Quantifying Lymphedema with Noninvasive Methodology

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2 Quantifying Lymphedema with Noninvasive Methodology Physical Principles Practical Aspects Potential Limitations NLN2014 Washington D.C. 9/5/2014 Harvey N. Mayrovitz PhD Professor of Physiology College of Medical Sciences Nova Southeastern University

3 Why Measure/Quantify? Track at-risk patients Early detection Early Tx Severity stratification Treatment outcomes Documentation aspects Research related

4 Early Detection of Lymphedema Pre-Surgical Baseline Periodic Follow-ups Threshold Change Detection Measures and Criteria Limb Volumes and Metrics Limb Bioimpedance Local Tissue Water Therapy Initiation Dr. HN Mayrovitz

5 Methods Applicable to LIMBS Limb Girth (Circumference) Girth Limb Volume or Sum of Girths Limb Volume Water Displacement Limb Volume Limb fluid content and its change Bioimpedance BIA & BIS Whole Limb Tissue Dielectric Constant (TDC) Local Physical and Structural Properties Tonometry / Indentometry Various Imaging: Ultrasound - MRI - Other

6 Methods Applicable to MOST Sites Head Face Neck Breast Trunk Foot Toe etc Fluid Content (TDC) Tissue Dielectric Constant

7 Methods Applicable to MOST Sites Indent (mm) Physical Properties Tonometry/Identometry Force Measure Force Tissue Hardness Indentation (mm) Mayrovitz HN Lymphology 2009;42:88-98 Force (F, g) Healthy legs measured 10 cm proximal to the medial malleolus F = g r = 0.996, p < N = 24 legs Indentation Depth (, mm)

8 Hardness Changes with LLLT Force (g) Arms P<0.001 P<0.001 Affected Arm Other Arm N = Pre-Treat Post LLLT Force (g) Legs P<0.001 Pre-Treat P<0.001 Treated Leg Other Leg Post LLLT Force Indentation (mm) Data from: Mayrovitz HN & Davey S. Lymphology 2011;44:

9 Commercial Tonometers Force Applied Displacement Determined Pallota O. J Lymphoedema 2011;6:34-41

10 Methods Applicable to MOST Sites Imaging Ultrasound MRI Other Ventral Forearm US-20 MHz 0.93 ± 0.13 Gel Entry Echo Dermis Sub cutis 1.83 ± 1.28 mm Normal Lymphedematous Modified from: Mellor et al. The Breast J. 2004;10:

11 Metric Measures for LIMBS Tape Measure Girth at multiple points Measure both limbs Inter-limb differentials and sequential changes Measure one limb Sequential data but miss systemic changes Mark then Measure Segment Length

12 Limb Girth Volume Geometric Model or Algorithm 4 12 cm intervals C 2 b A 2 a L Manual C 1 B A 1 A General Frustum Calculation Model V = L/3 ( A V = L(A2 1 B a + A 2 b) + (A 1 A 2 ) 1/2 3(A a) Volume Tracking Affected Limb Contralateral Limb Edema Volume

13 Perometer: Girth Volume Foot-Plate Frame IR diodes Rail Mayrovitz HN et al. Advances in Wound Care 2000;113:

14 Perometer: Basic Principle Frame D 2 IR Diode Array D 1 Area = KD 1 D 2 IR Diode Array

15 Limb Girth & Volume LE Thresholds Manual Automated GIRTH If unilateral then lymphedema if inter-side differential > C 1 cm or if unilateral or bilateral then change from pre-surgery > C 2 cm VOLUME If unilateral then lymphedema if inter-side differential > V 1 ml or inter-side ratio > if unilateral or bilateral then change from pre-surgery > V 2 ml

16 Arm Lymphedema Metric Criteria Lymphedema Rate (%) LE rate dependent on criteria used Differences Between sides or vs. baseline 2 cm 200 ml 10% volume 12 months 30 months Data from: Armer et al. J. Lymphoedema 2009;4:14-18

17 Practical Aspects of Limb Girth For Reproducibility: Mark along flat Mark in Relation To FLAT Surface NOT along limb Source of large Follow up error

18 What Segment Length to Use? Segment Length 4 cm 8 cm 12 cm Bilateral lower extremity lymphedema Volume Reduction (ml) (%) 1183 ± ± ± ± ± ± 7.0 N = 70 Leg Volume (ml) Pre-treatment Volumes 4 cm 8 cm 12 cm Leg Volume (ml) Post-treatment Volumes > = 10 MLD Tx 4 cm 8 cm 12 cm Mayrovitz et al. Physical Therapy 2007; 87:

19 Limb Shape as a Factor If you calculate on the basis of THIS and its really more like THIS Then you obtain a volume greater than the true value

20 Limb Shape as a Factor Volume Ratio (Ve/Vc) Ve = b/a % volume deviation Ve C 1 C 2 b B a A L C 1 = 31.4 cm C 2 = 28.3 cm L =10 cm Vc Ratio (b/a) Data from: Mayrovitz HN, Lymphology 2003;31:

21 Volumes via H 2 O Displacement Mostly used as a so called gold standard when comparing other methods and in research studies Photo from: K. Johansson & E Branje Acta Oncologica 2010;49: Arm lymphoedema in a cohort of breast cancer survivors 10 years after diagnosis LE if change in edema volume >= 5% from pre-surgery

22 Normal Arm Volume Differentials Right Arm Volume (RAV, ml) % +CI Given LAV predict RAV Line of Identity 95% 100 +Interval RH Females RAV > LAV (2%) Line of Identity Left Arm Volume (LAV, ml by H 2 O) Data from Gebruers N et al. Clin Physiol Funct Imaging 2007; 27:17-22

23 Normal Arm Volume Differentials 3SD Thresholds (ml) ml If dominant = at-risk Then Greater Threshold ARM Arm Segment (cm) At-risk Arm Is: Dominant Non-Dominant Dom NoDom N =204 Healthy Women Age > 40 Girths via Perometer Volumes via frustum calculation Data from: Dylke ES et al Lymphatic Res Biology 2012;10:

24 Hand Volume: H 2 O Displacement Metrics Ulna head Seg Vol = kz [A i + A i+1 + (A i A i+1 ) 1/2 ] Z Depth From: Mayrovitz HN et al. Lymphology 2006;39:95-103

25 Algorithm vs. Water Displacement Volume by Algorithm (V M, ml) V M = 1.02 V w 12.0 ml r=0.985, p<0.001 N=60 Hands LOA ±9.8% Volume by water displacement (V W, ml)

26 Hand Volume: H 2 O vs. Perometer Hand Volume (ml) Perometer values ~ 7.5% greater than H 2 O values with arm LE (n=20) Water Perometer r ~ 0.88 no arm LE (n=20) Data from: Lee MJ et al. Lymphatic Research Biology 2011;9:13-18

27 Figure-of-Eight: Hand volume Surrogate Pellecchia GL J Hand Therapy 2003;16: Maihafer GC J Hand Therapy 2003;16: cm (fig-8) vs. H 2 O displacement (ml) R = but only normal hands Tracking ability unproven

28 Foot Volume: H 2 O Displacement 12 A Outflow Tube 8 4 B C X D E F 12 cm 0 Y Water Displacement Compared to Metric Measures L1 L2 Foot in Water Filled Volumeter Mayrovitz HN et al. Lymphology 2005;38:20-27

29 Algorithm vs. Water Displacement N = 60 feet LOA = ± 9.3% Mayrovitz HN et al. Lymphology 2005;38:20-27

30 Water Displacement PRO CON Direct Accurate Limb/Hand/Foot volumes Especially for irregularly shaped limbs Impractical for whole limbs Bulky equipment sterilization procedures Patient mobility Patient flexibility Open wounds Manual Girth Optoelectronic (Perometer) Low cost Portable Easy to use Whole legs measureable Hand & Foot algorithms Limited ROM no issue Wounds are not an issue Quick Easy Small segment lengths Stored Measurements Automatic processing Selective processing Multiple measurements Time factor Volumes from calculations Site repeatability Accuracy depends on proper positioning Patient mobility Patient flexibility Not portable Space requirements $$$

31 Bioimpedance Analysis Electrical Impedance of a limb depends on the limb s volume and constituents Lymphedema increase in low resistance fluid content of the limb Bioimpedance (BIOZ) Bioimpedance Spectroscopy (BIS) Bioimpedance Analysis (BIA) Single Frequency BIA = SFBIA Multi-Frequency BIA = MFBIA

32 Limb Conducting Structures Skin 15-20% H 2 O 5KHz Relative to Bone Bone Muscle 1 Bone 20 Muscle Fat 5-10%H 2 O 70-75% H 2 O 2 Fat

33 Basic Operating Principle E ~ I No cells Just saline Sinusoidal Voltage Excitation Low Frequency Z = E/I High Frequency Current increases with frequency

34 Frequency Analysis Basis E ~ I R e C m R i Cell Membrane Cell Interior ICW Z = E / I Cell Exterior ECW

35 Cole-Cole Plot: estimate parameters MFBIA = BIS increasing frequency E ~ I R e C m Cell Membrane R i Cell Interior ICW High f Z = E / I Cell Exterior ECW Low f R i R e /(R i + R e ) R R 0 ECW + ICW ECW R e

36 Basic Operating Principle Current Injecting Electrodes Voltage Measuring Electrodes E I Z = E/I Mayrovitz HN Clinical Physiology 1998;18:

37 Leg Volumes: Supine Stand 2100 Blood volume shift to lower extremities Leg Volume (ml) Girth-Volume Measurements Supine Standing Supine Time (minutes)

38 Z Depends on Frequency & Volume KHz 110 Z ( ) Z ~ (1 / volume) Z ~ (1 / f) 500 KHz 080 Supine Standing Supine Time (minutes)

39 Assessing Arm Lymphedema Measured Voltage V I Current ~ Z = V / I Current Source

40 Single Frequency BIA ECW

41 Multi-Frequency BIA R 0 R Nondomnant Dominant 360.1± ± ± ± SD lymphedema thresholds nondom/dom R i R i R 0 R 0 DOM R 0 NONDOM ± ± ± ± ± paired arms dom = at-risk nondom = at-risk Data from: Ward LC et al. Lymphatic Research Biology 2011;9:47-51

42 SFBIA = MFBIA for estimating ECW Multiple Frequency Bio-impedance (BIS) Inter-Limb Z Ratios Arm LE Arm controls Leg LE Both estimate Re (Low f) Single Frequency Bio-impedance (BIA) York SL et al. Breast Cancer Res Treat 2009;117:

43 So. Why use MFBIA (BIS)? Proposed Concept If ICW relatively unchanged even with LE then may not have to depend on inter-arm ratios May be approximately true if muscle mass does not significantly change since the largest fraction of ICW is associated with muscle ECW ICW

44 ECW / ICW Ratios ECW / ICW Pre-Surgery Lymphedema Dx N = 20 0 Normal Arm At-Risk Arm Data from: Cornish BH et al. Angiology 2002;53:41-47

45 Local Tissue Water Assessment Tissue Dielectric Constant (TDC) Relative Permittivity ( r ) PRINCIPLE

46 What is Dielectric Constant? + H O H 2 O Molecule + H - Dipole Charge Separation

47 What is Dielectric Constant? + H H + O - Hook-up + H + - Hydrogen bonding between water molecules O - 2 molecules + H -

48 What is Dielectric Constant? + Time varying electric field of force - E - D = E = r 0 E Dipole movement Displacement - D of various types H 2 32 o C r = 76 Dielectric Constant r = ratio / 0 = TDC

49 Measurement Devices Multi-Probe Single Probe (compact)

50 Multi-Probe 300 MHz Signal Reflected Wave yields TDC Control Unit Signal Generation and Processing TDC readout mm Effective Measurement Depth p 0.5 mm 1.5 mm 2.5 mm 10 mm 15 mm 22 mm

51 Single Probe (Compact) Display has pressure bar indicator during measurement Effective measurement depth is between 1.5 & 2.5 mm Multi-Probe 20 mm Epidermis Dermis Hair Pore Duct Capillary Nerve Hypo-Dermis Arteriole Fat Artery

52 Effective Measurement Depth Skin Outer Conductor Center Conductor Outer Conductor Electric Field Lines Electric Field (% of Surface field) Effective Measurement Depth Depth (mm) 2.5 mm depth probe

53 Effective Measurement Depth 0.93 ± 0.13 mm Interrogation Depth (2.5 mm) Gel Entry Echo Dermis Sub cutis 1.83 ± 1.28 mm Low water content High water content Normal Lymphedematous Ventral Forearm Modified from Mellor et al. The Breast J. 2004;10: mm mm skin subcutis

54 TDC dependence on H 2 O TDC Calibration Example (2.5 mm probe) Y = X 22.1 r 2 = 0.998, p < Cable to Control Unit Probe inserted Into Mixture Ethanol-Water Mixture Water (%)

55 Skin Water Distribution Skin Water Content (%) Skin Depth ( m) yrs yrs N = 60 a Dermis 70-75% H 2 O b 70-90% Bound Epidermis Dermis a Data: Nakagawi N et al. SRT, 2010:16: ; Confocal Raman Spectroscopy b Data: Gniadecka et al. J Invest Dermatol 1998: 110: NIR-Raman Spec

56 Free and Bound Water Free Mobile Free Mobile Protein (1 g) Bound H 2 O ( g) Limited Mobility H 2 O ~ 20 g Free Mobile

57 Lymphatic Dysfunction Fluid Interstitium Protein Blood Vessel Bound and immobile water not readily measureable with Standard BIA X Lymph Vessel

58 Dermal Water in Lymphedema Contralateral Leg Lymphedema calf 1 mm 1 mm 40% increase in Calf Dermal Water in Lymphedema 11 primary LE 10 secondary LE Mobile water shows intense Data: Idy-Peretti et al. Int J Dermatol 1998;110: Hi-Res MRI N=21

59 TDC Features and Applications Forearm Signal Generation and Processing Foot Dorsum TDC measurement TDC Value Display Biceps

60 TDC Site Variability females years 1.5 mm Depth Forehead Thumb Palm-Thenar D. Hand Cntr 1st Toe Plantar L. Gaiter 1 st Toe Dorsum A. Gaiter Cheek Palm-Center M. Gaiter D. Hand Web D. Forearm D. Foot (1-2) A. Forearm M. Malleolus D. Foot (4=5) Data From: Mayrovitz HN et al. Skin Research and Technology 2013;19:47 54

61 TDC Site Variability Ophthalmic F L SUPINE Maxillary 42.2 ± ± 2.9 C L 38.5 ± ± 5.7 M L Mandibular 43.8 ± ± 4.4 N = 30 young adult males (25.0 ± mm depth Data from: Mayrovitz HN et al. Skin Research and Technology 2012;18:

62 Correlation with Total Body Water Forearm 5.0 mm Depth N = 130 (50 females) Age 26.1 ± 3.0 (19-39) BMI 24.5 ± 4.0 (16-40) Y = X 22.3 r = 0.740, p < Total Body Water (%)

63 TDC Depth Dependence: Forearm TDC 0.5 mm Pattern of Depth Dependence May Vary by Site mm Compact TDC = r 2 = 0.997, p<0.001 N = 80 females 2.5 mm 5.0 mm Measurement Depth, mm)

64 TDC Vascular Component

65 TDC Vascular Component Large vascular blood volume & flow changes Minor changes in TDC values Skin Blood Flow (a.u.) From: Mayrovitz HN et al. Clinical Physiology and Functional Imaging 2013;33:55-61

66 TDC Lymphedema Discriminations 2.2 TDC inter-arm ratio Patients Affected/Control 1.64 ± 0.30 N=18 Premenopausal Postmenopausal 1.04 ± ± 0.04 N=15 N=15 Mayrovitz HN Lymphology 2007;40:87 94

67 Pre-Surgery Reference TDC Ratios Cancer Side N=80 Healthy Side N =103 Biceps ± (1.45) Forearm ± (1.30) Axilla ± (1.60) Thorax ± (1.35) (3 SD Thresholds)

68 Sequential TDC Ratio Changes Thorax TDC Ratio (At-Risk/Control Side) Lateral Thorax * * * * * * * * * month (N=35) month (N=41) month (N=47) month (N=53) 0 3 month (N=60) * pre-surgery

69 Sequential TDC Ratio Changes Axilla month (N=35) month (N=41) month (N=47) Axilla TDC Ratio (At-Risk/control) * * * * * * month (N=53) 0 3 month (N=60) * * * * pre-surgery

70 Methods Features Comparison Operating principle TDC BIA/BIS (Delfin Technologies Ltd) (Impedimed Ltd) Frequency applied EMF 300 MHz khz Current flowing in the body Very Localized Much of the body Number of electrodes / probes 1 probe 4 electrodes Total single measurement time ~ 8 sec ~ 60 sec Measurement Depth mm Undefined Measurement quantity Tissue dielectric constant Resistance Measurement parameter Skin-to-fat tissue fluid Parameter ~ to ECF Applicability Practically all body sites Limbs Patient preparation Patient position Any body position Supine Arm-leg skin contact No effect Limbs must be abducted Arm and hand position No restriction Palms flat on surface Shoe and socks removal Not needed to remove Must be removed Bladder emptying necessary No Yes Dominant side affects No Yes Measurement sites Hairy skin shaving Yes (very hairy) Yes Precautions for measurement Patient metal contact problem No Yes

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