Lymphedema: Early Detection and Quantitative Assessment

Lymphedema: Early Detection and Quantitative Assessment Harvey N. Mayrovitz PhD Professor of Physiology College of Medical Sciences Nova Southeastern University mayrovit@nova.edu

Lymphedema Physiology Research into Early Detection Evolving Research Projects

The Lymphatic System and Lymphedema

Arterial Venous Lymphatic

Blood-Lymphatic Interaction Blood Capillary Lymphatic Capillary Endothelial Cell Anchoring Filaments Fluid & Protein enter Lymph Capillaries INTERSTITIUM

Normal Fluid Balance Resorption Filtration Blood Capillary ~27 liters/day ~30 liters/day TISSUE AND CELLS

Normal Fluid Balance Resorption Filtration Blood Capillary ~27 liters/day ~30 liters/day Start of the Lymphatic System ~3 liters/day (10% of filtered) protein Lymphatic Capillary Back to Venous System

Lymphangions Lymphatic Hearts Peristaltic-like contractions propel lymph to next segment Lymph Capillary Walls have a muscular media Lymphangion (lymph micro heart) Valve Contraction force (& frequency) is preload & afterload dependent - analogous to heart

MOVIE 1 MOVIE 2

Pressure (mmhg) Flow (ul) Effects of Muscular Contractions on lymphatic Flow and pressure Olszewski & Engeset, 1988

Factors Affecting Lymph Transport

Entry and Exit to and from Lymph Nodes Axillary Glands (20-30 nodes) Veins Afferent Lymph Enters LN Superficial Lymphatics Efferent Lymph Exits

Lymphatic Drainage LN Veins NORMAL Transverse Watershed Vertical Watershed Lymph flow and drainage determined by normal physiological processes and lymphatic pathways

Normal Lymphatic Function capillary Fluid + Protein Excess --> Lymphatics If Net Filtration Exceeds Lymphatic Transport Capacity Overload = Edema + [Protein] = Lymphedema

Lymphatic Drainage LN Veins NORMAL LN Veins LYMPHEDEMA Transverse Watershed Vertical Watershed Transverse Watershed Vertical Watershed Lymph flow and drainage determined by normal physiological processes and lymphatic pathways Lymph flow through normal pathways reduced or absent due to nodal or lymph vessel obstruction and dysfunction

Potential Outcome System Works OK Here System Not OK Here

General Principles of Care for Persons At-Risk for Lymphedema

Overall Goals Reduce Risk Detect Early Pre-surgical Assessment Periodic test via emerging early detection methods Self recognition of symptoms Arrest & Reduce Maintain Gains - Complications

Lymphedema Severity Worsens Without Treatment Fibrosis Develops Surgery Radiation Time Seek Therapy Symptoms Arrest & Reduce Late Treat

Lymphedema Severity Worsens Without Treatment Catch it Early More Treatable Less Complications Early Detection Sub-Clinical Fibrosis Develops Arrest & Reduce Late Treat Surgery Radiation Pre-surgical Assessment Early Treat Time Seek Therapy Symptoms

Quantitative Assessment Methods Early Detection and Treatment Effectiveness Limb Volumes Bioimpedance Limbs Local Tissue Fluid Tissue Properties Any at Risk Location (e.g. Trunk, Face and etc.)

Goal: Early Detection Timely Intervention Goal: Earlier Detection and Intervention A Rationale and Sensible Approach 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

Goal: Early Detection Timely Intervention Goal: Earlier Detection and Intervention Not Often Done Can We Estimate Impact? 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

Limb Limb Volume Volumes or and Girth Circumference Assessments Mainly for Tracking and Documenting Circumference If unilateral then lymphedema if difference > X cm Automated Multiple Circumferences Manual Limb Volumes Geometric Model or Algorithm If unilateral then lymphedema if volume difference > Y ml If volume difference > Z % www.limbvolumes.org

Lymphedema Rate (%) Arm Lymphedema Metric Criteria LE rate dependent on criteria used 80 60 Differences Between sides or vs. baseline >=10% vol >=200 ml >=2 cm 40 20 0 6 Months 12 Months Data from: Armer and Stewart Lymphat Res Biol. 2005;3(4):208-217.

Bioimpedance Measurements Arm Electrical Impedance ~ Total Arm Tissue Water ImpediMed (50 KHz) Dr. HN Mayrovitz

Resistance Ratio Between Arms Arm Lymphedema 1.6 Contol Ratios (N=60) 3SD = 0.102 1.4 Patients > 3SD of Controls and Confirmed LE 1.2 1 3SD 10 8 6 4 LE confirmation (20/22) N total = 102 2 0 0 1 2 4 6 10 0.8 Months after positive test Data from: Cornish BH et al. Lymphology. 2001;34(1):2-11.

Tissue Water via Dielectric Constant Low power 300 MHz incident wave Reflected wave depends on the tissue s dielectric constant MoistureMeter-D Penetration Depth (0.5 5 mm) Dielectric constant depends on total tissue water (free + bound) Pure water has a dielectric constant of about 78 Can measure at almost any site! Calibrated for each probe from 1-80 0.5 1.5 2.5 5.0 mm Dr. HN Mayrovitz

Recent NLN Survey of 2899 persons with lymphedema 40% reported co-present edema Face/Neck 4% Breast 7% Trunk 8% Abdomen 9% Genitalia 5% Other 7% Lymphedema does not just occur in limbs!

Recent Survey of 50 Lymphedema Therapists Therapist IPC Important Features Average Importance 5 YES 4 3 Multi- Chamber Wound Treat Use or recommend IPC? Trunk Treat Calibrated Pressure NO * * Work and Release N=28 N=22 Fibrosis Treat * p<0.01

Goal: Earlier Detection and Intervention Ongoing Research Study Women A Rationale Diagnosed and Sensible with Breast Approach Cancer Pre-Surgical Baseline N=50 Periodic Follow-ups Threshold Change Detection Measures and Criteria Limb Volumes and Metrics Limb Bioimpedance Local Tissue Water Therapy Initiation Dr. HN Mayrovitz

TDC Measurement Sites 2.5 mm Probe Forearm Biceps Lateral Thorax Axilla Dr. HN Mayrovitz

TDC BIOZ VOLUME N = 50 Z=305±39 Cancer vs. Healthy Sides Pre-surgery Assessments No difference between sides Cancer Side Healthy Side 34.5±7.6 35.3±7.9 Z=305±39 21.7±3.0 25.5±4.6 25.4±4.8 21.9±2.7 Arm Volumes (ml) 2249±701 2271±702 24.9±3.1 24.7±3.3 Insignificant Side-to-Side Differentials Dr. HN Mayrovitz

Number of Patients Evaluated 60 Number of Patients 50 40 30 20 10 50 32 22 15 12 7 4 0 1 2 3 4 5 6 7 Visit Number Getting close but insufficient follow-ups for conclusions

Some Newly Initiated Research Studies

Measure and Characterize Lymphedema Related Fibrosis Complications Fluid + Protein capillary Proteins Accumulate if Lymphatic Dysfunction Macrophages PROTEINS Stimulus for Chronic Inflammation Fibrosis More Filtration Bacterial Growth Vasodilation Increased filtration Tissue warming Bacterial/Fungal Infections

Principle: Indentation Force ~ Tissue Hardness Fibrosis and Tissue Property Changes Force Indentation

Force (g) Some Initial Applications and Outcomes 500 pre-mld pst-mld Lower Extremity Lymphedema 400 300 200 100 ~ N=22 N=6 P<0.001 Calf Single MLD Treatment Tissue softening P<0.01 Thigh

Evaluate Efficacy of Low Level Laser Therapy (LLLT) Single Laser Treatment Fibrosis Hardness Tissue Water Initial Results are Encouraging Conclusions Premature

Develop a Reference Framework for Facial Edema Ophthalmic F L Maxillary Different Innervation Territories C L M L Mandibular

Cross section of upper arms, autopsy samples. Hypertrophied adipose tissue of the lymphedematous left arm. Dr. C-H Håkansson, Dept of Oncology, Lund University Hospital

Liposuction in Chronic Lymphedema

15 years later Courtesy H. Brorson M.D.

HUMAN MOUSE

TREATMENT

Overall Goals Reduce Risk Detect Early Arrest & Reduce PHASE I Manual Lymphatic Drainage Compression Bandaging Decongestive Exercise Skin Care Maintain Gains - Complications

Phase I - Intensive Complete Decongestive Physiotherapy (CDP) Manual Lymph Drainage (MLD) Compression Bandaging Exercise and Skin Care ± Intermittent Pneumatic Compression (IPC)

Phase I - Intensive Complete Decongestive Physiotherapy (CDP) MLD Compressive Bandage Decongestive Exercise

Lymphatic Drainage LN Veins NORMAL Transverse Watershed Vertical Watershed Lymph flow and drainage determined by normal physiological processes and lymphatic pathways

Therapeutic Strategy Use Alternate Routes & Optimize Conditions Lymph LN P LV Veins Treatment Related Lymph Flow LN P T1 P LV P T2 LN Lymphatic Flow P L Q L Q L ~ P L - P LV R Q L P L Lymphatic Pressure NORMAL LYMPHEDEMA Lymph flow depends on pathway pressure gradient and resistance Pressure Gradient Intra-Lymphatic Pressure Gradient Truncal Tissue

MLD and New IPC Approach 3 LN Clear 2 affected trunk areas 1 Clear normal adjacent trunk areas Veins LN First sequentially treat lymph receiving regions (1 5) to optimize gradient and minimize resistance for subsequent limb drainage procedures 4 5 Prepare abdominal region LN Inguinal Nodes Mayrovitz et al. (2009) Home Health Care Management & Practice (in press)

MLD and New IPC Approach 3 LN Clear 2 affected trunk areas 1 Clear normal adjacent trunk areas Veins LN First sequentially treat lymph receiving regions (1 5) to optimize gradient and minimize resistance for subsequent limb drainage procedures 4 5 Prepare abdominal region LN Inguinal Nodes Then progressive treatment of limb and trunk with suitable manual or pump pressures starting at the most peripheral region (5 1)

Adjunctive IPC Therapy ROLE Phase I Component of in-clinic therapy Phase II Component of at-home maintenance therapy TYPES Basic Limited Adjustability Non-Programmable Advanced Calibrated Sequential - Programmable With Truncal Clearance Capability No Truncal Clearance Capability

IPC Parameters Calibrated Pressure setting (manual or programmed) corresponds to pressure delivered to skin Sequential During drainage phase, compression progresses distal proximal consistent with physiological concepts Programmable Software control to permit customization of compression parameters to account for variable patient conditions e.g. painful, ulcerated or fibrotic areas

Adjunctive IPC Therapy Newer IPC Approach Initial preparation phase Work & Release Flexitouch Older generation IPC Limb drainage Squeeze & Hold Lympha Press Differences Among Therapy Parameters

Pressure (mmhg) Pressure Timing and Pattern 70 Flexitouch System 60 50 40 30 20 10 Work & Release Drainage G1 G2 G3 G4 G5 0 70 60 50 40 30 20 10 0 10 20 30 40 50 Squeeze & Hold Lympha Press System Mayrovitz HN Physical Therapy 2007;87:1379-1388 G1 G2 G3 G4 G5 0 0 10 20 30 40 50 Seconds

Pressure-Time (mmhg x sec) 1600 1200 800 400 0 Mayrovitz HN Physical Therapy 2007;87:1379-1388 ** Pressure-Time Integral ** ** Lymphapress Flexitouch Preparation Phase Flexitouch Drainage Phase G1 G2 G3 G4 G5 ** ** Concerns of too high a pressure have been raised in the literature regarding older generation IPC 1 and poor pressure calibration 2 1 Eliska & Eliskova Lymphology 1995;28:21-30 2 Segers et al. Phys Ther 2002;82:1000-1008 Compression pumps should be used only under the supervision of a trained health care professional because high external pressure can damage the lymphatic vessels near the skin surface. http://www.cancer.gov/cancertopics

Average Importance Therapist IPC Important Features 5 YES Use or recommend IPC? NO N=28 N=22 4 * * 3 Multi- Chamber Wound Treat Trunk Treat Calibrated Pressure Work and Release * p<0.01 Fibrosis Treat

Average Concern Therapist IPC Use Concerns 5 YES Use or recommend IPC NO N=28 N=22 4 p<0.001 3 Truncal Edema Fibrotic Cuff Genital Edema High Pressure Patient Tolerance

Overall Goals Reduce Risk Detect Early Arrest & Reduce Maintain Gains - Complications PHASE II Self MLD Compression Garment Self Bandaging

Potential Risks of Ineffective Home Self Maintenance Loss/Reversal of Phase I Achievements Interim Development of Complications e.g. Fibrosis, Inflammation, Cellulitis, Pain Therapeutic Interventions for Complications and new rounds of Phase I therapy requiring additional patient time, suffering and costs

Breast Cancer Treatment-Related Lymphedema Lymphedema Volume (ml) N=537 newly diagnosed pts Compared to end of Phase I Increased > 10% 51% Stable ± 10% 20% Decrease >-10% 29% N= 426 356 Self MLD Elastic Sleeve LS Bandage After Vignes et al. Breast Cancer Res Treat (2007) 101:285 290 Start Phase I 6 months 12 months End 2 wks 10 Tx Phase II

Compliance Risk of Increase No added risk? Vignes et al. Breast Cancer Res Treat (2007) 101:285 290

Phase II Outcomes: Compliance Fairly Conclusive Low Stretch Bandaging Compression Garment MLD - Inconclusive 1. Phase I MLD Major initial reductions 2. Self reported use/non-use as an index may or may not be valid 3. Impact of MLD on stable and decrease? 4. No measure or knowledge that proper self-mld technique was used!

Personal View IF Phase I outcome is very effective and IF patients are ~100% compliant with respect to garment use, bandages and exercises THEN Self MLD may not add much to outcome BUT --- the above is at best only sometimes true SO ---- Assistance in MLD compliance is needed ROM and Functional impairments Aging population of cancer survivors Physical demands of effective MLD Difficulty of properly done self-mld ~35% of patients report doing self-mld 1 1 Ridner et al. Oncol Nurs Forum 2008;35:671-680.

% Excess Volume Short-Term Home Maintenance MLD Assistance via Advanced IPC 18 Flexitouch 16 Self-M LD BCRL N=10 2 wks tx with each modality 14 * 12 P<0.001 NS 10 ~ Pre-Treat Post-Treat Data from: Wilburn et al. BMC Cancer 2006, 6:84

Phase II Outcomes: Compliance IPC Usage Users Abandoning Pump Use by 6-7 Months 40 Older Generation 35 Pumps - 1 37.7% Advanced Pump (Flexitouch) - 2 30 25 20 15 10 5 0 4.0 % 1. Lynnworth, M. NLN Newsletter 1997;(10) 2. Ridner et al. Oncol Nurs Forum 2008;35:671-680

Overall Goals Reduce Risk Detect Early Pre-surgical Assessment Periodic test via emerging early detection methods Self recognition of symptoms Arrest & Reduce Maintain Gains - Complications

Quantitative Assessment Methods Early Detection & Treatment Effectiveness Limb Volumes Bioimpedance Limbs Local Tissue Fluid Tissue Properties Any at Risk Location (e.g. Trunk, Face and etc.)

TDC Value Mayrovitz et al. Lymphology 2008;41:87-92 Single MLD Treatment Lower Extremity Lymphedema 50 pre-mld pst-mld 40 30 20 N=20 N=6 P<0.001 P<0.05 Calf Thigh

Breast Cancer Pre-Surgical N=30 TDC Cancer Side Healthy Side TDC Bioz 306±34 34.7±8.3 33.4±9.0 Bioz 307±34 22.4±2.9 24.9±5.2 24.3±4.5 22.3±2.9 Arm Volumes (ml) 2160±564 2164±509 25.7±3.1 25.2±3.6 Insignificant Side-to-Side Differentials at Baseline Mayrovitz et al. Clinical Physiology and Functional Imaging 2008;28:337-342

Fibrosis & Tissue Property Changes Principle: Indentation Force ~ Tissue Hardness Force Indentation

Force (g) Single Flexitouch Application 350 300 250 Pre-FT Pst-FT N = 12 P<0.001 200 150 100 50 0 Tissue Softening 30 minute below knee application 1 2 3 4 5 Indentation Depth (mm)

Force (g) Single MLD Treatment 500 pre-mld pst-mld Lower Extremity Lymphedema 400 300 Tissue softening 200 100 ~ N=22 N=6 P<0.001 P<0.01 Calf Thigh

Summary Risk Reduction Catch it early Treat it intensively Maintain Gains Historically and Generally Accepted Approaches CDP ± IPC Phase I: MLD + SS Compression Bandage + Exercise + Skin Care Phase II: Self MLD + Elastic Garment + Bandage + Exercise + Skin Care Phase II compliance is a factor in maintaining gains IPC use if programmable and if it provides truncal clearance prior to limb pumping may increase compliance and improve outcomes Early detection with biophysical measures should be actively pursued Pre-surgical assessments can likely aid in the early detection process

Pulmonary Circulation Lymphatic System Lymphatic Vessels Lymph Nodes Lymphatic Capillaries Venous System RA RV LA LV Arterial system Heart Arteries Arterioles Blood Capillaries Systemic Circulation

Fluid + Protein Complications capillary Proteins Accumulate if Lymphatic Dysfunction More Filtration PROTEINS Lymphatic vessel/node Trauma Removal Radiation Blockage Overload Genetic - Primary

Fluid + Protein Complications capillary Proteins Accumulate if Lymphatic Dysfunction Macrophages PROTEINS Fibrosis More Filtration

Fluid + Protein Complications capillary Proteins Accumulate if Lymphatic Dysfunction PROTEINS Stimulus for Chronic Inflammation Macrophages Fibrosis More Filtration Bacterial Growth Vasodilation Increased filtration Tissue warming Bacterial/Fungal Infections

Overall Goals Reduce Risk Detect Early Arrest & Reduce Maintain Gains - Complications

Overall Goals Reduce Risk Detect Early Patient do s & don ts soon after they become at risk Patient precaution compliance Multiple Web Sites with Good Info Not all precautions validated Some may be over-kill Informed and educated patient Common Sense Approach Arrest & Reduce Maintain Gains - Complications

Mayrovitz HN (2007) Lymphology 2007;40:87-94 Potential Diagnostic Utility Dielectric Constant (Ratio) 2.2 1.8 1.4 1.0 0.6 No overlap between Patients vs. Controls Patient Arms Affected/Control 1.64 ± 0.30 N=18 Control Arms (Max/Min) Premenopausal Postmenopausal 1.04 ± 0.04 1.04 ± 0.04 N=15 N=15