Background

Nerve Damage and Disease

Nerve damage and nerve diseases can reduce functional capacity and lead to neuropathic pain.

Treatment

There is a need for tests that can objectively measure sensory thresholds. Moreover, quantitative sensory testing (QST) could aid in the early diagnosis of disease, before patients would be diagnosed clinically. Also, although the criterion standard for evaluation of myelinated, large fibers is electromyography nerve conduction study, there are no criterion standard reference tests to diagnose small fiber dysfunction.

Quantitative Sensory Testing

QST systems measure and quantify the amount of physical stimuli required for sensory perception to occur. As sensory deficits increase, the perception threshold of QST will increase, which may be informative in documenting the progression of neurologic damage or disease. QST has not been established for use as a sole tool for diagnosis and management but has been used with standard evaluative and management procedures (e.g., physical and neurologic examination, monofilament testing, pinprick, grip and pinch strength, Tinel sign, and Phalen and Roos test) to enhance the diagnosis and treatment-planning process, and to confirm physical findings with quantifiable data. Stimuli used in QST includes touch, pressure, pain, thermal (warm and cold), or vibratory stimuli.

The criterion standard for evaluation of myelinated, large fibers is the electromyography nerve conduction study. However, the function of smaller myelinated and unmyelinated sensory nerves, which may show pathologic changes before the involvement of the motor nerves, cannot be detected by nerve conduction studies. Small fiber neuropathy has traditionally been a diagnosis of exclusion in patients who have symptoms of distal neuropathy and a negative nerve conduction study.

Depending on the type of stimuli used, QST can assess both small and large fiber dysfunction. Touch and vibration measure the function of large myelinated A alpha and A beta sensory fibers. Thermal stimulation devices are used to evaluate pathology of small myelinated and unmyelinated nerve fibers; they can be used to assess heat and cold sensation, as well as thermal pain thresholds. Pressure-specified sensory devices assess large myelinated sensory nerve function by quantifying the thresholds of pressure detected with light, static, and moving touch. Finally, current perception threshold testing involves the quantification of the sensory threshold to transcutaneous electrical stimulation. In current perception threshold testing, typically 3 frequencies are tested: 5 Hz, designed to assess C fibers; 250 Hz, designed to assess A delta fibers; and 2000 Hz, designed to assess A beta fibers. Results are compared with those of a reference population.

Because QST combines the objective physical, sensory stimuli with the subject patient response, it is psychophysical and requires patients who are alert, able to follow directions, and cooperative. Also, to get reliable results, examinations need to include standardized instructions to the patients, and stimuli must be applied consistently by trained staff. Psychophysical tests have greater inherent variability, making their results more difficult to reproduce.

QST has primarily been applied in patients with conditions associated with nerve damage and neuropathic pain. There have also been preliminary investigations to identify sensory deficits associated with conditions such as autism spectrum disorder, Tourette syndrome, restless legs syndrome, musculoskeletal pain, and response to opioid treatment.

Regulatory Status

A number of QST devices have been cleared for marketing by the U.S. Food and Drug Administration through the 510(k) process. Examples are listed in Table 1.

Table 1. FDA-Approved Quantitative Sensory Testing Devices

Device	Manufacturer	Date Cleared	510(k)	Indications
FDA product code: LLN
Neurometer®	Neurotron	Jun 1986	K853608	Current perception threshold testing
NK Pressure-Specified Sensory Device, Model PSSD	NK Biotechnical Engineering	Aug 1994	K934368	Pressure-specified sensory testing
AP-4000, Air Pulse Sensory Stimulator	Pentax Precision Instrument	Sep 1997	K964815	Pressure-specified sensory testing
Neural-Scan	Neuro-Diagnostic Assoc.	Dec 1997	K964622	Current perception threshold testing
Vibration Perception Threshold (VPT) METER	Xilas Medical	Dec 2003	K030829	Vibration perception testing
FDA product code: NTU
Contact Heat-Evoked Potential Stimulator (Cheps)	Medoc, Advanced Medical Systems	Feb 2005	K041908	Thermal sensory testing

FDA: Food and Drug Administration.

Related Policies

• Nerve Fiber Density Testing (Policy #051 in the Medicine Section)

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

Literature searches focus on types of quantitative sensory testing (QST) approved or cleared by the U.S. Food and Drug Administration (FDA). This includes current perception threshold testing, pressure-specified sensory testing (PSST), vibration perception threshold (VPT) testing, and thermal threshold testing.

Quantitative Sensory Testing

Current Perception Threshold Testing

Clinical Context and Test Purpose

The purpose of current perception threshold testing is to provide a diagnostic option and a treatment that is an alternative to or an improvement on existing tests, such as standard clinical evaluation and other sensory assessment tests, in patients with conditions linked to nerve damage or disease (e.g., diabetic neuropathy, carpal tunnel syndrome).

The question addressed in this policy is: Does QST improve the net health outcome in patients with conditions linked to nerve damage or disease?

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

Patients

The relevant population of interest are individuals with conditions linked to nerve damage or disease (e.g., diabetic neuropathy, carpal tunnel syndrome).

Interventions

The test being considered is current perception threshold testing.

QST systems are used for the noninvasive assessment and quantification of sensory nerve function in patients with symptoms of or the potential for neurologic damage or disease. Types of sensory testing include current perception threshold testing. Information on sensory deficits identified using QST has been used in research settings to understand neuropathic pain better. It could be used to diagnose conditions linked to nerve damage and disease, and to improve patient outcomes by impacting management strategies.

Patients with conditions linked to nerve damage or disease (e.g., diabetic neuropathy, carpal tunnel syndrome) are actively managed by occupational therapists, physical therapists, neurologists, and primary care providers in an outpatient clinical setting.

Comparators

Comparators of interest include standard clinical evaluation and other sensory assessment tests. Comparators are managed by occupational therapists, physical therapists, neurologists, and primary care providers in an outpatient clinical setting.

Outcomes

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

Study Selection Criteria

Below are selection criteria for studies to assess whether a test is clinically valid.

a. The study population represents the population of interest. Eligibility and selection are described.

b. The test is compared with a credible reference standard.

c. If the test is intended to replace or be an adjunct to an existing test; it should also be compared with that test.

d. Studies should report sensitivity, specificity, and predictive values. Studies that completely report true- and false-positive results are ideal. Studies reporting other measures (e.g., receiver operating characteristic [ROC], area under receiver operating characteristic [AUROC]), c-statistic, likelihood ratios) may be included but are less informative.

e. Studies should also report reclassification of diagnostic or risk category.

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

Clinically Valid

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

Limited published evidence is available on diagnostic performance. Several studies have compared current perception threshold testing with other testing methods, but sensitivity and specificity have not been reported. For example, Ziccardi et al (2012) evaluated 40 patients presenting with trigeminal nerve injuries involving the lingual branch.^1, Patients underwent current perception threshold testing and standard clinical sensory testing. Statistically significant correlations were found between findings of electrical stimulation testing at 250 Hz and the reaction to pinprick testing (p=0.02), reaction to heat stimulation (p=0.01), and reaction to cold stimulation (p=0.004). Also, significant correlations were found between electrical stimulation at 5 Hz and the reaction to heat stimulation (p=0.017), to cold stimulation (p=0.004), but not to pinprick testing (p=0.096).

In addition, Park et al (2001) compared current perception threshold testing with standard references for thermal sensory testing and von Frey tactile hair stimulation in a randomized, double-blind, placebo-controlled trial with 19 healthy volunteers.² All current perception threshold measurements showed a higher degree of variability than thermal sensory testing and von Frey measurements but there was some evidence that similar fiber tracts can be measured, especially C-fiber tract activity at 5 Hz, with current perception threshold, thermal sensory, and von Frey testing methods. This study only included healthy volunteers.

Clinically Useful

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

Direct Evidence

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

No direct evidence from comparative studies evaluating the impact of current perception testing on patient management decisions or health outcomes was identified.

Chain of Evidence

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

Because the evidence is insufficient to demonstrate test performance for current perception threshold testing, no inferences can be made about clinical utility.

Section Summary: Current Perception Threshold Testing

There is insufficient evidence on the accuracy of current perception threshold testing for diagnosing any condition linked to nerve damage or disease using current perception threshold testing. Several studies have compared current perception threshold testing with other testing methods but sensitivity and specificity were not reported. No direct evidence was identified for the clinical utility of current perception testing and, since there is insufficient evidence on test performance, a chain of evidence for clinical utility cannot be constructed.

Pressure-Specified Sensory Testing

Clinical Context and Test Purpose

The purpose of PSST is to provide a diagnostic option that is an alternative to or an improvement on existing tests, such as standard clinical evaluation and other sensory assessment tests, in patients with conditions linked to nerve damage or disease (e.g., diabetic neuropathy, carpal tunnel syndrome).

The question addressed in this policy is: Does QST improve the net health outcome in patients with conditions linked to nerve damage or disease?

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

Patients

The relevant population of interest are individuals with conditions linked to nerve damage or disease (e.g., diabetic neuropathy, carpal tunnel syndrome).

Interventions

The test being considered is PSST .

Comparators

Comparators of interest include standard clinical evaluation and other sensory assessment tests. Comparators are managed by occupational therapists, physical therapists, neurologists, and primary care providers in an outpatient clinical setting.

Outcomes

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

Study Selection Criteria

Below are selection criteria for studies to assess whether a test is clinically valid.

a. The study population represents the population of interest. Eligibility and selection are described.

b. The test is compared with a credible reference standard.

c. If the test is intended to replace or be an adjunct to an existing test; it should also be compared with that test.

d. Studies should report sensitivity, specificity, and predictive values. Studies that completely report true- and false-positive results are ideal. Studies reporting other measures (e.g., ROC, AUROC, c-statistic, likelihood ratios) may be included but are less informative.

e. Studies should also report reclassification of diagnostic or risk category.

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

Clinically Useful

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

Standard evaluation and management of patients with potential nerve compression, disease, or damage consists of physical examination techniques and may include Semmes-Weinstein monofilament testing and, in more complex cases, nerve conduction velocity testing. Several studies have compared the performance of PSST devices. For example, a study by Weber et al (2000) evaluated the sensitivity and specificity of PSST and nerve conduction velocity testing in 79 patients, including 26 healthy controls.^2, The nerve conduction velocity test had a sensitivity of 80% and a specificity of 77%; the PSST had a sensitivity of 91% and a specificity of 82%. The difference between the two tests was not statistically significant.

A study by Nath et al (2010) evaluated 30 patients with winged scapula and upper trunk injury and 10 healthy controls.^3, They used the PSST device by Sensory Management Services cleared by the FDA to measure the minimum perceived threshold in both arms for detecting 1-point static and 2-point static stimuli. The authors used a published standard reference threshold value for the dorsal hand first web (DHFW) skin and calculated threshold values for both the DHFW and the deltoid using the upper limit of the 99% normal confidence interval. No published threshold values were available for the deltoid location. PSST was done on both arms of all participants, and electromyography testing only on the affected arms of symptomatic patients. Using calculated threshold values, patients with normal electromyography results had positive PSST results on 50% (8/16) of 1-point static deltoid, 71% (10/14) of 2-point static deltoid, 65% (11/17) of 1-point static DHFW, and 87% (13/15) of 2-point static DHFW tests. Study findings suggested that PSST is more sensitive than needle electromyography in detecting brachial plexus upper trunk injury.

A systematic review by Hubscher et al (2013) evaluated the relation between QST and self-reported pain and disability in patients with spinal pain.^4, Twenty-eight of 40 studies identified used PSST devices. The overall analysis found low or no correlations between pain thresholds, as assessed by QST and self-reported pain intensity or disability. For example, the pooled estimate of the correlation between pain threshold and pain was -0.15 (95% confidence interval, -0.18 to -0.11) and -0.16 (95% confidence interval, -0.22 to -0.10) between pain threshold and disability. The findings suggested that QST provides low accuracy for diagnosing patients' level of spinal pain and disability.

Clinically Useful

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

Direct Evidence

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

No direct evidence from clinical trials identified has demonstrated that use of the PSST resulted in changes in patient management or improved patient outcomes. Suokas et al (2012) published a systematic review of studies evaluating QST for painful osteoarthritis; most studies used pressure testing.^5, Reviewers did not report finding any studies evaluating the impact of QST on health outcomes.

Chain of Evidence

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

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

Section Summary: PSST

The available evidence on the diagnostic accuracy of PSST for conditions linked with nerve damage or disease is limited, but available studies have reported relatively low diagnostic accuracy. There is insufficient direct evidence on the clinical utility of PSST and, because there is insufficient evidence on test performance, an indirect chain of evidence for clinical utility cannot be constructed.

Vibration Perception Testing

Clinical Context and Test Purpose

The purpose of VPT is to provide a diagnostic option that is an alternative to or an improvement on existing tests, such as standard clinical evaluation and other sensory assessment tests, in patients with conditions linked to nerve damage or disease (e.g., diabetic neuropathy, carpal tunnel syndrome).

The question addressed in this policy is: Does QST improve the net health outcome in patients with conditions linked to nerve damage or disease?

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

Patients

The relevant population of interest are individuals with conditions linked to nerve damage or disease (e.g., diabetic neuropathy, carpal tunnel syndrome).

Interventions

The test being considered is VPT.

Comparators

Comparators of interest include standard clinical evaluation and other sensory assessment tests. Comparators are managed by occupational therapists, physical therapists, neurologists, and primary care providers in an outpatient clinical setting.

Outcomes

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

Study Selection Criteria

Below are selection criteria for studies to assess whether a test is clinically valid.

a. The study population represents the population of interest. Eligibility and selection are described.

b. The test is compared with a credible reference standard.

c. If the test is intended to replace or be an adjunct to an existing test; it should also be compared with that test.

d. Studies should report sensitivity, specificity, and predictive values. Studies that completely report true- and false-positive results are ideal. Studies reporting other measures (e.g., ROC, AUROC, c-statistic, likelihood ratios) may be included but are less informative.

e. Studies should also report reclassification of diagnostic or risk category.

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

Clinically Valid

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

A study from India, Mythili et al (2010) evaluated 100 patients with type 2 diabetes using a VPT device (Sensitometer; Dhansai Lab).^6, The device is not FDA-approved or cleared. The authors reported on sensitivities and specificities for the device and standard nerve conduction study (NCS). For vibration testing, a positive finding (i.e., the presence of neuropathy) was defined as patients reporting no vibration sensation at more than 15 volts. According to NCSs, 70 of 100 patients had evidence of neuropathy. VPT had a sensitivity of 86% and a specificity of 76%. Semmes-Weinstein monofilament testing, which was also done, had a higher sensitivity than vibration testing (98.5%) but lower specificity (55%). Finally, a Diabetic Neuropathy Symptom Score, determined by responses to a patient questionnaire, had a sensitivity of 83% and a specificity of 79%. The authors noted that the simple neurologic examination score appeared to be as accurate as vibration testing. It is not known how similar the Sensitometer device is to FDA-approved vibration threshold testing devices.

Abraham et al (2015) retrospectively reviewed the charts of 70 patients with chronic inflammatory demyelinating polyneuropathy (CIDP) who were evaluated with a VPT device (Neurothesiometer).^7,The stimulus was applied to the first finger and toe on each side; the voltage was gradually increased, and patients were asked to state when they first perceived vibration. The threshold for a normal test result was 5 volts or less in the fingers and 15 volts or less in the toes. Data on the results of neurologic examinations were also reviewed, including testing using semiqualitative vibration testing with a 128-Hz tuning fork. Fifty-five (79%) patients had elevated VPT values. Abnormal neurologic findings were more common in CIDP patients with elevated VPT scores (92.7%) at the toes than those without elevated VPT scores (46.7%; p<0.001). Compared with patients with normal VPT values, patients with elevated VPT values were more likely to meet European Federation of Neurological Societies and Peripheral Nerve Society electrophysiologic criteria for CIDP (51% vs 13%, p=0.01) and had significantly lower treatment response rates (54% vs 93%, p=0.03). The authors did not report the sensitivity or specificity of the device compared with standard diagnostic tests. The Neurothesiometer is not FDA-approved or cleared.

Goel et al (2017) published a cross-sectional study comparing the diagnostic performance of several testing methods to detect early symptoms of diabetic peripheral neuropathy (DPN).^8,Five hundred twenty-three patients with type 2 diabetes between the ages of 18 and 65 (mean, 49.4 years) were first assessed with the modified Neuropathy Disability Score as the reference standard; then both feet were tested with electrochemical skin conductance, VPT, and Diabetic Neuropathy Symptom Score. For feet electrochemical skin conductance less than 60 μS, VPT, and Diabetic Neuropathy Symptom Score, the sensitivity was 85%, 72%, and 52%, respectively; specificity was 85%, 90%, and 60%, respectively. There was a significant inverse linear relation between VPT and feet electrochemical skin conductance (r = -0.45, p<0.001); feet electrochemical skin conductance was determined to be superior to VPT for identifying early signs ofDPN). The study lacked follow-up data.

Azzopardi et al (2018) published a prospective multicenter cross-sectional study comparing 3 types of vibration screening used to diagnose DPN.^9, The study collected data from 100 patients (age range, 40-80 years) who had type 2 diabetes for at least 10 years. Each participant was assessed with a VibraTip (not registered with the FDA), neurothesiometer, and 128-Hz tuning fork in both feet. Vibrations were not perceived by 28.5% of patients when using VibraTip, 21% using a neurothesiometer, and 12% using a tuning fork; a small-to-moderately strong association (Cramer's V, 0.167) was found between the instruments. The study lacked a criterion standard for assessing neuropathy. The authors concluded that multiple methods of assessment would be necessary to avoid a false-negative diagnosis.

Clinically Useful

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

Direct Evidence

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

No direct evidence from clinical trials was identified demonstrating that use of vibration testing resulted in changes in patient management or improved patient outcomes.

Chain of Evidence

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

Indirect evidence on clinical utility rests on clinical validity. Because the evidence does not demonstrate the test performance of VPT, no inferences can be made about clinical utility.

Section Summary: VPT

A few studies have evaluated the diagnostic performance of VPT using devices not FDA-cleared. In one study, a neurologic examination score had similar diagnostic accuracy to vibration testing, and Semmes-Weinstein monofilament testing had a higher sensitivity than VPT but a lower specificity. The other study did not report sensitivity or specificity for VPT but reported that patients with elevated VPT findings were significantly more likely to meet society criteria for CIDP compared with patients with normal VPT results. Another study compared VPT with electrochemical skin conductance and determined that electrochemical skin conductance was superior for early identification of DPN, while a fourth study concluded that multiple methods of assessment were necessary to diagnose DPN. No direct evidence for the clinical utility of VPT was identified and, because there is since there is insufficient evidence about test performance, an indirect chain of evidence on clinical utility cannot be constructed.

Thermal Sensory Testing

Clinical Context and Test Purpose

The purpose of thermal sensory testing is to provide a diagnostic option that is an alternative to or an improvement on existing tests, such as standard clinical evaluation and other sensory assessment tests, in patients with conditions linked to nerve damage or disease (e.g., diabetic neuropathy, carpal tunnel syndrome).

The question addressed in this policy is: Does QST improve the net health outcome in patients with conditions linked to nerve damage or disease?

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

Patients

The relevant population of interest are individuals with conditions linked to nerve damage or disease (e.g., diabetic neuropathy, carpal tunnel syndrome).

Interventions

The test being considered is thermal sensory testing.

Comparators

Comparators of interest include standard clinical evaluation and other sensory assessment tests. Comparators are managed by occupational therapists, physical therapists, neurologists, and primary care providers in an outpatient clinical setting.

Outcomes

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

Study Selection Criteria

Below are selection criteria for studies to assess whether a test is clinically valid.

a. The study population represents the population of interest. Eligibility and selection are described.

b. The test is compared with a credible reference standard.

c. If the test is intended to replace or be an adjunct to an existing test; it should also be compared with that test.

d. Studies should report sensitivity, specificity, and predictive values. Studies that completely report true- and false-positive results are ideal. Studies reporting other measures (e.g., ROC, AUROC, c-statistic, likelihood ratios) may be included but are less informative.

e. Studies should also report reclassification of diagnostic or risk category.

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

Clinically Valid

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

Devigili et al (2008) assessed 150 patients referred for suspected sensory neuropathy and tested with a Medoc thermal perception testing device.^10, Patients underwent (1) clinical examination, (2) a sensory and motor NCS, (3) warm and cooling thresholds assessed by QST, and (4) skin biopsy with distal intraepidermal nerve fiber (IENF) density. Based on the combined assessments, neuropathy was ruled out in 26 patients; 124 patients were diagnosed with sensory neuropathy and, of these, 67 patients were diagnosed with small nerve fiber neuropathy. Using a cutoff of 7.63 IENF per millimeter at the distal leg (based on the 5th percentile of controls), 59 (88%) patients were considered to have abnormal IENF (small nerve fiber) density. Only 7.5% of patients had abnormal results for all 3 examinations (clinical, QST, skin biopsy), 43% of patients had both abnormal skin biopsy and clinical findings, and 37% of patients had both abnormal skin biopsy and QST results. The combination of abnormal clinical and QST results was observed in only 12% of patients. These results indicated that most patients evaluated showed an IENF density of less than 7.63 together with either abnormal spontaneous or evoked pain (clinical examination) or abnormal thermal thresholds (QST). Study authors recommended a new diagnostic criterion standard based on the presence of at least two of three abnormal results (clinical, QST, IENF density).

Lefaucheur et al (2015) compared 5 tests for diagnosing small fiber neuropathy (SFN), including QST using a Medoc thermal perception testing device.^11, The QST device was used to assess the warm detection threshold and cold detection threshold. Other tests were laser-evoked potential (LEP), sympathetic skin response, and electrochemical skin conductance. The study enrolled 87 consecutive patients being evaluated for definite (n=33) or possible (n=54) painful SFN. All five tests were conducted in a single session. Findings were compared with those for 174 healthy subjects, matched for age and sex. Results of each test were categorized as normal or abnormal, using findings in healthy subjects as the reference range for normal values. All patients with definite SFN and 70% of those with possible SFN had at least 1 abnormal test. The sensitivity and specificity of each test in the series of 87 patients are shown in Table 2.

Table 2. Sensitivity and Specificity (N=87)

Test	Sensitivity, %	Specificity, %
Warm detection threshold	44.8	91.4
Cold detection threshold	26.4	97.1
Laser-evoked potential	64.4	87.4
Sympathetic skin response	33.3	77.6
Electrochemical skin conductance	49.4	92.5

Adapted from Lefaucheur et al (2015).^11,

LEP was the most sensitive test. However, not all patients were correctly categorized with LEP. Fifteen patients with at least one abnormal test had normal LEP tests, but abnormal warm detection threshold or electrochemical skin conductance tests. Findings of the other two tests (cold detection threshold, sympathetic skin response) were redundant. As noted by the authors, their study lacked a definitive criterion standard for SFN with which to compare test findings.

Anand et al (2017) assessed 30 patients with nonfreezing cold injury, or trench foot, described as a peripheral vaso-neuropathy.^12,The authors evaluated use of skin biopsies immunohistochemistry, clinical examination of the feet, including pinprick, as well as QST assessments, and NCSs as diagnostic tools. Abnormal pinprick sensation was reported in 67% of patients. Monofilament perception threshold was abnormal in 63% of patients, 40% for VPT thresholds, and between 67% and 83% for the various thermal thresholds; NCSs showed 23% of subjects had axonal neuropathy. It was noted that performing QST could be difficult for patients with cutaneous hypersensitivity and severe limb pain. No study limitations were reported.

Clinically Useful

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

Direct Evidence

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

No direct evidence from clinical trials was identified demonstrating that use of thermal testing resulted in changes in patient management or improved patient outcomes.

Chain of Evidence

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

Indirect evidence on clinical utility rests on clinical validity. Because of limited evidence about test performance for thermal threshold testing, no inferences can be made about clinical utility.

Section Summary: Thermal Sensory Testing

Two studies have evaluated the diagnostic accuracy of thermal QST using the same FDA-cleared device. Neither found a high diagnostic accuracy of thermal QST but both found the test had potential when used in combination with other tests. The optimal combination of tests is not well-defined. No studies reporting on the clinical utility for thermal sensory testing were identified, and, because there is insufficient evidence on test performance, an indirect chain of evidence on clinical utility cannot be constructed.

Summary of Evidence

For individuals who have conditions linked to nerve damage or disease (e.g., diabetic neuropathy, carpal tunnel syndrome) who receive current perception threshold testing, the evidence includes several studies on technical performance and diagnostic accuracy. The relevant outcomes are test accuracy and validity, symptoms, and functional outcomes. The existing evidence does not support the accuracy of current perception threshold testing for diagnosing any condition linked to nerve damage or disease. Studies comparing current perception threshold testing with other testing methods have not reported on sensitivity or specificity. Also, there is a lack of direct evidence on the clinical utility of current perception testing and, because there is insufficient evidence on test performance, an indirect chain of evidence on clinical utility cannot be constructed. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have conditions linked to nerve damage or disease (e.g., diabetic neuropathy, carpal tunnel syndrome) who receive PSST, the evidence includes several studies on diagnostic accuracy. The relevant outcomes are test accuracy and validity, symptoms, and functional outcomes. Current evidence does not support the diagnostic accuracy of PSST for diagnosing any condition linked to nerve damage or disease. A systematic review found that PSST had low accuracy for diagnosing spinal conditions. Also, there is a lack of direct evidence on the clinical utility of current perception testing and, because there is insufficient evidence on test performance, an indirect chain of evidence on clinical utility cannot be constructed. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have conditions linked to nerve damage or disease (e.g., diabetic neuropathy, carpal tunnel syndrome) who receive VPT, the evidence includes several studies on diagnostic accuracy. The relevant outcomes are test accuracy and validity, symptoms, and functional outcomes. A few studies have assessed the diagnostic performance of vibration testing using devices not cleared by the FDA. Also, there is a lack of direct evidence on the clinical utility of VPT and, in the absence of sufficient evidence on test performance, an indirect chain of evidence on clinical utility cannot be constructed. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have conditions linked to nerve damage or disease (e.g., diabetic neuropathy, carpal tunnel syndrome) who receive thermal sensory testing, the evidence includes diagnostic accuracy. The relevant outcomes are test accuracy and validity, symptoms, and functional outcomes. Two studies identified evaluated the diagnostic accuracy of thermal QST using the same FDA-cleared device. Neither found a high diagnostic accuracy for thermal QST but both studies found the test had potential when used with other tests. The optimal combination of tests is currently unclear. Also, there is a lack of direct evidence on the clinical utility of thermal sensory testing and, because there is insufficient evidence on test performance, an indirect chain of evidence on clinical utility cannot be constructed. The evidence is insufficient to determine the effects of the technology on health outcomes.

SUPPLEMENTAL INFORMATION

Clinical Input From Physician Specialty Societies and Academic Medical Centers

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

In response to the requests from physician specialty societies and academic medical centers, input was received from 1 specialty society and 1 academic medical center while the policy was under review in 2008. Input from both sources agreed with the policy statement that quantitative sensory testing is considered investigational.

Practice Guidelines and Position Statements

American Academy of Neurology

The American Academy of Neurology (2003; reaffirmed 2016) concluded that quantitative sensory testing (QST) is probably (level B recommendation) an effective tool for documenting of sensory abnormalities and changes in sensory thresholds in longitudinal evaluation of patients with diabetic neuropathy.^13,14, Evidence was weak or insufficient to support the use of QST in patients with other conditions (small fiber sensory neuropathy, pain syndromes, toxic neuropathies, uremic neuropathy, acquired and inherited demyelinating neuropathies, or malingering).

American Association of Neuromuscular & Electrodiagnostic Medicine

The American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM; 2004) published a technology literature review on QST (light touch, vibration, thermal, pain).^15, The review concluded that QST is a reliable psychophysical test of large- and small-fiber sensory modalities but is highly dependent on the full patient cooperation. Abnormalities do not localize dysfunction to the central or peripheral nervous system, and no algorithm can reliably distinguish between psychogenic and organic abnormalities. The AANEM review also indicated that QST had been shown to be reasonably reproducible over a period of days or weeks in normal subjects, but, for individual patients, more studies are needed to determine the maximum allowable difference between two quantitative sensory tests that can be attributed to experimental error.

The AANEM with American Academy of Neurology and American Academy of Physical Medicine & Rehabilitation (2005) developed a formal case definition of distal symmetrical polyneuropathy based on a systematic analysis of peer-reviewed literature supplemented by consensus from an expert panel.¹⁸ QST was not included as part of the final case definition, given that the reproducibility of QST ranged from poor to excellent, and the sensitivities and specificities of QST varied widely among studies.

U.S. Preventive Services Task Force Recommendations

Not applicable.

Ongoing and Unpublished Clinical Trials

A search of ClinicalTrials.gov in April 2019 did not identify any ongoing or unpublished trials that would likely influence this review.]
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Horizon BCBSNJ Medical Policy Development Process:

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

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Index:
Quantitative Sensory Testing
CASE IV Computer Aided Sensory Evaluator
CPT (Current Perception Threshold Testing)
Current Perception Threshold (CPT) Testing
Medi-Dx 7000 Device
Neurometer Current Perception Threshold Device
Nk Pressure-Specific Sensory Device
Pressure-Specific Sensory Testing
Thermal Sensory Analyzer (TSA)
Thermal Threshold Tester (TTT)
Thermal Threshold Testing
Vibration Perception Threshold (VPT) Meter
Vibration Perception Threshold Testing

References:
1. Ziccardi VB, Dragoo J, Eliav E, et al. Comparison of current perception threshold electrical testing to clinical sensory testing for lingual nerve injuries. J Oral Maxillofac Surg. Feb 2012;70(2):289-294. PMID 22079068

2. Weber RA, Schuchmann JA, Albers JH, et al. A prospective blinded evaluation of nerve conduction velocity versus Pressure-Specified Sensory Testing in carpal tunnel syndrome. Ann Plast Surg. Sep 2000;45(3):252-257. PMID 10987525

3. Nath RK, Bowen ME, Eichhorn MG. Pressure-specified sensory device versus electrodiagnostic testing in brachial plexus upper trunk injury. J Reconstr Microsurg. May 2010;26(4):235-242. PMID 20143301

4. Hubscher M, Moloney N, Leaver A, et al. Relationship between quantitative sensory testing and pain or disability in people with spinal pain-A systematic review and meta-analysis. Pain. Sep 2013;154(9):1497-1504. PMID 23711482

5. Suokas AK, Walsh DA, McWilliams DF, et al. Quantitative sensory testing in painful osteoarthritis: A systematic review and meta-analysis. Osteoarthritis Cartilage. Jul 11 2012;20(10):1075-1085. PMID 22796624

6. Mythili A, Kumar KD, Subrahmanyam KA, et al. A comparative study of examination scores and quantitative sensory testing in diagnosis of diabetic polyneuropathy. Int J Diabetes Dev Ctries. Jan 2010;30(1):43-48. PMID 20431806

7. Abraham A, Albulaihe H, Alabdali M, et al. Elevated vibration perception thresholds in CIDP patients indicate more severe neuropathy and lower treatment response rates. PLoS One. Nov 2015;10(11):e0139689. PMID 26545096

8. Goel A, Shivaprasad C, Kolly A, et al. Comparison of electrochemical skin conductance and vibration perception threshold measurement in the detection of early diabetic neuropathy. PLoS One. Sep 2017;12(9):e0183973. PMID 28880907

9. Azzopardi K, Gatt A, Chockalingam N, et al. Hidden dangers revealed by misdiagnosed diabetic neuropathy: A comparison of simple clinical tests for the screening of vibration perception threshold at primary care level. Prim Care Diabetes. Apr 2018;12(2):111-115. PMID 29029862

10. Devigili G, Tugnoli V, Penza P, et al. The diagnostic criteria for small fibre neuropathy: from symptoms to neuropathology. Brain. Jul 2008;131(Pt 7):1912-1925. PMID 18524793

11. Lefaucheur JP, Wahab A, Plante-Bordeneuve V, et al. Diagnosis of small fiber neuropathy: A comparative study of five neurophysiological tests. Neurophysiol Clin. Dec 2015;45(6):445-455. PMID 26596193

12. Anand P, Privitera R, Yiangou Y, et al. Trench foot or non-freezing cold injury as a painful vaso-neuropathy: clinical and skin biopsy assessments. Front Neurol. Sep 2017;8:514. PMID 28993756

13. Shy ME, Frohman EM, So YT, et al. Quantitative sensory testing: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology. Mar 25 2003;60(6):898-904. PMID 12654951

14. American Academy of Neurology. Quantitative Sensory Testing (reaffirmed 2016). 2003; https://www.aan.com/Guidelines/home/GuidelineDetail/87. Accessed May 18, 2018.

15. Chong PS, Cros DP. Technology literature review: quantitative sensory testing. Muscle Nerve. May 2004;29(5):734-747. PMID 15116380

16. Centers for Medicare & Medicaid Services (CMS). National Coverage Determination (NCD) for sensory Nerve Conduction Threshold Tests (sNCTs) (160.23). 2004; https://www.cms.gov/medicare-coverage-database/details/ncd-details.aspx?CALId=192&CalName=Prothrombin+Time+(PT)+(Addition+of+ICD-9-CM+V58.83%2C+Encounter+for+therapeutic+drug+monitoring%2C+as+a+covered+indication)&ExpandComments=y&CommentPeriod=0&NCDId=270&ncdver=2&CoverageSelection=Both&ArticleType=All&PolicyType=Final&s=New+York+-+Upstate&CptHcpcsCode=36514&bc=gAAAABABAEAAAA%3D%3D&. Accessed May 18, 2018.

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

CPT*

0106T
0107T
0108T
0109T
0110T

G0255