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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.
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
Raw muscle data• Gives us the capability of relating surface data to
intrinsic muscle data and vice versa• Measure muscle conductivity and permittivity
Repeatability
0 5 10 150
5
10
15
Test
Ret
est
ICC = 0.98
Rats Mice
Healthy
ALS
CMD system-humans
Adhesive electrodes-humans
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
ALS Rat Data: Measuring Disease Progression16 animals followed from pre-symptomatic to death
Early
Advanced
Early
AdvancedEarly
Advanced
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 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
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
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
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