Lymphedema Research

HN Mayrovitz, PhD, Professor of Physiology

College of Medical Sciences, Nova Southeastern

University, Ft. Lauderdale, Florida 33328

mayrovit@nova.edu

• Lymphedema Physiology

• Research into Early Detection

• Research into a New Therapy

• ‘Evolving’ Research Projects

The Lymphatic System

and Lymphedema

Arterial

system

Venous

System

Blood

Capillaries

Lymphatic

Capillaries

Lymphatic

Vessels

Lymph

Nodes

Lym

ph

ati

c S

ys

tem

The Third

Circulatory

System

Heart

Arteries

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

Overload = Edema

+ [Protein]

= Lymphedema

If Net Filtration Exceeds

Lymphatic Transport Capacity

Excess --> Lymphatics

Fluid +

Protein

capillary

Excess

Fluid +

Protein Lymphatics

blood

capillary

NORMAL

Excess

Accumulates

Fluid +

Protein Lymphatics

ABNORMAL

Overload = Edema

+ Protein = Lymphedema

Overload = Edema

+ [Protein]

= Lymphedema

If net filtration exceeds

lymphatic transport capacity

Complications

System

Works

OK Here

System

Not OK

Here

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

Research into Early Detection

“Recognizing lymphedema early and

treating it promptly is the best way

to manage the condition”

Judith R. Casley-Smith & J.R. Casley-Smith

Surgery

Radiation

Lym

ph

ed

em

a S

eve

rity

70 - 80 % of patients at risk = 0 lymphedema

Time

Ultimate Goal - Catch it EarlyMore Treatable – Less Complications

Surgery

Radiation

Symptoms

Seek TherapyLym

ph

ed

em

a S

eve

rity

70 - 80 % of patients at risk = 0 lymphedema

Fibrosis

Time

Ultimate Goal - Catch it EarlyMore Treatable – Less Complications

•Feeling of heaviness

•Tingling

•A ring or watch gets tight

•Skin feels “tight”

•Diminished flexibility

•Limb more easily fatigued

•Visual swelling

Surgery

Radiation

Symptoms

Seek Therapy

Reduce & Arrest

Lym

ph

ed

em

a S

eve

rity

70 - 80 % of patients at risk = 0 lymphedema

Fibrosis

Time

Ultimate Goal - Catch it EarlyMore Treatable – Less Complications

CDP

Surgery

Radiation

Symptoms

Seek Therapy

Reduce & Arrest

Lym

ph

ed

em

a S

eve

rity

70 - 80 % of patients at risk = 0 lymphedema

Early Detection

“Sub-Clinical”

Fibrosis

Time

Ultimate Goal - Catch it EarlyMore Treatable – Less Complications

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 mm

Modified from Mellor et al. 2004

Gel

Entry

Echo

Dermis

Subcutis0.80 - 1.2 mm

ventral

1.8 - 2.8 mm

Low water

content

High water

content

Normal Arm Lymphedematous Arm

20 MHz Ultrasound Imaging

Subjects and Protocol

12 women with unilateral arm lymphedema (74 ± 16 yrs)

12 premenopausal women (25.5 ± 3.7 yrs)

12 postmenopausal women (61.0 ± 6.7 yrs)

Affected

Arm

Control

Arm

Segment

Volume4 cm VA VC

Measurements on lymphedema patients prior to treatment

Measurements on premenopausal 4 days after menses

0

40

80

120

160

200

240

280

320

360

Right or Control Arm

Left or Affected Arm

Segmental Volumes

Premenopausal Postmenopausal Lymphedema

Vo

lum

e (

ml)

P<0.001

%Edema

39 ± 16%

0

10

20

30

40

50

60

Right or Control Arm

Left or Affected Arm

Tissue Water (2.5 mm)D

iele

ctr

ic C

on

sta

nt

Premenopausal Postmenopausal Lymphedema

P<0.001

0.6

1

1.4

1.8

2.2 No overlap

Normal vs. Patients

Premenopausal Postmenopausal1.021 ± 0.068 1.014 ± 0.063

Dominant/Non-Dominant

PatientsAffected/Control

1.600 ± 0.315

Die

lectr

ic C

on

sta

nt

(Rati

o)

Diagnostic Utility

Study Outcome

Criteria as of now for the limited data set:

• For at-risk unilateral arms: Arm TDC ratio > 1.2

• For bilateral arms or using absolute values:

Threshold depends on depth (3 sd)

Depth 0.5 mm 1.5 mm 2.5 mm 5.0 mm

TDC >42 >37 >37 >32

Currently an ongoing study with assessments

prior to and for up to two years after surgery

Tissue water measured at multiple ‘at-risk’ sites

Early Detection Research Study

Research into a ‘New’ Therapy

‘Standard’ Pump

New Approach

• Initial ‘preparation phase’

• ‘Light-touch’ drainage

0

10

20

30

40

50

60

70

0 10 20 30 40 50

G1

G2

G3

G4

G5

Pressure Timing and Pattern

Lympha Press® System

Pre

ss

ure

(m

mH

g)

Seconds

0

10

20

30

40

50

60

70

0 10 20 30 40 50

G1

G2

G3

G4

G5

Pressure Timing and Pattern

Flexitouch® System

Pre

ss

ure

(m

mH

g)

Seconds

‘Standard’ ‘New Approach’

Pump pressures and patterns widely different!

Current Research Study

How important is it to use a preparatory phase?

In women with unilateral arm lymphedema

will using the full garment set result in

greater tissue fluid reductions?

Research into Tissue Properties

• Pitting Edema

• Fibrosis

Goal: Simple but accurate ways to

assess therapeutic effectiveness

Evolving ResearchQuantifying ‘pitting’ edema

Evolving Research

Fibrosis and tissue property changes

‘New’ Therapies: All needing validation

‘Electromagnetic Therapies’

Radio waves

Microwaves

Infrared Waves

Light Waves

Pulsed Radio Frequency Waves

Coil

Current

B-Field

• Seven post-mastectomy

patients in pilot study

• Unilateral Lymphedema

All had prior CDT Tx

• Each Pt. treated 4-6

times over 2-weeks

• During this interval

no other Tx provided

Subjects and Protocol

• Skin blood perfusion

(SBF) by laser-Doppler

on affected arm

• Transcutaneous O2

(PO2) on affected and

contralateral arm

SBF

PO2

PO2

Physiological Measurements

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

0.64 0.50 0.42 0.41 0.35

0 1 2 3 4

Treatments* p< 0.01 vs. initial edema volume

** *

*

N=7

Ed

em

a V

olu

me

(L

)

Further

Reduction

Through

4th Tx

Edema Volume

Decreased

After one Tx

Example SBF Response

Skin

Blood

Flow

BASE ACTIVE OFF

10” 60” 20”

0.5

4.5

SBF Increased

Mean

Pulsatile

• PRFT shows potential benefit

• Lymphedema reduced with one treatment

• Initial PILOT findings are encouraging, BUT

need placebo controlled studies

Pilot Study Outcomes

SPECULATION Mechanisms similar to those

that increased SBF also

increase lymph drainage

Expanding collateral channels

Increasing lymphoangiomotoricity