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

[email protected]

• Lymphedema Physiology

• Research into Early Detection

• ‘Evolving’ Research Projects

The Lymphatic System

and Lymphedema

Arterial Venous Lymphatic

Anchoring

Filaments

Lymphatic Capillary

INTERSTITIUM

Fluid & Protein enter

Lymph Capillaries

Endothelial Cell

Blood Capillary

Blood-Lymphatic Interaction

FiltrationResorption

~30 liters/day

Normal Fluid Balance

Blood Capillary

~27 liters/day

TISSUE AND CELLS

Lymphatic Capillary

Normal Fluid Balance

protein~3 liters/day

(10% of filtered) Back to

Venous

System

Start of the

Lymphatic

System

FiltrationResorption

~30 liters/day

Blood Capillary

~27 liters/day

ValveLymphangion(lymph micro heart)

Lymph

CapillaryWalls have a

muscular media

Peristaltic-like contractions

propel lymph to next segment

Contraction force (& frequency) is preload

& afterload dependent - analogous to heart

Lymphatic “Hearts”

Lymphangions

MOVIE 1 MOVIE 2

Olszewski & Engeset, 1988

Effects of Muscular Contractions

on lymphatic Flow and pressureF

low

(ul)

Pre

ss

ure

(mm

Hg

)

Factors Affecting Lymph Transport

Axillary Glands

(20-30 nodes)

Superficial Lymphatics

Veins

Afferent Lymph Enters

Efferent

Lymph

Exits

LN

Entry and Exit to and from Lymph Nodes

LN

Vertical

Watershed

NORMAL

Transverse

Watershed

Veins

Lymphatic Drainage

Lymph flow and drainage

determined by normal

physiological processes

and lymphatic pathways

Overload = Edema

+ [Protein]

= Lymphedema

If Net Filtration Exceeds

Lymphatic Transport Capacity

Excess --> Lymphatics

Fluid +

Protein

capillary

Normal Lymphatic Function

LN

Vertical

Watershed

NORMAL

Transverse

Watershed

Veins LN

Vertical

Watershed

LYMPHEDEMA

Transverse

Watershed

Veins

Lymphatic Drainage

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

• Pre-surgical Assessment

• Periodic test via emerging

early detection methods

• Self recognition of symptoms

• Reduce Risk

• Detect Early

• Arrest & Reduce

• Maintain Gains

- Complications

Overall Goals

Surgery

RadiationSymptoms

Seek Therapy

Arrest & Reduce

Lym

ph

ed

em

a S

eve

rity

Fibrosis

Time

Develops

Late Treat

Worsens Without Treatment

Surgery

RadiationSymptoms

Seek Therapy

Arrest & Reduce

Lym

ph

ed

em

a S

eve

rity

Early Detection

“Sub-Clinical”

Fibrosis

Time

• Catch it Early

• More Treatable

• Less Complications

Develops

Late Treat

Early Treat

Pre-surgical

Assessment

Worsens Without Treatment

Quantitative Assessment Methods

• Limb Volumes

• Bioimpedance

• Local Tissue Fluid

• Tissue Properties

Early Detection and Treatment Effectiveness

Limbs

Any at Risk Location

(e.g. Trunk, Face and etc.)

Pre-Surgical

Baseline

Threshold Change Detection

Therapy

Initiation

Periodic Follow-ups

Measures and Criteria

•Limb Volumes and Metrics

•Limb Bioimpedance

•Local Tissue Water

Goal: Earlier Detection and Intervention

A Rationale and Sensible Approach

Dr. HN Mayrovitz

Goal: Early Detection – Timely Intervention

Pre-Surgical

Baseline

Threshold Change Detection

Therapy

Initiation

Not Often

Done

Periodic Follow-ups

Measures and Criteria

•Limb Volumes and Metrics

•Limb Bioimpedance

•Local Tissue Water

Can We Estimate Impact?

Goal: Earlier Detection and Intervention

Dr. HN Mayrovitz

Goal: Early Detection – Timely Intervention

Limb Volume or Girth AssessmentsMainly for Tracking and Documenting

CircumferenceIf unilateral then

lymphedema if

difference > X cm

Automated ManualMultiple Circumferences

Geometric Model

or Algorithm

If unilateral then lymphedema

if volume difference > Y ml

Limb Volumes

Limb Volumes and Circumference

www.limbvolumes.orgIf volume difference > Z %

Arm Lymphedema Metric CriteriaLE rate dependent on criteria used

Data from: Armer and Stewart Lymphat Res Biol. 2005;3(4):208-217.

0

20

40

60

80>=10% vol>=200 ml>=2 cm

Lym

ph

ed

em

a R

ate

(%

)

6 Months 12 Months

Differences • Between sides

• or vs. baseline

Bioimpedance Measurements

ImpediMed

(50 KHz)

Arm Electrical Impedance ~ Total Arm Tissue Water

Dr. HN Mayrovitz

0.8

1

1.2

1.4

1.6

Contol Ratios (N=60) 3SD = 0.102

Patients > 3SD of Controls and Confirmed LE

0

2

4

6

8

10

0 1 2 4 6 10

Re

sis

tan

ce

Ra

tio

Be

twe

en

Arm

s

LE confirmation (20/22)

Months after ‘positive’ test

3SD

Data from: Cornish BH et al. Lymphology. 2001;34(1):2-11.

Arm Lymphedema

N total = 102

Tissue Water via Dielectric Constant

MoistureMeter-D

• Low power 300 MHz

incident wave

• Reflected wave depends

on the tissue’s

dielectric constant

• Dielectric constant

depends on total tissue

water (free + bound)

• Pure water has a

dielectric constant of

about 78

• Calibrated for each

probe from 1 - 80

Penetration Depth (0.5 – 5 mm)

0.5 1.5 2.5 5.0 mmDr. HN Mayrovitz

Can measure at

almost any site!

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

3

4

5 YES

NO

Avera

ge I

mp

ort

an

ce Use or recommend IPC?

N=28

N=22

Multi-

Chamber

Wound

Treat

Trunk

Treat

Calibrated

Pressure

Work

and

Release

Fibrosis

Treat

* *

* p<0.01

Therapist IPC Important Features

Pre-Surgical

Baseline

Threshold Change Detection

Therapy

Initiation

Periodic Follow-ups

Measures and Criteria

•Limb Volumes and Metrics

•Limb Bioimpedance

•Local Tissue Water

Goal: Earlier Detection and Intervention

A Rationale and Sensible Approach

Dr. HN Mayrovitz

N=50

Ongoing Research Study

Women Diagnosed with Breast Cancer

TDC Measurement Sites

Lateral Thorax Axilla

Forearm Biceps

2.5 mm Probe

Dr. HN Mayrovitz

24.9±3.1 24.7±3.3

21.7±3.0 21.9±2.7

34.5±7.6 35.3±7.9

25.5±4.6 25.4±4.8

Arm Volumes (ml)

2249±701 2271±702

Z=305±39Z=305±39

Cancer vs. Healthy SidesNo difference between sides

Cancer

SideHealthy

Side

•TDC

•BIOZ

•VOLUME

Dr. HN Mayrovitz

N = 50

Pre-surgery Assessments

Insignificant Side-to-Side Differentials

Number of Patients Evaluated

50

32

22

1512

74

0

10

20

30

40

50

60

1 2 3 4 5 6 7

Visit Number

Nu

mb

er

of

Pa

tie

nts

Getting close but insufficient follow-ups for conclusions

Some Newly Initiated

Research Studies

Fluid +

Protein

PROTEINS

Proteins Accumulate if Lymphatic Dysfunction

Macrophages

Stimulus for Chronic Inflammation

Vasodilation

• Increased filtration

• Tissue warmingBacterial

Growth

Bacterial/Fungal Infections

Fibrosis

More

Filtration

capillary

ComplicationsMeasure and Characterize Lymphedema Related Fibrosis

Force

Indentation

Principle: Indentation Force ~ Tissue ‘Hardness’

Fibrosis and Tissue Property Changes

100

200

300

400

500 pre-MLD

pst-MLD

Fo

rce

(g

)

Calf Thigh

Single MLD Treatment

P<0.001 P<0.01~

N=22 N=6

Lower Extremity

Lymphedema

Tissue

‘softening’

Some Initial Applications and Outcomes

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

FL

CL

ML

Ophthalmic

Maxillary

Mandibular

Different

Innervation

Territories

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

Courtesy H. Brorson M.D.

15 years

later

HUMAN MOUSE

TREATMENT

PHASE I

• Manual Lymphatic Drainage

• Compression Bandaging

• Decongestive Exercise

• Skin Care

• Reduce Risk

• Detect Early

• Arrest & Reduce

• Maintain Gains

- Complications

Overall Goals

• 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

Phase I - Intensive

Complete Decongestive

Physiotherapy (CDP)

LN

Vertical

Watershed

NORMAL

Transverse

Watershed

Veins

Lymphatic Drainage

Lymph flow and drainage

determined by normal

physiological processes

and lymphatic pathways

LN

Vertical

Watershed

NORMAL

Transverse

Watershed

Veins LN

Vertical

Watershed

LYMPHEDEMA

Transverse

Watershed

Veins

Lymphatic Drainage

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

PL

PLV

QL

Lymphatic

Pressure

Lymphatic

Flow

LNVeins

Lymph

QL~PL - PLV

R

NORMAL

PL

PLV

QL

LYMPHEDEMA

LN LN

Treatment

Related

Lymph

Flow

PT1

PT2

Therapeutic StrategyUse Alternate Routes & Optimize Conditions

Lymph flow depends on pathway pressure gradient and resistance

Pressure Gradient

Intra-Lymphatic

Pressure Gradient

Truncal Tissue

LNVeins

3

4

5

Clear

normal

adjacent

trunk areas

LN

122Clear

affected

trunk areas

LNInguinal

Nodes

Prepare

abdominal

region

MLD and New IPC Approach

First sequentially treat

lymph receiving

regions (15) to

optimize gradient and

minimize resistance

for subsequent limb

drainage procedures

Mayrovitz et al. (2009) Home Health Care Management & Practice (in press)

LNVeins

3

4

5

Clear

normal

adjacent

trunk areas

LN

122Clear

affected

trunk areas

LNInguinal

Nodes

Prepare

abdominal

region

First sequentially treat

lymph receiving

regions (15) to

optimize gradient and

minimize resistance

for subsequent limb

drainage procedures

Then progressive treatment of limb and trunk

with suitable manual or pump pressures

starting at the most peripheral region (5 1)

MLD and New IPC Approach

Adjunctive IPC Therapy

Basic Limited Adjustability – Non-Programmable

Advanced Calibrated – Sequential - Programmable

ROLE

Phase I Component of in-clinic therapy

Phase II Component of at-home maintenance therapy

• With Truncal Clearance Capability

• No Truncal Clearance Capability

TYPES

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

Differences Among Therapy Parameters

Newer IPC Approach• Initial ‘preparation phase’

• ‘Work & Release’

‘Older generation’ IPC

• Limb drainage

• ‘Squeeze & Hold’

Flexitouch® Lympha Press®

Adjunctive IPC Therapy

0

10

20

30

40

50

60

70

0 10 20 30 40 50

G1

G2

G3

G4

G5

Flexitouch® SystemP

ressu

re (

mm

Hg

)Pressure Timing and Pattern

0

10

20

30

40

50

60

70

0 10 20 30 40 50

G1

G2

G3

G4

G5

Seconds

Lympha Press® System

Drainage

‘Work &

Release’

Mayrovitz HN

Physical Therapy

2007;87:1379-1388

‘Squeeze

& Hold”

0

400

800

1200

1600

Lymphapress®

Flexitouch® Preparation Phase

Flexitouch® Drainage PhaseP

res

su

re-T

ime

(m

mH

g x

se

c)

Pressure-Time Integral

G1 G2 G3 G4 G5

****

****

**

†

† † † †

Mayrovitz HN

Physical Therapy

2007;87:1379-1388

Concerns of too high a pressure have been raised in the literature

regarding ‘older generation’ IPC1 and poor pressure calibration2

“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

1Eliska & Eliskova Lymphology 1995;28:21-30 2Segers et al. Phys Ther 2002;82:1000-1008

3

4

5 YES

NO

Ave

rag

e I

mp

ort

an

ce Use or recommend IPC?

Therapist IPC Important Features

N=28

N=22

Multi-

Chamber

Wound

Treat

Trunk

Treat

Calibrated

Pressure

Work

and

Release

Fibrosis

Treat

* *

* p<0.01

3

4

5 YES

NO

Ave

rag

e C

on

ce

rn

Use or recommend IPCN=28

N=22

p<0.001

Truncal

Edema

Fibrotic

Cuff

Genital

Edema

High

Pressure

Patient

Tolerance

Therapist IPC Use Concerns

• Reduce Risk

• Detect Early

• Arrest & Reduce

• Maintain Gains

- Complications

PHASE II

• Self MLD

• Compression Garment

• Self Bandaging

Overall Goals

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

After Vignes et al.

Breast Cancer Res Treat

(2007) 101:285–290

Lym

ph

ed

em

a V

olu

me

(m

l)

Start Phase I 6 months 12 months

Phase II

N=537 newly

diagnosed pts

End

2 wks – 10 Tx

N= 426 356

Breast Cancer Treatment-Related Lymphedema

Self MLD

Elastic Sleeve

LS Bandage

Compared to end of Phase I

Increased > 10% 51%

“Stable” ± 10% 20%

Decrease >-10% 29%

Compliance – Risk of Increase

Vignes et al. Breast Cancer Res Treat (2007) 101:285–290

No added risk?

• Low Stretch Bandaging

• Compression Garment

Phase II Outcomes: Compliance

Fairly Conclusive

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!

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

Personal View

• 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-MLD1

1Ridner et al. Oncol Nurs Forum 2008;35:671-680.

10

12

14

16

18 Flexitouch

Self-MLD

% E

xc

es

s V

olu

me

~Pre-Treat Post-Treat

Data from: Wilburn et al. BMC Cancer 2006, 6:84

Short-Term Home MaintenanceMLD Assistance via Advanced IPC

BCRL N=10

2 wks tx with

each modality

P<0.001 NS

*

Phase II Outcomes: Compliance

IPC Usage

1. Lynnworth, M. NLN Newsletter 1997;(10)

2. Ridner et al. Oncol Nurs Forum 2008;35:671-680

Users Abandoning Pump Use by 6-7 Months

0

5

10

15

20

25

30

35

40 Older GenerationPumps - 1

Advanced Pump(Flexitouch) - 2

37.7%

4.0 %

• Pre-surgical Assessment

• Periodic test via emerging

early detection methods

• Self recognition of symptoms

• Reduce Risk

• Detect Early

• Arrest & Reduce

• Maintain Gains

- Complications

Overall Goals

Quantitative Assessment Methods

• Limb Volumes

• Bioimpedance

• Local Tissue Fluid

• Tissue Properties

Early Detection & Treatment Effectiveness

Limbs

Any at Risk Location

(e.g. Trunk, Face and etc.)

20

30

40

50 pre-MLD

pst-MLD

Calf Thigh

TD

C V

alu

eSingle MLD Treatment

Lower Extremity Lymphedema

P<0.001 P<0.05

N=20 N=6

Mayrovitz et al. Lymphology 2008;41:87-92

25.7±3.1 25.2±3.6

22.4±2.9 22.3±2.9

34.7±8.3 33.4±9.0

24.9±5.2 24.3±4.5

Cancer Side Healthy Side

Arm Volumes (ml)

2160±564 2164±509

Bioz306±34

Bioz307±34

Breast Cancer Pre-Surgical N=30

Insignificant Side-to-Side Differentials at Baseline

TDCTDC

Mayrovitz et al. Clinical Physiology and Functional Imaging 2008;28:337-342

Force

Indentation

Fibrosis & Tissue Property ChangesPrinciple: Indentation Force ~ Tissue ‘Hardness’

0

50

100

150

200

250

300

350

1 2 3 4 5

Pre-FT

Pst-FT

Single Flexitouch® ApplicationF

orc

e (

g)

Indentation Depth (mm)

N = 12

P<0.001

Tissue

‘Softening’

30 minute below

knee application

100

200

300

400

500 pre-MLD

pst-MLD

Fo

rce (

g)

Calf Thigh

Single MLD Treatment

P<0.001 P<0.01~

N=22 N=6

Lower Extremity

Lymphedema

Tissue

‘softening’

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

Arterial

system

Venous

System

Blood

Capillaries

Lymphatic

Capillaries

Lymphatic

Vessels

Lymph

Nodes

Ly

mp

ha

tic

Sy

ste

m

Heart

Arteries

Pulmonary

Circulation

Sy

ste

mic

Cir

cu

lati

on

RALA

LVRV

Arterioles

Fluid +

Protein

PROTEINS

Proteins Accumulate if Lymphatic Dysfunction

More

Filtration

capillary

Complications

Lymphatic vessel/node

•Trauma

•Removal

•Radiation

•Blockage

•Overload

•Genetic - Primary

Fluid +

Protein

PROTEINS

Proteins Accumulate if Lymphatic Dysfunction

Macrophages

Fibrosis

More

Filtration

capillary

Complications

Fluid +

Protein

PROTEINS

Proteins Accumulate if Lymphatic Dysfunction

Macrophages

Stimulus for Chronic Inflammation

Vasodilation

• Increased filtration

• Tissue warmingBacterial

Growth

Bacterial/Fungal Infections

Fibrosis

More

Filtration

capillary

Complications

• Reduce Risk

• Detect Early

• Arrest & Reduce

• Maintain Gains

- Complications

Overall Goals

• Patient do’s & don’ts soon

after they become at risk

• Patient precaution compliance

• Reduce Risk

• Detect Early

• Arrest & Reduce

• Maintain Gains

- Complications

Overall Goals

• Multiple Web Sites with Good Info

• Not all precautions validated

• Some may be ‘over-kill’

• Informed and educated patient

• Common Sense Approach

0.6

1.0

1.4

1.8

2.2

Patient ArmsAffected/Control

1.64 ± 0.30

N=18

Premenopausal Postmenopausal1.04 ± 0.04 1.04 ± 0.04

N=15 N=15

Die

lec

tric

Co

ns

tan

t (R

ati

o)

Control Arms (Max/Min)

No overlap between

Patients vs. Controls

Potential Diagnostic Utility

Mayrovitz HN (2007) Lymphology 2007;40:87-94