Sudoscan Clinical Data & ICD-10s: Autonomic Function Testing

SUDOSCAN® Clinical Data & ICD-10s: Autonomic Function Testing USA – Version 2

March 2016

Contents ICD-10 codes, Descriptions and supporting clinical research. ……………………………………………………… 1 Sudoscan, a noninvasive tool for detecting diabetic small fiber neuropathy and autonomic dysfunction. Vinik et aI. ……………………………………………………………………………………………………………….. 2 SUDOSCAN: A Simple, Rapid, and Objective Method with Potential for Screening for Diabetic Peripheral Neuropathy. Tesfaye et al…………………………………………………………………………………………… 3

Assessment of small fiber neuropathy through a quick, simple and non-invasive method in a 4 German diabetes outpatient clinic. Winiecki et al. ……..………………………………………………………………..

Screening of cardiovascular autonomic neuropathy in patients with diabetes using noninvasive quick and simple assessment of sudomotor function. Yajnik et al. ……………………………...

5

The diagnostic utility of Sudoscan for distal symmetric peripheral neuropathy. Smith et al. ……… 6 Bariatric Surgery Restores Cardiac and Sudomotor Autonomic C-fiber Dysfunction towards Normal in Obese Subjects with Type 2 Diabetes. Vinik et aI. ………………………………………………………. 8 Electrochemical skin conductance in autonomic synucleinopathies. Kaufmann et al. ………………… 9 Quick, non-invasive and quantitative evaluation of small fiber neuropathy in patients receiving chemotherapy. Saad et al. ………………………………………………………………………………………………………….. 10 The diagnostic accuracy of Sudoscan in Transthyretin Familial Amyloid Polyneuropathy. Castro et al. ………………………………………………………………………………………………………………………………………..…… 11 Sudoscan as a noninvasive tool to assess sudomotor dysfunction in patients with Fabry disease: results from a case–control study. Pouget et al. ………………………………………………………….… 12 Autonomic dysfunction in psoriatic arthritis. Syngle et al. ………………………………………………………….. 13 Disease-modifying anti-rheumatic drugs improve autonomic neuropathy in arthritis: DIANA study. Syngle et al. ……………………………………………………………………………………………………………………….. 14 Disclaimer: Information for user regarding Autonomic Function Testing: Indications for use and utilization guidelines are provided as suggestions only. Physicians should ensure that the billing and coding complies not only with carrier guidelines, but also with applicable laws, rules and regulations. It is incumbent upon the physician to determine the medical necessity and utilization for any test on individual patients. This information is not intended to be and should not be construed as legal or regulatory advice.

0 SUDOSCAN® Clinical Data & ICD-10s: Autonomic Function Testing

ICD-10 codes, Descriptions and supporting clinical research.

ICD-10 Code E10.42 E10.43 E10.49 E10.610 E11.42 E11.43 E11.49 E11.610 E13.42 E13.43 E13.49 E13.610 E85.1 G23.2 G23.8 G60.3 G60.8 G90.3 G90.09 I95.1 * R00.0 * R55 * R61 *

Description Type 1 diabetes mellitus with diabetic polyneuropathy Type 1 diabetes mellitus with diabetic autonomic (poly)neuropathy Type 1 diabetes mellitus with other diabetic neurological complication Type 1 diabetes mellitus with diabetic neuropathic arthropathy Type 2 diabetes mellitus with diabetic polyneuropathy Type 2 diabetes mellitus with diabetic autonomic (poly)neuropathy Type 2 diabetes mellitus with other diabetic neurological complication Type 2 diabetes mellitus with diabetic neuropathic arthropathy Other specified diabetes mellitus with diabetic polyneuropathy Other specified diabetes mellitus with diabetic autonomic (poly)neuropathy Other specified diabetes mellitus with other diabetic neurological complication Other specified diabetes mellitus with diabetic neuropathic arthropathy Neuropathic heredofamilial amyloidosis Striatonigral degeneration Other specified degenerative diseases of basal ganglia Idiopathic progressive neuropathy Other hereditary and idiopathic neuropathies Multi-system degeneration of the autonomic nervous system Other idiopathic peripheral autonomic neuropathy Orthostatic hypotension Tachycardia, unspecified Syncope and collapse Generalized hyperhidrosis

Supporting clinical research (page) 2, 3, 4, 5, 6 2, 3, 4, 5, 6 2, 3, 4, 5, 6 2, 3, 4, 5, 6 2, 4, 5, 6, 8 2, 4, 5, 6, 8 2, 4, 5, 6 2, 4, 5, 6 2, 4, 5, 6, 8 2, 4, 5, 6, 8 2, 4, 5, 6 2, 4, 5, 6 11 9 9 2, 4, 5, 6, 8, 10 2, 4, 5, 6, 9, 10-14 9 8, 9, 10, 13, 14

*These ICD-10 codes do not relate to specific medical conditions; the physician may elect to perform autonomic testing on a patient presenting with one or more of these symptom(s) when the physician suspects an autonomic etiology.

1 SUDOSCANÂŽ Clinical Data & ICD-10s: Autonomic Function Testing

Sudoscan, a noninvasive tool for detecting diabetic small fiber neuropathy and autonomic dysfunction.

Casellini CM, Parson HK, Richardson MS, Nevoret ML, Vinik AI. Diabetes Technol Ther. 2013 Nov;15(11):948-53.

Aim & Background: Major clinical manifestations of diabetic neuropathy are autonomic dysfunction and pain. The aim of this study was to evaluate SUDOSCAN as a tool for assessing autonomic neuropathy and neuropathic pain.

Method: 83 patients (20 with type 1 diabetes and 63 with type 2 diabetes) were tested: • Sudomotor function (ESC) using SUDOSCAN device.

• Time and frequency quantitative autonomic function testing (QAFT) • Neurological evaluation with measurement of neuropathy impairment (NIS-LL) score • Quantitative sensory testing (QST) • Symptomatic pain using a visual analog scale (NRS II Point Scale).

Results are reported as mean ± standard error.

Results: • Diabetic patients with peripheral neuropathy had lower hand and foot ESC compared to patients without neuropathy (51.9±1.5 vs 67.5±2.7 µS, p <0.0001 and 56.3±1.6 vs 75.9±3.0 µS, p <0.01).

Corresponding values for hand and foot ESC in healthy controls were 73.1±0.8 and 84.4±0.9 µS. • Patients with painful diabetic neuropathy had worse foot ESC than patients with non-painful neuropathy (52.8±3.6 vs 68.0±6.6 µS, p <0.05).

• Sensitivity was 78% and specificity 92% for foot ESC (threshold, 77 µS), while AUC for the NIS-LL score was 0.84 with a sensitivity of 76% and specificity of 86%.

• Correlation between hand ESC and E/I ratio and deep breathing Low Frequency component (sympathetic) were 0.42, p =0.0003 and 0.41 p=0.0006 respectively.

Figure 1: Feet and Hand ESC in Healthy Control and Diabetes patients with and without Diabetic Neuropathy

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SUDOSCAN: A Simple, Rapid, and Objective Method with Potential for Screening for Diabetic Peripheral Neuropathy.

Selvarajah D, Cash T, Davies J, Sankar A, Rao G, Grieg M, Pallai S, Gandhi R, Wilkinson ID, Tesfaye S. PLoS One. 2015 Oct 12;10(10):e0138224.

Aim & Background: Clinical methods of detecting diabetic peripheral neuropathy (DPN) are not objective and reproducible. The aim of this study was to evaluate if SUDOSCAN, a rapid, non-invasive and quantitative assessment of sudomotor function can reliably screenfor DPN.

Method: 70 subjects (45 with type 1 diabetes and 25 healthy controls) were tested: • Sudomotor function (ESC) using SUDOSCAN device.

• Cardiovascular reflex tests (CARTs) for autonomic neuropathy • Clinical neurological exam and nerve conduction studies (NCS) • Classification into DPN or no-DPN based on American Academy of Neurology criteria

Results: • Foot ESC was significantly lower in subjects with DPN compared to those without DPN or healthy controls: 53.5(25.1) vs. 77.0(7.9) and 77.1(14.3) μS, p<0.001.

• Sensitivity and specificity of foot ESC for classifying DPN were 87.5% and 76.2%, respectively.

• Subjects with CAN had significantly lower foot [55.0(28.2)] and hand [53.5(19.6)] ESC compared to No-CAN [foot ESC, 72.1(12.2); hand ESC 64.9(14.4)] and HV groups (ANCOVA p<0.001 and 0.001, respectively).

• CAN risk score correctly classified CAN with a sensitivity of 65.0% and specificity of 80.0%.

Figures 2 and 3: Graphic presentation of the diagnostic performance of (A) Foot Electrochemical Skin Conductance (FESC, μS) and (B) Cardiac Autonomic Neuropathy Risk Score (CAN-RS) by Receiver Operating Curve (ROC) analysis for diabetic peripheral neuropathy (A) and cardiac autonomic neuropathy (B, CAN).

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Assessment of small fiber neuropathy through a quick, simple and non-invasive method in a German diabetes outpatient clinic.

Calvet JH, Dupin J, Winiecki H, Schwarz PE. Exp Clin Endocrinol Diabetes. 2013 Feb;121(2):80-3.

Aim & Background: Intensive therapy with insulin has been shown to delay the onset and slow the progression of retinopathy, nephropathy and peripheral neuropathy. The aim of this observational study was to assess sweat function in patients at a diabetes outpatient consult clinic in Germany.

Method: 52 patients with type 1 diabetes and 115 patients with type 2 diabetes (69 receiving insulin) were tested at baseline and 1 year follow-up.

• SUDOSCAN • HbA1c

Results: • A slight decrease in hand and foot conductances was observed in patients with type 2 diabetes not taking insulin while an improvement was observed in patients receiving insulin (-3.8±9.7 vs 1.0±9.7 µS, p =0.02 for the hands and -2.2±7.5 vs 4.1±8.8 µS, p<0.001 for the feet).

• Coefficient of correlation between measurements performed with the two different devices was 0.85 for hands and 0.93 for feet, p<0.001.

Figure 4: Changes in feet Electrochemical Skin Conductances (ESC) during one-year follow-up in patients with type 2 diabetes receiving insulin (solid black line) or not (dotted line) or with type 1 diabetes (grey line).

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Screening of cardiovascular autonomic neuropathy in patients with diabetes using non-invasive quick and simple assessment of sudomotor function.

Yajnik CS, Kantikar V, Pande A, Deslypere JP, Dupin J, Calvet JH, Bauduceau B. Diabetes Metab. 2013 Apr;39(2):126-31.

Aim & Background: Cardiovascular Autonomic Neuropathy (CAN) is a common but overlooked complication of diabetes. SUDOSCAN was compared to Heart Rate Variability (HRV) and Ewing tests, known to be reliable methods for the investigation of CAN.

Method: 232 patients with diabetes were assessed for: • HRV at rest and during moderate activity (stair climbing): – Time and frequency domain analysis techniques, including measurement of Standard Deviation of the average NN intervals over 5 minutes (SDNN) – High Frequency domain component (HF) – Low Frequency domain component (LF) • Heart rate variability during deep breathing and heart rate and blood pressure responses while standing, as described by Ewing • Electrochemical Skin Conductance (ESC) on the hands and feet, and calculated risk score.

Results: • When taking two abnormal Ewing tests as reference the AUC of the ROC curve for the Sudoscan risk score was 0.74 with a sensitivity of 92% and a specificity of 49% using a risk score cut-off value of 35%.

• For the ROC curve analysis using the LF power component during moderate activity at a threshold of 90 ms2 (1st quartile) as reference, sensitivity and specificity were 88% and 54% respectively using a cut-off of 35% for SUDOSCAN risk score.

Figure 5 & 6: Graphic representation of the diagnostic performance of the SUDOSCAN risk-score, E:I ratio, 30:15 ratio and blood pressure (BP) change on standing by receiver operating curve (ROC) analysis, using (a) the low-frequency power component during moderate activity at a threshold of 90 ms² (first quartile) and (b) the high-frequency power component during moderate activity at a threshold of 20 ms² (first quartile).

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The diagnostic utility of Sudoscan for distal symmetric peripheral neuropathy.

Smith AG, Lessard M, Reyna S, Doudova M, Singleton JR. J Diabetes Complications. 2014 Jul-Aug;28(4):511-6.

Aim: To evaluate SUDOSCAN’s diagnostic utility for Distal Symmetric Polyneuropathy.

Method: The study investigated patients with suspected DSP: 55 general neurology clinic patients with DSP (22 DM, 2 pre-DM, 31 idiopathic) (DM: Diabetes mellitus), 42 healthy controls.

• SUDOSCAN • UENS: Utah Early Neuropathy Scale (a clinical exam of large and small nerve fibers) • IENFD: skin biopsy for intraepidermal nerve fiber density • QSART: Quantitative Sudomotor Axon Reflex Testing • NCS: Nerve conduction studies

Results: • Feet and hands SUDOSCAN scores (ESC) were significantly lower in DSP subjects than controls, regardless of the etiology of DSP: 64 ± 22 vs. 76 ± 14 μS, and 58 ± 19 vs. 66 ± 18 μS. • ESC and IENFD had similar diagnostic performance in detecting DSP. By ROC curve analysis, area under the curve (AUC) were 0.761 and 0.752 respectively, when DSP was defined as neuropathic symptoms + abnormal UENS. • ESC correlated with neuropathy signs (UENS), symptoms (MNSI) and QSART at the foot – whereas IENFD correlated with neuropathy signs and NCS measures.

• ESC had a very high negative predictive value (83%), which makes it a valuable and rapid tool to exclude neuropathy in patients with suggestive sensory symptoms.

Figure 7: Receiver operating characteristics (ROC) curves for Sudoscan and skin biopsy using abnormal Utah Early Neuropathy Score (UENS) as the gold standard

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Figure 8: Electrochemical skin conductance (ESC) in the feet and hands was significantly reduced in those with abnormal Utah Early Neuropathy Score (UENS)

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Bariatric Surgery Restores Cardiac and Sudomotor Autonomic C-fiber Dysfunction towards Normal in Obese Subjects with Type 2 Diabetes.

Casellini CM, Parson HK, Hodges K, Edwards JF, Lieb DC, Wohlgemuth SD, Vinik AI. Plos ONE 2016 [in press].

Aim: To determine if sudomotor function, together with peripheral and cardiac autonomic nervous system dysfunction improve after bariatric surgery.

Method: Obese diabetic and non-diabetic patients who underwent Roux-en-Y or sleeve gastrectomy.

• SUDOSCAN • Neuropathy Impairment Score – Lower Limbs (NIS-LL) and Quantitative Sensory Testing (QST) • Time and Frequency domains of quantitative autonomic function testing (QAFT) • Blood samples for HbA1c, lipids, insulin, C-peptide, inflammatory markers

Results: • 70 subjects completed up to 24-weeks of follow-up (24 non-T2DM, 29 pre-DM and 17 T2DM).

• Feet ESC improved significantly at 12 and 24 weeks post-bariatric surgery in T2DM: • Baseline=56.71±3.98 vs 12-weeks=62.69±3.71 vs 24-weeks=70.13±2.88 μS, p<0.005 • Heart rate variability (sdNN and rmsSD) improved significantly in T2DM subjects from baseline to 12 and 24 weeks.

• Basal heart rate, weight, body mass index (BMI), percent body fat, waist circumference and HDL improved significantly in all groups.

• NCS, NIS-LL, QST showed no significant change.

Figure 9: Improvement in ESC of hands and feet after bariatric surgery

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Electrochemical skin conductance in autonomic synucleinopathies Martinez J, Palma JA, Percival L, Kaufmann H. American Autonomic Society Annual meeting poster. 2014 Puerto Rico.

Aim: To determine sudomotor function using SUDOSCAN in autonomic synucleinopathies and healthy controls and correlated findings with markers of sympathetic dysfunction

Method: Healthy controls (HC), Multiple System Atrophy (MSA), Pure Autonomic Failure (PAF) and Parkinson Disease (PD) patients were evaluated.

• Standardized autonomic testing including Valsalva maneuver, deep breathing test, tilt-table test with continuous recordings of heart rate and blood pressure • Blood sample measures of norepinephrine in the supine and tilted position • SUDOSCAN

Results: • 22 HC, 11 MSA, 11 PAF, 12 PD • Significant positive correlation between: – Hands ESC and phase IV BP overshoot during Valsalva (r=0.50, p=0.012) – Δ in norepinephrine from supine to head-up tilt (r=0.43, p=0.033) • Test-retest correlation on 23 patients: feet ESC r=0.985, hands ESC r=0.969 • Results support findings by Anne Pavy-Le Traon • Sudoscan may differentiate PD from MSA early

Figure 10: Feet ESC in patients with autonomic synucleinopathies and controls

Correlation between ESC of the palms and blood pressure overshoot during valsalva maneuver in patients with autonomic dysfunction and healthy controls 40

Partial correlation= .500; p<0.012 (age as covariate)

(baseline - phase IV)

Figure 11: Correlation between ESC of the palms and blood pressure overshoot during Valsalva maneuver in patients with autonomic dysfunction and healthy controls

Delta blood pressure

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-20

-40

-60 10

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30

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micro-siemens

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Quick, non-invasive and quantitative evaluation of small fiber neuropathy in patients receiving chemotherapy.

Saad M, Psimaras D, Tafani C, Sallansonnet-Froment M, Calvet JH, Vilier A et al.

J Neurooncol. 2016 Apr;127(2):373-80.

Background: This study aimed at comparing the ability of Sudoscan to Total Neuropathy Score – clinical (TNSc) to detect and quantify chemotherapy-induced polyneuropathy (CIPN).

Method: 88 patients receiving at least two infusions of Oxaliplatin only (45.4 %), Paclitaxel only (14.8 %), another drug only (28.4 %) or two drugs (11.4 %) were enrolled.

• Sudoscan • TNSc: a composite clinical neuropathy scale (0-28) including neuropathy signs and symptoms • Follow-up Sudoscan and TNSc at each chemotherapy session

Results: • TNSc increases during the follow-up, suggesting the occurrence of CIPN. • ESC decreased as TNSc increased.

• Mean time between first visit and occurrence of the lowest hands and feet ESC were 27 ± 5 days and 32 ± 9 days, respectively while it was 46 ± 9 days for occurrence of highest TNSc value (p< 0.01), suggesting that Sudoscan can detect nerve damage prior to signs or symptoms.

Table 1: Changes in ESC values according to treatment received. All numeric values in microSiemens (μS) Chemotherapy

First Hands ESC (μS)

Lowest Hands ESC

p value

First Feet ESC (μS)

Lowest Feet ESC p value

Oxaliplatin (n=40)

73.4 ± 1.7

62.9 ± 2.1

p<0.0001

76.8 ± 1.9

65.7 ± 2.5

p<0.0001

Paclitaxel (n=13)

63.1 ± 5.7

44 ± 4.6

p=0.0002

73.6 ± 4.8

62.4 ± 3.3

p=0.002

Other drug (n=25)

60.2 ± 4.4

46.5 ± 7.3

p<0.0001

60.8 ± 4.5

49.6 ± 4.2

p<0.0001

Figure 12: Comparison of first and lowest hands ESC values with TNSc scores according to treatment received)

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The diagnostic accuracy of Sudoscan in Transthyretin Familial Amyloid Polyneuropathy.

Castro J, Miranda B, Castro I, de Carvalho M, Conceição I. Clin Neurophys. 2016 Feb 27.

Background: Transthyretin familial amyloid polyneuropathy (TTR-FAP) is an inherited amyloidosis that involves primarily the unmyelinated and thinly myelinated nerve fibers. This disease has a rapid clinical progression, and death occurs within a decade of symptom onset. Sudomotor function can represent an attractive tool to evaluate the speed of progression and/or response to therapy of peripheral autonomic system in TTR-FAP. This study aimed to evaluate SUDOSCAN® performance in patients with TTR-FAP.

Method: 133 TTR-FAP Val30Met carriers, divided in asymptomatic and symptomatic stage 1, were compared with 37 healthy controls.

Results: • All neurophysiological measures were significantly worse in the symptomatic group.

• Feet ESC were significantly reduced in Stage I patients compared to asymptomatic carriers and controls: 57 ± 24.3 vs. 76.5 ± 7.8 and 79.7 ± 5.1 μS, p< 0.000.

• Feet ESC was the only test distinguishing symptomatic patients with autonomic dysfunction from those without autonomic dysfunction, and both groups from asymptomatic subjects and healthy controls.

• Feet ESC showed 76% sensitivity and 85% specificity for detection of dysautonomia.

• There was a significant correlation between feet ESC and sural nerve amplitude (0.320, p<0.001)

Figure 13: Boxplot of feet ESC for each subject group. Dark gray=95% confidence interval, light gray=1 S.D. *p<0.05, **p<0.001

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Sudoscan as a noninvasive tool to assess sudomotor dysfunction in patients with Fabry disease: results from a case–control study.

Sahuc P, Chiche L, Dussol B, Pouget J, Franques J. Ther Clin Risk Manag. 2016 Feb 2;12:135-8.

Background: Fabry disease (FD), a lysosomal-storage disorder with X-linked inheritance, is caused by mutations in the gene encoding the enzyme α-galactosidase A. Small-fiber neuropathy is an early manifestation. This study aimed to evaluate the utility of Sudoscan in 18 patients with Fabry disease and 18 age- and sex-matched controls.

Results: • Hand and feet ESCs were significantly lower in FD patients compared to controls (54.4±24.4 vs.

76.3±10.9 μS, P=0.0015 and 58.5±25.8 vs 77.7±7.5 μS, P=0.0047, respectively).

• Hands and feet ESC were significantly decreased in patients with hypohidrosis compared to those without (42±22 vs 74±11 µS, p =0.0014 and 48±27 vs 76±10 µS, p=0.0056 respectively).

• No significant difference was found in sensory peroneal nerve amplitude between FD patients and controls. No correlation was observed with renal dysfunction.

Figure 14: P = 0.0017

Figure 15: P = 0.0045

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Autonomic dysfunction in psoriatic arthritis.

Syngle A, Verma I, Garg N, Krishan P. Clin Rheumatol. 2013 Jul;32(7):1059-64

Background: Autonomic nervous system (ANS) involvement has not been studied in psoriatic arthritis (PsA). The aim of this study was to investigate the prevalence and nature of autonomic neuropathy in patients with PsA.

Method: 16 patients with PsA and 15 control subjects were studied prospectively • Cardiovascular autonomic neuropathy (CAN) using 4 cardiovascular reflex tests.

• Sudoscan.

Results: • 50 % (n=8) of PsA patients had two or more abnormal CAN parameters; of these, 18.75 % (n=3) had abnormal parasympathetic and sympathetic dysfunction.

• 68.7 % (n=11) and 25 % (n=4) of the PsA patients had at least one abnormal parasympathetic or sympathetic parameter, respectively.

• 37.5 % (n=6) of the patients had moderate sudomotor dysfunction.

• Feet ESC were lower in patients with PsA compared to controls 65 ± 4 vs 74 ± 2 µS (p=0.01)

Cardiovascular autonomic and peripheral sympathetic neuropathy occur in PsA. Parasympathetic function is more commonly found to be abnormal than sympathetic function.

13 SUDOSCAN® Clinical Data & ICD-10s: Autonomic Function Testing

Disease-modifying anti-rheumatic drugs improve autonomic neuropathy in arthritis: DIANA study.

Syngle A, Verma I, Krishan P, Garg N, Syngle V. Clin Rheumatol. 2014 Jun 15.

Background: Autonomic neuropathy (AN) is a risk predictor for sudden cardiac death in rheumatoid arthritis (RA) and ankylosing spondylitis (AS). However, the effect of most commonly employed diseasemodifying anti-rheumatic drugs (DMARD) on autonomic neuropathy in rheumatic diseases is not known.

The aim of the study was to investigate the efficacy of DMARDs on autonomic neuropathy in RA and AS.

Method: Open-label, 12-week pilot study • 60 patients including 42 patients with RA, 18 with AS, and 30 aged-matched healthy subjects.

• Cardiovascular autonomic reflex tests (CARTs) according to Ewing.

• Sudoscan.

Results: • CARTs were significantly impaired among patients as compared to healthy subjects (p<0.05).

• Autonomic neuropathy was more pronounced in biologic-naive RA and AS patients.

• After treatment with combination synthetic DMARDs, parasympathetic and sudomotor dysfunction significantly (p<0.05) improved in RA and AS. • Biologic DMARDs significantly improved parasympathetic, sympathetic and peripheral sympathetic autonomic neuropathy (p<0.05) in biologic-naive RA and AS patients.

Figure 16: Changes in feet ESC after 12 weeks of therapy versus baseline in RA patients by treatment type. * p<0.05

Figure 17: Changes in feet ESC after 12 weeks of therapy versus baseline in AS patients by treatment type. * p<0.05

14 SUDOSCAN® Clinical Data & ICD-10s: Autonomic Function Testing