Populations	Interventions	Comparators	Outcomes
Individuals: Signs and/or symptoms of autonomic nervous system dysfunction	Interventions of interest are: Autonomic nervous system testing	Comparators of interest are: Clinical workup without autonomic nervous system testing	Relevant outcomes include: Test accuracy Symptoms Functional outcomes Quality of life

Background

Autonomic Nervous System

The autonomic nervous system (ANS) has a primary role in controlling physiologic processes not generally under conscious control. They include heart rate, respirations, gastrointestinal (GI) motility, thermal regulation, bladder control, and sexual function.^1,2, The ANS is a complex neural regulatory network that consists of 2 complementary systems that work to maintain homeostasis: the sympathetic and the parasympathetic systems. The sympathetic nervous system is responsible for arousal, and sympathetic stimulation leads to increased pulse, increased blood pressure (BP), increased sweating, decreased GI motility, and an increase in other glandular exocrine secretions. This is typically understood as the "fight or flight" response. Activation of the parasympathetic nervous system will mostly have the opposite effects; BP and pulse will decrease, GI motility increases, and there will be a decrease in sweating and other glandular secretions.

Autonomic Nervous System Disorders

ANS disorders, also called dysautonomias, are heterogeneous in etiology, clinical symptoms, and severity. ANS disorders can be limited and focal, such as patients with isolated neurocardiogenic syncope or idiopathic palmar hyperhidrosis. At the other extreme, some ANS disorders can be widespread and severely disabling, such as multiple systems atrophy, which leads to widespread and severe autonomic failure.

Symptoms of autonomic disorders can vary, based on the etiology and location of dysfunction. Cardiovascular manifestations are often prominent. Involvement of the cardiovascular system causes abnormalities in heart rate control and vascular dynamics.^3, Orthostatic hypotension and other manifestations of BP lability can occur, causing weakness, dizziness, and syncope. Resting tachycardia and an inability to appropriately increase heart rate in response to exertion leads to exercise intolerance. There is a 2- to 3-fold higher incidence of major cardiac events in patients with diabetic autonomic neuropathy (myocardial infarction, heart failure, resuscitation from ventricular arrhythmia, angina, or the need for revascularization).^4, There is also an increase in sudden cardiac death and overall mortality for these patients.^3,

Many other organ systems can be affected by autonomic neuropathy. Involvement of the bladder can lead to incomplete emptying, resulting in urinary retention and possible overflow incontinence. GI involvement is commonly manifested as gastroparesis, which is defined as slowed gastric emptying and can cause nausea, vomiting, and a decreased tolerance for solid food and large meals. Constipation may also occur if the lower GI tract is involved. Impairment of sexual function in males can manifest as erectile dysfunction and ejaculatory failure. Dysfunction of thermal regulation and sweating can lead to anhidrosis and heat intolerance. Paradoxically, excessive sweating can also occur as a compensatory mechanism in unaffected regions.^5,

A classification of the different types of autonomic dysfunction, adapted from Freeman (2005)^5, and Macdougall and McLeod (1996),^6, can be made as follows:

• Diabetic autonomic neuropathy
• Amyloid neuropathy
• Immune-mediated neuropathy
  • Rheumatoid arthritis
  • Systemic lupus erythematosus
  • Sjögren syndrome
• Paraneoplastic neuropathy
• Inflammatory neuropathy
  • Guillain-Barré syndrome
  • Chronic inflammatory demyelinating polyneuropathy
  • Crohn disease
  • Ulcerative colitis
• Hereditary autonomic neuropathies
• Autonomic neuropathy secondary to infectious disease
  • HIV disease
  • Lyme disease
  • Chagas disease
  • Diphtheria
  • Leprosy
• Acute and subacute idiopathic autonomic neuropathy
• Toxic neuropathies.

Treatment

Much of the treatment for autonomic disorders is nonpharmacologic and supportive. However, there are specific actions that can improve symptoms in patients with specific deficits. For patients with orthostatic hypotension, this involves adequate intake of fluids and salt, moving to an upright position slowly and deliberately, use of lower-extremity compression stockings, and keeping the head of the bed elevated 4 to 6 inches (10-15 cm).^1, In severe cases, treatment with medications that promote salt retention, such as fludrocortisone, is often prescribed. Patients with symptoms of hyperhidrosis may benefit from cooling devices and potent antiperspirants such as Drysol, and patients with decreased tearing and dry mucous membranes can use over-the-counter artificial tears or other artificial moisturizers.^1,

Autonomic Nervous System Testing

ANS testing consists of a battery of tests. Any single test may be performed individually, or the entire battery of tests may be ordered. Individual components of testing may include cardiovagal function testing, sudomotor function, salivation testing, and tilt table testing.

Cardiovagal Function Testing

Beat-to-beat variability in the heart rate can be measured at rest, or in response to provocative measures, such as deep breathing or the Valsalva maneuver. Reduced, or absent, heart rate variability is a sign of autonomic dysfunction.^8,

Baroreflex sensitivity is measured by examining the change in pulse and heart rate variability in response to changes in BP. A medication such as phenylephrine is given to induce a raise in BP, and baroreflex sensitivity is calculated as the slope of the relation between heart rate variability and BP.^8,

Sudomotor Function (Sweat Testing)

Sweat testing evaluates the structure and function of nerves that regulate the sweat glands.

The Quantitative Sudomotor Axon Reflex Test is an example of a commercially available semiquantitative test of sudomotor function.^8, The test is performed by placing the color-sensitive paper on the skin, which changes color on contact with sweat. Measurement of the amount of color change is a semiquantitative measure of sudomotor function.

For the silastic sweat imprint, silastic material is placed on the skin, and the sweat droplets form indentations on the silastic surface, allowing quantitation of the degree of sweating present. The Neuropad test is an example of a commercially available silastic sweat imprint.

A more complex approach in some centers is the use of a thermoregulatory laboratory.^9, This is a closed chamber in which an individual sits for a defined period under tightly controlled temperature and humidity. An indicator dye is brushed on the skin, and it changes color when in contact with sweat. Digital pictures are taken and projected onto anatomic diagrams. Computer processing derives values for a total area of anhidrosis and the percent of anhidrotic areas.

Sympathetic skin response tests use an electric current to stimulate sympathetic nerves. The tests measure the change in electrical resistance, which is altered in the presence of sweat. In general, these tests are considered to be sensitive but have high variability and potential for false-positive results.^9,

A variant of sympathetic skin response testing is electrochemical sweat conductance measured by iontophoresis (eg, Sudoscan). In this test, a low-level current is used to attract chloride ions from sweat glands. The chloride ions interact with stainless-steel plate electrodes to measure electrochemical resistance.

Salivation Testing

The protocol for salivation testing involves the subject chewing on a preweighed gauze for 5 minutes. At the end of 5 minutes, the gauze is removed and reweighed to determine the total weight of saliva present.

Tilt Table Testing

Tilt table testing is intended to evaluate for orthostatic intolerance. The patient lies on the table and is strapped in with a foot rest. The table is then inclined to the upright position, with monitoring of the pulse and BP. Symptoms of light-headedness or syncope in conjunction with changes in pulse or BP constitute a positive test. A provocative medication, such as isoproterenol, can be given to increase the sensitivity of the test.

Composite Autonomic Severity Score

The Composite Autonomic Severity Score, which ranges from 0 to 10, is intended to estimate the severity of autonomic dysfunction. Scores are based on self-reported symptoms measured by a standardized symptom survey. Scores of 3 or less are considered mild, scores of 3 to 7 are considered moderate and scores greater than 7 are considered severe.

Regulatory Status

Since 1976, numerous ANS testing devices have been cleared for marketing by the U.S. Food and Drug Administration through the 510(k) process. Table 1 lists examples.

The Neuropad® test (TRIGOcare) is another example of a commercially available sudomotor function test.^10, No records were identified indicating that Neuropad® has been cleared for marketing by the US FDA, however.

Table 1. Autonomic Nervous System Test Devices

Device	Manufacturer	Measurement	510(k) No.	Clearance Date	Product Code
ANX 3.0	Ansar Group	Respiration and heart rate variability	K941252	1995	DRT
Sudoscan®	Impeto Medical	Electrochemical sweat conductance	K100233	2010	GZO
ZYTO Hand Cradle	ZYTO Technologies	Galvanic skin response	K111308	2011	GZO
Bodytronic® 200	Bauerfeind	Photoelectric plethysmograph	K123921	2013	JOM

Related Policies

• Neural Therapy (Policy #139 in the Treatment Section)

• Signs and/or symptoms of autonomic dysfunction are present; AND
• A definitive diagnosis cannot be made from clinical examination and routine laboratory testing alone; AND
• Diagnosis of the suspected autonomic disorder will lead to a change in management or will eliminate the need for further testing.

• chronic fatigue syndrome
• fibromyalgia
• anxiety and other psychologic disorders
• sleep apnea
• allergic conditions
• hypertension
• screening of asymptomatic individuals
• monitoring progression of disease or response to treatment.

• Cardiovagal function (heart rate variability, heart rate response to deep breathing and Valsalva maneuver)
• Vasomotor adrenergic function (blood pressure response to standing, Valsalva maneuver, and hand grip, tilt table testing)
• Sudomotor function (Quantitative Sudomotor Axon Reflex Test, quantitative sensory test, Thermoregulatory Sweat Test, silastic sweat imprint, sympathetic skin response, electrochemical sweat conductance).

There is little evidence on the comparative accuracy of different ANS tests, but the following tests are generally considered to have uncertain value in ANS testing:

• Pupillography
• Pupil edge light cycle
• Gastric emptying tests
• Cold pressor test
• Quantitative direct and indirect testing of sudomotor function test
• Plasma catecholamine levels
• Skin vasomotor testing
• The ANSAR® test.

For members enrolled in Medicaid and NJ FamilyCare plans, Horizon BCBSNJ applies the above medical policy.

FIDE SNP:

For members enrolled in a Fully Integrated Dual Eligible Special Needs Plan (FIDE-SNP): (1) to the extent the service is covered under the Medicare portion of the member’s benefit package, the above Medicare Coverage statement applies; and (2) to the extent the service is not covered under the Medicare portion of the member’s benefit package, the above Medicaid Coverage statement applies.

[RATIONALE: This policy was created in 2015 and has been updated regularly with searches of the PubMed database. The most recent literature update was performed through April 22, 2020.

Evidence reviews assess whether a medical test is clinically useful. A useful test provides information to make a clinical management decision that improves the net health outcome. That is, the balance of benefits and harms is better when the test is used to manage the condition than when another test or no test is used to manage the condition.

The first step in assessing a medical test is to formulate the clinical context and purpose of the test. The test must be technically reliable, clinically valid, and clinically useful for that purpose. Evidence reviews assess the evidence on whether a test is clinically valid and clinically useful. Technical reliability is outside the scope of these reviews, and credible information on technical reliability is available from other sources.

Autonomic Nervous System Testing
Clinical Context and Test Purpose

The purpose of autonomic nervous system testing is to provide a diagnostic option that is an alternative to or an improvement on existing tests, such as clinical workup without autonomic nervous system testing, in patients with signs and/or symptoms of autonomic nervous system dysfunction.

The question addressed in this policy is: does ANS testing improve the net health outcome in patients with a suspected autonomic disorder?

The following PICO was used to select literature to inform this policy.

Patients

The relevant population of interest is individuals with signs and/or symptoms of autonomic nervous system dysfunction.

Interventions

The test being considered is autonomic nervous system testing.

The autonomic nervous system (ANS) controls physiologic processes that are not under conscious control. ANS testing consists of a battery of tests intended to evaluate the integrity and function of the ANS, and generally consist of tests in 3 domains: Cardiovagal function (heart rate variability [HRV], heart rate response to deep breathing and Valsalva maneuver), vasomotor adrenergic function (blood pressure response to standing, Valsalva maneuver, and hand grip, tilt table testing), and sudomotor function (Quantitative Sudomotor Axon Reflex Test [QSART], quantitative sensory testing [QST], Thermoregulatory Sweat Test, silastic sweat imprint, sympathetic skin response, electrochemical sweat conductance). These tests are intended as adjuncts to the clinical examination in the diagnosis of ANS disorders.

Patients with signs and/or symptoms of autonomic nervous system dysfunction are actively managed by neurologists and primary care providers in an outpatient clinical setting.

Comparators

Comparators of interest include clinical workup without autonomic nervous system testing.

Comparators are actively managed by neurologists and primary care providers in an outpatient clinical setting.

Outcomes

The general outcomes of interest are test accuracy, symptoms, functional outcomes, and quality of life.

Much of the treatment for autonomic disorders is nonpharmacologic and supportive, but there are specific actions that can improve symptoms in patients with specific deficits and improve quality of life.

Study Selection Criteria

Below are selection criteria for studies to assess whether a test is clinically valid.
• The study population represents the population of interest. Eligibility and selection are described.
• The test is compared with a credible reference standard.
• If the test is intended to replace or be an adjunct to an existing test; it should also be compared with that test.
• Studies should report sensitivity, specificity, and predictive values. Studies that completely report true- and false-positive results are ideal. Studies reporting other measures (eg, ROC, AUROC, c-statistic, likelihood ratios) may be included but are less informative.
• Studies should also report reclassification of diagnostic or risk category.

Assessment of technical reliability focuses on specific tests and operators and requires review of unpublished and often proprietary information. Review of specific tests, operators, and unpublished data are outside the scope of this policy, and alternative sources exist. This policy focuses on the clinical validity and clinical utility.

Clinically Valid

A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse).

Review of Evidence

There are a number of challenges when evaluating the diagnostic accuracy of ANS testing:

• There is a lack of a true criterion standard for determining autonomic dysfunction. Comparisons with imperfect criterion standards, such as clinical examination or nerve conduction studies, may lead to biased estimates of accuracy.
• Most of the ANS is inaccessible to testing, and available tests are measures of end-organ response rather than direct measures of ANS function.
• There are numerous individual tests of ANS function, and a combination of them is typically used in ANS testing. Diagnostic accuracy could be reported for each test or the package of testing performed.
• Different types of equipment may be used for testing, and the accuracy of different systems may vary.

Table 2. Diagnostic Accuracy of Autonomic Nervous System Testing to Diagnose Distal Symmetric Polyneuropathy

Study	Disorder Studied	Test(s) Used	Reference Standard	N	Sensitivity, %	Specificity, %
Stewart et al (1992)	DSFN	HRV, QST, QSART	• Clinical exam • EDx studies	169	80	72
Dyck et al (1992)	Diabetic polyneuropathy	QAE	EDx studies	737	97	>90
Low et al (1997)	Parkinson, multisystem atrophy	QSART	Older scale for autonomic neuropathy	575	>90	>90
Tobin et al (1999)	DSFN	Clinical sx, QSART, QST	EDx studies	495	• 80 (QSART) • 67 (QST)	93
Novak et al (2001)	Painful neuropathy	QSART, ARTCASS	Clinical exam	483	• 93 (ART) • 73 (QSART)	94
Low et al (1993)	Diabetic polyneuropathy	CASS	• Clinical exam • EDx studies	428	>90	>90
Schrezenmaier et al (2007)	Adrenergic failure	BRSI	MSNA	113	86	>90
Vogel et al (2005)	Polyneuropathy, multisystem atrophy	PRT, CASS	Clinical exam	194	>90	>90
Singer et al (2004)	DSFN, diabetic and idiopathic neuropathy	CASS	Neurologic exam	49	95	90

Adapted from England et al (2009).^8,
ART: autonomic reflex testing; BRSI: baroreflex sensitivity index; CASS: Composite Autonomic Severity Score; DSFN: distal small fiber neuropathy; EDx: electrodiagnostic studies (electromyography/nerve conduction velocity); HRV: heart rate variability; MSNA: muscle sympathetic nerve activity; PRT: blood pressure recovery time; QAE: quantitative autonomic evaluation; QSART: Quantitative Sudomotor Axon Reflex Test; QST: quantitative sensory testing; sx: symptoms.

Bellavere et al (2019) published an observational study comparing 3 types of cardiovascular autonomic tests (deep breathing [DB], lying to standing [LS], and Valsalva maneuver [VM]) for diagnosis of cardiac autonomic neuropathy. Data from 334 patients who had shown previous DB impairment were included.^11, Test sensitivity for DB, LS, and VM were 0.667, 0.704, and 0.846, respectively, and specificity for DB, LS, and VM were 0.654, 0.726, and 0.482, respectively. No limitations to the study were reported.

A study by Park et al (2019) investigated the usefulness of various quantitative fractionalized autonomic indexes in distinguishing between idiopathic Parkinson disease (IPD) and multiple system atrophy-Parkinson type (MSA-P) in 36 individuals with PD treated at Soonchunhyang University Bucheon Hospital from February 2014 to June 2015.^12, This study also evaluated the correlations between these autonomic test indexes and functional status. This study found that among the test indices evaluated, use of a cut-off value of 5.5 seconds for pressure recovery time (PRT) stood out as distinguishing between the 2 diagnoses and had a sensitivity of 71.4% and a specificity of 72.7%. Additionally, valsalva ratio (r = -0.455, P = 0.009) and adrenergic baroreflex sensitivity (r = -0.356, P = 0.036) demonstrated significant correlations with the Unified Multiple System Atrophy Rating Scale and the Hoehn and Yahr (H&Y) score ≤3.

da Silva et al (2016) reported on a systematic review evaluating the accuracy of HRV for the diagnosis and prognosis of cardiac autonomic neuropathy in individuals with diabetes.^13, Reviewers included 8 studies, finding that HRV is useful to discriminate cardiac autonomic neuropathy. Measures of sample entropy, standard deviation of the instantaneous variability and long-term variability, standard deviation of mean of normal relative risk intervals every 5 minutes for a period of time, expressed in milliseconds, high-frequency component, and slope of heart rate turbulence had the best discriminatory power, with sensitivities ranging from 72% to 100% and specificities ranging from 71% to 97%.

Neuropad

Several studies have been identified that have compared the sensitivity and specificity of the silastic sweat testing device Neuropad to various other measures of nerve function.

The National Institute of Health and Care Excellence (NICE) (2017) published an evidence review on the Neuropad test for the early detection of diabetic neuropathy.^14, This review included 17 studies that evaluated the diagnostic accuracy of Neuropad against a reference standard, most commonly the Neuropathy Disability Score (NDS). In their meta-analysis of 5 diagnostic accuracy studies using an NDS score of 5 or greater as a reference standard, NICE reported that Neuropad had a pooled sensitivity and specificity of 89.4% and 60.3%, respectively. However, NICE reviewers noted that high heterogeneity limited interpretation of these findings. Additionally, the NICE review reported that in 2 published studies that assessed the diagnostic accuracy of Neuropad against the 10g monofilament test, results indicated that overall, the Neuropad has a higher sensitivity, but a much lower specificity than the monofilament. Finally, the NICE review reported that evidence was insufficient to evaluate the performance of Neuropad against vibration perception threshold testing (VPT). NICE concluded that “no clear or conclusive evidence was found for the use of Neuropad as a screening test for early neuropathy” and also noted that “while Neuropad may theoretically be able to detect earlier stage neuropathy, in the current pathway this is of limited benefit, as action is only triggered when moderate or advanced neuropathy is detected.”

Subsequent to the 2017 NICE review, Didangelos et al (2019) published a study of 174 patients with diabetes which evaluated the diagnostic accuracy of Neuropad compared with the Michigan Neuropathy Screening Instrument Questionnaire and Examination (MNSIQ and MNSIE, respectively), application of 10 g monofilament (MONO) and measurement of vibration perception threshold with biothesiometer (BIO).^15, Sensitivity of Neuropad testing was 95% verus MONO, 73% versus BIO, 73% versus MNSIE and 75% versus ΜNSIQ. Specificity was 69, 81, 90 and 92%, respectively.

Sudoscan

Rajan et al (2019) reported on the results of a systematic review of 37 studies of Sudoscan published between 2010 and 2018 and spanned several types of conditions, including types 1 and 2 diabetes, pre-diabetes or metabolic syndrome, rheumatoid arthritis, ankylosing spondylitis, small fiber neuropathy, distal symmetric polyneuropathy, Fabry’s disease, amyloidosis, cystic fibrosis, and chronic kidney disease.^16, Review authors reported that the studies typically compared the test performance of Sudoscan to various other physiologic parameters, such as nerve function, kidney function, metabolic function, disease state, and/or cardiovascular risk. These studies found significant, but variable and modest correlations (0.4-0.7). However, review authors raised 4 key concerns about the Sudoscan evidence that raise serious questions about the clinical utility of the device: (1) due to a failure to detect age-, gender-, and disease-appropriate variability, the published results violate biological plausibility; (2) inadequate information is available to determine the exact method by which the Sudoscan device calculates electrochemical skin conductance; (3) the majority of the studies have been funded by the device manufacturer; and (4) there is important inconsistency across publication in the device's normative values. Due to these limitations and the lack of evidence with detailed comparisons to standard sudomotor testing with longitudinal followup, the review authors concluded that they could not recommend the clinical use of Sudoscan.

A number of additional studies of Sudoscan have been published since the systematic review by Rajan et al (2020). These include studies in transthyretin familial amyloid polyneuropathy, diabetes, and Parkinson's disease. However, none of these studies addressed the limitations identified by the systematic review by Rajan et al (2019) discussed above.

A study by Fortanier et al (2020) evaluated the performance of Sudoscan in differentiating transthyretin familial amyloid polyneuropathy from chronic inflammatory demyelinating polyneuropathy and found that feet electrochemical skin conductance < 64 µS had a 89% sensitivity and a 96% specificity to differentiate between the 2 types.^17,

In diabetes, a study by D’Amato et al (2020), evaluated the combined use of composite autonomic symptom score (COMPASS) 31 and electrochemical skin conductance using Sudoscan to diagnose diabetic cardiovascular autonomic neuropathy (CAN) and diabetic polyneuropathy (DPN) in 102 participants with diabetes.^18, When the tests were combined, the sensitivity for CAN increased from 75%-83% to 100% and the specificity increased from 67%-67% to 89% for DPN. In a study by Carbajal-Ramirez et al (2019), the performance of Sudoscan in detecting small fibers neuropathy was compared to the Michigan Neuropathy Screening Instrument (MNSI) in 221 individuals with type 2 diabetes in Mexico.^19, Compared to the MNSI B, abnormal hands or feet electrochemical skin conductance as measured by Sudoscan (< 60 μS and 70 μS respectively) has a sensitivity of 97% in patients with diabetes duration of 5 years or more and 91% in patients with a diabetes duration of less than 5 years.

The use of Sudoscan has also been studied for its ability to identify autonomic neuropathy in people with Parkinson’s disease (PD). Two similar studies identified had conflicting results. A study by Xu et al (2019) compared Sudoscan's predictive ability to detect PD-related autonomic neuropathy among 43 hospitalized patients in the later stages of PD and 42 healthy controls.^20, Authors of the study by Xu et al (2019) reported that in individuals with PD, Sudoscan detected lower electrochemical skin conductance in both the hands (-28%) and the feet (-19.1%). However, in another study by Pepescu et al (2019), no significant reduction in electrochemical skin conductance measured by Sudoscan was found in 67 individuals with PD compare with 66 age-matches controls.^21,

Section Summary: Clinically Valid

It is not possible to determine the diagnostic accuracy of ANS testing. The lack of a criterion standard makes it difficult to perform high-quality research in this area. The available research has reported sensitivity in patients with clinically defined disease and specificity in health volunteers. This type of study design is known to produce inflated estimates of sensitivity and specificity; therefore, the diagnostic accuracy of testing in clinical practice is uncertain.

Clinically Useful

A test is clinically useful if the use of the results informs management decisions that improve the net health outcome of care. The net health outcome can be improved if patients receive correct therapy, or more effective therapy, or avoid unnecessary therapy, or avoid unnecessary testing.

Review of Evidence
Direct Evidence

Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. Because these are intervention studies, the preferred evidence would be from randomized controlled trials.

The use of ANS testing will improve outcomes if the test has incremental diagnostic accuracy over clinical exam alone, and if establishing the diagnosis leads to changes in management that improves outcomes. There is a lack of direct evidence on the impact of ANS testing on changes in management or health outcomes.

Chain of Evidence

Indirect evidence on clinical utility rests on clinical validity. If the evidence is insufficient to demonstrate test performance, no inferences can be made about clinical utility.

It is likely that these tests provide information beyond that obtainable from the clinical exam alone, given the limitations of the physical exam for assessing physiologic processes. Some autonomic disorders have specific treatments, such as medications to retain salt and preserve hydration status. In other cases, the use of autonomic testing may limit the need for further diagnostic testing, when symptoms are possibly autonomic related, but may be due to other pathology. In those cases, determining whether autonomic dysfunction is the cause of symptoms may end the need for further testing.

Summary of Evidence

For individuals who have signs and symptoms of ANS dysfunction who receive ANS testing, the evidence includes studies of diagnostic accuracy. Relevant outcomes are test accuracy, symptoms, functional outcomes, and quality of life. The evidence base is limited. There is a lack of a criterion standard for determining autonomic dysfunction, which limits the ability to perform high-quality research on diagnostic accuracy. Also, numerous tests are used in various conditions, making it difficult to determine values for the overall diagnostic accuracy of a battery of tests. Scattered reports of diagnostic accuracy are available for certain tests, most commonly in the diabetic population, but these reports do not specify estimates of accuracy for the entire battery of tests. Reported sensitivities and specificities are high for patients with clinically defined distal symmetric polyneuropathy using a symptom-based score as a reference standard, but these estimates are likely biased by study designs that used patients with clinically diagnosed disease and a control group of healthy volunteers. The evidence is insufficient to determine the effects of the technology on health outcomes.

SUPPLEMENTAL INFORMATION
Clinical Input From Physician Specialty Societies and Academic Medical Centers

While the various physician specialty societies and academic medical centers may collaborate with and make recommendations during this process, through the provision of appropriate reviewers, input received does not represent an endorsement or position statement by the physician specialty societies or academic medical centers, unless otherwise noted.

In response to requests, input was received from 1 physician specialty society and 7 academic medical centers while this policy was under review in 2014. There was a consensus that autonomic nervous system testing should be medically necessary for some indications, and there was agreement on the proposed criteria for medical necessity.

Practice Guidelines and Position Statements

Evidence-based guidelines on autonomic nervous system (ANS) testing are lacking. Even in guidelines that involve a systematic review of the literature, such as the joint American Academy of Neurology (AAN), American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM), and the American Academy of Physical Medicine & Rehabilitation guidelines (described below), recommendations were largely based on expert consensus.

American Academy of Neurology et al

AAN, AANEM, and American Academy of Physical Medicine & Rehabilitation (2009) issued a practice parameter, ^8, on the evaluation of distal symmetric polyneuropathy. This parameter was reaffirmed in July 2013, and an update is currently in progress. This document addressed the use of autonomic testing in the evaluation of patients with distal symmetric polyneuropathy. The following conclusion and recommendations were made:

"Autonomic testing is probably useful in documenting autonomic nervous system involvement in polyneuropathy (Class II and Class III). The sensitivity and specificity vary with the particular test. The utilization of the combination of autonomic reflex screening tests in the CASS [Composite Autonomic Severity Score] probably provides the highest sensitivity and specificity for documenting autonomic dysfunction (Class II).

• Autonomic testing should be considered in the evaluation of patients with polyneuropathy to document autonomic nervous system involvement (Level B).
• Autonomic testing should be considered in the evaluation of patients with suspected autonomic neuropathies (Level B) and may be considered in the evaluation of patients with suspected distal SFSN [small fiber sensory neuropathy] (Level C).
• The combination of autonomic screening tests in the CASS should be considered to achieve the highest diagnostic accuracy (Level B)."

AANEM (2017) published a position statement on the proper performance of autonomic function testing.^22, AANEM recommended that:

• "Autonomic testing procedures be performed by physicians with comprehensive knowledge of neurologic and autonomic disorders to ensure precise interpretation and diagnosis at completion of testing," and that
• "The same physician should directly supervise and interpret the data on-site…", and
• "It is inappropriate to interpret autonomic studies without obtaining a relevant history to understand the scope of the problem, obtaining a relevant physical examination to support a diagnosis, and providing the necessary oversight in the design and performance of testing."

AAN published a model coverage policy on autonomic testing in 2014.^2, The document addressed:

• The qualifications of physicians who perform ANS testing.
• Techniques used in ANS testing.
• The types of patients who will benefit from ANS testing.
• The clinical indications for testing.
• Diagnoses where testing is indicated.
• Indications for which data are limited.

The American Diabetes Association has published annual standards of care for treatment in diabetes.^23, The 2020 publication contained the following statements on screening for autonomic neuropathy in diabetes :

• "All patients should be assessed for diabetic peripheral neuropathy starting at diagnosis of type 2 diabetes and 5 years after the diagnosis of type 1 diabetes and at least annually thereafter. (B)
• Assessment for distal symmetric polyneuropathy should include a careful history and assessment of either temperature or pinprick sensation (small fiber function) and vibration sensation using a 128-Hz tuning fork (for large-fiber function). All patients should have annual 10-g monofilament testing to identify feet at risk for ulceration and amputation. (B)
• Symptoms and signs of autonomic neuropathy should be assessed in patients with microvascular complications. (E)"

European Society of Cardiology

The European Society of Cardiology (2017) published a position statement on potential treatments for dysfunction of the autonomic nervous system in context of heart failure. ^24,The statement cited some noninvasive ANS tests, such as standing, deep breathing, and Valsalva's maneuvers, but noted that none of these has shown "prognostic importance."

European Federation of Neurological Societies

The European Federation of Neurological Societies (2011) issued a revision of its guidelines on orthostatic hypotension.^25, The guidelines made a level C recommendation that ANS screening tests with other appropriate investigations should be considered depending on the possible etiology of the underlying disorder.

National Institute for Health and Care Excellence

The National Institute for Health and Care Excellence issued guidance (2018) on Neuropad for detecting preclinical diabetic peripheral neuropathy (MTG38).^26, The guidance states “The case for adopting Neuropad to detect preclinical diabetic peripheral neuropathy is not supported by the evidence”.

U.S. Preventive Services Task Force Recommendations

Not applicable.

Ongoing and Unpublished Clinical Trials

Some currently unpublished trials that might influence this policy are listed in Table 3.

Table 3. Summary of Key Trials

NCT No.	Trial Name	Planned Enrollment	Completion Date
Ongoing
NCT02985710	Assessment of Small Fiber Neuropathy in Rare Diseases Using Sudoscan	100	Aug 2019 (ongoing)
NCT03990142	Study of Abnormalities of the Vegetative Nervous System in the Occurrence of Intradialytic Arterial Hypotension (Intervention: SudoScan)	300	Jun 2020
NCT01568177	Cardiac Autonomic Function in Women With Microvascular Coronary Dysfunction	60	Feb 2021 (ongoing)
NCT03043768a	Cutaneous Autonomic Pilomotor Testing to Unveil the Role of Neuropathy Progression in Early Parkinson's Disease (CAPTURE PD)	104	Dec 2019 (unknown)
NCT04071535	Application of Skin Biopsy in the Early Diagnosis of Small Fiber Neuropathy in Chinese Patients With Diabetes (Intervention: SudoScan)	100	Jul 2021
NCT00608725	Pathophysiology of Orthostatic Intolerance	100	Dec 2021
Unpublished
NCT03156400	Assessment of Autonomic Function and Cardiovascular Response to Exercise Testing in Parkinson's Disease Patients	30	Jun 2018
NCT02767037	SudoScan as a Biomarker of Parkinson's Disease	140	Jun 2018

NCT: national clinical trial.
a Denotes industry-sponsored or cosponsored trial.]
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Horizon BCBSNJ Medical Policy Development Process:

This Horizon BCBSNJ Medical Policy (the “Medical Policy”) has been developed by Horizon BCBSNJ’s Medical Policy Committee (the “Committee”) consistent with generally accepted standards of medical practice, and reflects Horizon BCBSNJ’s view of the subject health care services, supplies or procedures, and in what circumstances they are deemed to be medically necessary or experimental/ investigational in nature. This Medical Policy also considers whether and to what degree the subject health care services, supplies or procedures are clinically appropriate, in terms of type, frequency, extent, site and duration and if they are considered effective for the illnesses, injuries or diseases discussed. Where relevant, this Medical Policy considers whether the subject health care services, supplies or procedures are being requested primarily for the convenience of the covered person or the health care provider. It may also consider whether the services, supplies or procedures are more costly than an alternative service or sequence of services, supplies or procedures that are at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of the relevant illness, injury or disease. In reaching its conclusion regarding what it considers to be the generally accepted standards of medical practice, the Committee reviews and considers the following: all credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, physician and health care provider specialty society recommendations, the views of physicians and health care providers practicing in relevant clinical areas (including, but not limited to, the prevailing opinion within the appropriate specialty) and any other relevant factor as determined by applicable State and Federal laws and regulations.

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Index:
Autonomic Nervous System Testing
ANX 3.0 System
Bodytronic 200
Dopplex Ability
QSART Test
Quantitative Sudomotor Axon Reflex Test
Sudomotor Function
Sweat Testing
Silastic Sweat Test
Thermoregulatory Sweat Test
Sympathetic Skin Response
Salivation Test
Sudoscan®

References:
1. Klein CM. Evaluation and management of autonomic nervous system disorders. Semin Neurol. Apr 2008; 28(2): 195-204. PMID 18351521

2. Gibbons CH, Cheshire WP, Fife TD. American Academy of Neurology Model Coverage Policy: Autonomic Nervous System Testing. 2014; https://www.aan.com/siteassets/home-page/tools-and-resources/practicing-neurologist--administrators/billing-and-coding/model-coverage-policies/14autonomicmodel_tr.pdf Accessed April 20, 2020.

3. Vinik AI, Ziegler D. Diabetic cardiovascular autonomic neuropathy. Circulation. Jan 23 2007; 115(3): 387-97. PMID 17242296

4. Valensi P, Sachs RN, Harfouche B, et al. Predictive value of cardiac autonomic neuropathy in diabetic patients with or without silent myocardial ischemia. Diabetes Care. Feb 2001; 24(2): 339-43. PMID 11213889

5. Freeman R. Autonomic peripheral neuropathy. Lancet. Apr 2005; 365(9466): 1259-70. PMID 15811460

6. McDougall AJ, McLeod JG. Autonomic neuropathy, II: Specific peripheral neuropathies. J Neurol Sci. Jun 1996; 138(1-2): 1-13. PMID 8791232

7. Goldstein DS, Robertson D, Esler M, et al. Dysautonomias: clinical disorders of the autonomic nervous system. Ann Intern Med. Nov 05 2002; 137(9): 753-63. PMID 12416949

8. England JD, Gronseth GS, Franklin G, et al. Practice Parameter: evaluation of distal symmetric polyneuropathy: role of autonomic testing, nerve biopsy, and skin biopsy (an evidence-based review). Report of the American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, and American Academy of Physical Medicine and Rehabilitation. Neurology. Jan 13 2009; 72(2): 177-84. PMID 19056667

9. Low PA. Testing the autonomic nervous system. Semin Neurol. Dec 2003; 23(4): 407-21. PMID 15088262

10. TRIGOcare International GmbH. Neuropad: Diagnostic test for sudomotor dysfunction and early detection of diabetic foot syndrome, diabetic neuropathy. 2014; https://www.neuropad.com/. Accessed April 24, 2020.

11. Bellavere F, Ragazzi E, Chilelli NC, et al. Autonomic testing: which value for each cardiovascular test? An observational study. Acta Diabetol. Jan 2019; 56(1): 39-43. PMID 30159748

12. Park JY, Yang D, Yang HJ, et al. Quantitative autonomic function test in differentiation of multiple system atrophy from idiopathic Parkinson disease. Chin Med J. Aug 20 2019; 132(16): 1919-1924. PMID 31373907

13. Franca da Silva AK, Penachini da Costa de Rezende Barbosa M, Marques Vanderlei F, et al. Application of Heart Rate Variability in Diagnosis and Prognosis of Individuals with Diabetes Mellitus: Systematic Review. Ann Noninvasive Electrocardiol. May 2016; 21(3): 223-35. PMID 27226209

14. Kings Technology Evaluation Centre. Neuropad test for the early detection of diabetic foot neuropathy. 2017; https://www.nice.org.uk/guidance/mtg38/documents/assessment-report. Accessed April 24, 2020.

15. Didangelos T, Zografou I, Iliadis F, et al. Validation of Neuropad in the assessment of peripheral diabetic neuropathy in patients with Diabetes Mellitus versus the Michigan Neuropathy Screening Instrument, 10 g Monofilament application and Biothesiometer measurement. Curr Vasc Pharmacol. Jul 23 2019. PMID 31340739

16. Rajan S, Campagnolo M, Callaghan B, et al. Sudomotor function testing by electrochemical skin conductance: does it really measure sudomotor function?. Clin Auton Res. Feb 2019; 29(1): 31-39. PMID 29956008

17. Fortanier E, Delmont E, Verschueren A, et al. Quantitative sudomotor test helps differentiate transthyretin familial amyloid polyneuropathy from chronic inflammatory demyelinating polyneuropathy. Clin Neurophysiol. May 2020; 131(5): 1129-1133. PMID 32217467

18. D'Amato C, Greco C, Lombardo G, et al. The diagnostic usefulness of the combined COMPASS 31 questionnaire and electrochemical skin conductance for diabetic cardiovascular autonomic neuropathy and diabetic polyneuropathy. J Peripher Nerv Syst. Mar 2020; 25(1): 44-53. PMID 31985124

19. Carbajal-Ramirez A, Hernandez-Dominguez JA, Molina-Ayala MA, et al. Early identification of peripheral neuropathy based on sudomotor dysfunction in Mexican patients with type 2 diabetes. BMC Neurol. May 31 2019; 19(1): 109. PMID 31151430

20. Xu X, Liao J, Dong Q, et al. Clinical utility of SUDOSCAN in predicting autonomic neuropathy in patients with Parkinson's disease. Parkinsonism Relat Disord. Jul 2019; 64: 60-65. PMID 30890381

21. Popescu C. Small fiber neuropathy in Parkinson's disease explored by the sudoscan. Parkinsonism Relat Disord. Sep 2019; 66: 261-263. PMID 31416687

22. Policy Department, American Association of Neuromuscular & Electrodiagnostic Medicine, Rochester, Minnesota, USA. Proper performance of autonomic function testing. Muscle Nerve. Jan 2017; 55(1): 3-4. PMID 27786371

23. American Diabetes Association. 11. Microvascular Complications and Foot Care: Standards of Medical Care in Diabetes-2020. Diabetes Care. Jan 2020; 43(Suppl 1): S135-S151. PMID 31862754

24. van Bilsen M, Patel HC, Bauersachs J, et al. The autonomic nervous system as a therapeutic target in heart failure: a scientific position statement from the Translational Research Committee of the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail. Nov 2017; 19(11): 1361-1378. PMID 28949064

25. Lahrmann H, Cortelli P, Hilz M, et al. Orthostatic hypotension. In: Gilhus NE, Barnes MP, Brainin M, eds. European Handbook of Neurological Management: Volume 1, 2nd Edition. Hoboken, NJ: Wiley-Blackwell; 2011.

26. National Institute for Health and Care Excellence (NICE). Neuropad for detecting preclinical diabetic peripheral neuropathy [MTG38]. 2018; https://www.nice.org.uk/guidance/mtg38. Accessed April 23, 2020.

Codes:
(The list of codes is not intended to be all-inclusive and is included below for informational purposes only. Inclusion or exclusion of a procedure, diagnosis, drug or device code(s) does not constitute or imply authorization, certification, approval, offer of coverage or guarantee of payment.)

CPT*

95921
95922
95923
95924
95943