Autoimmune Autonomic Disorders (Autonomic Disorders February 2020)

Educational Objectives

The goal of this program is to improve diagnosis and management of disorders of the autonomic nervous system. After hearing and assimilating this program, the clinician will be better able to:

1. Diagnose autoimmune autonomic ganglionopathy.
2. Treat a patient with autoimmune autonomic ganglionopathy.
3. Recognize autonomic manifestations of common autoimmune disorders and neuropathies.

Summary

Autoimmune autonomic disorders: Autonomic disorders common; main findings are changes in gastrointestinal function, orthostatic intolerance, exercise intolerance, and other nonspecific symptoms; familiar autonomic disorders include degenerative conditions such as multiple system atrophy (MSA), Parkinson disease, and metabolic neuropathies such as diabetes mellitus.

Autoimmune autonomic ganglionopathy: Rare disorder characteristically presents in middle-aged patients; patient typically healthy before dramatic subacute or acute onset of autonomic failure; main symptoms are orthostatic hypotension, fainting, lightheadedness, confusion when standing, severe constipation, gastroparesis with nausea, heat intolerance because of impaired sweating, dry eyes, dry mouth, and urinary retention; orthostatic changes may include decrease of 80 mm Hg to 100 mm Hg in systolic blood pressure upon standing, with minimal to no compensatory increase in heart rate; lack of increase in heart rate indicates origination of symptoms in autonomic nervous system rather than as result of dehydration or effects of medications; onset of autoimmune autonomic ganglionopathy sometimes sudden; in severe cases, pupils may exhibit sluggish or absent response to light.

Pathophysiology of autoimmune autonomic ganglionopathy: Disorder mediated by antibodies that target receptors in autonomic ganglia; ganglionic nicotinic acetylcholine (ACh) receptor responsible for communication between central nervous system and autonomic nerves in periphery; antibodies block signaling along this pathway; presence of antibodies demonstrated to cause autoimmune autonomic ganglionopathy (ie, transferring antibodies to another animal induces autonomic failure).

Management of autoimmune autonomic ganglionopathy: Patients respond well to immunosuppressants or plasma exchange therapy; unlike neurodegenerative conditions, antibody-mediated diseases treatable; commercially available antibody tests used to detect autoimmune autonomic ganglionopathy; outcomes often good.

Manifestations of autoimmune autonomic ganglionopathy: Although condition sometimes referred to as “autonomic myasthenia,” patients with autoimmune autonomic ganglionopathy do not have muscle weakness and fatigue or sensory loss; antibodies target ganglionic synapse rather than neuromuscular junction and affect sympathetic and parasympathetic ganglia; effects of sympathetic nervous system largely mediated via norepinephrine, but at ganglia, ACh responsible for signaling; parasympathetic ganglionic synapses affect end organs via ACh; autoimmune autonomic ganglionopathy causes failure of sympathetic and parasympathetic nervous systems.

Differential diagnosis of autoimmune autonomic disorders: Includes degenerative disorders and peripheral neuropathies.

Neurodegenerative disorders: Include MSA and Parkinson disease; these disorders usually progress more slowly than autoimmune conditions; however, cases of autoimmune autonomic ganglionopathy that develop slowly may masquerade as pure autonomic failure (degenerative disorder of autonomic nerves); patients with Parkinson disease and MSA often have other symptoms that indicate involvement of central nervous system, such as ataxia, tremor, and bradykinesia; patients with degenerative syndromes characterized by deposition of α-synuclein often have rapid eye movement (REM) sleep behavior disorder; patient with autonomic failure who reports memory deficit, REM sleep behavior disorder, tremor, or ataxia likely to have neurodegenerative disease.

Peripheral autonomic neuropathies: Affect nerves more generally; patient may exhibit sensory loss or pain; autonomic nerves small and unmyelinated; disorders such as diabetes mellitus that cause small fiber neuropathy may be associated with autonomic problems but also involve sensory and pain fibers; length-dependent pattern typically seen in patient with peripheral neuropathy, and symptoms such as loss of sweating affect distal extremities; in contrast, ganglionopathies do not exhibit length-dependent pattern.

Diagnosis: Testing for antibodies or assessing patient in quantitative autonomic laboratory may help clinician determine diagnosis; however, in most cases, clinical history and examination reveal diagnosis.

Evaluation: Case — older patient presents with severe orthostatic hypotension and constipation; autoimmune autonomic ganglionopathy suspected; assessment — antibody tests positive in 50% to 60% of patients with autoimmune autonomic ganglionopathy; in older patient, clinician should also consider paraneoplastic form of autonomic neuropathy or ganglionopathy; such patients may develop subacute autonomic failure with gastrointestinal dysmotility and orthostatic hypotension; other antibodies associated with paraneoplastic forms of autonomic failure; false-positive results possible on antibody tests in patients with autonomic failure, but level of antibody usually helpful; most patients with subacute onset of autonomic failure due to autoimmune autonomic ganglionopathy have high levels of antibody (greater than 1 nmol/L on radioimmunoprecipitation assay); lower levels of antibody (less than 0.2 nmol/L) nonspecific and may be present in other autoimmune conditions but also seen in 2% to 3% of healthy population; clinical correlation needed when results of antibody test equivocal.

Traditional autonomic testing: Autoimmune autonomic ganglionopathy associated with characteristic features on autonomic testing; testing useful for distinguishing between neurodegenerative disorder, peripheral autonomic neuropathy, and autonomic ganglionopathy; properly equipped laboratory can perform quantitative sudomotor axon reflex test (QSART), assess heart rate and blood pressure responses to Valsalva and deep breathing, and continuously monitor blood pressure during tilt-table testing; in office, assessment of supine and standing blood pressure and heart rate often allows differentiation of autonomic failure from other autonomic disorders.

Management of autoimmune autonomic ganglionopathy: Because no clinical trials performed on patients with autoimmune autonomic ganglionopathy, therapeutic principles based on those used for myasthenia gravis; pyridostigmine may improve synaptic cholinergic transmission; plasma exchange or IV immunoglobulin (IVIg) useful for short-term treatment of autoimmune autonomic ganglionopathy; long-term therapy relies on traditional immunosuppressants, including mycophenolate mofetil, azathioprine, prednisone, other corticosteroids, and rituximab.

Paraneoplastic autonomic neuropathies: Gastroparesis often seen in patients with lung cancer, whose symptoms of nausea and vomiting may not be brought to attention of neurologic clinician; other features of paraneoplastic disorders may include limbic encephalitis, peripheral neuropathy, and ataxia; orthostatic hypotension possible; paraneoplastic syndrome should be considered in patient with multisystem progressive disorder that includes autonomic dysfunction; commonly associated tumors include small cell lung cancer and thymoma.

Other autoimmune conditions: Sjögren syndrome and other systemic inflammatory autoimmune diseases may present with neuropathy; sensory neuropathy most common, but autonomic features possible; autonomic findings in these patients usually less dramatic than those encountered in autoimmune autonomic ganglionopathy or degenerative autonomic disorders; patient may present with gastrointestinal symptoms including constipation, orthostatic intolerance (dizziness), and sensory neuropathy of small fibers reminiscent of that seen in diabetes mellitus; in patient with sensory and autonomic neuropathies, clinician should consider diabetes mellitus as well as systemic autoimmune disease and ask about symptoms of Sjögren syndrome such as dry eyes, dry mouth, and joint symptoms; rheumatologic consultation may be indicated.

Guillain-Barré syndrome and other neuropathies: Some immune-mediated autonomic and sensory neuropathies not associated with systemic autoimmune disease; subacute onset may herald Guillain-Barré syndrome (GBS); in GBS, sensory and autonomic manifestations more common than motor symptoms; some of these conditions respond to steroids, IVIg, and plasma exchange; these patients do not have antibodies to ACh receptor; demyelination of preganglionic fibers in GBS possible cause of autonomic symptoms; several autonomic presentations seen in patients with GBS, including arrhythmia and hypertension.

Autoimmune encephalitides: Often feature autonomic findings; most prominent disorder N-methyl-d-aspartate (NMDA) receptor encephalitis; these patients present with predominant behavioral and encephalopathic symptoms, such as seizures; they may have high or low blood pressure and tachyarrhythmia; similar findings may be seen in patients with encephalitis related to antibodies to voltage-gated potassium channel complex (eg, antibodies to leucine-rich glioma inactivated protein 1 [LGI1]); such patients may have hyperautonomic function, with excessive sweating, salivation, and tachyarrhythmia.

Summary: Autonomic disorders common and may have autoimmune etiology; clinician should seek underlying cause; autoimmune and paraneoplastic autonomic ganglionopathies rare but treatable; commercial antibody testing and autonomic testing helpful for making diagnosis; many other more common autonomic disorders (including autonomic neuropathies and postural orthostatic tachycardia syndrome [POTS]) may have autoimmune etiology.

Readings

Vernino S. Autoimmune autonomic disorders. Continuum (Minneap Minn) 2020;26(1 Autonomic Disorders).

Disclosures

For this program, the following was disclosed: Dr. Vernino serves on the board of directors of the American Autonomic Society, the scientific advisory boards of Argenx and Dysautonomia International, and the editorial boards of Autonomic Neuroscience: Basic & Clinical and Clinical Autonomic Research. Dr. Vernino receives research/grant support from Dysautonomia International; Genentech, Inc; Grifols, SA; the Rex Griswold Foundation; and Theravance and licensing fees to support his laboratory from Quest/Athena.

Unlabeled Use of Products/Investigational Use Disclosure: Dr. Vernino discusses the unlabeled/investigational use of immunomodulatory treatments for autoimmune disorders.

To view disclosures of planning committee members with relevant financial relationships, visit: legacy.audio-digest.org/continuumaudio/committee. All other members of the planning committee report nothing to disclose.

The material presented in Continuum Audio has been made available by the AAN for educational purposes only and is not intended to represent the only method or procedure for the medical situations discussed but rather to present an approach, view, statement, or opinion of the speaker(s), which may be helpful to others who face similar situations. Opinions expressed by the speakers are not necessarily those of the AAN, its affiliates, or the publisher. The AAN, its affiliates, and the publisher disclaim any liability to any party for the accuracy, completeness, efficacy, or availability of the material contained in this program (including drug dosages) or for any damages arising out of the use or nonuse of any of the material contained in this program.

Acknowledgements

CME/CE INFO

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The Audio- Digest Foundation is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

The Audio- Digest Foundation designates this enduring material for a maximum of 0 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

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Lecture ID:

CA090103

Expiration:

This CME course qualifies for AMA PRA Category 1 Credits™ for 3 years from the date of publication.

Instructions:

To earn CME/CE credit for this course, you must complete all the following components in the order recommended: (1) Review introductory course content, including Educational Objectives and Faculty/Planner Disclosures; (2) Listen to the audio program and review accompanying learning materials; (3) Complete posttest (only after completing Step 2) and earn a passing score of at least 80%. Taking the course Pretest and completing the Evaluation Survey are strongly recommended (but not mandatory) components of completing this CME/CE course.

Estimated time to complete this CME/CE course:

Approximately 2x the length of the recorded lecture to account for time spent studying accompanying learning materials and completing tests.