but remains insufficiently studied (14). Further research will be important to enable early diagnosis, accurate differential diagnosis, symptom management as disease progresses, and prevention of falls. • Diabetes mellitus is the most common cause of peripheral neuropathy worldwide. Diabetic autonomic neuropathy, which affects ~20% of individuals with diabetes, can present with orthostatic hypotension, tachycardia, exercise intolerance, constipation, gastroparesis, sudomotor dysfunction, or erectile dysfunction. Diabetic cardiovascular autonomic neuropathy, in particular, is significantly associated with increased mortality and morbidity, including silent myocardial ischemia and stroke (15). Further research is needed into early detection, improved metabolic control, and pharmacologic therapies to ameliorate the symptoms and end-organ effects of autonomic neuropathy in people with diabetes. • Supine hypertension and its adverse consequences have increasingly been recognized as a troublesome accompaniment of neurogenic orthostatic hypotension (16, 17). Further research is needed to guide clinical decisions about balancing the treatment of orthostatic hypotension with the potential to exacerbate supine hypertension in order to navigate between undertreatment and overtreatment. • Whether interventions intended to treat orthostatic hypotension, if used over a long time, might increase the risk of developing hypertension is an understudied question. Midodrine and droxidopa, which are indicated for treating neurogenic orthostatic hypotension, are well-known to exacerbate supine hypertension, but their longterm efficacy and end-organ effects have not been well-studied (11). The potential longterm consequences of hydration with sodium chloride supplementation, which is considered first-line treatment for chronic orthostatic intolerance and posturally related syncope, are also largely unexplored (18). Evidence-based best practices for long-term therapy have yet to be well-defined. • As data accumulate regarding the health effects of survivors of the COVID-19 pandemic, symptoms and signs of acute and chronic autonomic dysfunction are a topic of increasing interest. An estimated 2.5% of post-COVID patients have persistent symptoms of orthostatic intolerance (19). Further research is needed to elucidate the mechanisms of long-COVID fatigue and orthostatic intolerance, which may include direct tissue damage, cytokine storm, immune dysregulation, hormonal imbalance, or persistent low-grade infection (20), and to identify effective treatments. • The detection of phosphorylated alpha-synuclein in cholinergic and adrenergic nerve fibers in the skin is a sentinel discovery in the search for an understanding of the pathophysiology of sympathetic neurodegeneration and holds promise as a potentially useful biomarker to diagnose Parkinson disease and multiple system atrophy (21–25). • Gastroenterologic autonomic impairment is an important yet understudied area of autonomic medicine. Esophageal, gastric, and intestinal motility disturbances are frequently encountered in clinical practice, alone or in combination with other autonomic disturbances. More effective treatments are greatly needed. • Another rich area for investigation is the role of the immune system in autonomic disorders, including sorting out which antibodies cause disease and might be targets for therapeutic intervention, and how to discern when antibodies are present incidentally without clinical consequence. Valid indications for intravenous immunoglobulin and objective criteria for assessing the response to treatment should be rigorously defined. • The explosion of genetic information and the decreasing cost of some forms of genetic testing provide unprecedented opportunities to delve into the genetic and epigenetic influences on autonomic dysfunction including their vast implications for personalized medicine (26, 27). • The appropriate role for wearable technologies such as smart watches in monitoring autonomic signs and assessing the results of therapy over time represent yet another frontier in autonomic medicine that has the potential to change medical practice profoundly. Distinguishing critical alerts from false alarms will continue to challenge patients and their physicians. • Loss of thermoregulatory function can increase the risk of serious acute illness related to heat or cold exposure. Patients with global anhidrosis, for example, are at increased risk of potentially fatal heat stroke (28). The development of non-invasive methods for monitoring of core temperature during physical exercise or prolonged exposure to ambient heat or cold could save lives. • The shift to telemedicine during the COVID-19 pandemic presents opportunities to define what optimal autonomic healthcare delivery to autonomic patients by virtual technologies should look like (29). The creation of multispecialty clinics and development of innovative care models for autonomic patients represent additional opportunities. • Patients with autonomic disorders have needs that are not always met by current models of medical practice. Further research should examine these deficiencies and promote ways to improve the delivery of care to autonomic patients. Priorities include identifying barriers, discovering cost-effective models of care, and attaining more accurate diagnosis, better disease prevention, better symptom management, more individualized pharmacologic and non-pharmacologic therapies, and enhanced education. These needs exist not only in the developed world, but also in resource-poor regions. https://www.frontiersin.org/articles/10.3389/fneur.2022.1052137/full
A useful article. Many of us have orthostatic issues and currently I am looking to see if mine can be treated. "Whether interventions intended to treat orthostatic hypotension, if used over a long time, might increase the risk of developing hypertension is an understudied question". I am facing this issue at the moment. My orthostatic hypotension is severe and the doctor ( actually clinical pharmacologist) at Bart's, in Prof Lobo's team, is wanting to remove a drug prescribed to manage fairly mild hypertension. She is insistent that this is the correct way forward to correct my orthostatic problem but my GP has refused so far. I await her letter advising her treatment in more detail for further discussion with my GP. I don't want to end up with major hypertension but the orthostatic issue severely depletes my life quality. Yes please to more research.
One more possibility: monitor the nerve signals, and process that data to look for abnormalities. Maybe signals are travelling differently on different sides of the vagus nerve, or the signal levels or patterns are different in POTS. Computers are excellent for that sort of data processing, so give them data and see what they turn up. Adding in other data, such as heart rate, BP, or whatever else might be useful too.
Management of patients with hypertension and orthostatic hypotension. Parallel progress: https://www.ahajournals.org/doi/10.1161/HYPERTENSIONAHA.122.19113
