Electrical impedance myography:
past, present, and future
Seward B. Rutkove, MD
Professor of Neurology
Harvard Medical School
Conflicts
• I have equity in, and serve as a consultant and
scientific advisor to, Skulpt, Inc. a company
that designs impedance devices for clinical
and research use; I am also a member of the
company’s Board of Directors. The company
also has an option to license patented
impedance technology of which I am named
as an inventor.
Disclaimer: I’m not an engineer!
My naïve question in 1999:
Is there a better way?
Only 60.5% reproducibility for
diagnosis of spinal nerve root injury:
Kendall, et al 2006
This is gonna hurt like hell.
There are some imaging approaches:
but hard to quantify
The neurologists “go-to” technology
1999
Description of muscle impedance
measurements in vivo
Carl Shiffman
Ron Aaron
Previous studies of muscle
1961
1963
In all cases,
excised muscle tissue
1963
1983
Different disorders,
different pathologies
Normal
Myopathy/Dystrophy
Neurogenic
Disuse Atrophy
My “obvious” hypothesis:
Alterations in composition and structure
of muscle with disease will impact the
impedance of muscle in unique and
reproducible ways.
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)
How might muscle abnormalities
impact impedance measures?
• Decreasing intra and extracellular free water
may increase resistance parameters (as
muscle tissue is lost).
• Increasing endomysial fat will increase
resistance
• Cell size changes (atrophy) will impact the
reactance and phase values.
• Fat and connective tissue will alter the normal
anisotropic nature of the tissue.
Phase (degrees)
Resistance (ohms)
Reactance (ohms)
Multifrequency data
EIM feature of interest: Anisotropy
Why physicians might be interested
• Painless
– Improvement over EMG and NCS
•
•
•
•
•
•
•
Non-invasive
In general, highly reproducible
Quantitative
Extremely fast
Relatively inexpensive technology
Convenient (small devices possible)
Can be tailored easily for specific needs
– Superficial or deep muscles; children and adults
Muscle impedance limitations
• Studies have limited spatial specificity
– Imaging possible, but not a major effort
• Alterations are relatively non-specific
– Easy to identify changes; more challenging to
understand how the change relates to a specific
aspect of muscle pathology
– Also hard to predict how a specific therapy may effect
the data
• Subcutaneous fat impacts data
– Degree of impact depends on electrode topology
How we did human measurements
1999-2007: current electrodes placed
far from voltage
Collecting data more simply
(2009 onward): moving voltage
electrodes over muscle of interest
Reproducibility
Rutkove et al, Clin Neurophys
Generally straightforward to analyze
Another key concept: extending
technology to lab animals (2004)
• Ability to better understand what is going in
humans
– Things can happen much faster
• More rapid progression
• Easier to “recruit” animals then people
• Potential sensitivity to drug effect
– Predict human response
• Pathological correlation
– Ex vivo assessments simple
Jia Li, PhD
Animal measurement techniques
Used in conjunction with a variety of impedance analyzers
Animal repeatability
Rat Reproducibility
Ahad et al, 2009
Mouse Reproducibility
Li et al, 2012
Ex Vivo Assessments
Ahad et al, 2009,
Physiological
Measurement
Back to 2001 : Single Frequency Data
Realization: Probably best used
as a disease-tracker/biomarker
than as a true diagnostic
DISEASE SPECIFIC APPLICATIONS
Amyotrophic Lateral Sclerosis
(Motor neuron disease, Lou Gehrig’s Disease)
• Universally fatal disease, with
death anywhere from 6 months
to 5 years after onset.
• Progressive generalized
weakness due to motor neuron
cell death in brain and spinal
cord
• Symptoms include limb
weakness, swallowing and
speaking difficulties, breathing
difficulties
• No truly effective therapies.
• Many drug trials ongoing and
much basic research.
Multifrequency data in ALS comparing 2
legs asymmetrically affected by disease.
Esper et al, 2006
Muscle & Nerve
Study in 15 ALS patients at one center
Trajectories of progression
Rutkove et al, 2007, Clin Neurophys
In ALS: initial multi-center study
• Patient visits approximately 3 months
apart (a total of 5 visits over 1 year)
• 8 Sites involved, 60 patients
• EIM measurements performed on
multiple muscles
• Also performed handheld
dynamometry, ALSFRS, Motor unit
number estimation
Trajectories of progression
Results: In patient terms for 6-month trial
Test
Number needed per arm
for clinical trial
EIM
95
Motor unit number estimation
162 (over one year)
Handheld dynamometry
266
ALSFRS-R based on our natural history
study
220
ALSFRS-R based on past placebo
controlled studies
> 400
Assuming 6 month, placebo-controlled trial, 3 measurements, 20% treatment
effect, p < 0.05, one-sided
EIM measured over 6 months also predicts survival:
Hazard ratio of 1.40 [1.02–1.90] p = 0.035
Ability to measure tongue
ALS Rat Data: Measuring Disease Progression
16 animals followed from pre-symptomatic to death
Advanced
Early
Early
Early
Advanced
Advanced
Wang et al, 2011, Clin Neurophys
In the ALS SOD1 g93a mouse
Li et al, 2012, PLoS One
Spinal muscular atrophy (SMA)
• Relatively common recessive disorder of
children affecting 1/7000 live births; 1/80
people carry mutant gene.
• Like ALS in that motor nerve cells die
– But usually only for a time then stabilizes.
– Primary muscle and neuromuscular junction
issues as well
• Severe forms (death before 3 months) to
very mild forms (clinical onset identified
in adulthood).
• Getting very close to effective therapies!
Natural history study in SMA
– Done in cooperation with
Basil Darras and Boston
Children’s Hospital
Basil Darras, MD
– 28 SMA children (Type 2
and 3) mean age 9.6 years,
followed for mean of 16
months
– 20 healthy children
enrolled, mean age 9.8
years, followed for mean of
17 months
Rutkove et al, Muscle & Nerve, 2012
HEALTHY
SMA
Spinal muscular atrophy therapy
• SMA Delta7 mouse:
– Treated with antisense oligos at
different times; measured P12
20
A. EIM 50kHz Phase
15
Degrees
* *
10
5
0
WT
Arnold et al, Neurobiology of Disease, 2016
P2
Rx
P6
Rx
No
Rx
Duchenne muscular dystrophy (DMD)
• Debilitating and fatal disease that affects boys
only
– Common: 1/3500 boys born; 30% of time
spontaneous mutation in dystrophin gene
• Initially relatively normal development
• At age 7 years, start losing motor milestones
– Wheelchair bound by age 12-13 years
– Death usually from cardiac/pulmonary failure
around 25-30 years
• Several new potential therapies now being
investigated with good promise
EIM and quantitative US in DMD
(QED study): Cross-sectional data
28 healthy boys, 35 boys with DMD
Aged 2-14 years; 2 years of follow-up
Hot off press: progression in DMD
boys versus healthy 3-24 months
Data at 3 months already shows difference as compared to normal boys.
40
Ex vivo transverse phase (Degrees)
Ex vivo transverse phase (Degrees)
Correlation to other parameters:
mdx mice
rho = -0.66
p < 0.01
35
30
25
20
15
10
1
2
3
4
5
Hydroxyproline (g/mg)
WT mouse
6
40
35
30
25
20
rho = 0.68
p < 0.01
15
10
500
1000
1500
2000
2500
3000
Muscle fiber area (m2)
Mdx mouse
3500
Muscular dystrophy dogs
Combined L&R side, probe config 3
30
25
Phase (deg)
20
15
10
5
0
<9 Months
Affected
>9 Months
Not Affected
Chady Hakim, PhD
Dongshang Duan, PhD
“Noel”
University of Missouri, Columbia
Disuse, Sarcopenia, and Space Travel
• Alterations in the pathology in healthy muscle
that undergoes disuse use or aging should also
show impedance change
• Type 2 fiber atrophy is the signature change in
these conditions.
• In sarcopenia (muscle wasting in older people),
fat and connective tissue also intervene.
– Can also happen with anyone bedbound for
sufficiently long period of time
Disuse atrophy
• 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, Arch Phys Med Rehab
EIM values correlate to function in
healthy older individuals:
Aaron et al, 2006
Ex vivo data on microgravity: 2011
10 control, 7 space flight
Mary Bouxsein, PhD
Moving beyond following disease
progression: discriminating disease type
Li et al, 2014, Muscle & Nerve
Ex-vivo data on slow- versus fast-twitch muscle
Small arcs reveal impedance characteristic of
organelles, including mitochondria
Benjamin Sanchez, PhD
Sanchez et al, Phys Med Biol, 2014
Wider width and lower peak frequency of the small red arc in Type 1 (slow-twitch) fibers
suggests, larger and more numerous mitochondria than in Type 2 (fast-twitch) fibers.
But can we make the technology
accessible to physicians?
My vision: In 2006
Collaboration with MIT: 2006-2009
Mike Sharfstein
Joel Dawson, PhD
Hong Ma
Muyiwa Ogunnika
Roshni Cooper
MIT EIM reconfigurable probe (2009)
Latpop
Computer
Handyscope
HS3 USB
Oscillocope
EIM Probe
• 2 CIMIT grants later
• Entire system
powered by USB and
9 Volt batteries
Data
Normal subject
ALS Patient
Myositis patient
Next necessary step:
commercialization
• Convergence Medical
Devices, Inc founded 7/8/09
• Funded mostly by small
business grants from NIH
and NSF (SBIRs)
• My Role: Consultant/Advisor
Jose Bohorquez, PhD
Late 2011
Convergence EIM system
Currently being used in about
30-40 medical centers
throughout US and Europe for
research purposes
Demo
BUT: Huge challenges to creating a
new medical device/procedure
• MDs don’t understand it.
– Why do we want this?
– What is Phase? Reactance?
• How can I trust something I don’t understand?
• How could it fit into my practice?
• Most important: There is no reimbursement code
– Complex process—need to obtain CPT code
– The easier the test is to perform, the lower the reimbursement!!
• Need professional organizations to support it, but they see it
as a potential threat to existing reimbursed technologies!
• Only exception: drug companies are interested as a new
outcome measure in clinical trials
– But they need proof it works in a specific disease: Catch-22
Digital Fitness: A simpler goal?
Track your
fitness
Fitbit
iPhone
Summer 2013: A change of direction
• Plan to create FDA-approved medical device put
on hold
• Pivot to creation of fitness device
– No health claims—hence no FDA approval required;
no CPT code needed.
• Additional fundraising and hiring
• But still not giving up on medical application
– Multiple ongoing NIH-funded studies in SMA, DMD,
ALS, Back pain and sarcopenia
Lo and Behold: Spring 2015
An aside: we are bad at envisioning
the future
“Paleofuture”
My extrapolations
2016
2006
What’s the difference?
•
•
•
•
More limited electronics
Less flexibility in terms of electrode design
Limited frequency range
Output is “dummied down”
– Simplified value of muscle quality and % fat
– But actually full impedance data are being
collected and stored
Which would you rather have?
One of these:
Or 100 of
these?
ALS clinical trial in 2016:
Data from a single patient coming to
hospital every 3 months for evaluation
45
43
95% confidence limits of slope
41
ALS score
39
37
35
33
31
29
27
25
0
100
200
Days
300
400
ALS clinical trial in 2020:
Data from a single patient performing
at home measurements daily
45
43
41
95% confidence limits of slope
ALS score
39
37
35
33
31
29
27
25
0
100
200
Days
300
400
Let’s actually model it and see
• Mixed effects model
– Kush Kapur, PhD, Biostatistician
• Assumptions :
–
–
–
–
–
–
1 year length study
1:1 Drug:placebo
Linear progression of 0.02SD/month
25% treatment effect
Alpha = 0.05, two-tailed Wald test
Within-subject and between-subject variation of 0.50
How many people would you need for
a clinical trial?
5 subjects/arm
with
daily
approach
Answer: 218
subjects/arm
with
standard
approach
What could it mean?
• Better drug trials
–
–
–
–
–
–
Faster assessment of drug effect
Studies in many populations around the world
Dosing
Subpopulations of people with disease
Studies in really rare diseases
Increased ease of studying combination therapies
• Improved individual patient care for office use
– Most effective drugs
– Dosing
– Convenient bedside use in clinic or on wards
• Improved self-monitoring of muscle and health
Future directions
• Aiming to use impedance to
image muscle contraction—
with Ryan Halter at Dartmouth
Recently funded to begin at
home study in ALS monitoring
using Skulpt device and other at
home tools.
The virtual muscle biopsy: correlations
between pathological characteristics and
impedance data
Other updates…
• Closed Series A funding round in December
• Release of Skulpt Chisel in 2 weeks
– Improved battery life, improved electronics, no screen,
only $99 USD.
– Refined and improved app
– With personalized fitness recommendations
– To be in major retailers in US, UK and Canada
• Renaming/repositioning of health portion of
company
– Skulpt Health to become MyoLex, Inc
– The EIM1103 device to become the MyoLex View®
– Will finally begin road to FDA approval
• “It takes years of hard work to have an overnight
success.”
Exciting times on the clinical front:
results of many studies forthcoming
•
•
•
•
•
•
•
NeuroNEXT SMA biomarker
QED study in Duchenne
ALS longitudinal (SBIR-funded study)
Study of technology for back pain assessment
Second longitudinal Duchenne study
Cross-sectional aging/sarcopenia analyses
Multiple Pharma studies
My bad predictions
What I envisioned in 1999
• A technology to replace
needle EMG
• Use by MDs as a new
diagnostic
• Lab-based technology
What is happening in 2016
• A technology for assessing
muscle condition
longitudinally
• For potential clinical trial
use for new drug evaluation
• For home use and selfevaluation
I could have fared worse….
Thanks
Rutkove Lab
Jia Li, PhD
Courtney McIlduff, MD
Benjamin Sanchez, PhD
Adam Pacheck and Sung Yim
and all past research assistants/
post-docs over the years
Close Collaborators
Basil Darras, MD
Jeremy Shefner, MD, PhD
Jose Bohorquez, PhD
Joel Dawson, PhD
Jim Wu, MD
Mary Bouxsein, PhD
Craig Zaidman, MD
David Arnold, MD
Kush Kapur, PhD
Glenn Rosen, PhD
Jonathan Bean, MD
Carl Shiffman and Ron Aaron, PhDs
Critical Colleagues
Elizabeth Raynor, MD
Pushpa Narayanaswami, MD
Andrew Tarulli, MD
Clifford Saper, MD, PhD
Funders:
NIH/NINDS
NIH/NIAMS
NIH/NIA
Prize4Life
ALS Association
SMA Foundation
Cure SMA
NASA
CIMIT
In line at Starbucks…
Courtney Jia Li
McIlduff
Sung
Yim
Adam
Pacheck
Benjamin
Sanchez