Special Issue on Dysautonomia

Jose-Alberto Palma, MD, PhD

Horacio Kaufmann, MD, FAAN, FAAS

The autonomic nervous system innervates and regulates all body organs. Thus, damage to the autonomic nervous system can manifest with a variety of signs and symptoms affecting the multiple organs and systems regulating cardiovascular, genitourinary, gastrointestinal, or sudomotor functions. Therefore, it is essential that neurologists understand these issues and address them. Indeed, neurologists should be comfortable with using a reflex hammer, but also a sphygmomanometer or a bladder ultrasound, because dysfunction of the autonomic nervous system can be managed, but only if it is properly recognized.

Our goal in this issue of Seminars in Neurology is to provide a comprehensive overview of the epidemiology, diagnosis, and management of frequent and not so frequent disorders of the autonomic nervous system, that is, dysautonomias. The issue begins with Dr. Lefcort's outline of the autonomic nervous system development during embryogenesis. Dr. Lefcort highlights how specific genetic defects affecting the development of neural crest neurons can result in rare, although archetypal, autonomic disorders, such as familial dysautonomia (also known as Riley-Day syndrome, or hereditary sensory and autonomic neuropathy type 3) or Hirschsprung's disease. Novel technologies targeting these disrupted pathways (e.g., gene therapy) could eventually result in much needed disease-modifying treatments.

The issue continues with a series of articles focusing on specific syndromes or underlying pathologies causing autonomic dysfunction, most notably baroreflex dysfunction resulting in abnormal blood pressure regulation. Drs. Scott and Rabinstein discuss paroxysmal sympathetic hyperactivity, a common but often unrecognized complication of brain injury. Paroxysmal sympathetic hyperactivity is associated with increased morbidity and mortality in patients in the intensive care unit setting; so, prompt recognition and treatment is key to prevent ominous outcomes. Dr. Coon comprehensively reviews autonomic dysfunction in the synucleinopathies, neurodegenerative disorders characterized by accumulation of the abnormally misfolded protein α-synuclein in the nervous system. In a thought-provoking contribution, Dr. Goldstein argues that, in addition to synuclein-mediated autonomic neurons loss, there are functional abnormalities in the remaining neurons (i.e., those “sick but not dead”), possibly caused by catecholamine autotoxicity. Because treating neurons that are dead is impossible, but sick-but-not-dead neurons might be salvageable, this could have important therapeutic implications.

Among the most debilitating manifestations of autonomic dysfunction in the synucleinopathies is orthostatic hypotension (OH), that is, a sustained reduction of blood pressure when standing that can result in symptoms of cerebral hypoperfusion such as dizziness, lightheadedness, feeling about to faint, and syncope. Drs. Shibao and Biaggioni discuss the management of OH, as well as that of postprandial hypotension (i.e., hypotension after meals) and of supine hypertension. Both OH and supine hypertension typically coexist in patients with synucleinopathies. Because treating one usually exacerbates the other, treatment of both can be challenging. In the following article of the issue, we (Drs. Palma and Kaufmann) offer readers a comprehensive view of the challenges of designing and conducting clinical trials for OH. The article outlines the clinical trials conducted so far in OH, highlighting difficulties and potential solutions, with emphasis on midodrine and droxidopa, which are the only two drugs specifically approved by the U.S. Food and Drug Administration for the treatment of symptomatic neurogenic OH.

The issue continues with a unique article on afferent baroreflex dysfunction, whose leading author is Dr. Norcliffe-Kaufmann. The afferent baroreceptor pathways convey information from baroreceptors embedded in the walls of major arteries and veins, via the vagus and glossopharyngeal cranial nerves. Damage to these nerves (e.g., due to radiotherapy or surgery, or due to rare genetic mutations in the case of familial dysautonomia) results in severe blood pressure variability with paroxysmal hypertension and hypotension. Conversely, hyperactivation of these nerves (e.g., due to paragangliomas) can result in vasovagal-like reactions and frequent syncope. Dr. Norcliffe-Kaufmann's contribution is seminal: not only it educates on the two opposing faces of afferent baroreflex dysfunction (i.e., failure and hyperactivation) but also includes the largest series of patients with these disorders reported thus far in the literature.

The spinal cord is a key structure in the central autonomic pathways. Spinal cord injury (SCI), particularly at or above the sixth thoracic vertebral level (T6), can result in devastating autonomic problems, including autonomic dysreflexia. Dr. Wecht and colleagues review the prevalence of cardiovascular autonomic dysfunction depending on the level, duration, and severity of the SCI, as well as their presentation, diagnosis, consequences, and management strategies.

Venturing outside the realm of cardiovascular autonomic dysfunction, the issue includes articles on sudomotor and urinary dysfunction. Dr. Cheshire reviews the physiology and pathophysiology of sweat production, as well as its evaluation and management, whereas Dr. Panicker summarizes the epidemiology, diagnosis, and management of neurogenic bladder dysfunction in patients with neurological disorders.

The issue concludes with an article led by Dr. Gutierrez outlining the characteristics of acute sensory and autonomic neuronopathy (ASANN), a rare and devastating disorder. To that end, the article reports three patients and reviews the pathophysiology, epidemiology, diagnosis, and management on the disorder. As Dr. Gutierrez and colleagues explain, ASANN is a poorly understood and frequently mislabeled disorder, frequently misdiagnosed as Guillain–Barre or other syndromes. The diagnosis requires the presence of severe sensory and autonomic deficits, with preservation of motor function. Spinal magnetic resonance imaging typically shows hyperintensities in the ascending sensory cords. Although infrequent, the disorder is a paradigmatic example of a ganglionopathy affecting both sensory and autonomic ganglia, presumably due to an autoimmune cause.

We appreciate the expertise and dedication of all the contributors to this issue of Seminars in Neurology. We thank them for sharing their knowledge and expertise in these outstanding reviews. We also thank Dr. David Greer, editor-in-chief of Seminars in Neurology, for his thoughtful input to the articles. We hope that readers will find this issue informative and helpful to improve the identification and management of autonomic disorders.

Publication History

Article published online:
27 October 2020