Clinical UM Guideline

This document addresses three types of autonomic testing:

• Cardiovagal (Parasympathetic) Function Tests
• Vasomotor Adrenergic (Sympathetic) Function Tests
• Sudomotor (Sympathetic Cholinergic) Function Tests.

While there is not a standardized battery of tests that are part of autonomic testing, a full battery of tests generally consists of individual tests in the three (3) categories listed above.

Note: This document does not address standalone Tilt-Table testing.

Note: Please see the following related document for additional information:

• CG-LAB-13 Skin Nerve Fiber Density Testing

Note: For a high-level overview of this document, please see “Summary for Members and Families” below.

Medically Necessary:

Autonomic testing is considered medically necessary when all of the following criteria are documented in the medical record by the treating provider as met (A and B and C):

1. Clinical features consistent with autonomic dysfunction are present (see Definition section); and
2. A conclusive diagnosis cannot be established based solely on clinical evaluation and standard laboratory testing (for example, including but not limited to one or more the following conditions):
   1. Amyloid autonomic neuropathy; or
   2. Autoimmune autonomic ganglionopathy; or
   3. Autonomic failure; or
   4. Baroreflex failure; or
   5. Chagas disease; or
   6. Chronic inflammatory demyelinating neuropathy; or
   7. Diabetic autonomic neuropathy (DAN); or
   8. Distal small fiber neuropathy; or
   9. Guillain-Barré syndrome; or
   10. Hereditary sensory and autonomic neuropathies; or
   11. Idiopathic neuropathy; or
   12. Lambert Eaton myasthenic syndrome; or
   13. Leprosy; or
   14. Lewy body dementia; or
   15. Long-COVID syndrome with suspected autonomic disorder; or
   16. Morvan syndrome; or
   17. Multiple system atrophy (MSA); or
   18. Paraneoplastic autonomic neuropathy; or
   19. Parkinson disease (PD); or
   20. Postural tachycardia syndrome (POTS); or
   21. Pure autonomic failure; or
   22. Recurrent, unexplained syncope; or
   23. Reflex sympathetic dystrophy or causalgia (sympathetically maintained pain); or
   24. Ross syndrome; or
   25. Sjogren syndrome; or
   26. Unexplained orthostatic hypotension
       and
3. Confirmation of the suspected diagnosis is expected to alter clinical management or render additional diagnostic testing unnecessary.

Not Medically Necessary:

Autonomic testing is considered not medically necessary when the criteria above have not been met, and for all other situations, including but not limited to evaluation of the following primary diagnostic considerations:

1. Allergic conditions
2. Anxiety and other psychologic disorders
3. Chronic fatigue syndrome/myalgic encephalomyelitis
4. Concussion (including detecting concussion and determining recovery of concussion symptoms)
5. Fibromyalgia
6. Flushing syndrome
7. Hypertension
8. Irritable bowel syndrome
9. Predicting foot ulcers
10. Raynaud phenomenon
11. Screening for asymptomatic individuals
12. Sleep apnea
13. Somatic symptom disorder
14. Traumatic brachial plexus injury
15. Traumatic brain injury

The following are considered not medically necessary for any indication:

1. Quantitative direct and indirect reflex test (QDIRT)
2. Quantitative pilomotor axon reflex test (QPART)
3. SUDOSCAN^®

This document describes clinical studies and expert recommendations, and explains whether autonomic testing is clinically appropriate. The following summary does not replace the medical necessity criteria or other information in this document. The summary may not contain all of the relevant criteria or information. This summary is not medical advice. Please check with your healthcare provider for any advice about your health.

Key Information

Autonomic testing is a group of tests that checks how the body controls automatic functions of the body such as heart rate, blood pressure, and sweating. A full set of testing often includes heart and blood pressure tests and sweat tests. This type of testing may help when a problem with the autonomic nervous system (ANS) is suspected and usual exams and lab tests have not given a clear answer. Studies and expert groups support using several types of autonomic tests together, because one test alone may miss part of the problem. Some parts of testing can be uncomfortable, such as skin stimulation, heat during sweat testing, or standing and breathing maneuvers. The overall benefit of this type of testing depends on the proper selection of tests to match the symptoms of the person.

What the Studies Show

Studies and expert statements by the American Autonomic Society (AAS), the American Academy of Neurology (AAN), and International Federation of Clinical Neurophysiology (IFCN) suggest that a battery of autonomic tests can help describe patterns of nerve problems that affect heart rate, blood pressure, and sweating. This can be useful in some people with conditions like unexplained fainting, postural tachycardia syndrome (POTS), diabetic nerve damage, multiple system atrophy (MSA), Parkinson disease (PD), and long COVID. Research also suggests that using several types of tests together is better than relying on one test alone.

In sweat testing, the quantitative sudomotor axon reflex test (QSART) and the thermoregulatory sweat test (TST) can show different patterns of sweat loss. These patterns may help doctors tell some disorders apart. Still, results do not always clearly show how care will change, and test findings can vary from one person to another.

Some newer or less studied tests have important limits. Quantitative direct and indirect reflex testing (QDIRT) and quantitative pilomotor axon reflex testing (QPART) were studied in small early studies done at one center, mostly in healthy people, and better studies are needed to know if these tests improve health outcomes. Studies of electrochemical skin conductance testing (SUDOSCAN) have shown mixed results. In diabetes and PD, some studies found possible value as a screening tool, but other studies found only modest accuracy or inconsistent results compared with standard testing. Unnecessary or unproven tests can lead to treatment that does not help. Some tests may also cause discomfort, lightheadedness, or changes in blood pressure during testing. The balance of benefits and harms is not clear for these newer tests.

When is Autonomic Testing Clinically Appropriate?

Autonomic testing may be appropriate in these situations:

• A treating provider documents symptoms or signs that fit autonomic dysfunction; and
• The person has one or more conditions linked with suspected autonomic dysfunction, such as amyloid autonomic neuropathy, autoimmune autonomic ganglionopathy, autonomic failure, baroreflex problems, Chagas disease, chronic inflammatory demyelinating neuropathy, delayed orthostatic hypotension, diabetic autonomic neuropathy (DAN), distal small fiber neuropathy, Guillain-Barré syndrome, hereditary sensory and autonomic neuropathies, idiopathic neuropathy, Lambert-Eaton myasthenic syndrome, leprosy, Lewy body dementia, long COVID with suspected autonomic disorder, Morvan syndrome, MSA, paraneoplastic autonomic neuropathy, PD, POTS, pure autonomic failure, recurrent unexplained syncope, reflex sympathetic dystrophy or causalgia, Ross syndrome, or Sjogren syndrome; and
• A clear diagnosis cannot be made from the clinical exam and standard lab testing alone; and
• The test results are expected to change treatment decisions or make more testing unnecessary.

Depending on the suspected condition, testing must include one or more of the following:

• For heart rate control problems, at least two of the following:
  • 30:15 ratio test; or
  • Heart rate variability with deep breathing (HRDB); or
  • Valsalva maneuver.
• For blood pressure control problems, all of the following:
  • Beat to beat blood pressure monitoring; and
  • Head up tilt table test for at least 5 minutes; and
  • Valsalva maneuver.
• For sweating problems, at least one of the following:
  • Quantitative sudomotor axon reflex test (QSART); or
  • Silastic Sweat Test (SSI); or
  • Sympathetic skin response (SSR); or
  • Thermoregulatory sweat test (TST).
• For combined testing of heart rate and blood pressure control:
  • Head up tilt table test for at least 5 minutes; and
  • Any two or more of the following:
    • 30:15 ratio test; or
    • Active standing test; or
    • Beat to beat blood pressure monitoring; or
    • Heart rate variability with deep breathing (HRDB); or
    • Plasma norepinephrine levels measured lying down and standing; or
    • Valsalva maneuver.

When is this not Clinically Appropriate?

Autonomic testing is not clinically appropriate when the criteria above are not met. It is also not appropriate for other uses, including:

• Allergic conditions
• Anxiety or other mental health conditions
• Chronic fatigue syndrome
• Concussion or tracking recovery after concussion
• Fibromyalgia
• High blood pressure
• Irritable bowel syndrome
• Screening people without symptoms
• Sleep apnea
• Traumatic brain injury

The following tests are not clinically appropriate for any use because they have not been proven to improve health outcomes:

• Quantitative direct and indirect reflex test, QDIRT
• Quantitative pilomotor axon reflex test, QPART
• SUDOSCAN

These products are not recommended because studies have been limited, results have been inconsistent, or both.

(Return to Description)

The following codes for treatments and procedures applicable to this guideline are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.

When services may be Medically Necessary when criteria are met:

When services are Not Medically Necessary:
For the procedure codes listed above when criteria are not met, for services specified in the Clinical Indications as not medically necessary, or for the following diagnosis codes

When services are also Not Medically Necessary:

Summary

This document outlines the appropriate use of autonomic testing across cardiovagal, adrenergic, and sudomotor domains for evaluation of suspected autonomic dysfunction when results are expected to clarify diagnosis or guide management. It supports use of a multi-domain testing battery rather than single tests, consistent with expert consensus from organizations such as the American Autonomic Society (AAS), American Academy of Neurology (AAN), and International Federation of Clinical Neurophysiology (IFCN), with additional condition-specific guidance from groups including American College of Cardiology (ACC)/American Heart Association (AHA)/Heart Rhythm Society (HRS) for syncope and from the American Diabetes Association (ADA) and American Association of Clinical Endocrinology (AACE). Evidence indicates autonomic testing can aid in characterizing disorders such as syncope, postural tachycardia syndrome (POTS), diabetic autonomic neuropathy (DAN), and neurodegenerative conditions, although findings may be variable and not always clearly linked to changes in management. The guideline also identifies several emerging or less validated technologies as not medically necessary and emphasizes that results should be interpreted in conjunction with clinical evaluation and other diagnostic data.

Discussion

Sudomotor Testing

Sudomotor testing is used to evaluate the small nerve fibers associated with sweating and aid in the evaluation of neuropathy, specifically assessing distal sympathetic polyneuropathy. A 2021 consensus statement on Electrodiagnostic Assessment of the Autonomic Nervous System (ANS) endorsed by the AAS, AAN, and the IFCN (Cheshire, 2021) states:

Autonomic peripheral neuropathies are subject to investigation and quantification by electrodiagnostic autonomic testing. Laboratory evidence of autonomic neuropathy may be found with or without corresponding symptoms. The most common laboratory changes comprise a concomitant involvement of distal postganglionic sudomotor and cardiovagal autonomic neuropathy without orthostatic hypotension.

The guidance is based on expert consensus and includes the following recommendations:

Testing of the autonomic nervous system in the clinical autonomic laboratory should be performed by healthcare professionals with comprehensive knowledge of the neuroanatomy, physiology, and pathological profiles of autonomic disorders. Interpretation of autonomic test results should be based also on a medical history and physical examination, from which autonomic testing assists in confirming or eliminating potential conditions in a differential diagnosis.

A combination of autonomic tests in a screening battery provides a more accurate measure of autonomic function, as a single test alone cannot distinguish the type or severity of autonomic failure. Ideally, assessment of autonomic function should include tests of cardiovascular adrenergic, cardiovagal, and sudomotor function. In resource limited settings the knowledge and expertise of the person interpreting autonomic tests is no less important. Before the results are interpreted as normal or abnormal, consideration should be given to potentially confounding factors, such as medications, equipment settings, room conditions, or patient factors that might have altered the findings.

Quantitative Sudomotor Axon Reflex Test (QSART)

QSART evaluates postganglionic sympathetic sudomotor fibers. Acetylcholine is delivered into the skin via iontophoresis, triggering an axon reflex that stimulates eccrine sweat glands. Sweat latency and volume are recorded over a 10-minute period (5 minutes stimulation, 5 minutes recovery) at 4 standardized sites: forearm, proximal leg, distal leg, and foot.

According to the 2021 AAS/AAN/IFCN consensus statement (Cheshire, 2021), “The QSART has the advantage of assessing the distribution of sudomotor impairment. The test is sensitive and reproducible in healthy controls and in patients with diabetic neuropathy.”

Thermoregulatory Sweat Test (TST)

TST evaluates both central and peripheral sympathetic sudomotor pathways. It assesses the entire sudomotor axis from hypothalamus to sweat glands. Under tightly controlled environmental conditions (heat and humidity), body temperature is raised to 38°C to provoke sweating. Indicator powder is applied to the anterior body surface, and digital imaging is used to document sweat distribution and calculate percentage of anhidrosis (TST%).

The 2021 AAS/AAN/IFCN consensus statement (Cheshire, 2021) points out that “Advantages of the test are its ability to detect abnormalities anywhere along the sudomotor neuraxis, from brain to the periphery. By testing the whole anterior body surface, it also has greater sensitivity than tests such as QSART or skin biopsy, where testing is confined to sampled sites.”

Sympathetic Skin Response (SSR)

SSR measures transient electrical changes in palms and soles in response to emotional or nociceptive stimuli. Unlike QSART and TST, SSR reflects emotionally mediated rather than thermoregulatory sweating.

Quantitative direct and indirect reflex test (QDIRT)

A prospective methodological study by Gibbons (2008) describes a new technique to assess sudomotor function using the QDIRT of sudomotor function. There were 10 participants who had stimulated sweat on both forearms. Impressions were made and indicator dyes were photographed every 15 seconds for 7 minutes. The droplets of sweat were measured by size, location and percent surface area. Each participant had the tests again 8 more times on alternating arms over a 2-month period. Another 10 participants had impressions, QDIRT, and QSART performed on the right foot. The percentage of sweat that was photographed correlated with the silicone impressions at 5 minutes on the forearm and foot. The number of sweat droplets measured with QDIRT correlated with the silicone impression. While QDIRT measured the sudomotor response with temporal resolution that is similar to QSART and spatial resolution that is similar to silicone impressions, there are limitations to QDIRT such as ambient room temperature and lack of humidity control. Also, there was a small sample size, limited testing in neuropathic individuals (only two cases), potential variability due to hydration, caffeine intake, and environmental conditions, lack of direct skin temperature control at the test site, and susceptibility to evaporation effects. There is no information provided about the clinical utility of QDIRT and the authors state “Additional investigation is necessary to determine the utility of QDIRT in disease states that alter sudomotor structure or function.”

Quantitative Pilomotor Axon-Reflex Test (QPART)

There have not been many studies done on QPART. A pilot study (Siepmann 2012) introduced the QPART as a novel method to assess pilomotor (piloerector muscle) function, an aspect of sympathetic cutaneous autonomic activity that previously lacked a standardized quantitative test. In 22 healthy volunteers, iontophoresis of 1% phenylephrine on the dorsal forearm reliably evoked piloerection both directly at the stimulation site and indirectly in a surrounding region via an axon-reflex mechanism. Silicone impressions were used to quantify the number and area of erect hair follicles. The indirect (axon-reflex-mediated) response was significantly reduced by topical lidocaine and abolished by subcutaneous lidocaine, confirming neural mediation, while iontophoresis of saline alone did not provoke piloerection. The axon-reflex response also demonstrated a markedly delayed latency compared to the direct response, further supporting distinct mechanisms. Nitroprusside pretreatment did not alter pilomotor responses, indicating that vasoconstriction was not the primary driver. These findings suggest that phenylephrine can provoke pilomotor activity via an axon-reflex pathway and that QPART may complement existing sudomotor and vasomotor tests for evaluating small fiber autonomic function. However, the study is limited by its small sample size, restriction to healthy participants without neuropathy, lack of normative reference ranges, absence of test-retest reliability data, and reliance on labor-intensive silicone impression analysis. Further validation in larger cohorts, particularly individuals with peripheral neuropathies, is needed to determine clinical utility and reproducibility.

Silastic Sweat Imprint (SSI)

According to Illigens and Gibbons (2009), the silicone sweat imprint technique is a historically important and physiologically sound method for quantifying postganglionic sudomotor function. It provides spatial mapping of sweat gland activity and can detect abnormalities in autonomic small fiber function. However, material variability, susceptibility to artifacts, lack of standardization, and evolving dental silicone chemistry limit its reliability and widespread clinical use. While still useful in research settings, it has largely been replaced by more standardized autonomic testing modalities in routine practice.

Cardiovagal and Adrenergic Testing

Cardiovagal innervations and vasomotor adrenergic innervations can be used to assess conditions such as tachycardia and orthostatic hypotension. POTS is a condition defined as orthostatic intolerance with heart rate increments greater than 30 beats per minute on head-up tilt test. Some of the symptoms can include syncope, palpitations, and lightheadedness. A study by Kimpinski (2012b) reported on 58 individuals with POTS who received autonomic testing and were followed for 1 year. All participants received the following autonomic testing: QSART, heart rate response to deep breathing and Valsalva ratio; blood pressure and heart rate responses to Valsalva maneuver; and head-up tilt. For the 1-year follow-up, 54 participants were available. All participants were given information about conservatively treating their orthostatic symptoms at baseline and at the 1-year follow-up. At baseline, 20 participants were taking β-blockers and 28 were taking them at 1 year. The dosages were not significantly different at 1 year when compared to baseline. The heart rate increment during head-up tilt did not significantly differ between baseline and 1 year, but 20 of the participants no longer met the criteria for POTS. With no significant changes in dosages in medications from baseline to 1-year follow-up, it is unclear how autonomic testing influenced clinical management.

A 2012 retrospective review by Sukul looked at 142 children who had autonomic testing consisting of tilt table test, Valsalva maneuver, cardiac response to deep breathing, QSART, and TST. The relevance of the autonomic test results to clinical presentation was ranked using a 3-point scale with 1 being unhelpful, 2 somewhat helpful and 3 very helpful. After review of clinical data, the treatments prescribed following autonomic testing were recorded and any associated symptom benefit was ranked on a 5-point scale with 1 = severe worsening of symptoms, 2 = mild worsening of symptoms, 3 = no change in symptoms, 4 = mild symptom relief, 5 = excellent symptom relief. POTS was the most frequently revealed condition following autonomic testing, with orthostatic hypertension being the least frequently revealed. The tests were normal in 4% of the participants, Valsalva maneuver was abnormal in 15%, and deep breathing was abnormal in 13%. Treatment following autonomic testing included β-blockers, vitamin supplements and salt supplements. β-blockers were prescribed in 30 of the 142 children. Symptom relief (rank 4 or 5) following treatment was reported in 73% of children. The author concludes that pediatric autonomic testing can provide meaningful insights into symptom mechanisms and may help guide management.

Peltier (2010) published the results of a study aimed at determining the incidence of sudomotor abnormalities and the relationship between QSART findings and other biochemical and physiological measures of autonomic function in a well characterized inpatient cohort of individuals with POTS. The study involved 30 individuals who were free of medications that could alter autonomic tone for at least 5 half-lives and placed on a controlled diet. A total of 17 (56%) participants had abnormal QSART which was typically patchy and involved the lower extremity, while 13 (43%) participants had normal QSART results. Other autonomic tests such as catecholamines and spectral indices did not correlate with QSART results. No differences in autonomic tests or spectral indices were observed between hyperadrenergic and non-hyperadrenergic POTS. The results indicate that although sudomotor abnormalities are common in POTS, they do not clearly align with other physiological markers of dysautonomia, suggesting that endophenotyping based on a single autonomic domain may be insufficient. Limitations include the relatively small sample size and restriction to female individuals, limiting generalizability and statistical power. The study was conducted in a well-characterized inpatient research cohort, which may not represent the broader POTS population.

Zhang (2022) published a retrospective review of the medical records of 356 individuals with POTS. A total of 211 (59%) of the individuals underwent QSART, 80 (22%) underwent skin biopsy, 51 (14%) had both types of testing. The median time between QSART and skin biopsy was 4 weeks. There was poor agreement between the results of QSART and skin biopsy among individuals who had both tests. The study found that 70 (33%) of the individuals who underwent QSART had reduced sweat output in at least 1 of the 4 testing sites. In addition, 19 (24%) individuals who underwent skin biopsy had reduced intraepidermal nerve fiber density (IENFD) in at least 1 site. Compared to individuals with normal IEFND, those with reduced IENFD were significantly older; there were no significant differences in the two groups in terms of comorbid autoimmune disease or frequency of reported symptoms. This study was designed to characterize a cohort of individuals with POTS, not to evaluate the diagnostic accuracy of autonomic testing.

The ACC/AHA/HRS Guideline for the Evaluation and Management of Syncope (Shen, 2017) states referral for autonomic evaluation “can be useful to improve diagnostic and prognostic accuracy in selected patients with syncope and known or suspected neurodegenerative disease.”

Neurodegenerative Diseases

Multiple system atrophy (MSA) is a progressive neurodegenerative disorder which is characterized by symptoms of ANS failure such as fainting spells, orthostatic hypotension, bladder control problems and motor control symptoms. There is no cure for MSA and treatment is aimed at controlling symptoms. Diagnosis is made using clinical criteria initially established by a consensus conference in 1998 and reviewed and modified by a second consensus conference in 2007 (Gilman, 2008). While autonomic dysfunction is required to establish the diagnosis of definite, probable, or possible MSA or MSA with predominant Parkinson or predominant cerebellar ataxia, the specific testing described in this document is not essential for the diagnosis of MSA.

In a prospective cohort study, Lipp (2009) evaluated whether comprehensive autonomic testing could distinguish MSA from Parkinson disease (PD), including a subset with prominent PD with autonomic failure (PD_AF), at baseline and after 1 year of follow-up. A total of 81 individuals (52 with MSA and 29 with PD) underwent standardized autonomic symptom assessment, quantitative autonomic reflex testing, TST, plasma catecholamine measurement, and functional evaluation. At baseline, individuals with MSA had significantly greater autonomic symptom burden and more severe autonomic deficits than those with PD, particularly in measures reflecting diffuse anhidrosis and overall autonomic severity. Patterns of sweat loss were more regional and progressive in MSA, consistent with preganglionic dysfunction, whereas PD more commonly demonstrated distal, length-dependent changes suggestive of postganglionic involvement. These differences were maintained and amplified over 12 months, with MSA showing faster progression of autonomic dysfunction and functional decline. The findings support the concept that severity, distribution, and progression of autonomic failure can help differentiate MSA from PD, even in cases where orthostatic hypotension is present in both conditions.

A retrospective review by Iodice (2012) sought to evaluate if premorbid autonomic testing and consensus criteria are accurate in autopsy confirmed MSA. Of the 29 individuals identified, all 29 received autonomic testing and subsequently had MSA confirmed with autopsy findings. All of the individuals had QSART; 8 had normal results, 10 had reduced widespread postganglionic sudomotor function. The remaining participants had either patchy, distal or length dependent, or focal postganglionic sudomotor function. There were 22 individuals who had TST, 2 of which had normal results, the other 20 individuals had anhidrosis with 18 having anhidrosis greater than 30%. Composite Autonomic Severity Score (CASS) was 7.2 ± 2.3 and defined as severe. The author concluded the presence of severe generalized autonomic failure, widespread anhidrosis, and rapid progression of autonomic failure is highly predictive of MSA.

Researchers have explored whether autonomic testing enhances the clinical differentiation between MSA and PD. Kimpinski (2012a) reported on a prospective study that compared standardized autonomic reflex testing, TST, and cardiac iodine-123 meta-iodobenzylguanidine (¹²³I-MIBG) myocardial scintigraphy in differentiating MSA from PD in 29 participants (10 PD, 9 MSA, 10 controls). Individuals with MSA demonstrated significantly greater overall and adrenergic autonomic dysfunction compared with PD and controls, reflecting more severe and generalized autonomic failure. TST showed markedly greater and more diffuse anhidrosis in MSA with minimal overlap between groups, supporting a predominantly preganglionic pattern in MSA versus the postganglionic involvement more typical of PD. Cardiac MIBG uptake was significantly reduced in PD compared with controls, consistent with postganglionic cardiac sympathetic denervation, but did not reliably distinguish PD from MSA due to overlap and variability within groups. Plasma catecholamines were not helpful diagnostically. The author concludes that detailed autonomic testing, particularly TST combined with composite autonomic scoring, provides greater discriminatory value than MIBG alone, and that a multimodal approach alongside clinical judgment improves differentiation between MSA and PD.

In 2020, Indelicato and colleagues sought to evaluate the diagnostic yield of cardiovascular autonomic function tests as an aid in the root-cause investigation of cerebellar ataxia. A series of cardiovascular autonomic tests were administered to a cohort of individuals with neurodegenerative cerebellar ataxia, as well as matched healthy controls. Sporadic cases were followed-up (median 15 months [range 12-33 months]) for an eventual conversion to MSA-C (cerebellar type). A total of 42 individuals with cerebellar ataxia were recruited (n= 23 hereditary cases and n=19 sporadic cases [2 probable MSA-C, 6 possible MSA-C, 11 sporadic adult-onset ataxia]). Sporadic and hereditary cases showed no difference concerning ataxia severity at baseline. At head-up tilt, non-orthostatic hypertension blood pressure-related falls were detected in 9 cases (n=7 sporadic cases and n=2 hereditary cases), but 0 matched controls. A total of 5 of 7 sporadic cases with a non-orthostatic hypertension blood pressure-related fall post head-up tilt test, converted to possible or probable MSA-C. Authors concluded, in the work-up of cerebellar ataxia, a battery of cardiovascular autonomic tests may detect early signs of blood pressure dysregulation, potentially alluding to an underlying or developing possible or probablable MSC-C etiology. Studies determining the clinical utility of these cardiovascular autonomic tests and their impact on net health outcomes are warranted.

SUDOSCAN technology has been studied in the evaluation of identifying autonomic neuropathy in people with PD. In a 2019 study by Xu and colleagues, the authors assessed sudomotor function in individuals with PD using SUDOSCAN. They analyzed risk factors for autonomic neuropathy using electrochemical skin conductance (ESC), which can be recorded with SUDOSCAN. Included in the study were 43 individuals in the later stages of PD and 42 individuals serving as controls. The authors noted ESC of the hands and feet was reduced in the SUDOSCAN group compared to the control group; 28% lower in the hands and 19.1% lower in the feet of the individuals with PD. Conversely, in a 2019 study by Popescu, 67 individuals with moderate stage idiopathic PD had evaluation of small fibers function by ESC using SUDOSCAN technology compared to 66 age-matched controls. The authors noted no significant reduction in ESC in the individuals with PD compared to the control group. Popescu does note the Xu, 2019 study was conducted on individuals with later stages of PD compared to moderate stages in their cohort. Larger studies are necessary to evaluate efficacy.

Jerčinović (2025) reported on a cross-sectional study which examined sudomotor dysfunction in 75 individuals with multiple sclerosis using individual-reported symptoms (COMPASS-31), QSART, and SUDOSCAN to better characterize sweating abnormalities and their underlying mechanisms. Nearly one-third of participants reported subjective sweating changes, most commonly hyperhidrosis, while objective testing identified sudomotor dysfunction in 17.3% by QSART and 10.7% by SUDOSCAN, indicating that laboratory abnormalities are less frequent than self-reported symptoms. A modest but significant correlation was observed between QSART sweat volume at the foot and SUDOSCAN ESC at the corresponding leg, supporting partial concordance between the two objective methods in detecting hypohidrosis. QSART identified a broader range of abnormalities, including hyperhidrosis and persistent sweating, whereas SUDOSCAN primarily detected reduced sweating, highlighting that the two tests capture different aspects of sudomotor dysfunction. Interestingly, higher hand ESC values were observed in individuals with cervical spinal cord lesions, suggesting that central lesions may influence sudomotor output in complex and potentially compensatory ways. Overall, the findings indicate that sudomotor dysfunction is common in MS and that combining complementary tools is necessary to capture its heterogeneous mechanisms. Key limitations include the cross-sectional, single-center design, relatively small sample size, focus on early-stage MS, and lack of longitudinal follow-up to assess progression. In addition, SUDOSCAN cannot detect hyperhidrosis and lacks established upper normal thresholds, limiting its ability to characterize the full spectrum of sweating abnormalities, while discrepancies between subjective symptoms and objective measures complicate clinical interpretation.

Diabetes

Numerous studies have explored the presence and impact of autonomic dysfunction in individuals with diabetes. A 2004 study by Low and colleagues looked at 231 participants with diabetes and 245 healthy age-matched controls and aimed to estimate comprehensive autonomic symptom profile in diabetes using a laboratory evaluation of autonomic function and a validated self-report. Autonomic neuropathy was found to be present in 54% of type 1 diabetics and 73% of type 2 diabetics.

A retrospective review by Chen (2008) looked at 997 individuals with type 2 diabetes who complained of autonomic-like symptoms or who presented with clinical manifestations of DAN. These individuals underwent heart rate variation testing and postural blood pressure testing. Participants had also completed a questionnaire in which they were asked about autonomic-like symptoms experienced during the previous year. Of the 674 individuals in the analysis, 562 of them complained of at least 1 autonomic symptom. For the asymptomatic individuals, 47% of them were shown to have autonomic neuropathy upon testing. The authors also noted that the more autonomic symptoms an individual complained about, the higher their prevalence of autonomic neuropathy.

A 2008 study by Lykke and colleagues followed 391 type 1 diabetic individuals for 10 years to investigate the effect of cardiovascular autonomic neuropathy on morbidity and mortality. During the follow-up period, 62 individuals died (43 of them were due to cardiovascular events). Individuals with borderline heart rate variation did not have mortality rates significantly different from those individuals with normal heart rate variation. For those individuals who had decreased heart rate variability, there was an excess overall mortality that diminished after adjusting for conventional cardiovascular risk factors compared to individuals with normal heart rate variability.

Maguire (2007) retrospectively studied the significance of subclinical autonomic nerve test abnormalities in adolescents. A total of 59% of the original study group who had undergone autonomic testing were available for a 12-year follow-up. There was no association between cardiovascular testing and complications related to diabetes, however the authors suggest an association between baseline pupillometry tests and the presence of microalbuminuria and retinopathy at 12 years of follow-up. This study is methodologically limited in part by a retrospective design and the limited number of children available for follow up. The clinical utility of this finding is uncertain.

A cross-sectional study by Eranki (2013) evaluated the performance of SUDOSCAN, a noninvasive electrochemical sweat conductance device, as a screening tool for microvascular complications in 309 individuals with type 2 diabetes. Among participants, 120 had at least 1 microvascular complication (peripheral neuropathy, retinopathy, or nephropathy). Individuals with complications had significantly lower hand and foot ESC values and higher autonomic risk scores compared with those without complications. The autonomic risk score demonstrated moderate diagnostic performance for detecting at least one microvascular complication, with relatively high sensitivity and modest specificity. Similar performance was observed for identifying individual complications such as peripheral neuropathy, retinopathy, and nephropathy. No adverse events were reported during testing. The authors conclude that sudomotor assessment with SUDOSCAN may serve as a simple, rapid screening method to identify individuals at higher risk for diabetic microvascular complications before proceeding to more specialized evaluations. Limitations include the single-center design and limited study population, which may restrict generalizability. Peripheral neuropathy was defined solely by vibration perception threshold testing, nephropathy by estimated glomerular filtration rate, and retinopathy by fundoscopy, without confirmatory or gold-standard assessments, potentially affecting diagnostic accuracy. The cross-sectional design precludes determination of causality or predictive value over time. The specificity of the screening tool was modest, raising the possibility of false positives. Additionally, employees of the device manufacturer were involved in the study, introducing potential conflict-of-interest bias. Prospective longitudinal studies with standardized complication definitions are needed to confirm clinical utility and prognostic value.

Krieger and colleagues (2018) reported on a cross-sectional study that evaluated the performance of SUDOSCAN ESC compared with QSART for detecting distal symmetric diabetic peripheral neuropathy (DPN) in 47 individuals with type 2 diabetes (27 with DPN, 20 without) and 16 matched controls. ESC values at the hands and feet were significantly lower in individuals with DPN and correlated inversely with clinical neuropathy disability and symptom scores, as well as sensory impairment measures, suggesting meaningful clinical association. Diagnostic performance analysis showed moderate sensitivity and specificity for ESC in identifying DPN, whereas QSART sweat latency and volume did not differentiate between groups. ESC demonstrated lower inter-individual variability than QSART and appeared more sensitive for early or mild neuropathy. The authors conclude that SUDOSCAN may be a practical screening tool for DPN and possibly small fiber neuropathy in diabetic individuals. Limitations include the small sample size, which limits statistical power and generalizability; inclusion of mostly mild DPN cases, which may influence optimal cutoff thresholds; restriction to type 2 diabetes, limiting applicability to other neuropathic etiologies; and absence of IENFD measurement, the gold standard for small fiber neuropathy confirmation. Local skin temperature was not controlled, which can affect sweat testing results. Additionally, the study only included white participants. The inclusion of only one racial group limits generalizability, as the study population does not reflect the racial diversity of the broader real-world population. Larger studies are needed to confirm diagnostic accuracy and clinical utility.

Zhao (2022) compared findings of SUDOSCAN and electromyography (EMG) findings in 326 hospitalized individuals with type-1 or type-2 diabetes. All participants underwent a SUDOSCAN sweat function test and an EMG examination during hospitalization. A total of 176 of the 326 individuals (54%) had abnormal SUDOSCAN results and 299 (92%) had abnormal EMG results. Consistency between SUDOSCAN and EMG results was 53%; the consistency of findings was not statistically significant (p=0.868). The sensitivity and specificity of the SUDOSCAN for diagnosing distal symmetric polyneuropathy (DSPN) were 53.5% and 48.2%, respectively. According to the authors, “differences existed between the SUDOSCAN and EMG results, and the results of the two examination methods were inconsistent, indicating that SUDOSCAN examinations cannot replace EMG examinations for DSPN.” A limitation in the study was not exploring why the two tests were inconsistent.

Nica (2024) reported on a single-center cross-sectional study which evaluated the effectiveness of SUDOSCAN ESC testing as a noninvasive screening tool for chronic kidney disease (CKD) in 271 Romanian adults with type 2 diabetes mellitus (T2DM). CKD prevalence in the cohort was 26.5%, defined by reduced estimated glomerular filtration rate (eGFR) and/or elevated albumin-to-creatinine ratio (ACR). SUDOSCAN-Nephro® scores showed moderate correlations with traditional renal markers, including eGFR and albuminuria, and were lower in individuals with more advanced CKD stages and higher albuminuria levels. Receiver operating characteristic analyses demonstrated modest diagnostic performance for identifying CKD and microalbuminuria, with moderate sensitivity but limited specificity. Lower SUDOSCAN-Nephro scores were also associated with older age, longer diabetes duration, higher urea and creatinine levels, worse autonomic dysfunction scores, and higher estimated risk of progression to dialysis. The authors conclude that SUDOSCAN may serve as a rapid, painless adjunctive screening tool to identify early renal dysfunction and potentially stratify risk in individuals with T2DM. Limitations include the cross-sectional design, which precludes assessment of causality or predictive value over time; relatively modest sample size for subgroup analyses; and the single-center setting, limiting generalizability. SUDOSCAN demonstrated only moderate diagnostic performance, with particularly low specificity for CKD detection, raising the possibility of false positives. The study population consisted exclusively of individuals with type 2 diabetes, so applicability to other CKD etiologies remains uncertain. Larger prospective, multicenter studies are needed to determine whether SUDOSCAN meaningfully improves early detection, risk stratification, or clinical outcomes in CKD screening.

Figueroa-Perez and colleagues (2025) reported on a retrospective cross-sectional study that evaluated whether detecting DAN using SUDOSCAN could reclassify cardiovascular risk in individuals with T2DM when applying the 2023 European Society of Cardiology guidelines. Among 161 individuals from a single center in Northern Mexico, sudomotor dysfunction, an early marker of DAN, was highly prevalent (67%) and its inclusion in European Society of Cardiology 2023 risk stratification significantly shifted individuals toward higher cardiovascular risk categories, particularly increasing the proportion classified as very high risk (from 3% to 16%). In contrast, commonly used risk calculators (ASCVD Plus, SCORE-2, ADVANCE, SMART, and Globo Risk), which do not account for neuropathy, largely categorized individuals as low or moderate risk, suggesting potential underestimation of cardiovascular risk in T2DM. While the findings support SUDOSCAN as a practical, non-invasive tool to improve identification of microvascular complications and refine cardiovascular risk assessment, there were numerous limitations in the study. Limitations include the retrospective, cross-sectional design, non-probabilistic convenience sampling, relatively small sample size, and single-center setting, which may limit generalizability and causal inference; additionally, risk calculators themselves are population-dependent and may introduce inherent bias. Longitudinal studies are needed to confirm whether reclassification based on DAN translates into improved clinical outcomes.

A cross-sectional study by Anghel (2025) evaluated 288 adults with type 1 or type 2 diabetes to determine whether sudomotor dysfunction, measured non-invasively by ESC using SUDOSCAN, is associated with autonomic neuropathy and cardiovascular risk. The authors found that reduced ESC, particularly in the feet, was common and strongly inversely correlated with validated cardiovascular risk scores, with the right foot showing the strongest association (r= −0.455, p<0.001) and the best diagnostic performance for autonomic neuropathy (Area Under the Curve [AUC], 0.750). Lower ESC values were also linked to longer diabetes duration and poorer glycemic control, supporting sudomotor dysfunction as an early marker of small-fiber and autonomic nerve involvement that may reflect broader systemic and cardiovascular risk. These findings suggest that SUDOSCAN could serve as a practical screening tool for early identification and risk stratification of diabetic complications in outpatient settings. However, interpretation is limited by the cross-sectional design, which limits the ability to establish causality, the single-center outpatient population that may limit generalizability, and the inability of SUDOSCAN to distinguish diabetic neuropathy from other causes of sudomotor dysfunction. ESC measurements may also be influenced by external factors such as skin hydration and temperature. Longitudinal studies are needed to validate prognostic value and clinical impact over time.

A cross-sectional study by Cobuz (2025) evaluated 254 individuals with T2DM in northern Romania to assess whether the SUDOSCAN nephropathy risk, derived from ESC, could support the identification of CKD. Individuals with more advanced CKD (stages 2-3, defined by lower eGFR) had significantly lower ESC values and lower SUDOSCAN nephropathy risk scores, along with higher serum creatinine levels. The nephropathy risk score showed a statistically significant but weak positive correlation with eGFR and a weak negative correlation with creatinine, indicating an association between sudomotor dysfunction and renal impairment. In predictive analyses, the SUDOSCAN nephropathy risk score demonstrated only modest discriminatory ability for CKD (AUC, 0.61), and multivariable modeling showed that its usefulness depended largely on incorporating age, diabetes duration, and body mass index, with age being the dominant contributor. Overall, the findings suggest that SUDOSCAN may function as a supportive, non-invasive screening tool for CKD risk in individuals with T2DM, rather than a standalone diagnostic test. Key limitations include the relatively small, single-center sample and limited representation of advanced CKD stages, the cross-sectional design which prevents assessment of predictive or longitudinal value, grouping of CKD into three stages instead of five, and the absence of albuminuria data, a core marker of diabetic kidney disease. Additionally, ESC measurements may be influenced by external factors such as skin hydration, temperature, and neuropathy variability, underscoring the need for standardized protocols and larger longitudinal studies to clarify clinical utility.

Much of the literature on the SUDOSCAN in diabetes is limited to small group sizes (Calvet, 2013; Casellini, 2013; Keet, 2014; Smith, 2014). While a study by Yajnik and colleagues (2012) compared SUDOSCAN to conventional measures of peripheral and cardiac neuropathy in 265 individuals with T2DM, the authors of that study noted that the SUDOSCAN is not a substitute for conventional neuropathy testing.

Delayed Orthostatic Hypotension

Park (2023) conducted a large retrospective study that analyzed 390 individuals undergoing autonomic function testing to determine whether Valsalva maneuver (VM) metrics can help identify individuals with late-onset delayed orthostatic hypotension (dOH); a form of orthostatic blood pressure drop occurring after more than10 minutes of standing that may be missed by routine 10-minute head-up tilt table testing (HUTT). Compared with controls (n=114), individuals with late-onset dOH (n=32) had significantly prolonged pressure recovery time (PRT) and reduced heart rate increment during phase 3 of the VM (∆HR_VM3), reflecting impaired sympathetic and cardiovagal responses. These differences remained significant after age- and sex-matching and multivariable adjustment. Receiver operating characteristic (ROC) analyses suggested that PRT ≥ 2.14 seconds and ∆HR_VM3 ≤ 15 bpm could help identify candidates who require prolonged (>10-30 minute) HUTT to diagnose late-onset dOH. Severity of impairment in VM parameters followed a gradient from controls to late-onset dOH to early-onset dOH to immediate orthostatic hypotension, supporting the concept that dOH represents an early or milder stage of autonomic failure. VM metrics also correlated with the magnitude of BP drop during HUTT. The authors conclude that VM may provide a practical screening tool to guide selection for prolonged tilt testing. However, limitations include the retrospective design, potential selection bias in referral for autonomic testing, incomplete prolonged HUTT in some controls (raising possibility of missed dOH cases), heterogeneity in comorbidities and medication use (antihypertensives not discontinued), absence of plasma volume data, overlap in VM parameter distributions between groups, and lack of prospective validation of the proposed cutoff values. Consequently, while VM-derived PRT and ∆HR_VM3 show diagnostic promise, prospective studies are needed to confirm their utility in routine clinical decision-making.

Orthostatic Intolerance Syncope

The HRS (Sheldon, 2015) published an expert consensus statement on the Diagnosis and Treatment of Postural Tachycardia Syndrome, Inappropriate Sinus Tachycardia, and Vasovagal Syncope. The following recommendation was made on the investigation of POTS:

• Detailed autonomic testing, transthoracic echocardiogram, tilt-table testing, and exercise stress testing may be considered for selected patients being assessed for POTS. (Class IIb; Level E)

The same expert consensus statement included the following recommendation on the investigation of inappropriate sinus tachycardia:

• It might be worth considering autonomic testing. (Class IIb; Level E)
  Recommendation Class IIb: benefit equivalent or possibly exceeding risk.
  Recommendation Level E: consensus opinion in the absence of credible published evidence.

The ADA (2026) recommendations on neuropathy screening and treatment state:

12.17    All people with diabetes 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
12.18    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 (large fiber function). All people with diabetes should have annual 10-g monofilament testing to identify feet at risk for ulceration and amputation. B
12.19    Symptoms and signs of autonomic neuropathy should be assessed in people with diabetes starting at diagnosis of type 2 diabetes and 5 years after the diagnosis of type 1 diabetes, and at least annually thereafter, and with evidence of other microvascular complications, particularly kidney disease and diabetic peripheral neuropathy. Screening can include asking about orthostatic dizziness, syncope, early satiety, erectile dysfunction, changes in sweating patterns, or dry cracked skin in the extremities. Signs of autonomic neuropathy include orthostatic hypotension, a resting tachycardia, or evidence of peripheral dryness or cracking of skin. E

Long COVID

In a large retrospective, single-center study, Novak (2026), compared 143 individuals with long COVID and 170 with pre-pandemic myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) to 73 healthy controls and 290 individuals with hypermobile Ehlers-Danlos syndrome (hEDS), using comprehensive autonomic testing (including deep breathing, sudomotor function, Valsalva maneuver and tilt-table test), transcranial Doppler-based cerebral blood flow velocity (CBFv) monitoring during tilt, skin biopsies for small fiber neuropathy (SFN), invasive cardiopulmonary exercise testing (iCPET), and laboratory profiling. Long COVID and ME/CFS showed strikingly similar profiles: high rates of orthostatic CBFv reduction, widespread mild-to-moderate autonomic failure, frequent SFN, and comparable prevalence of POTS and neurogenic orthostatic hypotension. Overall, the findings support a shared autonomic and cerebrovascular phenotype between Long COVID and ME/CFS, consistent with overlapping pathophysiology. Limitations include the retrospective referral-center design (potential selection bias), use of historical controls, substantially longer symptom duration in ME/CFS, and incomplete laboratory data. While the physiologic similarities are compelling, causality and generalizability remain uncertain.

Keller (2026) presented a cross-sectional study that compared quantitative autonomic testing results in 78 individuals with long COVID (≥12 weeks post-acute infection) to 25 control participants with normal autonomic testing and 38 individuals with pure autonomic failure (PAF). Using cardiovascular autonomic testing, including active standing, Valsalva maneuver, respiratory sinus arrhythmia, and tilt-table testing, the author found that individuals with long COVID exhibited significantly greater heart rate increases with tilt, larger blood pressure drops with active standing and tilt, and reduced Valsalva ratios and respiratory sinus arrhythmia compared with controls. When adjusted for age and sex, the severity of autonomic abnormalities in long COVID was comparable to that seen in PAF. Abnormal findings persisted across a wide time range (3-40 months post-infection), suggesting prolonged autonomic dysfunction. These results support a measurable association between long COVID and cardiovascular autonomic impairment involving both sympathetic and parasympathetic components. Limitations include the retrospective referral-based design and a small sample size. The study demonstrates persistent autonomic abnormalities in long COVID.

Ross Syndrome

In a retrospective single-center study by Lamotte (2021a), the author reviewed 26 individuals with Ross syndrome evaluated at Mayo Clinic between 1998 and 2020 to characterize clinical features, autoimmune associations, and autonomic profiles. The most common initial presentation was abnormal segmental sweating (hyperhidrosis in 12, anhidrosis in 4), while tonic pupil was first noted in 10 individuals; ultimately all exhibited the classic triad (tonic pupils, hyporeflexia, segmental anhidrosis). Heat intolerance was common (76.9%), and additional symptoms such as fatigue (65%), chronic cough (27%), and urinary frequency (31%) were reported, suggesting a broader phenotype beyond the classic triad. TST showed variable patterns, segmental (n=15), widespread (n=7), or global (n=4) anhidrosis, with small islands of preserved sweating in 88.5% of individuals, and slow progression over time in those with serial testing. Autonomic reflex testing demonstrated predominantly postganglionic sudomotor impairment, whereas cardiovagal and adrenergic functions were largely preserved, yielding low CASS cardiovagal and adrenergic scores. Although the study was small, overall, the findings support Ross syndrome as a limited, predominantly (post)ganglionic cholinergic autonomic neuropathy with slow progression and selective sudomotor involvement.

Baroreflex Function

A large retrospective series analyzed standardized autonomic testing in 90 individuals with probable radiation-induced afferent baroreflex failure (R-ABF) following neck radiation, Lamotte (2022). The cohort demonstrated a characteristic pattern of severe cardiovascular adrenergic impairment, with neurogenic orthostatic hypotension (94%), prolonged blood PRT after Valsalva (79%, median 17.4 seconds), and marked blood pressure lability including hypertensive surges and loss of nocturnal dipping on ambulatory monitoring. Despite orthostatic hypotension, plasma norepinephrine levels were elevated supine and increased appropriately with standing, consistent with a hyperadrenergic form of neurogenic orthostatic hypotension reflecting baroreflex deafferentation with relatively preserved sympathetic efferent pathways. Cardiovagal impairment was also common (abnormal Heart Rate Variability with Deep Breathing [HRDB] 79.5%, abnormal Valsalva ratio 87.2%), while postganglionic sudomotor function was generally preserved except for focal anhidrosis in irradiated neck regions, indicating local radiation effects rather than generalized autonomic failure. Blood pressure variability correlated with impaired vagal baroreflex sensitivity but not with norepinephrine levels, suggesting dysregulated baroreflex buffering rather than primary sympathetic failure as the mechanism of lability. Overall, the findings support R-ABF as a syndrome of afferent baroreflex disruption characterized by hyperadrenergic blood pressure instability and orthostatic hypotension.

Lamotte (2021b) conducted a large retrospective cohort study of 104 adults with afferent baroreflex failure (ABF) evaluated at Mayo Clinic between 2000 and 2020 that characterizes the natural history, etiologies, clinical manifestations, and outcomes of this underrecognized autonomic disorder. The vast majority of cases (86.5%) were attributable to prior head and neck radiation, with smaller proportions due to surgery (5.8%) or other causes. Individuals commonly presented with labile hypertension (87.5%), orthostatic hypotension (91.3%), syncope (58.6%), and episodic tachycardia, often requiring both antihypertensive and pressor medications for management. Latency from radiation to ABF onset was significantly longer than after surgery, suggesting differing mechanisms of injury (progressive radiation-induced fibrosis versus immediate surgical disruption). Standardized autonomic testing demonstrated severe adrenergic impairment (median CASS adrenergic score 4) with frequent neurogenic orthostatic hypotension, relatively preserved sudomotor function, and elevated supine and upright plasma norepinephrine, consistent with dysregulated but intact sympathetic efferent pathways. Over 20 years, all-cause mortality was high (39.4%), particularly in the radiation group (42%), and comorbidities related to prior radiation were common. These findings highlight the substantial morbidity and mortality associated with ABF. Limitations include the retrospective design with potential recall and referral bias toward more severe cases, inability to precisely determine symptom onset timing, lack of confirmatory pharmacologic testing of the afferent limb in all individuals, absence of a control group with similar radiation exposure, and limited ability to distinguish acute from chronic phases of ABF. Despite these constraints, the study provides the largest description to date of the natural history and clinical burden of ABF.

Traumatic Brain Injury

Li (2022) reported on a cross-sectional study that evaluated subjective and objective autonomic dysfunction in survivors of moderate-to-severe traumatic brain injury (msTBI) using 2 complementary cohorts. In a prospective clinic-based cohort (n=39) compared with healthy controls (n=44), individuals with msTBI had significantly higher total COMPASS-31 scores (mean 23.3 vs. 7.3, p<0.001) and elevated orthostatic, gastrointestinal, and secretomotor subscores, indicating multidomain autonomic symptom burden. Higher symptom scores strongly correlated with worse self-rated health, greater fatigue, and pain, but not with anxiety or depression. In a retrospective autonomic laboratory cohort (n=18), formal testing revealed a broad spectrum of objective abnormalities in 13 out of 18 individuals, including impaired cardiovagal function (abnormal HRDB in 10 out of 18), mixed dysfunction (low Valsalva ratio in 6 out of 18), abnormal tilt responses consistent with vasovagal syncope or POTS in several individuals, and 1 case of neurogenic orthostatic hypotension. Most abnormalities were mild and often intermittent, but persisted months to years post-injury (median 65 months). Together, the findings support clinically meaningful parasympathetic and sympathetic dysfunction in chronic msTBI, even among ambulatory, community-dwelling individuals. Limitations include small sample sizes, retrospective recruitment of the autonomic testing cohort, cross-sectional design precluding causal inference, potential over-reporting on symptom questionnaires, absence of pre-injury autonomic baselines, restriction to moderate-to-severe TBI, and lack of mechanistic imaging correlates. Larger prospective studies are needed to define prevalence, mechanisms, and treatment implications of post-TBI autonomic dysfunction.

30:15 Ratio: A test of heart rate response to standing. The heart rate is analyzed at 15 and 30 seconds after standing.

Autonomic Dysfunction: Autonomic dysfunction presents with diverse clinical features affecting multiple organ systems, reflecting impairment of sympathetic and parasympathetic nervous system regulation. The manifestations vary depending on which autonomic functions are affected and the severity of involvement. Cardiovascular manifestations are among the most prominent features. Orthostatic hypotension is a hallmark finding, causing dizziness, lightheadedness, syncope, blurred vision, or fatigue upon standing. Individuals may also experience palpitations, exercise intolerance, supine hypertension, and abnormal heart rate variability with either tachycardia or bradycardia. In severe cases, blood pressure drops can be so pronounced that individuals cannot tolerate sitting or standing positions. Gastrointestinal symptoms include constipation, diarrhea (or alternating between both), gastroparesis with early satiety and postprandial vomiting, and postprandial diarrhea. These manifestations can lead to progressive weight loss and dehydration that worsens orthostatic symptoms. Sudomotor abnormalities include anhidrosis (decreased sweating), hyperhidrosis (excessive sweating), or abnormal sweating patterns, typically affecting distal extremities in length-dependent neuropathies. Other manifestations include dry eyes and dry mouth from impaired secretomotor function, pupillary abnormalities, cognitive dysfunction, fatigue, and difficulty concentrating. Sleep disturbances and acrocyanosis have also been reported. The clinical presentation depends on whether autonomic dysfunction is generalized (pandysautonomia) or selective, and whether it occurs as a primary disorder or secondary to conditions like diabetes, Guillain-Barré syndrome, or autoimmune disorders.

Autonomic Nervous System: The part of the nervous system which controls involuntary actions.

Autonomic Nervous System Function, combined parasympathetic and sympathetic adrenergic function testing, must consist of all of the following (1 and 2):

1. Head-Up Tilt Table Test (blood pressure response component, greater than or equal to 5 minutes); and
2. Any 2 or more of the following:
   1. 30:15 Ratio (heart rate response to standing); or
   2. Active Standing Test (orthostatic vital signs); or
   3. Beat-to-beat Blood Pressure Monitoring (for example, Finapres); or
   4. Heart Rate Variability with Deep Breathing (HRDB); or
   5. Plasma Norepinephrine Levels (supine and standing); or
   6. Valsalva Maneuver (blood pressure phases and adrenergic response); or
   7. Valsalva Maneuver (heart rate response and Valsalva ratio).

Beat-to-beat Blood Pressure Monitoring: A continuous, noninvasive method of measuring arterial blood pressure with each heartbeat to evaluate sympathetic adrenergic and baroreflex function during autonomic reflex testing.

Cardiovagal Function testing must consist of two of the following:

1. 30:15 Ratio (heart rate response to standing); or
2. Heart Rate Variability with Deep Breathing (HRDB); or
3. Valsalva Maneuver (heart rate response and Valsalva ratio);
   *Head-Up Tilt Table Test may be considered a component of cardiovagal function testing with any two or more of the above tests (cardioinhibitory response component).

Head-Up Tilt Table Test (HUTT): A standardized autonomic test in which an individual is secured to a motorized table and passively tilted from a supine to an upright position (typically 60-70 degrees) while continuous heart rate and blood pressure are monitored to assess cardiovascular autonomic responses to orthostatic stress.

Heart Rate Variability with Deep Breathing (HRDB): A standardized autonomic test that measures the variation in heart rate during controlled deep breathing to assess parasympathetic (cardiovagal) function.

Parasympathetic: Refers to the cardiovagal component of the autonomic nervous system responsible for regulating resting heart rate and rapid beat-to-beat heart rate changes, typically assessed through measures such as heart rate variability with deep breathing and Valsalva maneuver responses.

Quantitative Direct and Indirect Reflex Test: A technique which combines the technique of QSART measuring sudomotor function with temporal resolution and measures spatial resolution (droplet size and number) similar to the sweat imprint technique.

Quantitative Sudomotor Axon Reflex Test (QSART): A test to evaluate the integrity of the postganglionic sudomotor system along the axon reflex to define the distribution of sweat loss. This is accomplished by the release of acetylcholine into the skin which activates receptors on the eccrine sweat gland. The sweat response is recorded from four sites (forearm and three lower extremity sites) and assessed for deficits.

Silastic Sweat Imprint: Formed by the secretion of active sweat glands into a plastic imprint. The test is used to determine the density of sweat glands, sweat droplet size and sweat volume per area.

Sudomotor function: Refers to the activity of postganglionic sympathetic cholinergic fibers that innervate eccrine sweat glands, assessed through tests that measure sweat production or sweat gland activation to evaluate small fiber autonomic integrity. Tests include quantitative sudomotor axon reflex test (QSART), the thermoregulatory sweat test (TST), silastic sweat imprint (SSI), sympathetic skin response (SSR), quantitative direct and indirect reflex test of sudomotor function (QDIRT), or SUDOSCAN.

Sudomotor Function testing must consist of any of the following tests:

1. Quantitative Sudomotor Axon Reflex Test (QSART); or
2. Silastic Sweat Imprint (SSI): or
3. Sympathetic Skin Response (SSR); or
4. Thermoregulatory Sweat Test (TST).

Sympathetic Skin Response: A change of the electrical potential of the skin. The recorded skin potential comes from the activated eccrine sweat gland. The amplitude and configuration are adjusted by sweat gland epithelium and the overlying epidermis.

Thermoregulatory Sweat Test: A test where sweating is brought on by thermoregulatory warming which results in a rise of core temperature. When the rise in core temperature goes beyond the thermoregulatory set point of the hypothalamus, sweating occurs. TST can check the thermoregulatory sympathetic pathways from the hypothalamus to the eccrine sweat gland by use of an indicator powder mixture. When the body is warmed to a core temperature of 38°C, sweat is recognized by a change in color in the indicator powder. Digital photography is used to document the sweat distribution which can be characteristic of neuropathy, ganglionopathy or generalized autonomic failure.

Valsalva Maneuver: The Valsalva maneuver is performed by trying to breathe out forcefully while keeping the mouth and nose closed, creating pressure in the chest.

Vasomotor Adrenergic Function testing must consist of all of the following tests:

1. Beat-to-beat Blood Pressure Monitoring (for example, Finapres); and
2. Head-Up Tilt Table Test (blood pressure response component, greater than or equal to 5 minutes); and
3. Valsalva Maneuver (blood pressure phases and adrenergic response).

Peer Reviewed Publications:

1. Anghel L, Cobuz C, Benchea LC, et al. Sudomotor dysfunction as an early marker of autonomic and cardiovascular risk in diabetes: insights from a cross-sectional study using SUDOSCAN. Biosensors (Basel). 2025; 15(6):372.
2. Calvet JH, Dupin J, Winiecki H, Schwarz PE. Assessment of small fiber neuropathy through a quick, simple and non invasive method in a German diabetes outpatient clinic. Exp Clin Endocrinol Diabetes. 2013; 121(2):80-83.
3. Casellini CM, Parson HK, Richardson MS, et al. Sudoscan, a noninvasive tool for detecting diabetic small fiber neuropathy and autonomic dysfunction. Diabetes Technol Ther. 2013; 15(11):948-953.
4. Chen HT, Lin HD, Won JG, et al. Cardiovascular autonomic neuropathy, autonomic symptoms and diabetic complications in 674 type 2 diabetes. Diabetes Res.Clin.Pract. 2008; 82(2):282-290.
5. Cobuz C, Ungureanu-Iuga M, Anton-Paduraru DT, Cobuz M. Possible use of the SUDOSCAN nephropathy risk score in chronic kidney disease diagnosis: application in patients with Type 2 Diabetes. Biosensors (Basel). 2025; 15(9):620.
6. Eranki VG, Santosh R, Rajitha K, et al. Sudomotor function assessment as a screening tool for microvascular complications in type 2 diabetes. Diabetes Res Clin Pract. 2013; 101(3):e11-13.
7. Figueroa-Perez CA, Romero-Ibarguengoitia ME, Garza-Silva A, et al. Sudoscan^® reclassifies cardiovascular risk in patients with type 2 diabetes mellitus according to the ESC 2023. J Diabetes Metab Disord. 2025; 24(1):50.
8. Gibbons CH, Illigens BM, Centi J, Freeman R. QDIRT: quantitative direct and indirect test of sudomotor function. Neurology. 2008; 70(24):2299-2304.
9. Gilman S, Wenning GK, Low PA, et al. Second consensus statement on the diagnosis of multiple system atrophy. Neurology. 2008; 71(9):670-676.
10. Illigens BM, Gibbons CH. Sweat testing to evaluate autonomic function. Clin Auton Res. 2009; 19(2):79-87.
11. Indelicato E, Fanciulli A, Nachbauer W, et al. Cardiovascular autonomic testing in the work-up of cerebellar ataxia: insight from an observational single center study. J Neurol. 2020; 267(4):1097-1102.
12. Iodice V, Lipp A, Ahlskog JE, et al. Autopsy confirmed multiple system atrophy cases: Mayo experience and role of autonomic function tests. J Neurol Neurosurg Psychiatry. 2012; 83(4):453-459.
13. Jerčinović K, Tešija K, Sredanović M, et al. Characterizing sweating problems in multiple sclerosis: insights from QSART, SUDOSCAN, and COMPASS-31: sweating problems in Multiple Sclerosis. Neurophysiol Clin. 2026; 56(1):103124.
14. Keet SW, Bulte CS, Sivanathan A, et al. Cardiovascular autonomic function testing under non-standardised and standardised conditions in cardiovascular patients with type-2 diabetes mellitus. Anaesthesia. 2014; 69(5):476-483.
15. Keller C, Mascarenhas L, Reyes JL, et al. Association of autonomic dysfunction with long COVID: evaluation using quantitative autonomic testing. J Am Coll Cardiol. 2026; 87(2):216-230.
16. Kimpinski K, Figueroa JJ, Singer W, et al. A prospective, 1-year follow-up study of postural tachycardia syndrome. Mayo Clin Proc. 2012b; 87(8):746-752.
17. Kimpinski K, Iodice V, Burton DD, et al. The role of autonomic testing in the differentiation of Parkinson's disease from multiple system atrophy. J Neurol Sci. 2012a; 317(1-2):92-96.
18. Krieger SM, Reimann M, Haase R, et al. Sudomotor testing of diabetes polyneuropathy. Front Neurol. 2018; 9:803.
19. Lamotte G, Coon EA, Suarez MD, et al. Natural history of afferent baroreflex failure in adults. Neurology. 2021b; 97(2):e136-e144.
20. Lamotte G, Coon EA, Suarez MD, et al. Standardized autonomic testing in patients with probable radiation-induced afferent baroreflex failure. Hypertension. 2022; 79(1):50-56.
21. Lamotte G, Sandroni P, Cutsforth-Gregory JK, et al. Clinical presentation and autonomic profile in Ross syndrome. J Neurol. 2021a; 268(10):3852-3860.
22. Li LM, Vichayanrat E, Del Giovane M, et al. Autonomic dysfunction after moderate-to-severe traumatic brain injury: symptom spectrum and clinical testing outcomes. BMJ Neurol Open. 2022; 4(1):e000308.
23. Lipp A, Sandroni P, Ahlskog JE, et al. Prospective differentiation of multiple system atrophy from Parkinson disease, with and without autonomic failure. Arch.Neurol. 2009; 66(6):742-750.
24. Low PA, Benrud-Larson LM, Sletten DM, et al. Autonomic symptoms and diabetic neuropathy: a population-based study. Diabetes Care. 2004; 27(12):2942-2947.
25. Lykke JA, Tarnow L, Parving HH, Hilsted J. A combined abnormality in heart rate variation and QT corrected interval is a strong predictor of cardiovascular death in type 1 diabetes. Scand J Clin Lab Invest. 2008; 68(7):654-659.
26. Maguire AM, Craig ME, Craighead A, et al. Autonomic nerve testing predicts the development of complications: a 12-year follow-up study. Diabetes Care. 2007; 30(1):77-82.
27. Nica AE, Rusu E, Dobjanschi CG. et al. Sudoscan's effectiveness in identifying chronic kidney disease in patients with type 2 diabetes. Cureus. 2024; 16(5):e60344.
28. Novak P, Systrom DM, Witte A, et al. Shared autonomic phenotype of long COVID and myalgic encephalomyelitis/chronic fatigue syndrome. PLoS One. 2026; 21(1):e0341278.
29. Park JW, Okamoto LE, Kim SH, et al. Use of valsalva maneuver to detect late-onset delayed orthostatic hypotension. Hypertension. 2023; 80(4):792-801.
30. Peltier AC, Garland E, Raj SR, et al. Distal sudomotor findings in postural tachycardia syndrome. Clin Auton Res. 2010; 20(2):93-99.
31. Popescu C. Small fiber neuropathy in Parkinson's disease explored by the sudoscan. Parkinsonism Relat Disord. 2019; 66:261-263.
32. Siepmann T, Gibbons CH, Illigens BM, et al. Quantitative pilomotor axon reflex test: a novel test of pilomotor function. Arch Neurol. 2012; 69(11):1488-1492.
33. Smith AG, Lessard M, Reyna S, et al. The diagnostic utility of Sudoscan for distal symmetric peripheral neuropathy. J Diabetes Complications. 2014; 28(4):511-516.
34. Sukul D, Chelimsky TC, Chelimsky G. Pediatric autonomic testing: retrospective review of a large series. Clin Pediatr (Phila). 2012; 51(1):17-22.
35. 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. 2019; 64:60-65.
36. Yajnik CS, Kantikar VV, Pande AJ, Deslypere JP. Quick and simple evaluation of sudomotor function for screening of diabetic neuropathy. ISRN Endocrinol. 2012; 2012:103714.
37. Zhang R, Mayuga K, Shields R, et al. Skin biopsy and quantitative sudomotor axon reflex testing in patients with postural orthostatic tachycardia syndrome. Cureus. 2022; 14(11):e31021.
38. Zhao Y, Bao JJ, Ye LF, Zhou L. Consistency analysis between SUDOSCAN examinations and electromyography results in patients with diabetes. Diabetes Metab Syndr Obes. 2022; 15:3397-3402.

Government Agency, Medical Society, and Other Authoritative Publications:

1. American Association of Neuromuscular and Electrodiagnostic Medicine. Proper performance of autonomic function testing. Muscle Nerve. 2017 (reaffirmed 2025); 55(1):3-4.
2. American Diabetes Association. Standards of Care in Diabetes-2026. Diabetes Care. 2026; 49(Suppl 1):S1-S371.
3. Cheshire WP, Freeman R, Gibbons CH, et al. Electrodiagnostic assessment of the autonomic nervous system: a consensus statement endorsed by the American Autonomic Society, American Academy of Neurology, and the International Federation of Clinical Neurophysiology. Clin Neurophysiol. 2021; 132(2):666-682.
4. Sheldon RS, Grubb BP 2nd, Olshansky B, et al. 2015 Heart Rhythm Society expert consensus statement on the diagnosis and treatment of postural tachycardia syndrome, inappropriate sinus tachycardia, and vasovagal syncope. Heart Rhythm. 2015; 12(6):e41-e63.
5. Shen WK, Sheldon RS, Benditt DG, et al. ACC/AHA/HRS guideline for the evaluation and management of patients with syncope: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. Circulation. 2017; 136(5):e60-e122.
6.  Vinik AI, Camacho PM, Davidson JA, et al. American Association of Clinical Endocrinologists and American College of Endocrinology position statement on testing for autonomic and somatic nerve dysfunction. Endocr Pract. 2017; 23(12):1472-1478.

1. MedlinePlus [Internet]. Bethesda (MD): National Library of Medicine (US). Autonomic Testing. Last reviewed September 26, 2024. Available at: https://medlineplus.gov/lab-tests/autonomic-testing/. Accessed on March 4, 2026.

30:15 Ratio
Autonomic Nervous System
Beat-to-beat Blood Pressure Monitoring
Cardiovagal innervations
Head-Up Tilt Table Test
Heart Rate Variability with Deep Breathing (HRDB)
Parasympathetic
Quantitative Direct and Indirect Reflex Test
Quantitative Sudomotor Axon Reflex Test (QSART)
Silastic Sweat imprint
Sudomotor function
Sympathetic Skin Response
Thermoregulatory Sweat Test
Valsalva Maneuver
Vasomotor Adrenergic innervations

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