| Coverage Policy Manual | |
| Policy #: | 2014022 |
| Category: | Medicine |
| Initiated: | November 2014 |
| Last Review: | November 2023 |
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| Autonomic Nervous System Testing | |
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| Description: |
The ANS has a primary role in controlling physiologic processes that are not generally under conscious control. These include heart rate, respirations, gastrointestinal (GI) motility, thermal regulation, bladder control, and sexual function. It is a complex neural regulatory network that consists of 2 complementary systems that work together to maintain homeostasis. 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 on 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.
ANS 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 patients with multiple systems atrophy, which leads to widespread and severe autonomic failure.
Symptoms of autonomic disorders can be varied, 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 (Vinik, 2007). 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 an approximately 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) (Valensi, 2001). There is also an increase in cardiac sudden death and overall mortality for these patients (Vinik, 2007).
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 (Freeman, 2005).
A classification of the different types of autonomic dysfunction, adapted from Freeman et al and Macdougall et al (McDougall, 1996), can be made as follows:
A variety of other chronic diseases may involve an imbalance of the ANS, without outright dysfunction of the nerves themselves. Approximately 40% of individuals with essential hypertension will show evidence of excess sympathetic activity (Goldstein, 2002). Sympathetic overactivity is also a prominent feature of generalized anxiety, panic disorder, and some types of depression, as well as certain cardiac disorders such as chronic heart failure. These types of ANS imbalances are not usually classified as ANS disorders.
Much of the treatment of autonomic disorders is nonpharmacologic and supportive. However, there are specific actions that can be taken to 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 (Klein, 2008). 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 (Klein, 2008).
ANS Testing
ANS testing consists of a battery of individual tests. Any one test may be performed individually, or the entire battery of tests may be ordered. Individual components of testing may include:
Composite Autonomic Severity Score
The Composite Autonomic Severity Score, which ranges from 0 to 10, is intended to estimate 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.
At least 1 test in each category is usually performed. More than 1 test from a category will often be included in a battery of tests, but the incremental value of using multiple tests in a category is unknown.
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:
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.
The Neuropad test (TRIGOcare) is another example of a commercially available sudomotor function test (TRIGOcare, 2014). No records were identified indicating that Neuropad® has been cleared for marketing by the US FDA, however.
Autonomic Nervous System Test Devices
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Policy/ Coverage: |
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
Autonomic nervous system testing, consisting of a battery of tests in several domains meets member benefit certificate primary coverage criteria when the following criteria are met:
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
Autonomic nervous system testing does not meet member benefit certificate primary coverage criteria in all other situations when criteria are not met, including but not limited to the evaluation of the following conditions:
For members with contracts without primary coverage criteria, autonomic nervous system testing is considered investigational in all other situations as outlined above. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Autonomic nervous system testing using portable automated devices has not been validated and does not meet member benefit certificate primary coverage criteria for all indications.
For members with contracts without primary coverage criteria, autonomic nervous system testing using portable automated devices is considered investigational for all indications.
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| Rationale: |
Assessment of a diagnostic technology typically focuses on 3 categories of evidence: (1) technical performance (test-retest reliability or interrater reliability); (2) diagnostic accuracy (sensitivity, specificity, and positive and negative predictive value) in relevant populations of patients; and (3) demonstration that the diagnostic information can be used to improve patient outcomes. In addition, subsequent use of a technology outside of the investigational setting may also be evaluated. These categories of evidence, although not always evaluated in sequence, can be considered similar to the 4 phases of therapeutic studies.
Technical Performance
Autonomic nervous system (ANS) testing is essentially the only laboratory method available to evaluate dysfunction of the ANS. Because of the lack of a true criterion standard of autonomic dysfunction, the validity of results of ANS testing cannot be determined.
Some evidence was identified about the reliability of ANS testing, particularly for heart rate variability (HRV). A number of studies have reported that the test-retest reliability of ANS is high over short periods of time,10 but reliability over longer time periods is less certain. A systematic review of published studies on the reliability of HRV was published in 2005 (Sandercock, 2005). The author identified 8 studies (183 individuals) that reported on the reliability of short-term recordings (ie, excluding studies that used 24-hour monitoring). Four studies included healthy patients, 3 included patients with cardiac disease, and 1 included both healthy and cardiac patients. Studies used different measures of HRV, and the authors performed a qualitative synthesis of the results. For 3 of the 5 studies that included healthy individuals, the reliability was high, with coefficients of variation (CV) ranging from 6% to 15%. However, in 2 studies the CV was much higher, 20% in one and 45% in the other. For patients with cardiac disease, the reliability was lower, with CVs being higher and reaching 100% in 1 study.
Less evidence was available for other specific tests. For sudomotor testing, 2 small studies of reliability were identified (Berger, 2013; Peltier, 2009). Berger et al evaluated the reliability of the Quantitative Sudomotor Axon Reflex Test (QSART) measure in 20 healthy individuals (Berger, 2013). They reported intraclass correlation coefficients (ICCs) at 3 different body sites ranging from 0.49 to 0.75 indicating moderate reliability, and standard error of measurements ranging from 0.273 to 0.978 indicating large standard errors. Peltier et al evaluated both QSART and the Quantitative Sensory Test (QST) measures in 23 patients with impaired glucose regulation and neuropathy (Peltier, 2009). The ICCs were high for both measures, ranging from 0.52 to 0.80. The QST measure was more reliable (ICC range, 0.75-0.80) than the QSART (ICC=0.52) indicating suboptimal reliability.
Some studies have evaluated the reproducibility of tilt testing, usually by repeating the study in patients with an initial positive test. An example of this type of study was published by Kochiadakis et al in 1998 (Kochiadakis, 1998). This study evaluated 35 patients with syncope and a positive tilt table test with a repeat tilt table test. The study also included a comparison group of 15 healthy volunteers who underwent 2 tilt table tests. In conjunction with tilt table testing, the study also recorded HRV. A total of 21 of the 35 patients (60%) had a second positive test, while none of the healthy controls had any positive test. HRV results showed that high parasympathetic predicted a second positive test.
Section Summary
The main evidence on the technical performance of ANS testing is on the reliability of some individual tests, mostly test-retest reproducibility. The available evidence is incomplete, and there is a lack of high-quality studies reporting on reliability. The research that is available is variable, but in most cases does not show high reproducibility. Therefore, there is a concern that these tests are not reliable, although further research is needed to evaluate this with more certainty.
Diagnostic Accuracy
There are a number of challenges in evaluating the diagnostic accuracy of ANS testing:
Scattered reports of diagnostic accuracy for specific tests in specific patient groups were available, but high-quality research on the diagnostic accuracy of testing is lacking. The most rigorous evaluation of diagnostic accuracy identified was in the systematic review by the American Academy of Neurology (AAN), the American Association of Neuromuscular and Electrodiagnostic Medicine (AANEM), and the American Academy of Physical Medicine and Rehabilitation (AAPM&R), which focused on the accuracy of autonomic testing for distal symmetric polyneuropathy (American Academy of Neurology, 2013). While reported sensitivity and specificity are high, the populations in these studies include patients with known disease and healthy volunteers. These populations are not optimal for determining diagnostic accuracy and are known to lead to inflated estimates of both sensitivity and specificity.
Evidence on the sensitivity and specificity of a silastic sweat testing device, the Neuropad® device (Crawford Healthcare, Knutsford Chesire, UK) was identified. Kamenov et al enrolled 264 inpatients with diabetes (Kamenov, 2010). Patients with autonomic neuropathy were identified by the Neuropathy Disability Score, with a cutoff of 5 indicating autonomic neuropathy. An abnormal silastic sweat test had a sensitivity of 76%, a specificity of 56%, a positive predictive value of 86% and a negative predictive value of 40%. In a similar study, Quattrini et al evaluated 57 diabetic patients with several autonomic tests, including the Neuropad® device (Quattrini, 2008). The sensitivity of silastic sweat testing in this study was 85%, the specificity was 45%, the positive predictive value was 69% and the negative predictive value was 71%.
A 2013 publication by Casselini et al evaluated the accuracy of an electrochemical sweat conductance test, compared with other available tests of sudomotor function (Cassellini, 2013). This study evaluated 83 patients with diabetes mellitus (DM) (60 with peripheral neuropathy, 20 without peripheral neuropathy) and 210 normal controls with the Sudoscan test. Electrochemical skin conductance of the feet was lowest for patients with DM and neuropathy (56.3±3), intermediate for patients with DM without neuropathy (75.9±5.5) and highest for normal volunteers (84.4±0.9, p<0.001 for group differences). Using clinically defined neuropathy as the criterion standard, sensitivity was 78% and specificity was 92%. Results of the test correlated significantly with a number of other measures, including symptom scores, QST, and measures of HRV. The correlations were in the low-to-moderate range with Spearman’s correlation coefficient rho ranging from 0.24 to 0.47.
Section Summary
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 reports 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 results of these studies probably do not reflect the diagnostic accuracy of testing in clinical practice.
Impact on Health Outcomes
Use of autonomic 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 autonomic testing on changes in management or health outcomes. It is likely that these tests provide information beyond that obtainable from the clinical exam alone, given the limitations of 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 as well. In those cases, determining that autonomic dysfunction is the cause of symptoms may end the need for further testing.
Evaluation of Clinical Practice Guidelines
This section will evaluate the existing clinical practice guidelines, with a focus on whether they are evidence-based. The consistency of recommendations will also be considered. In cases where guidelines differ from each other, the ones which are more evidence-based will be favored.
For autonomic testing in general, there are few guidelines that focus on indications for testing. The guidelines that do exist restrict their recommendations to specific diagnoses.
A single evidence-based guideline was identified (American Academy of Neurolgoy, 2013). This document addressed the use of autonomic testing in the evaluation of patients with distal symmetric polyneuropathy, developed jointly by AAN, AANEM, and AAPM&R. The societies convened a Polyneuropathy Task Force, consisting of 19 physician representatives from the 3 societies. All had expertise in polyneuropathy, in addition 4 had expertise in evidence-based methodology and practice parameter development. The taskforce developed a set of questions, and subcommittees were formed to address each question.
Each subcommittee performed a systematic review of the literature on their specific question. The subcommittee members determined whether articles were potentially relevant to the evaluation of polyneuropathy. For each included article, 3 physicians reviewed independently for risk of bias, disagreements were resolved by discussion. The strength of recommendations and levels of evidence were taken from existing procedures used by AAN.
Section Summary
There is a lack of evidence-based guidelines on ANS testing. Even in guidelines that involve a systematic review of the literature, such as the joint AAN/AANEM/AAPM&R guidelines previously discussed, the recommendations are largely based on expert consensus.
Summary of Evidence
The evidence base on the diagnostic accuracy of autonomic nervous system (ANS) testing, and the impact on health outcomes, is incomplete. 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, there are numerous different tests that are used in a variety of different conditions, making it difficult to determine values for overall diagnostic accuracy of a battery of tests. The evidence on reliability of individual tests raises concerns about the reproducibility of testing. Scattered reports of diagnostic accuracy are available for certain individual tests, most commonly in the diabetic population, but this does not provide estimates of accuracy for the entire battery of tests. Reported sensitivities and specificities were 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 the study designs that use patients with clinically diagnosed disease and a control group of healthy volunteers.
There are also few clinical practice guidelines from specialty societies, and the available recommendations are based primarily on expert opinion. The guidelines give general recommendations for testing as an adjunct to clinical examination for the diagnosis of autonomic disorders.
Despite the deficiencies in the evidence base, these tests provide information that cannot be obtained by other methods. Given the limitations of clinical examination, it is likely that ANS testing adds incremental information on the likelihood of an ANS disorder in patients with signs and symptoms of ANS dysfunction. Improved ability to make a diagnosis will lead to management changes that are likely to improve outcomes in some patients, and in others, may end the need for further diagnostic testing. In addition, expert opinion strongly supports the use of ANS testing as a diagnostic aid in situations of suspected ANS disorders.
ANS testing should be performed in the setting of a dedicated ANS testing laboratory. Testing in a dedicated laboratory can be performed under closely controlled conditions, and interpretation of the results performed by an individual with expertise in ANS testing. Portable, automated testing that is intended for office use has not been validated and has a greater potential to lead to erroneous results.
Therefore, based on the available evidence and clinical input, ANS testing in a dedicated ANS testing laboratory may be considered to be medically necessary in patients with signs and symptoms of autonomic dysfunction when criteria are met.
Practice Guidelines and Position Statements
The American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation issued a 2009 practice parameter (American Academy of Neurology, 2013), which was reaffirmed in July of 2013 on the evaluation of distal symmetric polyneuropathy. The following conclusion and recommendation was made: “Autonomic testing is probably useful in documenting autonomic nervous system involvement in polyneuropathy (class II and III). The sensitivity and specificity vary with the particular test. The utilization of the combination of autonomic reflex screening tests in the CASS 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 (level C). The combination of autonomic screening tests in the CASS should be considered to achieve the highest diagnostic accuracy (level B).
The American Diabetes Association published standards of care for treatment in diabetes in 2010 (American Diabetes Association, 2010). This document contained the following statement about autonomic neuropathy in diabetes:
The European Federation of Neurological Societies issued a 2011 revision of their guideline on orthostatic hypotension (European Federation of Neurological Societies, 2011). The guideline made a level C recommendation stating that ANS screening tests with other appropriate investigations, should be considered depending on the possible etiology of the underlying disorder.
2015 Update
A literature search conducted through October 2015 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
A more recent diagnostic accuracy study of the Neuropad® device was published in 2014 (Ponirakis, 2014). This study included 38 patients with diabetic peripheral neuropathy and 89 patients without neuropathy. The diagnostic performance of Neuropad was compared to a number of other measures of nerve function. When compared to other measures of large-fiber dysfunction, the Neuropad had a sensitivity ranging from 70- 83% and a specificity ranging from 50-54%. When compared to a measure of small fiber function, the corneal nerve fiber length, the sensitivity was 83% and the specificity was 80%.
The evidence on the diagnostic accuracy of ANS testing for patients with signs and symptoms of autonomic nervous system dysfunction includes studies of diagnostic accuracy. Relevant outcomes include test accuracy, test validity, other test performance measures, symptoms, functional outcomes, health status measures, and quality of life. The evidence base is limited by a number of factors. 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, there are numerous different tests that are used in a variety of different conditions, making it difficult to determine values for overall diagnostic accuracy of a battery of tests. The evidence on reliability of individual tests raises concerns about the reproducibility of testing. Scattered reports of diagnostic accuracy are available for certain individual tests, most commonly in the diabetic population, but this does not provide estimates of accuracy for the entire battery of tests. Reported sensitivities and specificities were 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 the study designs that use patients with clinically diagnosed disease and a control group of healthy volunteers. There are also few clinical practice guidelines from specialty societies, and the available recommendations are primarily based on expert opinion. The evidence is insufficient to determine the effects of the technology on health outcomes.
November 2017
A literature search using the MEDLINE database through October 2017 did not reveal any new literature that would prompt a change in the coverage statement. The key identified literature is summarized below.
In 2016, da Silva et al reported on a systematic review of the accuracy of HRV for the diagnosis and prognosis of cardiac autonomic neuropathy in individuals with diabetes (da Silva, 2016). Reviewers included 8 studies, finding that HRV is useful to discriminate cardiac autonomic neuropathy. Measures of sample entropy, SD1/SD2 indices (standard deviation of the instantaneous variability and long-term variability), SDANN (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 sensitivity ranging from 72% to 100% and specificity ranging from 71% to 97%.
American Association of Neuromuscular and Electrodiagnostic Medicine
AANEM published a positon statement in 2017 on the proper performance of autonomic function Testing (AANEM, 2017). AANEM recommends that:
2018 Update
A literature search was conducted through October 2018. There was no new information identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
European Society of Cardiology
The European Society of Cardiology published a position statement on potential treatments for dysfunction of the autonomic nervous system in context of heart failure (ESC, 2017). 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.”
2019 Update
Annual policy review completed with a literature search using the MEDLINE database through October 2019. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
Bellavere et al published an observational study comparing three 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 (Bellavere, 2019). 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.
2020 Update
Annual policy review completed with a literature search using the MEDLINE database through October 2020. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
A study by Park et al 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 (Park, 2019). 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.
The Neuropad® test (TRIGOcare) is another example of a commercially available sudomotor function test (TRIGOcare, 2014). No records were identified indicating that Neuropad® has been cleared for marketing by the US FDA, however.
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) published an evidence review on the Neuropad test for the early detection of diabetic neuropathy (Kings Technology Evaluation Centre, 2017). 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 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) (Didangelos, 2019). 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.
The National Institute for Health and Care Excellence issued guidance on Neuropad for detecting preclinical diabetic peripheral neuropathy (NICE, 2018). The guidance states “The case for adopting Neuropad to detect preclinical diabetic peripheral neuropathy is not supported by the evidence”.
Rajan et al 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 type 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 (Rajan, 2019). 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 follow-up, 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. 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 discussed above.
A study by Fortanier et al 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 (Fortanier, 2020).
In diabetes, a study by D’Amato et al, 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 (D’Amato, 2020). 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, 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 (Carbajal-Ramirez, 2019). 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 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 (Xu, 2019). Authors of the study by Xu et al 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 Popescu et al, no significant reduction in electrochemical skin conductance measured by Sudoscan was found in 67 individuals with PD compare with 66 age-matches controls (Popescu, 2019).
The American Diabetes Association annual standards of care for treatment in diabetes (American Diabetes Association, 2020). The 2020 publication contained the following statements on screening for autonomic neuropathy in diabetes:
Recommendation ratings B: supportive evidence from well conducted cohort studies.
Recommendation ratings E: expert consensus or clinical experience.
2021 Update
Annual policy review completed with a literature search using the MEDLINE database through October 2021. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
In diabetes, a study by Lai et al (2021) evaluated the combination of Sudoscan and HRV, measured as the standard deviation of the RR interval, in diagnosing cardiovascular autonomic neuropathy in 90 patients with type 2 diabetes (Lai, 2021). When combined, the specificity increased from 56.2% (HRV) and 40.6% (Sudoscan) to 70%, and the specificity remained relatively unchanged at 79.4% from 76.1% (HRV) and 82.6% (Sudoscan).
2022 Update
Annual policy review completed with a literature search using the MEDLINE database through October 2022. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
Compared to the Michigan Neuropathy Screening Instrument, 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. Lin et al evaluated the use of Sudoscan in 515 patients with type 2 diabetes and found a sensitivity of 79% and specificity of 65% when evaluating the feet for peripheral neuropathy (Lin, 2022).
The American Diabetes Association has published annual standards of care for treatment in diabetes (Draznin, 2022). The 2022 publication contained the following statements on screening for autonomic neuropathy in diabetes:
Recommendation ratings B: supportive evidence from well conducted cohort studies.
Recommendation ratings E: expert consensus or clinical experience
2023 Update
Annual policy review completed with a literature search using the MEDLINE database through October 2023. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
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 (Gibbons, 2014).
In 2014, the AAN published a model coverage policy on autonomic testing (Gibbons, 2014). The document addressed:
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 (England, 2009).
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 (England, 2009).
The Quantitative Sudomotor Axon Reflex Test is an example of a commercially available semiquantitative test of sudomotor function (England, 2009). 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.
The most rigorous evaluation of diagnostic accuracy identified is in the 2009 systematic review by the American Academy of Neurology, the American Association of Neuromuscular and Electrodiagnostic Medicine, and the American Academy of Physical Medicine & Rehabilitation, which focused on the accuracy of autonomic testing for distal symmetric polyneuropathy (England, 2009).
The AAN, AANEM, and American Academy of Physical Medicine & Rehabilitation (2009) issued a practice parameter on the evaluation of distal symmetric polyneuropathy (England, 2009). This parameter was reaffirmed in July 2013 and retired in 2019. 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).
A systematic review evaluating the accuracy of HRV for the diagnosis and prognosis of cardiac autonomic neuropathy in individuals with diabetes was reported (Franca da Silva, 2016). 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 the mean of normal relative risk (RR) intervals every 5 minutes for a period of time expressed in milliseconds (i.e., intervals between heartbeats), 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%.
Subsequent to the 2017 NICE review, Didangelos et al (2019) published a study of 174 patients with diabetes that evaluated the diagnostic accuracy of Neuropad compared with the Michigan Neuropathy Screening Instrument Questionnaire and Examination (MNSIQ and MNSIE, respectively), application of 10 g MONO, and measurement of vibration perception threshold with biothesiometer (BIO) (Zografou, 2020). Sensitivity of Neuropad testing was 95% versus MONO, 73% versus BIO, 73% versus MNSIE, and 75% versus ΜNSIQ. Specificity was 69%, 81%, 90%, and 92%, respectively.
An evaluation of the diagnostic accuracy of Sudoscan compared with MONO and tuning fork tests (N=2243) for detecting diabetic peripheral neuropathy (Garcia-Ulloa, 2022).
In 2020, a consensus statement endorsed by the AAN, American Autonomic Society, and the International Federation of ClinicalNeurophysiology on assessment of the ANS was published (Cheshire, 2021). The consensus statement recommends that a combination of autonomic tests should be used for better accuracy compared to a single test, which should ideally assess cardiovascular adrenergic, cardiovagal, and sudomotor function. Recommended tests include: continuous beat-to-beat heart rate and blood pressure responses to the Valsalva maneuver, postural changes on a tilt table, or sinusoidal deep breathing; the Valsalva ratio; quantitative sudomotor axon reflex test; and the thermoregulatory sweat test.
In 2023, the AANEM updated its recommended policy for electrodiagnostic medicine (AANEM, 2023). The policy states that the purpose of ANS function testing is "to determine the presence of autonomic dysfunction, the site of autonomic dysfunction, and the various autonomic systems which may be disordered." The policy includes testing of cardiovagal innervation; vasomotor adrenergic innervation; and evaluation of sudomotor function (specifically, the quantitative sudomotor axon reflex test, silastic sweat imprint, thermoregulatory sweat test, and sympathetic skin response). Conditions for which testing may be appropriate include idiopathic orthostatic hypotension, diabetic neuropathy, and other neuropathies affecting autonomic nerves.
In 2021, the AANEM published a revised position statement on the proper performance of autonomic function testing (AANEM, 2021). The statement recommended that:
The statement recommended the following series of tests as reliable and reproducible:
The American Diabetes Association publishes annual standards of care for treatment of diabetes (ElSayed, 2023). The 2023 publication contained the following statements on screening for autonomic neuropathy in diabetes:
Recommendation ratings B: supportive evidence from well conducted cohort studies.
Recommendation ratings E: expert consensus or clinical experience.
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Group specific policy will supersede this policy when applicable. This policy does not apply to the Wal-Mart Associates Group Health Plan participants or to the Tyson Group Health Plan participants.
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