neuromuscular ultrasound for the evaluation of … · could detect changes in peripheral nerves and...
TRANSCRIPT
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NEUROMUSCULAR ULTRASOUND FOR THE EVALUATION OF
AMYOTROPHIC LATERAL SCLEROSIS
By
MICHAEL S. CARTWRIGHT, M.D.
A Thesis Submitted to the Graduate Faculty of
WAKE FOREST UNIVERSITY GRADUATE SCHOOL OF ARTS AND SCIENCES
in Partial Fulfillment of the Requirements for the Degree of
MASTER OF SCIENCE
in the Clinical and Population Translational Science Program
May 21st, 2012
Winston-Salem, North Carolina
Approved by:
Francis O. Walker, M.D., Advisor
Examining Committee:
Paul J. Laurienti, M.D., Ph.D., Committee Chair
Carol E. Milligan, Ph.D.
Gregory W. Evans, M.A.
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TABLE OF CONTENTS
Page
LIST OF ABBREVIATIONS…………………………………………………….. iii
LIST OF TABLES AND FIGURES……………….……………………………... iv
NEUROMUSCULAR ULTRASOUND DEFINITIONS………………………… v
ABSTRACT……………………..………………………………………………..... vi
Chapters
I. INTRODUCTION……………………………………………………... 1
II. PERIPHERAL NERVE AND MUSCLE ULTRASOUND IN AMYOTROPHIC LATERAL SCLEROSIS………………………..
Published in Muscle & Nerve, September 2011
22
III. DISCUSSION……………………………………………………….…. 40
IV. CURRICULUM VITAE………………………………………………... 52
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LIST OF ABBREVIATIONS
ALS: amyotrophic lateral sclerosis
ALSFRS-R: revised ALS functional rating scale
EI: echo intensity
EMG: electromyography
FVC: forced vital capacity
MIP: maximal inspiratory pressure
MND: motor neuron disease
MUNE: motor unit number estimation
SMA: spinal muscular atrophy
SOD1: superoxide dismutase 1
TDP-43: TAR DNA-binding protein 43
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LIST OF TABLES AND FIGURE
TABLES Page 1.1
Current and Potential ALS Biomarkers……………………………
6
1.2 Neuromuscular Ultrasound Findings in Motor Neuron Disease.......
8
2.1 Participant Demographics………………………………………….. 31 2.2 ALS Participant Characteristics……………………………………. 31 2.3 Ultrasonographic Comparisons
Between ALS Patients and Controls……………………..…………
32 2.4 Correlation Between Ultrasonographic
Parameters and Other Variables…………………………………….
33 3.1 Neuromuscular Ultrasound Studies in ALS……………………….. 41 FIGURES 1.1
ALS Diagnostic Criteria……………………………………………..
4
2.1
Ultrasonography of the Median Nerve.……………………………..
28
2.2 Ultrasonography of the Sural Nerve……………………………….. 29 2.3 Ultrasonography of the Biceps Brachii
and Brachialis Muscle Complex……………….……………………
30 3.1 Improved Diagnostic Accuracy of ALS with EMG
and Ultrasound Detection of Fasciculations…………………………
44 3.2 Prospective Study Design for Complete Assessment
of ALS using Neuromuscular Ultrasound………………………….
48
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NEUROMUSCULAR ULTRASOUND DEFINTIONS
Anechoic: An absence of returning echoes, resulting in an image that is black.
Echogenicity: The degree to which a structure reflects echoes back toward the transducer.
Increased echogenicity results in brighter images.
Echointensity: A quantitative assessment of echogenicity or brightness, typically
presented as a single mean value obtained using gray-scale analysis of a region of
interest.
Echotexture: The perceived texture of the image created after processing of the returning
echoes recorded by the transducer.
Gray-scale analysis: A quantitative technique used to assess black and white pictures,
such as ultrasound images, in which each pixel is assigned a value from 0 (black) to 255
(white) based on the shade of the gray in the pixel.
Hyperechoic: Increased echo signal, which results in a brighter image.
Hypoechoic: Decreased echo signal, which results in a darker image.
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ABSTRACT
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that causes
progressive loss of motor neurons, which results in weakness, respiratory compromise,
and typically death within 5 years of disease onset. The diagnosis is often delayed up to a
year from the time of onset because it is a clinical diagnosis and there are few tests
available to assist in the diagnostic evaluation. Neuromuscular ultrasound is an emerging
tool for the diagnosis of a variety of conditions, but it has not been studied extensively in
individuals with ALS. This study was designed to determine if neuromuscular ultrasound
could detect changes in peripheral nerves and muscles of individuals with ALS, which
could then be used to assist in diagnosis. Several neuromuscular ultrasound parameters
were compared between 20 individuals with ALS and 20 age and gender matched
controls. The cross-sectional area of the median nerve in the mid-arm was smaller in the
ALS group than controls (10.5 mm2 vs. 12.7 mm2, p = 0.0023), and the ALS group also
had a thinner biceps/brachialis muscle complex than controls (2.1 cm vs. 2.9 cm, p =
0.0007). These findings show that neuromuscular ultrasound can detect nerve and
muscle atrophy in ALS, so it should be further explored prospectively as a diagnostic tool
and possible disease biomarker.
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CHAPTER I
INTRODUCTION
Amyotrophic lateral sclerosis (ALS), which is also known as Lou Gehrig’s disease in
the United States and Charcot’s or motor neuron disease (MND) in Europe, is a condition
in which motor neurons in the brain and spinal cord progressively die, which results in
limb weakness, dysarthria, dysphagia, dyspnea, and eventually respiratory compromise
and death.1 Onset can occur at any age after the second decade of life, but prevalence
escalates with increasing age and the peak age of onset is about 74 years old.2 The
incidence in the United States and Europe ranges between 1.5 and 2.7 cases per 100,000
per year, 2, 3 and the incidence may be lower amongst African, Asian, and Hispanic
ethnicities compared to whites.4 It occurs more often in men than women, and other
identified factors that slightly increase the risk of developing ALS include cigarette
smoking, United States military service, manual labor, athleticism, and trauma.2, 5-9 The
clinical presentation is variable, with asymmetric limb-onset weakness occurring in about
80% of cases, bulbar onset in nearly 20%, and diaphragmatic onset in fewer than 1%.10
Because both upper motor neurons (in the brain and spinal cord) and lower motor
neurons (starting in the spinal cord and extending outward) are lost, the pattern of clinical
manifestations is relatively unique and often involves progressive spasticity in addition to
atrophy and weakness.1 There is no cure for ALS, and the glutamate inhibitor riluzole,
which results in an increased life expectancy of just a few months, is the only approved
medical treatment.11, 12 Supportive care and interventions such as percutaneous
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endoscopic gastrostomy feeding tubes and non-invasive ventilation have resulted in mild
increases in life expectancy for those with ALS, but the mean time of death is still 3-4
years from disease onset.13, 14
The etiology of ALS remains unknown. Approximately 90% of cases are sporadic
and 10% are familial, with the majority of inherited cases following an autosomal
dominant pattern. Until recently, the most commonly identified form of familial ALS
was caused by mutations in the superoxide dismutase 1 (SOD1) gene.15 While SOD1
mutations remain a cause in about 25% of familial ALS cases, very recent data indicate
that a hexanucleotide repeat expansion on chromosome 9p21 causes 46.0% of familial
ALS in a Finnish population. In addition, this gene is also linked to 21.1% of sporadic
ALS in the same population.16 While the complete pathophysiology of ALS remains
unknown, these recent genetic discoveries indicate that a large portion of ALS cases are
characterized by TAR DNA-binding protein (TDP-43) positive inclusions throughout the
nervous system.17 It has also been shown that mutations in the gene encoding the protein
ubiqulin 2 result in defects in the protein degradation pathway, which causes abnormal
protein aggregation and perhaps explains a common mechanism for familial and sporadic
ALS.18 Putting these recent genetic discoveries together has led to the intriguing theory
that perhaps ALS results from the accumulation of toxic RNA, which interferes with
normal cellular metabolism.16 Other implicated pathophysiologic mechanisms include
glutamate excitotoxicity, glial cell mediated processes, mitochondrial dysfunction,
growth factor deficiencies, and others.19
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Diagnosing ALS
Despite advances in understanding the pathophysiology of ALS, there remains no
biochemical assay for the disease and establishing the diagnosis still requires a detailed
history and physical examination. For clinical and research purposes, diagnostic criteria
have been established through expert consensus, with the most commonly used criteria
being the revised El-Escorial clinical criteria and the Awaji electrodiagnostic criteria
(Figure 1.1).20, 21 These criteria are rooted in the basic premise that ALS causes death of
upper and lower motor neurons, which spreads to contiguous spinal segments. This
results in lower motor neuron findings of weakness, atrophy, fasciculations, and
denervation potentials seen with electromyography (EMG), and upper motor neuron
findings of spasticity, brisk reflexes, and the presence of normally absent pathologic
reflexes. Exclusion of other conditions that mimic ALS is also an important aspect of the
diagnostic process, and electrodiagnostic techniques (nerve conduction studies and EMG)
help confirm denervation and reinnervation and exclude sensory nerve involvement and
demyelination, which are uncommon in ALS.22 Taking all this information together, the
diagnosis of ALS is usually clear to clinicians experienced with the disease, but it can be
quite confusing to primary care physicians, non-neurologist specialists, and even
neurologists not accustomed to seeing individuals with ALS.23 This results in a mean
delay in diagnosis between 9 and 16 months, which can limit treatment options, decrease
enrollment in clinical trials, increase patient and family distress and anxiety, and perhaps
even close a window of time when motor neuron function is impaired but not irreversibly
damaged, as has been suggested by animal and human research.24-26
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Figure 1.1. The revised El-Escorial and Awaji criteria are shown above. The Awaji criteria consider fasciculations to be evidence of lower motor neuron involvement and gives electrodiagnostic evidence of lower motor neuron dysfunction the same weight as clinical evidence.27 (LMN, lower motor neuron; UMN, upper motor neuron).
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Development of other diagnostic tools is needed in ALS to help clinicians and
researchers diagnose the condition earlier and more accurately.25 Even clinicians with
extensive ALS experience encounter patients in which the diagnosis is not clear until
months have elapsed and the disease has progressed as expected, so new diagnostic tools
are actively being sought by those who treat and study this disease.
Surrogate Markers of Disease Progression in ALS
Several markers have been proposed for tracking disease progression in ALS and
some are used routinely in clinical care and treatment trials (Table 1.2).28 The revised
ALS Functional Rating Scale (ALSFRS-R) is a valid and reliable tool consisting of
questions pertaining to daily function.29 It has high construct validity and is used in
almost all clinical trials, although it may lack sensitivity for detecting progression that
does not result in changes in activities of daily living. Forced vital capacity (FVC),
maximal inspiratory pressure (MIP), and other measures of respiratory insufficiency are
also used routinely in clinical and research settings, but these surrogate markers of
disease progression also lack sensitivity, particularly in those who have not yet
experienced respiratory involvement.30 Finally, motor unit number estimation (MUNE)
is an electrodiagnostic technique that provides objective data of motor unit loss.31 It is
reliable and demonstrates rates of decline in ALS that compare favorably to other
biomarkers, but it is uncomfortable and its use has only been demonstrated in a small
subset of muscles. In addition, MUNE can be time consuming and is not used in routine
clinical practice.
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Table 1.1. Current and potential biomarkers for diagnosis and tracking of disease progression in ALS.
Biomarker Used Routinely? ALS Functional Rating Scale29 Yes Forced Vital Capacity/Maximal Inspiratory Pressure30 Yes Electrodiagnostic Studies Motor unit number estimation31 Neurophysiological index32 Electrical impedance myography33 Phrenic nerve compound muscle action potential34
Yes No No No
Cerebrospinal fluid analyses TDP-4335 Tau protein36 S100beta37 sCD1437 Cystatin C38
No No No No No
Plasma analyses L-ferritin39 Monocyte chemoattractant 139 Granulocyte-macrophage colony stimulating factor39
No No No
Magnetic resonance image techniques Diffusion weighted image40 Diffusion tensor imaging40
No No
Other surrogate markers of disease progression have been developed for following
individuals with ALS (Table 1.2),32, 33, 37 but the ALSFRS, FVC, and MUNE are
employed most often, and a combination of these markers are typically used in clinical
trials as they have complementary characteristics.28 Ideally, future biomarkers for ALS
will be reliable, sensitive (even to pre-clinical changes), painless, quick, applicable to
different muscle groups that may be affected (and different sub-types of ALS), and
responsive to meaningful changes in disease progression. Such biomarkers will increase
the accuracy and decrease the length of clinical trials.40
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Neuromuscular Ultrasound
Neuromuscular ultrasound involves the use of high-resolution ultrasound to image
peripheral nerves and muscles, which can assist in the diagnosis of a variety of
neuromuscular diseases.41 Its use was first described in the early 1980s in patients with
muscular dystrophy, but since then it has been used to improve diagnostic capabilities in
focal neuropathies, inherited neuropathies, inflammatory muscle diseases, and
autoimmune mediated neuropathies.42-46 In general, diseased muscle has increased
echogenicity and increased homogeneity of echotexture, and some diseases result in
muscle atrophy with others showing edema and hypervascularity.41 Diseased nerves
often enlarge, are hypoechoic, and may have increased vascularity.41 In addition to
providing information about muscle and nerve anatomy and pathophysiology,
neuromuscular ultrasound is also a promising technique because it is painless, does not
use radiation, is relatively inexpensive, is readily available, and often can be performed
rapidly.41 While it has been used to assess many conditions, neuromuscular ultrasound
has been studied only minimally in the evaluation of ALS.
Neuromuscular Ultrasound in ALS
There are several potential methods in which neuromuscular ultrasound could be used
to assess individuals with ALS, some which have been explored preliminarily and others
which have not. Muscle ultrasound has been evaluated in the motor neuron disease
spinal muscular atrophy (SMA) and in ALS, with typical echotexture findings listed in
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Table 1.2.47-50 Muscle ultrasound has also been used to detect the presence of
fasciculations, with ultrasound
demonstrating higher sensitivity than both visual inspection and EMG.51 Three
longitudinal studies have examined muscle thickness, as measured by ultrasound, in
individuals with ALS, and all have demonstrated a small but statistically significant
decrease in muscle thickness over several months.52-54 Conversely, neuromuscular
ultrasound of peripheral nerves in those with motor neuron disease has not previously
been reported, and while autopsy studies have shown nerve root atrophy,55 there is a
surprising lack of any imaging studies confirming this finding in peripheral nerves in
vivo. Since peripheral nerve imaging has not previously been reported in ALS and
muscle imaging has only been preliminarily explored, this study was designed to explore
these two imaging targets further using high resolution neuromuscular ultrasound.
Study Design and Specific Aims
This project was designed as a pilot study to examine the use of neuromuscular
ultrasound as a potential tool for diagnosis and possibly as a surrogate marker of disease
Table 1.2 Neuromuscular Ultrasound Findings in Motor Neuron Disease
1. Increased muscle echogenicity 2. Increased muscle heterogeneity 3. Increased subcutaneous tissue thickness 4. Muscle atrophy 5. Increased subcutaneous tissue-to-muscle thickness ratio 6. Increased calf size 7. Long duration fasciculations
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progression in those with ALS. Two questions were of specific interest. First, do
peripheral nerves carrying motor fibers change in size (either increase or decrease), as
measured with neuromuscular ultrasound, in individuals with ALS compared to controls?
Second, does neuromuscular ultrasound demonstrate muscle atrophy in those with ALS
compared to controls?
To address these questions, a prospective study with 20 individuals with ALS and 20
age and sex matched controls was designed. A specific effort was made to target and
enroll individuals with advanced weakness and atrophy of at least one upper extremity, so
this proof-of-concept pilot study would not be limited by the presence of subtle changes
in those early into the disease process. In all 40 individuals neuromuscular ultrasound
was performed to assess the following:
1. Cross-sectional area of the median nerve at the mid-point of the upper arm.
This site was chosen because it is a nerve that is commonly studied with
neuromuscular ultrasound, it carries motor fibers to many muscles in the distal
arm and hand, it is a site that is easy to visualize, and it is site at which the
nerve is not often compressed (as opposed to the wrist, where it is frequently
entrapped and causes carpal tunnel syndrome and nerve enlargement).
2. Cross-sectional area of the sural nerve 10 cm above the lateral malleolus.
This nerve was chosen because it is a pure sensory nerve that should not be
affected by the neurodegeneration that occurs in motor and mixed nerves in
ALS. It is also a nerve that is easily visualized with neuromuscular ultrasound
and is not frequently entrapped.
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3. Thickness of the biceps brachii and brachialis muscle complex at the mid-
point of the upper arm.
It was hypothesized that there would be no difference in sural nerve area between the two
groups and there would be significant atrophy in the biceps/brachialis muscle complex in
patients with ALS. However, it was difficult to speculate whether the median nerve
would show an increase or decrease in size in ALS compared to controls. One line of
thought was that the nerve would increase in size because other neuropathic conditions,
such as entrapment, inflammatory neuropathies, and inherited neuropathies have all
demonstrated nerve enlargement as part of the disease process.44, 56, 57 This includes
processes that involve progressive axon death, such as CMT Type 2 and diabetic
polyneuropathy, although nerve enlargement is greater in demyelinating hereditary
polyneuropathies compared to axonal hereditary polyneuropathies.58, 59 Alternatively,
one might expect the median nerve to be smaller in those with ALS compared to controls,
since there is significant axon loss in ALS once distal atrophy is present,60 and autopsy
studies reveal thinning of nerve roots.55
These thoughts led to the development of the following Specific Aims:
Specific Aim 1. To determine if neuromuscular ultrasound measurement of the
median nerve in the upper arm can demonstrate measurable changes in nerve
cross-sectional area in 20 adults with ALS compared to 20 age and gender
matched controls.
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Specific Aim 2. To determine if neuromuscular ultrasound measurement of the
biceps brachii/brachialis muscle complex can demonstrate measurable atrophy in
20 adults with ALS compared to 20 age and gender matched controls.
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19. Zinman L, Cudkowicz M. Emerging targets and treatments in amyotrophic lateral
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22. Shook SJ, Pioro EP. Racing against the clock: recognizing, differentiating,
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23. Li TM, Day SJ, Alberman E, Swash M. Differential diagnosis of motoneurone
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24. Kraemer M, Buerger M, Berlit P. Diagnostic problems and delay of diagnosis in
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26. Aggarwal A. Motor unit number estimation in asymptomatic familial amyotrophic
lateral sclerosis. Suppl Clin Neurophysiol 2009; 60:163-169.
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neurophysiological criteria used in the diagnosis of motor neuron disease. J Neurol
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and neurophysiological measurements. Amyotroph Lateral Scler Other Motor
Neuron Disord 2005; 6:202-212.
29. Cedarbaum JM, Stambler N, Malta E, Fuller C, Hilt D, Thurmond B, Nakanishi A.
The ALSFRS-R: a revised ALS functional rating scale that incorporates
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Sci 1999; 169:13-21.
30. Miller RG, Jackson CE, Kasarskis EJ, England JD, Forshew D, Johnston W, Kalra
S, Katz JS, Mitsumoto H, Rosenfeld J, Shoesmith C, Strong MJ, Woolley SC.
Practice parameter update: The care of the patient with amyotrophic lateral
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31. Shefner JM, Watson ML, Simionescu L, Caress JB, Burns TM, Maragakis NJ,
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number estimation as an outcome measure in ALS. Neurology 2011; 77:235-241.
32. de CM, Scotto M, Lopes A, Swash M. Quantitating progression in ALS. Neurology
2005; 64:1783-1785.
33. Tarulli AW, Garmirian LP, Fogerson PM, Rutkove SB. Localized muscle
impedance abnormalities in amyotrophic lateral sclerosis. J Clin Neuromuscul Dis
2009; 10:90-96.
34. Pinto S, Geraldes R, Vaz N, Pinto A, de CM. Changes of the phrenic nerve motor
response in amyotrophic lateral sclerosis: longitudinal study. Clin Neurophysiol
2009; 120:2082-2085.
35. Steinacker P, Hendrich C, Sperfeld AD, Jesse S, von Arnim CA, Lehnert S, Pabst
A, Uttner I, Tumani H, Lee VM, Trojanowski JQ, Kretzschmar HA, Ludolph A,
Neumann M, Otto M. TDP-43 in cerebrospinal fluid of patients with frontotemporal
lobar degeneration and amyotrophic lateral sclerosis. Arch Neurol 2008; 65:1481-
1487.
36. de CM, Swash M. Amyotrophic lateral sclerosis: an update. Curr Opin Neurol
2011; 24:497-503.
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37. Sussmuth SD, Sperfeld AD, Hinz A, Brettschneider J, Endruhn S, Ludolph AC,
Tumani H. CSF glial markers correlate with survival in amyotrophic lateral
sclerosis. Neurology 2010; 74:982-987.
38. Wilson ME, Boumaza I, Lacomis D, Bowser R. Cystatin C: a candidate biomarker
for amyotrophic lateral sclerosis. PLoS One 2010; 5:e15133.
39. Mitchell RM, Simmons Z, Beard JL, Stephens HE, Connor JR. Plasma biomarkers
associated with ALS and their relationship to iron homeostasis. Muscle Nerve 2010;
42:95-103.
40. Turner MR, Kiernan MC, Leigh PN, Talbot K. Biomarkers in amyotrophic lateral
sclerosis. Lancet Neurol 2009; 8:94-109.
41. Neuromuscular Ultrasound. Philadelphia: Elsevier; 2011.
42. Heckmatt JZ, Leeman S, Dubowitz V. Ultrasound imaging in the diagnosis of
muscle disease. J Pediatr 1982; 101:656-660.
43. Buchberger W, Schon G, Strasser K, Jungwirth W. High-resolution ultrasonography
of the carpal tunnel. J Ultrasound Med 1991; 10:531-537.
44. Cartwright MS, Brown ME, Eulitt P, Walker FO, Lawson VH, Caress JB.
Diagnostic nerve ultrasound in Charcot-Marie-Tooth disease type 1B. Muscle
Nerve 2009; 40:98-102.
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45. Reimers CD, Fleckenstein JL, Witt TN, Muller-Felber W, Pongratz DE. Muscular
ultrasound in idiopathic inflammatory myopathies of adults. J Neurol Sci 1993;
116:82-92.
46. Beekman R, Van Den Berg LH, Franssen H, Visser LH, van Asseldonk JT, Wokke
JH. Ultrasonography shows extensive nerve enlargements in multifocal motor
neuropathy. Neurology 2005; 65:305-307.
47. Kamala D, Suresh S, Githa K. Real-time ultrasonography in neuromuscular
problems in children. J Clin Ultrasound 1985; 13:465-468.
48. Heckmatt JZ, Pier N, Dubowitz V. Assessment of quadriceps femoris muscle
atrophy and hypertrophy in neuromuscular disease in children. J Clin Ultrasound
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49. Reimers CD, Schlotter B, Eicke BM, Witt TN. Calf enlargement in neuromuscular
diseases: a quantitative ultrasound study in 350 patients and review of the literature.
J Neurol Sci 1996; 143:46-56.
50. Arts IM, van Rooij FG, Overeem S, Pillen S, Janssen HM, Schelhaas HJ, Zwarts
MJ. Quantitative muscle ultrasonography in amyotrophic lateral sclerosis.
Ultrasound Med Biol 2008; 34:354-361.
51. Misawa S, Noto Y, Shibuya K, Isose S, Sekiguchi Y, Nasu S, Kuwabara S.
Ultrasonographic detection of fasciculations markedly increases diagnostic
sensitivity of ALS. Neurology 2011.
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52. Arts IM, Overeem S, Pillen S, Schelhaas HJ, Zwarts MJ. Muscle ultrasonography to
predict survival in amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry
2010.
53. Arts IM, Overeem S, Pillen S, Jurgen SH, Zwarts MJ. Muscle changes in
amyotrophic lateral sclerosis: A longitudinal ultrasonography study. Clin
Neurophysiol 2010.
54. Lee CD, Song Y, Peltier AC, Jarquin-Valdivia AA, Donofrio PD. Muscle
ultrasound quantifies the rate of reduction of muscle thickness in amyotrophic
lateral sclerosis. Muscle Nerve 2010; 42:814-819.
55. Konagaya M, Kato T, Sakai M, Kuru S, Matsuoka Y, Konagaya Y, Hashizume Y,
Tabira T. A clinical and pathological study of a Japanese case of Amyotrophic
Lateral Sclerosis/Parkinsonism-Dementia Complex with family history. J Neurol
2003; 250:164-170.
56. Wiesler ER, Chloros GD, Cartwright MS, Smith BP, Rushing J, Walker FO. The
use of diagnostic ultrasound in carpal tunnel syndrome. J Hand Surg [Am ] 2006;
31:726-732.
57. Zaidman CM, Al-Lozi M, Pestronk A. Peripheral nerve size in normals and patients
with polyneuropathy: an ultrasound study. Muscle Nerve 2009; 40:960-966.
58. Martinoli C, Schenone A, Bianchi S, Mandich P, Caponetto C, Abbruzzese M,
Derchi LE. Sonography of the median nerve in Charcot-Marie-Tooth disease. AJR
Am J Roentgenol 2002; 178:1553-1556.
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59. Watanabe T, Ito H, Sekine A, Katano Y, Nishimura T, Kato Y, Takeda J, Seishima
M, Matsuoka T. Sonographic evaluation of the peripheral nerve in diabetic patients:
the relationship between nerve conduction studies, echo intensity, and cross-
sectional area. J Ultrasound Med 2010; 29:697-708.
60. Swash M, Ingram D. Preclinical and subclinical events in motor neuron disease. J
Neurol Neurosurg Psychiatry 1988; 51:165-168.
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CHAPTER II
PERIPHERAL NERVE AND MUSCLE ULTRASOUND IN AMYOTROPHIC
LATERAL SCLEROSIS The following manuscript was published in the journal Muscle & Nerve September,
2011 and is reprinted with permission. Stylistic variations are due to requirements of the
journal. MS Cartwright performed the experiments, data analysis, and prepared the
manuscript. Drs. Walker and Caress acted in advisory and editorial capacities, and Ms.
Griffin assisted with statistical analyses.
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Peripheral Nerve and Muscle Ultrasound in Amyotrophic Lateral Sclerosis Michael S. Cartwright, MD; Francis O. Walker, MD; Leah P. Griffin, MS; James B. Caress, MD
1. Department of Neurology, Wake Forest University School of Medicine, Winston-Salem, NC 27157
2. Division of Public Health Sciences, Department of Biostatistics, Wake Forest University School of Medicine, Winston-Salem, NC 27157
Disclosure: Drs. Cartwright, Caress, and Walker, and Ms. Griffin have nothing to disclose. Financial Support: Dr. Cartwright had a Clinical Research Training Grant from the Muscular Dystrophy Association and has funding from the NIH/NINDS (1K23NS062892) to study neuromuscular ultrasound. Running Title: Ultrasound in ALS Contact: Michael S. Cartwright, MD Department of Neurology Wake Forest University School of Medicine Main Floor Reynolds Tower Winston-Salem, NC 27157 Phone: 336-716-5177 Fax: 336-716-7794 Email: [email protected]
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Abstract
Introduction: High-resolution ultrasound has been used to evaluate several
neuromuscular conditions, but it has only been used on a limited basis in ALS patients. It
has not been used to assess their peripheral nerves. This study was designed to use
neuromuscular ultrasound to investigate nerve cross-sectional area and muscle thickness
in ALS.
Methods: Twenty individuals with ALS and 20 matched controls underwent
neuromuscular ultrasound to measure the cross-sectional area of their median and sural
nerves and the thickness of their biceps/brachialis muscle complex.
Results: The cross-sectional area of the median nerve in the mid-arm was smaller in the
ALS group than controls (10.5mm2 vs. 12.7mm2, p=0.0023), but no difference was seen
in the sural nerve (4.5mm2 vs. 5.0mm2, p=0.1927). The ALS group also had thinner
biceps/brachialis than controls (2.1cm vs. 2.9cm, p=0.0007).
Discussion: Neuromuscular ultrasound demonstrates nerve and muscle atrophy in ALS
and should be further explored as a disease biomarker.
Key Words: Amyotrophic lateral sclerosis, ultrasound, median nerve, sural nerve, muscle
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Introduction
Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease for
which there is neither cure nor treatment to significantly slow the progressive weakness.
Multiple obstacles hinder the ability to study and effectively treat ALS, one of which is
the limited number of tests available to assist in the early diagnosis and monitoring of
disease progression. Diagnosis of ALS is not typically made until 9-10 months after the
onset of symptoms,1 and the diagnosis is based on history and clinical examination.
Excluding other causes of progressive weakness through the use of blood work, central
nervous system imaging, and electrodiagnostic studies helps support the diagnosis of
ALS.2 Monitoring disease progression can be done with manual strength testing,
assessment of forced vital capacity (FVC), the ALS functional rating scale (ALSFRS),
and motor unit number estimation (MUNE), but all of these techniques have limitations,
including lack of responsiveness, operator variability, and pain.3
Over the past decade, high-frequency diagnostic ultrasound of peripheral nerve and
muscle has emerged as a tool to assist in the evaluation of individuals with
neuromuscular conditions, and it has become known as neuromuscular ultrasound.4 This
technique has only been assessed on a limited basis in those with ALS, and the few
studies of neuromuscular ultrasound in ALS evaluated muscle and did not assess nerve
characteristics.5-8 In addition, there are surprisingly few studies of peripheral nerve
caliber and muscle thickness using other imaging modalities or macroscopic analysis at
autopsy in individuals with ALS.9 There exist reports of nerve root atrophy in ALS, but
the literature is sparse and does not examine nerve caliber in the limbs.10 Therefore, this
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study was undertaken to use neuromuscular ultrasound to compare nerve caliber and
muscle thickness in individuals with ALS and age and gender matched controls.
In other systemic conditions affecting the peripheral nerves, such as diabetes,
multifocal motor neuropathy, Charcot-Marie Tooth disease, and chronic inflammatory
demyelinating polyneuropathy, neuromuscular ultrasound has demonstrated increased
nerve cross-sectional area.11-14 It was unknown if a similar finding would be detected in
ALS, or if nerve cross-sectional area would be reduced because of progressive axon loss.
We hypothesized that muscle ultrasound would demonstrate atrophy.
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Materials and Methods
Participants
Prior to the collection of data, this study was approved by the Institutional Review
Board at Wake Forest University School of Medicine, and all participants provided
signed informed consent. Initially, 20 patients with “probable,” “laboratory-supported
probable,” or “definite” ALS based on Revised El Escorial Criteria were recruited.15
These participants were diagnosed with ALS by experienced ALS clinicians (MSC and
JBC), and each participant had extremity strength testing (performed by the diagnosing
physicians and graded on Medical Research Council scale), FVC (performed by a
respiratory therapist and recorded as “percent of predicted”), and ALSFRS (recorded as
the “global score”)16 on the same day the ultrasound was performed. The number of
months since the onset of symptoms, weight, height, and race were also recorded.
Once 20 participants with ALS were recruited and assessed, 20 age and gender
matched controls were recruited. The control group included friends and family of the
ALS participants and medical center employees. Controls were excluded if they reported
any symptoms referable to the nervous system. Controls underwent ultrasound and
strength testing, and their weight, height, and race were recorded.
Ultrasound
All 40 participants (20 with ALS and 20 controls) underwent neuromuscular
ultrasound, performed by the same physician (MSC). A Biosound MyLab 25 (Esaote
Group, Genoa, Italy) with an 18 MHz linear array transducer was used for each study.
The participants were in the supine or seated position, with the ultrasonographer facing
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the patient, and all imaging was performed bilaterally. First, the mid-point of the arm
was identified at the half-way mark between the medial epicondyle and the axilla, and the
median nerve was imaged at this site (Figure 2.1A). This point was selected for study
because the median nerve is commonly assessed with neuromuscular ultrasound,
reference values are available for the median nerve at this site,17 and it is an uncommon
site of entrapment. The transducer was placed so that a cross-sectional view of the
median nerve was obtained. The cross-sectional area of the nerve was measured using the
trace function on the ultrasound device and tracing along the hyperechoic rim of the
nerve, erring just to the inside of the rim (Figure 2.1B). This was performed three times,
and all three measurements were then averaged to obtain a final median nerve cross-
sectional area measurement. The right and left median nerves were recorded separately,
and the two were averaged to obtain a mean median nerve cross-sectional area for each
participant.
Figure 2.1. Image A demonstrates the transducer position used to visualize the median nerve in the mid-arm and obtain the ultrasound image shown in panel B. The arrow points to the median nerve (outlined in white), and the arrowhead points to the adjacent brachial artery. The “H” is placed over the humerus.
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Next, the sural nerve was assessed at 10 cm above the lateral malleolus (Figure 2.2A).
The transducer was again positioned to obtain a cross-sectional view of the nerve, and an
area measurement was obtained (Figure 2.2B). This was performed three times, and
mean values were recorded for each side. A total sural nerve mean cross-sectional area
was obtained by averaging both sides together. The sural nerve was selected because
there are reference values available and it is a pure sensory nerve that should not be
affected by ALS.18
Figure 2.2. Image A demonstrates the transducer position used to visualize the sural nerve and obtain the ultrasound image shown in panel B. The arrow points to the sural nerve (outlined in white), which is located between two superficial veins.
Finally, we returned to the mid-point of the arm to measure the thickness of the biceps
brachii and brachialis muscle complex. The transducer was placed over the anterior
portion of the mid-arm, with the elbow extended, to obtain a cross-sectional view of the
arm (Figure 2.3A). Using the straight line measuring function on the ultrasound device,
the thickness of the biceps/brachialis complex was measured from the most superficial
portion of the muscle to the hyperechoic reflection of the humerus (Figure 2.3B). Care
was taken to minimize pressure from the transducer on the muscle to avoid muscle
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compression. This measurement was repeated twice to obtain a mean value for each side,
and the two sides were averaged in each participant to obtain an overall mean
biceps/brachialis thickness value.
Figure 2.3. Image A demonstrates the probe position used to visualize the biceps/brachialis muscle complex shown in panel B. The superficial extent of the muscle and the echogenic reflection from the humerus are marked with plus signs (+).
Statistical Analyses
Descriptive statistics include means and ranges for continuous measures and counts
and percentages for categorical measures. All statistical tests were two-sided, and
significance was determined at the 0.05 probability level. Comparisons between the ALS
and control groups were done with two-tailed t-tests for continuous variables and chi-
squared tests for categorical variables. Pearson product-moment correlation coefficients
were calculated to determine correlation between ultrasonographic parameters and
strength testing, FVC, ALSFRS, and months since disease onset.
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Results
Twenty participants with ALS and 20 controls were included in this study. No
significant differences in age, gender, race, height, weight, or body mass index (BMI)
were noted between the two groups (Table 2.1). The 20 individuals with ALS had
symptoms for an average of 25.1 months prior to enrollment in this study, and their mean
FVC was 62.3% and the ALSFRS was 30.5 (Table 2.2).
Table 2.1 Demographics Variable Controls
n = 20 ALS Patients
n = 20 p-value
Mean Age (range) 58.1 (42 – 76) 58.4 (40 – 71) 0.9231 Gender (male) 10 (50%) 10 (50%) 1.0000 Race (Caucasian) 20 (100%) 19 (95%) 0.3112 Mean Height (range) 66.7 (61 – 75) 67.1 (61 – 71) 0.7140 Mean Weight (range) 171.6 (135 – 235) 162.3 (117 – 212) 0.2984 Mean BMI (range) 27.3 (20.9 – 39.5) 25.4 (19.3 – 33.8) 0.2090
Table 2.2 ALS Participant Characteristics Variable Mean (range) FVC (%) 62.3 (20 – 99)
ALSFRS 30.5 (12 – 48)
Months Since Onset 25.1 (6 – 60)
Significant differences were found when comparing median nerve cross-sectional area
and biceps/brachialis thickness between the two groups, and these differences were found
when using just the left arm and the total values for each individual (Table 2.3). The total
median nerve area was larger in controls (12.7 mm2 vs. 10.5 mm2, p = 0.0023), and the
total muscle thickness was greater in controls (2.9 cm vs. 2.1 cm, p = 0.0007). No
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differences were noted when comparing the sural nerve cross-sectional area between the
two groups (Table 2.3).
Table 2.3 Ultrasonographic Comparisons between ALS Patients and Controls. Variable Controls
n = 20 Mean (range)
ALS Patients n = 20
Mean (range)
p-value
Left Median Area (mm2) 12.6 (9.5 – 15.0) 9.9 (7.0 – 15.0) 0.0004 Average Median Area (mm2) 12.7 (9.3 – 16.3) 10.5 (7.0 – 15.5) 0.0023 Left Sural Area (mm2) 5.0 (3.0 – 8.0) 4.5 (2.0 – 7.0) 0.1858 Average Sural Area (mm2) 5.0 (3.0 – 8.0) 4.5 (2.5 – 6.5) 0.1927 Left Muscle Thickness (cm) 3.0 (1.7 – 4.2) 2.0 (0.4 – 3.7) 0.0001 Average Muscle Thickness (cm) 2.9 (2.0 – 4.3) 2.1 (0.4 – 3.8) 0.0007
Statistically significant correlation was only seen when comparing the thickness of the
biceps/brachialis muscle complex to the MRC-graded strength testing of the biceps
muscle (r=0.5062, p=0.0228), although the correlation between the cross-sectional area
of the left median nerve and the strength of the abductor pollicis brevis (APB) muscle
approached statistical significance (r=0.4206, p=0.0648). No significant correlation was
seen when comparing the total median nerve cross-sectional area to the FVC, ALSFRS or
months since onset, or when comparing the total biceps/brachialis thickness to the FVC,
ALSFRS or months since onset (Table 2.4).
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Table 2.4 Correlation Between Ultrasonographic Parameters and Other Variables Comparison Correlation
Coefficient p-value
Average Median Area vs. FVC -0.0075 0.9750 Average Median Area vs. ALSFRS 0.1280 0.5908 Left Median Area vs. Left APB strength 0.4206 0.0648 Muscle Thickness vs. Biceps Strength 0.5062 0.0228 Average Muscle Thickness vs. FVC 0.3721 0.1062 Average Muscle Thickness vs. ALSFRS 0.3325 0.1520 Average Median Area vs. Months since onset -0.3106 0.1825 Average Muscle Thickness vs Months since onset -0.0806 0.7356
Discussion
This study compared nerve cross-sectional area measurements in individuals with
ALS to age and gender matched controls. The 20 individuals in the control group
matched well with the ALS group, with no significant differences in the groups with
respect to age, gender, race, height, weight, or BMI. When the ultrasonographic cross-
sectional area of the median nerve was compared between the two groups, those with
ALS had significantly smaller median nerves than controls (12.7 mm2 in controls vs. 10.5
mm2 in ALS, p=0.0023), but no difference was noted in sural nerve cross-sectional area
between the groups. The cause of the median nerve difference is not definitely known,
but the most likely explanation is that progressive motor axon loss, which occurs in ALS,
results in mild atrophy of the nerve. Interestingly, a previous study to establish reference
values for median nerve cross-sectional area found an average area of 8.9 mm2 at the
mid-arm, which is much smaller than the median nerve area of controls in this study and
smaller than the area in those with ALS.17 At least some of this discrepancy may be
explained by age differences between the studies. The mean age in this study was 13
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years older than in the study to establish reference values (mean age of 58 years in the
current study and 45 in the reference values study), and it has been shown that median
nerve area positively correlates with age.17 It is also possible that differences in
ultrasound devices, transducer frequency, or examiner technique could have contributed
to the differences in median nerve cross-sectional area between the two studies.
The other significant difference between the two groups occurred when the thickness
of the biceps/brachialis muscle complex was compared; the control group had thicker
muscles (2.9 cm vs. 2.1 cm, p=0.0007). A difference in muscle thickness between the
two groups was expected, because those with ALS demonstrate visible muscle atrophy.
It was unknown how large a difference would be detected by assessing just one muscle
group, because there is variability in the body region affected in individuals with ALS.
The difference noted in this study was statistically significant, and those with ALS had
biceps/brachialis thickness less than 75% that of controls. This difference would likely
be even more striking if muscle volume, rather than thickness, was measured.
One objective of this study was to determine if neuromuscular ultrasound revealed
peripheral nerve or muscle abnormalities obvious enough to assist in the diagnosis of
ALS. While statistically significant differences were seen in median nerve cross-
sectional area and biceps/brachialis muscle thickness between the ALS and control
groups, the absolute differences were either not unique to ALS or difficult to apply as
universal diagnostic criteria. For example, decreased muscle thickness can be seen in
other neuropathic and chronic myopathic conditions, and the affect of age, body habitus,
and other factors on nerve area prohibits the establishment of a single cut-off level for the
detection of median nerve atrophy in ALS. Despite these limitations and the inability to
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establish universal diagnostic criteria, neuromuscular ultrasound can assist in the
diagnosis of ALS now that the typical findings are known. Neuromuscular ultrasound
findings consistent with ALS include normal to decreased nerve cross-sectional area (as
opposed to nerve enlargement described in demyelinating polyneuropathies12), muscle
atrophy (as opposed to muscle edema and swelling, which have been described in acute
inflammatory myopathies19), and the presence of fasciculations.5
The second objective was to initiate exploration of neuromuscular ultrasound as a
surrogate marker of disease progression in ALS. While this study did not have a
longitudinal component to directly address this issue, we showed that both median nerve
cross-sectional area and muscle thickness are decreased in those with ALS, indicating
they could be further explored as surrogate markers of disease progression. In addition,
thickness of the biceps/brachialis complex correlated with strength testing, which has
been used as a marker of disease progression. There is one recent study in which muscle
ultrasound was examined over 6 months as a potential marker of disease progression in
22 individuals with ALS, and the authors concluded there was too much variability in
their measures for it to serve as an effective marker of disease progression.8 However,
their study had limitations, including the use of two different ultrasound devices, not all
participants being assessed at all time points, repeated measures statistical analyses not
being performed, use of a composite ultrasound score from multiple different muscle
groups (not including a distal intrinsic hand or foot muscle), and a focus on the presence
of fasciculations. Conversely, another recent study of muscle ultrasound in spinal
muscular atrophy showed that calculating a ratio of echogenicity in subcutaneous tissue
compared to muscle could discriminate between degrees of disease severity, and the
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authors concluded that muscle ultrasound could potentially serve as a marker of
progression in this motor neuron disease.20 Given the results in our study, as well as the
limitations in other studies, muscle ultrasound as a surrogate marker of disease
progression deserves further investigation, and nerve cross-sectional area could also be
studied in a longitudinal manner. The likely small changes in nerve cross-sectional area
over time would make it necessary to closely standardize the ultrasonographic
examination, and it may be helpful to study a larger nerve, such as the sciatic.
While some limitations occurred in our study, including small sample size, the
ultrasonographer not being blinded to participant group, no measures of muscle or nerve
echotexture, and a lack of longitudinal data collection, it did permit an initial
investigation into neuromuscular ultrasound measurements in ALS and demonstrated
nerve and muscle atrophy in ALS compared to controls. Future investigations using
neuromuscular ultrasound to evaluate individuals with ALS are warranted. These could
include longitudinal data, study of other muscles such as the diaphragm and distal
extremity muscles, muscle volume measurements, and quantitative assessments of nerve
and muscle echotexture.
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Reference List
1. Kraemer M, Buerger M, Berlit P. Diagnostic problems and delay of diagnosis in
amyotrophic lateral sclerosis. Clin Neurol Neurosurg 2010; 112:103-105.
2. Shook SJ, Pioro EP. Racing against the clock: recognizing, differentiating,
diagnosing, and referring the amyotrophic lateral sclerosis patient. Ann Neurol
2009; 65 Suppl 1:S10-S16.
3. de Carvalho M, Costa J, Swash M. Clinical trials in ALS: a review of the role of
clinical and neurophysiological measurements. Amyotroph Lateral Scler Other
Motor Neuron Disord 2005; 6:202-212.
4. Walker FO, Cartwright MS, Wiesler ER, Caress J. Ultrasound of nerve and muscle.
Clin Neurophysiol 2004; 115:495-507.
5. Arts IM, van Rooij FG, Overeem S, Pillen S, Janssen HM, Schelhaas HJ, Zwarts
MJ. Quantitative muscle ultrasonography in amyotrophic lateral sclerosis.
Ultrasound Med Biol 2008; 34:354-361.
6. Arts IM, Overeem S, Pillen S, Schelhaas HJ, Zwarts MJ. Muscle ultrasonography to
predict survival in amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry
2010.
7. Yoshioka Y, Ohwada A, Sekiya M, Takahashi F, Ueki J, Fukuchi Y.
Ultrasonographic evaluation of the diaphragm in patients with amyotrophic lateral
sclerosis. Respirology 2007; 12:304-307.
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38
8. Arts IM, Overeem S, Pillen S, Jurgen SH, Zwarts MJ. Muscle changes in
amyotrophic lateral sclerosis: A longitudinal ultrasonography study. Clin
Neurophysiol 2010.
9. Hanyu N, Oguchi K, Yanagisawa N, Tsukagoshi H. Degeneration and regeneration
of ventral root motor fibers in amyotrophic lateral sclerosis. Morphometric studies
of cervical ventral roots. J Neurol Sci 1982; 55:99-115.
10. Wohlfart G, Swank R. Pathology of amyotrophic lateral sclerosis. Arch Neurol
Psychiat 1941; 46:783-799.
11. Watanabe T, Ito H, Sekine A, Katano Y, Nishimura T, Kato Y, Takeda J, Seishima
M, Matsuoka T. Sonographic evaluation of the peripheral nerve in diabetic patients:
the relationship between nerve conduction studies, echo intensity, and cross-
sectional area. J Ultrasound Med 2010; 29:697-708.
12. Beekman R, Van Den Berg LH, Franssen H, Visser LH, van Asseldonk JT, Wokke
JH. Ultrasonography shows extensive nerve enlargements in multifocal motor
neuropathy. Neurology 2005; 65:305-307.
13. Cartwright MS, Brown ME, Eulitt P, Walker FO, Lawson VH, Caress JB.
Diagnostic nerve ultrasound in Charcot-Marie-Tooth disease type 1B. Muscle
Nerve 2009; 40:98-102.
14. Zaidman CM, Al-Lozi M, Pestronk A. Peripheral nerve size in normals and patients
with polyneuropathy: an ultrasound study. Muscle Nerve 2009; 40:960-966.
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39
15. Brooks BR, Miller RG, Swash M, Munsat TL. El Escorial revisited: revised criteria
for the diagnosis of amyotrophic lateral sclerosis. Amyotroph Lateral Scler Other
Motor Neuron Disord 2000; 1:293-299.
16. Cedarbaum JM, Stambler N, Malta E, Fuller C, Hilt D, Thurmond B, Nakanishi A.
The ALSFRS-R: a revised ALS functional rating scale that incorporates
assessments of respiratory function. BDNF ALS Study Group (Phase III). J Neurol
Sci 1999; 169:13-21.
17. Cartwright MS, Shin HW, Passmore LV, Walker FO. Ultrasonographic Reference
Values for Assessing the Normal Median Nerve in Adults. J Neuroimaging 2008.
18. Cartwright MS, Passmore LV, Yoon JS, Brown ME, Caress JB, Walker FO. Cross-
sectional area reference values for nerve ultrasonography. Muscle Nerve 2008;
37:566-571.
19. Weber MA. Ultrasound in the inflammatory myopathies. Ann N Y Acad Sci 2009;
1154:159-170.
20. Wu JS, Darras BT, Rutkove SB. Assessing spinal muscular atrophy with
quantitative ultrasound. Neurology 2010; 75:526-531.
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CHAPTER III
DISCUSSION
This is the seventh published study in which neuromuscular ultrasound was used
specifically to evaluate individuals with ALS (Table).1-7 Of the previous studies, five
used high-resolution ultrasound to evaluate peripheral muscle size, echotexture, and/or
fasciculations, one studied bulbar musculature and function, and one assessed diaphragm
characteristics. None of the previous studies assessed ultrasonographic characteristics of
peripheral nerves.
Muscle Ultrasound in ALS
In this study, the thickness of the biceps brachii and brachialis muscle complex was
measured by placing the ultrasound transducer at the anterior portion of the mid-arm to
obtain a cross-sectional view of the biceps/brachialis muscle complex. The thickness of
this complex was obtained using the measuring tool function on the ultrasound device,
and care was taken to avoid compressing the tissue as the image was obtained. Those
with ALS had a mean muscle thickness of 2.0 cm in the left arm and 2.1 cm when the left
and right arms were averaged, whereas the controls had a left arm thickness of 3.0 cm
and a left/right average thickness of 2.9 cm. In addition to being statistically significant
(p = 0.0007), the difference seen in muscle thickness between those with ALS and
controls was large enough to visualize without relying on overly sensitive measurement
techniques, as the muscle thickness in ALS patients was less than 75% the thickness seen
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in controls. This was expected, as ALS causes visible atrophy, and four previous studies
have used ultrasound to demonstrate some degree of muscle atrophy in ALS.2, 4-6 The
current study showed a significant correlation between biceps/brachialis thickness and
biceps strength (0.5062, p = 0.0228), but no correlation between muscle thickness and
ALSFRS-R or FVC.
Table 3.1. Neuromuscular Ultrasound Studies in ALS
Year Author Was Extremity Muscle Atrophy Present?
Were Fasciculations Assessed?
Other Assessments
2011 Misawa S et al.7 Not studied Yes; US was more sensitive than exam and EMG
None
2011 Arts IM et al.5 Yes; muscle size declined over time
Yes Muscle EI increased over time
2011 Arts IM et al.6 Yes; muscle size declined over time
Yes Muscle EI increased over time
2010 Lee CD et al.4 Yes; muscle size declined over time
Yes Muscle EI without change
2010 Tamburrini et al.3 Not studied No Swallowing evaluated
2008 Arts IM et al.2 Yes Yes Muscle EI increased at baseline
2007 Yoshioka Y et al.1 Not studied No Diaphragm paralysis noted
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None of the previous studies of muscle thickness used matched controls, but two did
assess the progression of atrophy over time.4, 6 Both studies with longitudinal
components showed that muscle thickness decreased significantly in those with ALS over
several months. For example, Lee et al. showed the biceps/brachialis complex decreased
in thickness by 0.66 mm per month in those with ALS (p = 0.0014), and this correlated
with a summed strength score, but not the ALSFRS.4 In the study by Arts et al. the
progressive atrophy did not correlate with a summed strength score nor the ALSFRS.6 In
addition to assessing the biceps/brachialis complex, these previous studies also assessed
the thickness of the sternocleidomastoid, wrist flexor, wrist extensor, quadriceps, and
tibialis anterior muscles.
After completing our study, we were encouraged by the ability to detect muscle
atrophy with neuromuscular ultrasound, but it was clear that several methodological
changes could be made to improve the sensitivity of ultrasonographic measures of muscle
thickness. First, inclusion of distal muscles in the hands and feet, which are often
affected early in ALS, would be beneficial. Second, extreme precision needs to be
exercised in marking and measuring the exact same site each time, and this could be
accomplished with a small, permanent skin marking to guide transducer placement in
subsequent visits. Third, ultrasound settings, including gain, time gain compensation,
depth, and focus need to be standardized and applied in the same manner for each muscle
studied. Finally, it may be more sensitive, and less prone to error based on transducer
position, if muscle area or even volume was calculated, instead of depth, as the depth can
be changed with subtle pressured applied to the transducer.
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In this study the decision was made to not assess echotexture, but the four previous
studies did evaluate muscle echointensity using gray-scale analyses. In those studies, the
ultrasound images were downloaded and then assessed using software such as Adobe
Photoshop to obtain mean gray-scale numbers (termed echointensity), with a range of 0
(black) to 255 (white). Two studies, both by the same group, generated results that
suggested echointensity could be used to prognosticate and accurately follow ALS
patients over time,5, 6 but one study showed no trend in echointensity over 6 months.4
Our experience with echotexture analysis of muscle ultrasound images is that it is
variable, and it changes based upon factors such as transducer type, angle of insonation,
gain, and depth, and therefore it is a difficult technique for analyzing subtle changes over
time. Recent studies have confirmed this, and demonstrated that transducer selection can
significantly affect echotexture analyses.8 However, gray-scale analysis is a field that is
evolving, and future developments in image processing and analysis could improve the
reliability of muscle echotexture measurements.
The final use of muscle ultrasound in the assessment of those with ALS has been to
detect fasciculations. The first report of ultrasound for the detection of fasciculations was
in 1988, and it was demonstrated to be a sensitive technique as it allowed for scanning of
multiple muscles, painlessly and efficiently.9 Since then other studies have confirmed the
sensitivity of ultrasound for the detection fasciculations,2, 10 and very recent data from
Misawa et al. have demonstrated that the addition of ultrasound for the detection of
fasciculations greatly increases the sensitivity of the Awaji criteria for the diagnosis of
ALS (Figure 3.1).7 Taken together, these studies suggest that muscle ultrasound is
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sensitive for the detection of fasciculations and that it greatly increases the diagnostic
sensitivity of the currently used diagnostic criteria.
Figure 3.1. This shows that the proportion of people in the “probable” and “definite” category by El Escorial (EE) criteria was 48% and this increased to 79% when the Awaji criteria, along with the use of EMG and ultrasound, was applied.7
Nerve Ultrasound in ALS
Unlike muscle ultrasound, nerve ultrasound has not been previously examined as a
diagnostic technique in individuals with ALS. In this current study, ultrasound was used
to examine the cross-sectional area of the median nerve in the mid-portion of the upper
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arm. In 20 individuals with ALS, the mean cross-sectional area of the median nerve was
10.5 mm2, which was significantly smaller (p = 0.0023) than the 12.7 mm2 mean seen in
20 age and sex matched controls. In addition, no difference in cross-sectional area was
seen when the sural nerve was compared between these two groups (p = 0.1927). While
the median nerve in the upper arm was statistically significantly smaller in those with
ALS, the absolute difference in size between the two groups was not large and there was
overlap in the range of nerve sizes seen between the two groups. This indicates that
neuromuscular ultrasound as a tool to detect nerve atrophy is unlikely to be sensitive
enough to assist in the diagnosis of ALS. However, this finding is quite helpful because
other conditions that mimic ALS, such as multifocal motor neuropathy and chronic
inflammatory demyelinating polyneuropathy, are associated with increased cross-
sectional area of peripheral nerves.11, 12 It should also be noted that median nerve area
did not correlate with ALSFRS or FVC, but it did approach statistical significance in
correlating with strength of the abductor pollicis brevis muscle (0.4206, p = 0.0648).
Neuromuscular Ultrasound in the Diagnosis of ALS
Given the findings of the current study, as well as the results of the previous studies
listed in Table 3.1, neuromuscular ultrasound is a technique that can be considered to
improve diagnostic accuracy in the evaluation of individuals suspected to have ALS. If
used, based on the current state of knowledge, the highest yield parameters would be to
assess nerve cross-sectional area and muscle to detect fasciculations. Specifically,
neuromuscular ultrasound should first be used to assess the extremity in which weakness
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initially occurred or is most pronounced. In this extremity, the major nerve branches
(median, ulnar, and radial in the arm and sciatic, tibial, and fibular in the leg) should be
scanned with the transducer positioned to obtain cross-sectional images. Several
measurements should be obtained along the length of each nerve, and if the upper
extremity is assessed the brachial plexus should be imaged as well, as it is often enlarged
in multifocal motor neuropathy and chronic inflammatory demyelinating
polyneuropathy.11, 13 Next, at least one distal and one proximal muscle should be
assessed in the extremity of interest for the presence of fasciculations. The transducer
should be oriented to obtain a cross-sectional view of a large segment of the muscle and
imaging of each region should last for at least 10 seconds. Finally, the other extremities,
as well as the genioglossus and thoracic paraspinal muscles, should be assessed in the
same manner, looking for the presence of fasciculations. It may be appropriate to
perform the ultrasonographic evaluation first, as it can then be used to guide the
electrodiagnostic study and perhaps limit the number of electrical stimulations from
nerve conduction studies and EMG needle sticks needed.
Future Directions
Further exploration of neuromuscular ultrasound for the diagnosis, prognosis, and
tracking of disease progression in ALS is needed, and a single large, prospective, multi-
site study could address several questions. One potential design would be to invite all
individuals referred to select ALS Center for possible ALS to undergo a neuromuscular
ultrasound evaluation (Figure 3.2). Close to 10% of those referred to ALS Centers are
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ultimately diagnosed with an ALS mimic,14 so this design would enroll individuals with
ALS and those with conditions that mimic ALS. After the typical evaluation was
performed, including a thorough history, physical examination, and electrodiagnostic
evaluation, the participant would undergo a neuromuscular ultrasound examination by a
sonographer blinded to all clinical and electrodiagnostic information. The neuromuscular
ultrasound examination would be standardized and include peripheral nerve cross-
sectional areas at several sites in the weakest extremity; precise muscle size
measurements at distal and proximal sites in the arms and legs (area instead of depth,
when feasible); evaluation for fasciculations in the genioglossus, paraspinals, arms and
legs; and diaphragm thickness and excursion. Those with confirmed ALS would then be
followed every 3 months for the next 2 years with serial muscle size measurements of the
distal and proximal upper and lower extremity muscles. This design would allow for
comparison of all parameters between those with ALS and those with ALS mimics,
which is a design that would prevent the introduction of spectrum bias. Prospective data
collection and blinding of the ultrasonographer would also fulfill STARD criteria for the
complete and accurate reporting of tests of diagnostic accuracy.15 It would also allow
creation of statistical models to determine which neuromuscular ultrasound parameters
best predict prognosis. Finally, serial measurements of muscle size would permit
calculation of typical atrophy rates, which could then be used as surrogate markers of
disease progression. If this type of study was performed at approximately 10 ALS
Centers it could likely recruit at least 100 participants in a year,16 and a multi-site design
would allow for comparison of neuromuscular ultrasound techniques across sites, since
components of ultrasonographic examinations are operator dependent.
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Figure 3.2. Study design to assess the diagnostic accuracy, prognostic ability, and usefulness as a surrogate marker of disease progression of neuromuscular ultrasound in individuals with ALS.
US
ALS confirmed through routine clinical examination
Diagnosed with ALS mimic
Individuals referred for possible ALS
2 year follow-up; muscle US every 3 months
Nerve area, muscle size, and presence of fasciculations compared
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REFERENCES
1. Yoshioka Y, Ohwada A, Sekiya M, Takahashi F, Ueki J, Fukuchi Y.
Ultrasonographic evaluation of the diaphragm in patients with amyotrophic lateral
sclerosis. Respirology 2007; 12:304-307.
2. Arts IM, van Rooij FG, Overeem S, Pillen S, Janssen HM, Schelhaas HJ, Zwarts
MJ. Quantitative muscle ultrasonography in amyotrophic lateral sclerosis.
Ultrasound Med Biol 2008; 34:354-361.
3. Tamburrini S, Solazzo A, Sagnelli A, Del VL, Reginelli A, Monsorro M, Grassi R.
Amyotrophic lateral sclerosis: sonographic evaluation of dysphagia. Radiol Med
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4. Lee CD, Song Y, Peltier AC, Jarquin-Valdivia AA, Donofrio PD. Muscle
ultrasound quantifies the rate of reduction of muscle thickness in amyotrophic
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5. Arts IM, Overeem S, Pillen S, Schelhaas HJ, Zwarts MJ. Muscle ultrasonography to
predict survival in amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry
2010.
6. Arts IM, Overeem S, Pillen S, Jurgen SH, Zwarts MJ. Muscle changes in
amyotrophic lateral sclerosis: A longitudinal ultrasonography study. Clin
Neurophysiol 2010.
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7. Misawa S, Noto Y, Shibuya K, Isose S, Sekiguchi Y, Nasu S, Kuwabara S.
Ultrasonographic detection of fasciculations markedly increases diagnostic
sensitivity of ALS. Neurology 2011.
8. Hobson-Webb LD, Mhoon JT, Juel VC. Effect of transducer frequency on muscle
luminosity ratio. Muscle Nerve 2011; 44:612-613.
9. Reimers CD, Muller W, Schmidt-Achert M, Heldwein W, Pongratz DE.
[Sonographic detection of fasciculations]. Ultraschall Med 1988; 9:237-239.
10. Scheel AK, Toepfer M, Kunkel M, Finkenstaedt M, Reimers CD. Ultrasonographic
assessment of the prevalence of fasciculations in lesions of the peripheral nervous
system. J Neuroimaging 1997; 7:23-27.
11. Beekman R, Van Den Berg LH, Franssen H, Visser LH, van Asseldonk JT, Wokke
JH. Ultrasonography shows extensive nerve enlargements in multifocal motor
neuropathy. Neurology 2005; 65:305-307.
12. Zaidman CM, Al-Lozi M, Pestronk A. Peripheral nerve size in normals and patients
with polyneuropathy: an ultrasound study. Muscle Nerve 2009; 40:960-966.
13. Abrahams S, Goldstein LH, Simmons A, Brammer M, Williams SC, Giampietro V,
Leigh PN. Word retrieval in amyotrophic lateral sclerosis: a functional magnetic
resonance imaging study. Brain 2004; 127:1507-1517.
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14. Traynor BJ, Codd MB, Corr B, Forde C, Frost E, Hardiman O. Amyotrophic lateral
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15. Bossuyt PM, Reitsma JB, Bruns DE, Gatsonis CA, Glasziou PP, Irwig LM, Moher
D, Rennie D, de Vet HC, Lijmer JG. The STARD statement for reporting studies of
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16. Al-Chalabi A, Shaw PJ, Young CA, Morrison KE, Murphy C, Thornhill M, Kelly J,
Steen IN, Leigh PN, Ukmnd-Licals OB. Protocol for a double-blind randomised
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CURRICULUM VITAE
NAME: Michael S. Cartwright CURRENT ACADEMIC TITLE: Assistant Professor ADDRESS:
Department of Neurology, Reynolds Tower Wake Forest School of Medicine Winston-Salem, NC 27157 Phone: 336-716-5177 Fax: 336-716-2810 Email: [email protected] EDUCATION: 1994-1998 Wake Forest University Bachelor of Science in Biology Summa Cum Laude
Phi Beta Kappa
1998-2002 Wake Forest School of Medicine Doctor of Medicine Alpha Omega Alpha
2006-Present Wake Forest School of Medicine Master of Science in Health Science Research POSTDOCTORAL TRAINING:
2002-2003 Internship in Internal Medicine Wake Forest University Baptist Medical Center
2003-2005 Residency in Neurology
Wake Forest University Baptist Medical Center
2005-2006 Chief Residency in Neurology Wake Forest University Baptist Medical Center
2006-2008 MDA Clinical Research Training Fellowship Focus in Neuromuscular Disease Wake Forest University Baptist Medical Center PROFESSIONAL LICENSURE: 2006-Present State of North Carolina
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BOARD CERTIFICATION: 2007-Present Diplomat, American Board of Psychiatry and Neurology
2009-Present Diplomat, American Board of Electrodiagnostic Medicine (with recognition for scoring in top 10% on certification examination)
ACADEMIC APPOINTMENTS: 2006-2008 Instructor in Neurology Wake Forest School of Medicine 2008-Present Assistant Professor in Neurology Wake Forest School of Medicine 2010-Present Cross-appointment in Center for Worker Health Wake Forest School of Medicine 2011-Present Cross-appointment in Family Medicine, Sports Medicine Section Wake Forest School of Medicine EMPLOYMENT:
1993-2000 Tennis Instructor Rochester, MN Indoor and Outdoor Clubs
1996-1997 Teaching Assistant Aide
Wake Forest University
1996-1998 Academic Tutor Wake Forest University
PROFESSIONAL APPOINTMENTS AND ACTIVITIES: Ad hoc reviewer for:
• Prinses Beatrix Fonds, Funding Agency in the Netherlands • American Journal of Critical Care • Archives of Neurology • Archives of PMR • Atherosclerosis • BMC Medical Imaging • Clinical Neurology and Neurosurgery • Clinical Neurophysiology • Journal of Child Neurology • Journal of Neurology • Journal of the Peripheral Nervous System
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• Journal of Postgraduate Medicine • PLoS One • Muscle and Nerve
INSTITUTIONAL SERVICE:
1999-2002 Academic tutor for first and second year medical students 2000-2002 Student Identification and Recruitment Committee 2001-2008 AOA Executive Committee 2004-2005 Graduate Medical Education Committee 2005-2006 Chief Resident Committee
2008-2009 Dean’s Advisory Committee 2005-Present Neurology Residency Advisory Committee 2006-Present Medical School Admissions Interviewer 2006-Present Standardized Patient Assessment evaluator for medical students 2007-Present Core Mentoring Faculty Member for medical students 2007-Present WFUHS Translational Science Institute member 2009-Present WFUHS Center for Worker Health member 2009-Present WFUHS Intramural Research Support Committee ad hoc member 2009-Present WFU Neuroscience Faculty Member 2010-Present Translation Science Institute Scholar 2010-Present WFU Admissions and Premedical Relations Committee Member 2011-Present WFU Faculty Development Advisory Committee 2011-Present P&T Subcommittee – Standardized Order Sets
PROFESSIONAL MEMBERSHIP AND SERVICE:
2004-Present American Academy of Neurology (AAN), Member
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2004-Present American Association of Neuromuscular and Electrodiagnostic Medicine (AANEM), Member
2006-Present Huntington Study Group (HSG), Junior Investigator 2009-Present The Neuropathy Association, Member 2009-Present Western North Carolina Society for Neuroscience (WNCSN),
Executive Committee Clinical Councilor 2009-Present AANEM Neuromuscular Ultrasound Task Force 2010-Present AANEM Marketing Committee
HONORS AND AWARDS: Research
• 2009 AANEM President’s Research Initiative Award • 2002 G. Milton Shy AAN Clinical Research Award • 2002 Outstanding Scholarly Project Poster Teaching • Wake Forest Class of 2004 Resident Teaching Award
Scholarship • 2011 Best Doctors • 2011 Leading Physicians of the World • 2009 ABEM Top 10% Score on Certification Examination • 2007 ANA Junior Faculty Development Course Scholarship • 2002 WFSM Medical Alumni Association Excellence Award • 2002 WFSM Excellence in Neurology Student Award • 2002 AAN Annual Meeting Scholarship Recipient • 2001 Alpha Omega Alpha • 2000 WFSM Dewitt Cromer Cordell Scholarship • 1998 Phi Beta Kappa • 1996 WFU Carswell Scholarship • Dean’s List 1994-1998
PROFESSIONAL INTERESTS:
• Neuromuscular ultrasound • Polyneuropathy • Amyotrophic lateral sclerosis • Myasthenia gravis
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Current Research
1. Cartwright MS, Chloros G, Wiesler ER, Walker FO. Nerve ultrasound in carpal tunnel syndrome: a review of the literature.
2. Milligan CE, Cartwright MS, Oppenheim R, Delbono O, Caress JB. Early
changes in the spinal cord and neuromuscular junction with ALS.
3. Strowd R, Cartwright MS, Kapoor S, Siddiqui M. Intracranial hemorrhage following DBS.
4. Mohen S, Cartwright MS, Siddiqui M. Musculoskeletal complaints in
Parkinson’s Disease.
5. Cartwright MS, Reynolds PS, Lefkowitz D, Wilmshurst P, Nightingale S, Bettermann K, Argoff P. Migraine and right-to-left shunts: An AAN Clinical Guideline.
GRANTS: Active
2006-present NIH/NINDS RO1 NS049640-01 (Cudkowicz) A Clinical Trial of Ceftriaxone in Subjects with Amyotrophic Lateral Sclerosis Role: Co-investigator (enroll patients) PI: Cudkowicz
2007-present ALS Association Electrical Impedance Myography in ALS Role: Co-investigator (perform studies) PI: Rutkove
2008-present NIOSH R01OH009251 Work-relate Injuries in Migrant Poultry Workers Role: Co-investigator (5% effort, perform diagnostic studies) PI: S Quandt
2008-present ALS Association
ALS Biomarker Study Role: Co-investigator (enroll patients) PI: Cudkowicz
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2008-present NIH R21NS061084-01
CSF Indicators for Diagnosis and Disease Progression in ALS Role: Co-investigator (enroll patients)
PI: Milligan $275,000
2008-Present NINDS/NIH
1K23NS062892 Diagnostic Ultrasound for Focal Neuropathies Role: Principal Investigator (75% effort) $690,287
Completed
2006-2008 William E. Winter Clinical Research Training Fellowship Muscular Dystrophy Association Role: Principal Investigator (100% effort) $180,000
2007-2009 Translational Team Science Grant WFSM Translational Science Institute Amniotic Fluid Derived Stem Cell Therapy in a Canine Model of Duchenne Muscular Dystrophy Role: Co-investigator (performed studies) PI: MK Childers $125,000
2008-2010 Translational Team Science Grant WFSM Translational Science Institute Detection of Early Nervous System Changes in ALS Role: Co-investigator (enrolled patients, performed studies) PI: CE Milligan $125,000
2008-2010 NIH/NINDS
A clinical trial of lithium and riluzole in ALS Role: Co-investigator (enrolled patients) PI: Aggarwal
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BIBLIOGRAPHY:
Peer Reviewed Journals (* indicates the article was the focus of an editorial)
1. Caress JB, Becker CE, Cartwright MS, and Walker FO. Ultrasound in the diagnosis of ulnar neuropathy at the elbow. J Clin Neuromuscular Dis 2003;4:161-162.
2. * Caress JB, Cartwright MS, Donofrio PD, Peacock JE Jr. The clinical
features of 16 cases of stroke associated with administration of IVIG. Neurology 2003;60:1822-1824.
3. Cartwright MS, Jeffery DR, Nuss GR, Donofrio PD. Statin associated
exacerbation of myasthenia gravis. Neurology 2004;63:2188.
4. Walker FO, Cartwright MS, Wiesler ER, Caress JB. Ultrasound of nerve and muscle. Clin Neurophys 2004;115:495-507.
5. Cartwright MS, Donofrio PD, Ybema KD, Walker FO. Detection of a
brachial artery pseudoaneurysm using ultrasonography and EMG. Neurology 2005;65:649.
6. Gordon E, Cartwright M, Avasarala J. Neurocysticercosis causing obstruction
of CSF flow. Arch Neurol 2005:62:1018.
7. Cartwright MS, Reynolds PS. Intracerebral hemorrhage associated with over-the-counter inhaled epinephrine. Cerebrovasc Dis 2005;19:415-6.
8. Cartwright MS, McCarthy SC, Roach ES. Hemimegalencephaly and tuberous
sclerosis complex. Neurology 2005;64:1634.
9. Cartwright MS, Reynolds PS, Rodriguez ZM, Breyer WA, Cruz JM. Lumbar puncture experience among medical school graduates: the need for formal procedural skills training. Med Educ 2005;39:436-437.
10. Cartwright MS, Hickling WH, Roach ES. Ischemic stroke in an adolescent
with arterial tortuosity syndrome. Neurology 2006;67:360-1. 11. Wiesler ER, Chloros GD, Cartwright MS, Smith BP, Rushing J, Walker FO.
The use of diagnostic ultrasound in carpal tunnel syndrome. J Hand Surg [Am] 2006;31:726-32.
12. Wiesler ER, Chloros GD, Cartwright MS, Shin HW, Walker FO. Ultrasound
in the diagnosis of ulnar neuropathy at the cubital tunnel. J Hand Surg [Am] 2006;31:1088-93.
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13. Cartwright MS, Moore PS, Donofrio PD, Iskandar SS, Stratta RJ. Acute sensory neuropathy associated with rabbit anti-thymocyte globulin. Am J Transplant 2007;7:484-6.
14. Cartwright MS, Shin HW, Passmore LV, Walker FO. Ultrasonographic
findings of the normal ulnar nerve in adults. Arch Phys Med Rehabil 2007;88:394-6.
15. Jen JC, Klein A, Boltshauser E, Cartwright MS, Mamsa H, Baloh RW.
Prolonged hemiplegic episodes in children due to mutations in ATP1A2. J Neurol Neurosurg Psychiatry 2007;78:523-6.
16. Cartwright MS, Walker FO, Chloros GD, Wiesler ER, Campbell WW.
Diagnostic ultrasound for nerve transection. Muscle & Nerve 2007;35:796-9.
17. Cartwright MS, Jeffery DR, Lewis ZT, Koty PP, Stewart WT, Molnar I. Mitoxantrone for multiple sclerosis causing acute lymphoblastic leukemia. Neurology 2007;68:1630-1.
18. Yoon JS, Kim B, Kim SJ, Kim JM, Sim KH, Hong SJ, Walker FO, Cartwright
MS. Ultrasonographic measurements in cubital tunnel syndrome. Muscle & Nerve 2007;36:853-5.
19. Ginn SD, Cartwright MS, Chloros GD, Walker FO, Yoon JS, Wiesler ER.
Ultrasound in the diagnosis of a median neuropathy in the forearm. J Brachial Plex Periph Nerve Inj 2007;2:23.
20. Yoon JS, Kim BJ, Kim SJ, Kim JM, Hong SJ, Walker FO, Cartwright MS.
Ulnar nerve and cubital tunnel ultrasound in ulnar neuropathy at the elbow. Arch Phys Med Rehabil 2008;89(5):887-9.
21. * Cartwright MS, Passmore LV, Yoon JS, Brown ME, Caress JB, Walker FO.
Cross-sectional area reference values for nerve ultrasonography. Muscle & Nerve 2008;37(5):566-71.
22. Cartwright MS, Shin HW, Passmore LV, Walker FO. Ultrasonographic
reference values for assessing the normal median nerve in adults. J Neuroimaging 2009;19:47-51.
23. Yoon JS, Walker FO, Cartwright MS. Ultrasonographic swelling ratio in the
diagnosis of ulnar neuropathy at the elbow. Muscle & Nerve 2008;38:1231-5.
24. Cartwright MS, White D, Miller LM, Roach ES. Recurrent stroke in a child with incontinentia pigmenti. J Chil Neurol 2009;24:603-605.
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25. Caress JB, Hobson-Webb LD, Passmore LV, Finkbiner A, Cartwright MS. Case-control study of thromboembolic events associated with IV immunoglobulin. J Neurol 2009;256:339-342.
26. Cartwright MS, Brown ME, Eulitt P, Walker FO, Lawson VH, Caress JB.
Diagnostic nerve ultrasound in Charcot-Marie Tooth Type 1B. Muscle & Nerve 2009;40:98-102.
27. Chipman JN, Mott RT, Stanton CA, Cartwright MS. The Ultrasonographic
Tinel’s Sign. Muscle & Nerve 2009;40:1033-5.
28. White D, Rees CJ, Butler S, Cartwright MS. Positional dysphagia in Chiari malformation. ENT Journal 2010;89:318-9.
29. Yoon JS, Walker FO, Cartwright MS. Ulnar Neuropathy with Normal
Electrodiagnosis and Abnormal Nerve Ultrasound. Arch PM&R 2010; 91:318-20.
30. Kieburtz K, McDermott MP, Voss TS, The Dimebon in Subjects With
Huntington Disease (DIMOND) Investigators of the Huntington Study Group (Cartwright MS). A Randomized, Placebo-Controlled Trial of Latrepirdine in Huntington Disease. Arch Neurol 2010;67:154-160.
31. Strowd RE, Cartwright MS, Passmore LV, Ellis TL, Tatter SB, Siddiqui MS.
Weight change following deep brain stimulation for movement disorders. J Neurol 2010;257:1293-7.
32. Aggarwal SP, Zinman L, Simpson E, et al., the Northeast and Canadian
Amyotrophic Lateral Sclerosis consortia (Cartwright MS). Safety and efficacy of lithium in combination with riluzole for treatment of amyotrophic lateral sclerosis: a randomised, double-blind, placebo-controlled trial. Lancet Neurol 2010;9:481-8.
33. Strowd RE, Cartwright MS, Okun MS, Haq I, Siddiqui MS. Pseudobulbar
Affect: Prevalence and Quality of Life Impact in Movement Disorders. J Neurol 2010;257:1382-7.
34. * Cartwright MS, White DL, DeMar S, Wiesler ER, Sarlikiotis T, Chloros
GD, Yoon JS, Won SJ, Molnar JA, DeFranzo AJ, Walker FO. Median nerve changes following steroid injection for carpal tunnel syndrome. Muscle & Nerve 2011;44:25-9.
35. Cartwright MS, Yoon JS, Lee KH, Deal N, Walker FO. Diagnostic ultrasound for traumatic radial neuropathy. Am J Phy Med Rehabil 2010; in press.
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36. Cartwright MS, Walker FO, Griffn LP, Caress JB. Peripheral nerve and muscle ultrasound in amyotrophic lateral sclerosis. Muscle & Nerve 2011: in press.
37. Chahal PS, Sohail W, Cartwright MS. Neuromuscular Ultrasound in the Diagnosis of Focal Neuropathies Superimposed on Polyneuropathy: A Case Report. Clin Neurophysiol 2011: in press.
38. Cartwright MS, Walker FO, Blocker JN, Schulz MR, Arcury TA, Grzywacz JG, Mora D, Chen H, Marín AJ, Quandt SA. The Prevalence of Carpal Tunnel Syndrome in Latino Poultry Processing Workers and Other Latino Manual Workers. J Occup Environ Med 2012: in press.
39. Mayans D, Cartwright MS, Walker FO. Neuromuscular ultrasonography: Quantifying muscle and nerve measurements. Phys Med Rehabil Clin N Am 2012; 23:133-48.
Non-peer Reviewed Manuscripts 1. Chloros GD, Cartwright MS, Walker FO, Wiesler ER. Sonography and
electrodiagnosis in carpal tunnel syndrome, an analysis of the literature. Eur J Radiol 2009;71:141-3.
2. Walker FO, Alter KE, Boon AJ, Cartwright MS, Flores VH, Hobson-Webb
LD, Hunt CH, Primack SJ, Shook SJ. Qualifications for Practitioners of Neuromuscular Ultrasound: A Position Statement of the AANEM Ultrasound Task Force. Muscle & Nerve 2010;42:442-443.
3. Norbury JW, Cartwright MS, Walker FO, et al. Ultrasonographic Evaluation
of Entrapment Neuropathies in the Upper Limb. Practical Neurology 2011;10:38-44
4. Walker FO, Cartwright MS. Neuromuscular ultrasound: emerging from the
twilight. Muscle & Nerve 2011: in press Books and Chapters 1. Neuromuscular Ultrasound. 1st Edition. Eds. FO Walker and MS Cartwright.
Podcasts 1. Neuromuscular ultrasound: part I. Neurology 2010 2. Neuromuscular ultrasound: part II. Neurology 2010
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Abstracts
1. Cartwright MS, Wiesler ER, Caress JB, Donofrio PD, and Walker FO. High-resolution ultrasound in the evaluation of carpal tunnel syndrome. Neurology 2002;58 Suppl 3:A67.
2. Cartwright MS, Reynolds PS, Rodriguez ZM, Breyer WA, and Cruz JM.
Lumbar puncture experience among medical school graduates. Neurology 2004;62 Suppl 5:A77.
3. Cartwright MS, Shin HW, Walker FO. Detailed ultrasonographic
characteristics of the normal median nerve in adults. Neurology 2006;66 Suppl 2:A83.
4. Cartwright MS, Chloros GD, Walker FO, Wiesler ER, Campbell WW.
Diagnostic ultrasound for nerve transaction. Ann Neurol 2006;60:636. 5. Cartwright MS, Chloros GD, Walker FO, Wiesler ER, Campbell WW.
Diagnostic ultrasound for nerve transaction. Neurology 2007;68:Suppl 1:A67. 6. Brown M, Cartwright MS, Caress JB. Diagnostic ultrasound in HMSN1B.
Neurology 2007;68:Suppl 1:A67. 7. Caress JB, Hobson-Webb L, Passmore L, Cartwright MS. A case control
study of thrombo-embolic events associated with IVIg administration. Neurology 2007;68:Suppl 1:A395.
8. Milligan CE, Oppenheim RW, Delbono O, Caress JB, Cartwright MS and the
WFUSM ALS Research Group. Early changes in motoneurons and neuromuscular junctions in the mutant SOD1 mouse model of ALS. 2008 Sporadic Neurodegeneration Program, pg. 67.
9. Milligan CE, Oppenheim RW, Delbono O, Caress JB, Cartwright MS and the
WFUSM ALS Research Group. Early changes in motoneurons and neuromuscular junctions in ALS. 2008 International Symposium on ALS.
10. Yoon JS, Walker FO, Cartwright MS. Ultrasonographic diagnostic value of
area ratio in ulnar neuropathy at the elbow. AANEM 2008 pg 127.
11. Yoon JS, Walker FO, Cartwright MS. Ultrasonography in four cases of ulnar neuropathy with negative conduction studies. AANEM 2008 pg 128.
12. Vishwajit S, Patel B, Herco M, Siddiqui M, Cartwright MS, Badlani G. The
incidence of voiding difficulty and constipation in patients with essential tremor and Parkinson’s disease. Neurourol Urodyn 2009;28:157-158.
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13. Vishwajit S, Patel B, Herco M, Siddiqui M, Cartwright MS, Badlani G. The effect of deep brain stimulation on voiding dysfunction in Parkinson’s disease and essential tremor. Neurourol Urodyn 2009;28:140-141.
14. Yoshikawa M, Vinsant S, Mansfield C, Moreno RJ, Gifondorwa D, Pace L,
Messi LM, Leles B, Caress JB, Cartwright MS, Delbono O, Oppenheim R, and Milligan C. Identification of Changes in Muscle, Neuromuscular Junctions and Spinal Cord at Early Pre-symptomatic Stages in the Mutant SOD1 Mouse Model of ALS May Provide Novel Insight for Diagnosis and Treatment Development. Society for Neuroscience 2009.
15. Cartwright MS, Walker FO, Caress JB. Ultrasound in the Diagnosis of ALS.
AANEM 2009.
16. Cartwright MS, White DL,Yoon JS, Sarlikiotis T, Chloros GD, Wiesler ER, DeFranzo AJ, Molnar JA, Walker FO. Median nerve changes following steroid injection for carpal tunnel syndrome. AANEM 2009. President’s Initiative Award.
17. Cartwright MS, Walker FO, Caress JB. Ultrasound in the Diagnosis of ALS.
NEALS 2009.
18. Cartwright MS, Walker FO, Arcury TA, Blocker JN, Schulz MR, Quandt SA. Muscle intrusion into the tunnel in carpal tunnel syndrome. Muscle & Nerve 2010;42:630
19. Chukwueke UN, Cartwright MS, Griffin LP, Strowd R, Haq I, Ellis TL,
Abbott V, Herco M, Tatter SB, Siddiqui MS. Unilateral versus bilateral subthalamic stimulation in parkinson’s disease. Movement Disorders. 2011.
PRESENTATIONS:
International, National, and State-wide Presentations (* indicates symposium coordinator)
1. Neuromuscular ultrasound lecturer at the post-meeting symposium. American
Association of Neuromuscular and Electrodiagnostic Medicine Annual Meeting, October 2006, Washington DC.
2. Diagnostic ultrasound for nerve transection. Grand rounds lecture at
Vanderbilt University School of Medicine, October 2007, Nashville, TN.
3. * Neuromuscular ultrasound special interest group (SIG). SIG Coordinator at the American Association of Neuromuscular and Electrodiagnostic Medicine Annual Meeting, October 2007, Phoenix, AZ.
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4. Neuromuscular ultrasound lecturer at the post-meeting symposium. American
Association of Neuromuscular and Electrodiagnostic Medicine Annual Meeting, October 2007, Phoenix, AZ.
5. * Advances in neuromuscular ultrasound symposium. Symposium
Coordinator at the American Association of Neuromuscular and Electrodiagnostic Medicine Annual Meeting, September 2008, Providence, RI.
6. Neuromuscular ultrasound lecturer at the post-meeting symposium. American
Association of Neuromuscular and Electrodiagnostic Medicine Annual Meeting, September 2008, Providence, RI.
7. Medical Management of ALS. Keri B. Still Conference on ALS, November
2008, Winston-Salem, NC.
8. * Advances in neuromuscular ultrasound symposium. Symposium Coordinator at the American Association of Neuromuscular and Electrodiagnostic Medicine Annual Meeting, October 2009, San Diego, CA.
9. Neuromuscular ultrasound lecturer at the post-meeting symposium. American
Association of Neuromuscular and Electrodiagnostic Medicine Annual Meeting, October 2009, San Diego, CA.
10. Amyotrophic lateral sclerosis. Presentation at the 29th Annual Mountain
Medical Meeting, October 2009, Asheville, NC.
11. Evaluation of neuropathy. Presentation at the 29th Annual Mountain Medical Meeting, October 2009, Asheville, NC.
12. Assessment of Focal Neuropathy with Ultrasound. American Society of
Neuroimaging. January 2010, San Francisco, CA.
13. Evaluation of Peripheral Neuropathy. Presentation at the WFUSM Geriatrics Symposium. February 2010, Winston-Salem, NC.
14. Neuromuscular Ultrasound. Presentation at the North Carolina Neurological
Society Annual Meeting. February 2010, Charlotte, NC.
15. Assessing movement in focal nerve disease. Presentation at the American Association of Neuromuscular and Electrodiagnostic Medicine Annual Meeting, September 2011, San Francisco, CA.
16. Neuromuscular Ultrasound. 6th Annual AHEC Neuroscience Lecture Series,
November 2011, Winston-Salem, NC.
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International, National, and State-wide Hands-on Workshops 1. Neuromuscular ultrasound instructor at the post-meeting symposium
workshop. American Association of Neuromuscular and Electrodiagnostic Medicine Annual Meeting, October 2004, Savannah, GA.
2. Neuromuscular ultrasound instructor at the post-meeting symposium
workshop. American Association of Neuromuscular and Electrodiagnostic Medicine Annual Meeting, October 2005, Monterey, CA.
3. Neuromuscular ultrasound instructor at the post-meeting symposium
workshop. American Association of Neuromuscular and Electrodiagnostic Medicine Annual Meeting, October 2006, Washington DC.
4. Neuromuscular ultrasound instructor at the post-meeting symposium
workshop. American Association of Neuromuscular and Electrodiagnostic Medicine Annual Meeting, October 2007, Phoenix, AZ.
5. Neuromuscular ultrasound workshop. Course instructor at the American
Association of Neuromuscular and Electrodiagnostic Medicine Annual Meeting, September 2008, Providence RI.
6. Neuromuscular ultrasound instructor at the post-meeting symposium
workshop. American Association of Neuromuscular and Electrodiagnostic Medicine Annual Meeting, September 2008, Providence, RI.
7. Neuromuscular ultrasound workshop. Course instructor at the American
Association of Neuromuscular and Electrodiagnostic Medicine Annual Meeting, October 2009, San Diego, CA.
8. Neuromuscular ultrasound instructor at the post-meeting symposium
workshop. American Association of Neuromuscular and Electrodiagnostic Medicine Annual Meeting, October 2009, San Diego, CA.
9. Assessment of Focal Neuropathy with Ultrasound Workshop. American
Society of Neuroimaging. January 2010, San Francisco, CA.
10. Neuromuscular Ultrasound Workshop. Presentation at the North Carolina Neurological Society Annual Meeting. February 2010, Charlotte, NC.
11. Neuromuscular ultrasound for EMG technicians workshop. American
Association of Neuromuscular and Electrodiagnostic Medicine Annual Meeting, September 2011, San Francisco, CA.
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12. Advanced neuromuscular ultrasound workshop. American Association of Neuromuscular and Electrodiagnostic Medicine Annual Meeting, September 2011, San Francisco, CA.
International, National, and State-wide Poster Presentations
1. High-resolution ultrasound in the evaluation of carpal tunnel syndrome.
Poster at the American Academy of Neurology Annual Meeting, April 2002, Denver, CO.
2. Experiences with high-resolution ultrasound in the evaluation of carpal tunnel
syndrome. G. Milton Shy Essay Award poster at the American Academy of Neurology Annual Meeting, April 2002, Denver, CO.
3. Lumbar puncture experience among medical school graduates. Poster at the
American Academy of Neurology Annual Meeting, April 2004, San Francisco, CA.
4. Ultrasonographic characteristics of the normal median nerve. Poster at the
American Academy of Neurology Annual Meeting, April 2006, San Diego, CA.
5. Diagnostic ultrasound for nerve transection. Poster at the American
Neurological Association Annual Meeting, October 2006, Chicago. 6. Diagnostic ultrasound for nerve transection. Poster at the American Academy
of Neurology Annual Meeting, May 2007, Boston, MA. 7. Neuromuscular ultrasound workshop. Course instructor at the American
Association of Neuromuscular and Electrodiagnostic Medicine Annual Meeting, October 2007, Phoenix, AZ.
8. Neuromuscular ultrasound in the diagnosis of ALS. Poster presentation at the
American Association of Neuromuscular and Electrodiagnostic Medicine Annual Meeting, October 2009, San Diego, CA.
9. Median nerve changes following steroid injection for carpal tunnel syndrome.
Poster presentation at the American Association of Neuromuscular and Electrodiagnostic Medicine Annual Meeting, October 2009, San Diego, CA.
Institutional (Wake Forest School of Medicine) 1. Neuromuscular Ultrasonography Course: Coding and Billing – Center for
Medical Ultrasound, October 2005, January 2006, December 2006, March 2007, November 2007, May 2008, November 2008, March 2009, May 2010, March 2011.
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2. Neuromuscular Ultrasonography Course: Peripheral Nerve Appearance –
Center for Medical Ultrasound, October 2005, January 2006, December 2006, March 2007, November 2007, May 2008, November 2008, March 2009, May 2010, March 2011.
3. Evaluation of the unresponsive patient – Internal Medicine, Emergency
Lecture Series, September 2005. 4. Status epilepticus – Internal Medicine, Emergency Lecture Series, August
2005. 5. How to be a good rotating intern – Class of 2005 Phase 5 Lecture, May 2005. 6. Interpreting Nerve Conduction Studies and EMG – Internal Medicine Grand
Rounds, February 2006.
7. Neuromuscular Diseases – Family Medicine lecture series, September 2006, December 2008.
8. Neuromuscular Diseases – Internal Medicine lecture series, February 2007,
October 2007. 9. Evaluation of CSF – Neurology Update for Primary Care Providers, March
2007.
10. Common Neuropathies – Family Medicine lecture series, November 2007
11. Diabetic Neuropathy – Endocrinology lecture series, January 2008, May 2010, March 2011
12. Neuromuscular Ultrasound – SIGN meeting, January 2008
13. Meningitis and Encephalitis – Neurology Update for Primary Care Providers,
May 2008
14. Neurology for the Internal Medicine Board Examination – Internal Medicine lecture series, June 2008
15. Myasthenia Gravis – CT Surgery Grand Rounds, May 2009
16. Neuromuscular Emergencies – Critical Care Grand Rounds, July 2009
17. Introduction to Neurology – First Year Medical Students, August 2010,
August 2011
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18. The Brachial Plexus – First Year Medical Students, October 2010, October 2011
19. Utrasonographic Assessment of Carpal Tunnel Syndrome – Neuroscience
lecture series, April 2011
20. The Neurologic Examination – Organized and taught Phase 5 course, March 2011
21. Carpal Tunnel Syndrome in Poultry Workers – Workers Health Seminar,
April 2011 22. Neuromuscular Ultrasound – Medical Imaging Graduate Course, VT-Wake
Forest School of Biomedical Engineering, May 2011 23. HIV Neuropathies – HIV section meeting, May 2011 24. Guillain-Barre Syndrome – Hospitalists section meeting, May 2011 25. Neuromuscular Ultrasound in Sports Medicine – Sports Medicine Conference,
Family Medicine, June 2011
Departmental (Wake Forest School of Medicine, Department of Neurology)
1. ICH with over-the-counter inhaled epinephrine. Grand Rounds, November 2003.
2. Establishing the diagnosis of myasthenia gravis – EMG Conference,
November 2004. 3. Mimics of Guillain-Barre Syndrome – EMG Conference, October 2004. 4. Primary CNS tumors in the pediatric patient – Pediatric Conference,
September 2004. 5. General pediatrics for the neurologist – Pediatric Conference, August 2004. 6. Statin associated exacerbation of myasthenia gravis – Grand Rounds, March
2004. 7. Neuromuscular ultrasonography – Grand Rounds, February 2005. 8. Atrial septal defects and migraine headaches – Grand Rounds, November
2005.
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9. Neuromuscular diseases – Monthly lecture for medical students, July 2006 - Present.
10. Traumatic nerve injury – Grand Rounds, March 2007.
11. ALS Mimics – EMG Conference, October 2007.
12. Immunosuppression in Neuromuscular Diseases – EMG Conference,
November 2007.
13. Evaluation of Stupor and Coma – Emergency lecture series, July 2007, July 2008, July 2009
14. Post-polio syndrome – EMG Conference, February 2008.
15. Evaluation of pure cerebellar ataxia – EMG Conference, April 2008
16. Introduction to EMG – Emergency lecture series, July 2009
17. Steroid injection for carpal tunnel syndrome – Rehab Fellows Conference,
May 2010
18. Carpal Tunnel Syndrome in Poultry Workers – Neurology Grand Rounds, February 2011
FELLOWS TRAINED
1. 2008-2009: Kara Eickman, MD; Joseph Chipman, MD
2. 2009-2010: B. Lee Kennedy, MD; Kashyap Patel, MD
3. 2010-2011: Chaman Preet Chahal, MD; Waqas Sohail, MD