Electrical impedance myography
(and a little MUNE)
Seward B. Rutkove, MD
Beth 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
Myopathy/Dystrophy
Neurogenic
Disuse Atrophy
Electrical impedance in healthy muscle
Current Generator
Voltmeter
Applied
electrical
current
Measured
voltage
amplitude is
proportional
to muscle
resistance (R)
Tissue
reactance (X),
related to
capacitance,
causes shift in
timing
Measured voltage
Electrical impedance in diseased muscle
Current Generator
Voltmeter
Applied
electrical
current
Increased
tissue
Resistance
(R)
causes
higher
amplitude
voltage
From neuromuscular.wustl.edu
Reduced
tissue
Reactance
(X)
causes
reduced shift
in timing
Measured voltage
Phase will decrease
Phase = arctan(X/R)
Off-the-shelf bioimpedance devices
Useful, but limited
• Single Frequency
• Multifrequency
Instrumentation: Past and Present
2001
2005
2009
On the animal front
Phase (degrees)
Resistance (ohms)
Reactance (ohms)
What we measure
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
Adhesive electrodes-humans
ICC = 0.98
15
Retest
Healthy
10
5
ALS
0
0
5
10
15
Test
CMD system-humans
Rats
Mice
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
Outcome measure
Patients needed per
study arm
EIM steepest
95
EIM mean
182
HHD
266
ALSFRS-R
220*
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 Progression
16 animals followed from pre-symptomatic to death
Advanced
Early
Early
Early
Advanced
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
Healthy kids
SMA
P = 0.018
From Rutkove et al, 2012
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
Quadriceps
Tibialis anterior
From Aaron et al, 2006
EIM in 4 healthy older subjects over a
several year period
Two subjects
overlap
Quadriceps
From Aaron et al, 2006
And sensitive to improvement too…
• Improvement in EIM data upon returning to normal
activity after recovery from ankle fracture
Mean Value
Closed circles, upon partial or full recovery
Open circles, immediately after injury
Lower limit of normal
From Tarulli et al, 2009
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
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Carl Shiffman, PhD
Ronald Aaron, PhD
Joel Dawson, PhD
Jacob White, PhD
• Physician researchers
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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
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Mohammad Ahad, PhD
Jia Li, PhD
Lucy Wang
Phil Mongiovi
Minhee Sung
Mina Jafarpoor
Lindsay Garmirian
Anne Chin
Andrew Spieker
• Convergence Medical Devices
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Jose Bohorquez, PhD
Mike Rinehart, PhD
Neil Lupton, PhD
Laura Freeman, RN
Funding
R01 NS055099; R01 AR060850; K24 NS060951