Electrical impedance myography (and a little MUNE)

Seward B. Rutkove, MDBeth Israel Deaconess Medical Center

Harvard Medical School

Disclosures

1. Consultant and equity in Convergence Medical Devices, Inc.

2. Consulting for Neuralstem, Inc.,

3. Two patent applications in electrical impedance

4. Grant funding from NIH, ALSA Association, the Spinal

Muscular Atrophy Foundation, and NASA.

Electrical impedance testing?

• The assessment of characteristics of a material by measuring changes to an applied electrical current

• Used in forestry, metallurgy, geology

But also in humans…

• Whole body bioimpedance analysis– Total body water/fat

• Electrical impedance tomography– Imaging

• Electrical impedance mammography (also EIM)– Breast cancer detection

• Electrical impedance dermography

Electrical impedance myography

The broad hypothesis: Alterations in composition and structure

of muscle with disease will impact the electrical impedance of muscle in unique

and reproducible ways.

Different disorders,different pathologies

Normal Neurogenic

Myopathy/Dystrophy Disuse Atrophy

Measured voltage amplitude is proportional to muscle resistance (R)

Tissue reactance (X), related to capacitance, causes shift in timing

Electrical impedance in healthy muscle

Applied electrical current

Measured voltage

Voltmeter

Current Generator

Reduced tissue Reactance (X)causes reduced shift in timing

Increasedtissue Resistance (R)causes higher amplitude voltage

Applied electrical current

Measured voltage Phase will decrease Phase = arctan(X/R)

Electrical impedance in diseased muscle

Voltmeter

Current Generator

From neuromuscular.wustl.edu

Off-the-shelf bioimpedance devices

• Single Frequency

• Multifrequency

Useful, but limited

Instrumentation: Past and Present

20012005

2009

On the animal front

Pha

se (

degr

ees)

Res

ista

nce

(ohm

s)

What we measureR

eact

anc

e (o

hms)

Raw muscle data• Gives us the capability of relating surface data to

intrinsic muscle data and vice versa• Measure muscle conductivity and permittivity

Conductivity and permittivity plots

Ahad et al, 2009

Repeatability

0 5 10 150

5

10

15

Test

Ret

est

ICC = 0.98

Rats Mice

Healthy

ALS

CMD system-humans

Adhesive electrodes-humans

Current Data?

– ALS– SMA– DMD– Sarcopenia– Nerve injury (radiculopathy, crush models)– AMN

Follow-up ALSA-funded study• Patient visits approximately 3 months apart

(a total of 5 visits over 1 year)

• 8 Sites involved, 60 patients• EIM measurements performed on

• Biceps, wrist extensors, abductor pollicis brevis, quadriceps, and tibialis anterior

• Intra-session repeatability on biceps

• Also performed handheld dynamometry, ALSFRS, MUNE

• Major EIM outcome measure:– Rate of decline in 50 kHz phase

Results: In patient terms for 6 month trial

Assuming 6 month, placebo-controlled trial, 3 measurements, 20% treatment effect, p < 0.05, one-sided

Neuralstem study

Glass et al, 2012, Stem Cells

ALS Rat Data: Measuring Disease Progression16 animals followed from pre-symptomatic to death

Early

Advanced

Early

AdvancedEarly

Advanced

Wang et al, 2011

SOD1 g93a ALS rat data

Wang et al, 2011

As a biomarker in spinal muscular atrophy

• Natural history study of EIM in SMA, funded by SMA Foundation– Collaborative effort with Children’s

Hospital Boston, Dr. Basil Darras– 28 SMA children mean age 9.6 years,

followed for mean of 16 months– 20 Normal children enrolled, mean

age 9.8 years, followed for mean of 17 months

– Mainly Type 2 and Type 3 children

SMA Multifrequency Data

SMA cross-sectional data

Type 2

Type 3

healthy

SMA in older kids: no active motor neuron loss, but no muscle growth either

Healthy kids

From Rutkove et al, 2012

Healthy

SMA

P = 0.018

Primary muscle disease

Tarulli et al, 2006

Preliminary DMD data:

Quantitative Ultrasound and EIM in DMD (QED)

• Funded by NIH/NIAMS fall 2011• Basil Darras, MD: Co-PI• Enrolling 35 healthy kids and 35 with DMD and follow over 2

years• Frequent measurements early on; less frequent later • Started recruiting in March; about 17 DMD boys and 15

healthy boys already recruited

Sarcopenia

From Aaron et al, 2006

Quadriceps

Tibialis anterior

EIM in 4 healthy older subjects over a several year period

From Aaron et al, 2006

QuadricepsTwo subjects overlap

And sensitive to improvement too…

• Improvement in EIM data upon returning to normal activity after recovery from ankle fracture

From Tarulli et al, 2009

Open circles, immediately after injury

Closed circles, upon partial or full recovery

Lower limit of normal

Mean Value

Hind Limb Suspension studies in rats and mice: A model for assessing

sarcopenia and disuse

EIM phase declines and recovers with hind limb suspension

N = 45

Relationship between phase and muscle fiber size

What does it mean?• Is correlation sufficient?• How do we an answer the question?

– Animal models?– Tissue culture studies?– Single cell studies?

Thanks• Physicists and Engineers

• Carl Shiffman, PhD• Ronald Aaron, PhD• Joel Dawson, PhD• Jacob White, PhD

• Physician researchers• Andrew Tarulli, MD• Basil Darras, MD• Pushpa Narayanaswami, MD• Jeremy Shefner, MD, PhD• Ted Burns, MD (also for wine)• Mary Bouxsein, PhD• Jonathan Bean, MD• Jonathan Glass, MD• Eva Feldman, MD, PhD• Jim Caress, MD• Michael Benatar, MD

• Research Staff• Mohammad Ahad, PhD• Jia Li, PhD• Lucy Wang• Phil Mongiovi• Minhee Sung• Mina Jafarpoor• Lindsay Garmirian• Anne Chin• Andrew Spieker

• Convergence Medical Devices• Jose Bohorquez, PhD• Mike Rinehart, PhD• Neil Lupton, PhD• Laura Freeman, RN

Funding

R01 NS055099; R01 AR060850; K24 NS060951