Electrical impedance myography (and a little MUNE)

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Electrical impedance myography (and a little
MUNE)

• Seward B. Rutkove, MD
• Beth Israel Deaconess Medical Center
• Harvard Medical School

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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.

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Electrical impedance testing?

• The assessment of characteristics of a material
  by measuring changes to an applied electrical
  current
• Used in forestry, metallurgy, geology

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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

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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.

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Different disorders,different pathologies
Normal
Disuse Atrophy
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Electrical impedance in healthy muscle
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Electrical impedance in diseased muscle
Phase will decrease Phase arctan(X/R)
From neuromuscular.wustl.edu
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Off-the-shelf bioimpedance devices
Useful, but limited

• Single Frequency
• Multifrequency

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Instrumentation Past and Present
2001
2005
2009
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On the animal front
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What we measure
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Raw muscle data

• Gives us the capability of relating surface data
  to intrinsic muscle data and vice versa
• Measure muscle conductivity and permittivity

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Conductivity and permittivity plots
Ahad et al, 2009
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Repeatability
Adhesive electrodes-humans
Healthy
ALS
Rats
Mice
CMD system-humans
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Current Data?

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

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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

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Results In patient terms for 6 month trial
Assuming 6 month, placebo-controlled trial, 3
measurements, 20 treatment effect, p lt 0.05,
one-sided
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Neuralstem study
Glass et al, 2012, Stem Cells
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ALS Rat Data Measuring Disease Progression

• 16 animals followed from pre-symptomatic to death

Advanced
Early
Early
Early
Advanced
Advanced
Wang et al, 2011
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SOD1 g93a ALS rat data
Wang et al, 2011
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As a biomarker in spinal muscular atrophy

• Natural history study of EIM in SMA, funded by
  SMA Foundation
• Collaborative effort with Childrens 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

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SMA Multifrequency Data
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SMA cross-sectional data
Type 2
Type 3
healthy
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SMA in older kids no active motor neuron loss,
but no muscle growth either
Healthy kids
Healthy
SMA
From Rutkove et al, 2012
P 0.018
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Primary muscle disease
Tarulli et al, 2006
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Preliminary DMD data
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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

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Sarcopenia
Quadriceps
Tibialis anterior
From Aaron et al, 2006
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EIM in 4 healthy older subjects over a several
year period
Quadriceps
Two subjects overlap
From Aaron et al, 2006
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And sensitive to improvement too

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

Closed circles, upon partial or full recovery
Mean Value
Open circles, immediately after injury
Lower limit of normal
From Tarulli et al, 2009
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Hind Limb Suspension studies in rats and mice A
model for assessing sarcopenia and disuse
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EIM phase declines and recovers with hind limb
suspension
N 45
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Relationship between phase and muscle fiber size
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What does it mean?

• Is correlation sufficient?
• How do we an answer the question?
• Animal models?
• Tissue culture studies?
• Single cell studies?

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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

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Funding
R01 NS055099 R01 AR060850 K24 NS060951