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NEUROLOGY - LABORATORY AND CLINICAL
RESEARCH DEVELOPMENTS

SPINAL CORD STIMULATION
PRINCIPLES AND PRACTICE

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NEUROLOGY - LABORATORY AND CLINICAL
RESEARCH DEVELOPMENTS
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NEUROLOGY - LABORATORY AND CLINICAL
RESEARCH DEVELOPMENTS

SPINAL CORD STIMULATION
PRINCIPLES AND PRACTICE

ANTONIOS MAMMIS


EDITOR

New York


Copyright © 2016 by Nova Science Publishers, Inc.
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This book is dedicated to Admiral Edward Codrington,
who made the world a better place by choosing action over diplomacy.



CONTENTS
Preface

ix

About the Editor

xi


Contributors

xiii

Chapter 1

History of Spinal Cord Stimulation
Kelsey T. Vander Werff and Nitin Agarwal

1

Chapter 2

Indications and Patient Selection
Andrew Kaufman and Rita Shankar Shah

7

Chapter 3

Failed Back Surgery Syndrome and Spinal Cord Stimulation
Ferdinand Iannaccone, Neil Majmundar and Vanny Le

13

Chapter 4

Complex Regional Pain Syndrome and Spinal Cord Stimulation
Anant Parikh, Deepa Asokan and Anthony Sifonios


23

Chapter 5

Psychological Evaluation of Candidates for Spinal
Neurostimulation: An Overview of Current Clinical Practice
Donald S. Ciccone

35

Chapter 6

Trialing of Spinal Cord Stimulation
Kiran V. Patel

51

Chapter 7

Percutaneous Permanent Placement of Spinal Cord Stimulators
Konstantin V. Slavin and Dali Yin

63

Chapter 8

Thoracic Laminectomy for Spinal Cord Stimulator Placement
John C. Quinn and Antonios Mammis

79


Chapter 9

Electrophysiologic Assessment during Paddle Lead Placement
Alon Y. Mogilner and Antonios Mammis

87

Chapter 10

Complication Avoidance and Revision Surgery
Sameah A. Haider, Meghan E. Wilock and Julie G. Pilitsis

95

Chapter 11

Spinal Cord Stimulation Programming Strategies
Christina Sarris

115


viii
Chapter 12
Index

Contents
Emerging Spinal Cord Stimulation Technology
James C. Barrese and Jaimie M. Henderson


123
147


PREFACE
Spinal cord stimulation is a neuromodulation therapy for the treatment of chronic,
intractable, neuropathic pain. It involves the implantation of electrodes over the dorsal
columns of the spinal cord, in order to activate the dorsal column-medial lemniscal sensory
system, thus closing the gate on pain transmission. This therapy is used in patients with
neuropathic pain conditions such as post-laminectomy syndrome, spinal arachnoiditis, lumbar
radiculitis, and complex regional pain syndrome.
Spinal Cord Stimulation: Principles and Practice is written by experts in the field, with a
multidisciplinary approach to the chronic pain patient in mind. There are chapters describing
the history of this therapy, and the fundamentals of indications and patient selection. The
psychological considerations of spinal cord stimulation are described, and there are chapters
describing various trialing/implanting techniques, with an emphasis on patient outcomes and
complication avoidance. Finally, chapters on spinal cord stimulator programming and
emerging indications round out the volume.
Spinal Cord Stimulation: Principles and Practice is a valuable resource for clinicians, to
help direct decision making when treating patients with chronic pain. Patients and their
caretakers will also find value in this book, as a guide through the spinal cord stimulation
candidacy and implantation process. I hope this book serves to improve the care of chronic
pain patients while providing a beacon of hope to patients, their caretakers, and medical
providers.



ABOUT THE EDITOR
Dr. Antonios Mammis is the founder and director of the Functional and Restorative

Neurosurgery Program and Center for Neuromodulation, at Rutgers New Jersey Medical
School. Dr. Mammis is also an active faculty member of the NJ Spine Center. With
expertise in the treatment of movement disorders, such as Parkinson‘s Disease and essential
tremor, and refractory chronic pain conditions, Dr. Mammis is one of the busiest implanters
of neuromodulation devices in the country. Dr. Mammis also performs surgery for spinal
disorders, and heads the stereotactic radiosurgery program at New Jersey Medical School.
Dr. Mammis graduated from New York University College of Arts and Science, and
from Columbia University College of Physicians and Surgeons. He did a residency in
neurological surgery at New Jersey Medical School, and a fellowship in functional and
restorative neurosurgery at North Shore Hospital. He has academic appointments in the
Department of Neurological Surgery, and Department of Anesthesiology, is course director
for the 3rd and 4th year medical school neurosurgery electives, and is faculty for the pain
management fellowship.
Dr. Mammis is a prolific researcher and author. He has a multitude of peer-reviewed
articles, and book chapters. He is the editor of the textbook: Migraine Surgery, and is also
published in the prestigious Proceedings of the National Academy of Sciences.

Dr. Antonios Mammis, MD
Assistant Professor
Neurological Surgery,
Rutgers New Jersey Medical School
Email: ;



CONTRIBUTORS
Nitin Agarwal, M.D.
Resident
Department of Neurological Surgery
University of Pittsburgh School of Medicine

Pittsburgh, Pennsylvania
Deepa Asokan, M.D.
Resident
Department of Anesthesiology
Rutgers New Jersey Medical School
Newark, New Jersey
James C. Barrese, M.D.
Assistant Professor
Department of Neurosurgery
Drexel University College of Medicine
Philadelphia, Pennsylvania
Donald Ciccone, Ph.D.
Pain Psychologist
Department of Neurological Surgery
Rutgers New Jersey Medical School
Jaime Henderson, M.D.
Professor
Department of Neurological Surgery
Stanford University School of Medicine
Stanford, California
Ferdinand Iannaccone, M.D.
Resident
Department of Anesthesiology
Rutgers New Jersey Medical School
Newark, New Jersey


xiv

List of Contributors

Andrew Kaufman, M.D.
Director, Comprehensive Pain Center
Department of Anesthesiology
Rutgers New Jersey Medical School
Newark, New Jersey
Vanny Le, M.D.
Assistant Professor; Associate Residency Program Director
Department of Anesthesiology
Rutgers New Jersey Medical School
Newark, New Jersey
Neil Majmundar, M.D.
Resident
Department of Neurological Surgery
Rutgers New Jersey Medical School
Newark, New Jersey
Antonios Mammis, M.D.
Assistant Professor
Department of Neurological Surgery and Anesthesiology
Rutgers New Jersey Medical School
Newark, New Jersey
Alon Y. Mogilner, M.D., Ph.D.
Associate Professor
Department of Neurological Surgery
NYU Langone Medical Center
New York, New York
Anant Parikh, M.D.
Resident
Department of Anesthesiology
Rutgers New Jersey Medical School
Newark, New Jersey

Kiran V. Patel, M.D.
The Spine and Pain Institute of New York
New York, New York
Christina E. Sarris, M.D.
Resident
Barrow Neurological Institute
Phoenix, Arizona


List of Contributors
Rita Shankar Shah, M.D.
Resident
Department of Anesthesiology
Rutgers New Jersey Medical School
Newark, New Jersey
Anthony N. Sifonios, M.D.
Assistant Professor
Department of Anesthesiology
Rutgers New Jersey Medical School
Newark, New Jersey
Konstantin Slavin, M.D.
Professor
Department of Neurosurgery
University of Illinois College of Medicine
Chicago, Illinois
Kelsey Vander Werff, Ph.D., A.T.C.
Department of Neurological Surgery
Rutgers New Jersey Medical School
Newark, New Jersey
Dali Yin, M.D.

Fellow
Department of Neurosurgery
University of Illinois College of Medicine
Chicago, Illinois

xv



In: Spinal Cord Stimulation
Editor: Antonios Mammis

ISBN: 978-1-63484-098-9
© 2016 Nova Science Publishers, Inc.

Chapter 1

HISTORY OF SPINAL CORD STIMULATION
Kelsey T. Vander Werff1,*, PhD, and Nitin Agarwal, MD1,2
1

Department of Neurological Surgery, Rutgers New Jersey Medical School,
Newark, New Jersey, US
2
Department of Neurological Surgery, University of Pittsburgh Medical Center,
Pittsburgh, Pennsylvania, US

Keywords: history, neurostimulation, scribonius largus, galvani, norman shealy

INTRODUCTION

Neuromodulation is based on the principle that electrical stimulation inducing paresthesia
may be analgesic. In general, neurostimulation involves the application of electrical current to
the source of chronic pain, hence eliciting a pleasant sensation that blocks the brain‘s ability
to sense the previously perceived pain. This is currently known as the Gate Control Theory of
Pain Modulation [1]. Two commonly used forms of electric stimulation used to treat chronic
pain include; Spinal Cord Stimulation (SCS) and Peripheral Nerve Field Stimulation (PNFS).
Most common pathologies treatable with SCS include: failed back surgery syndrome,
peripheral neuropathy, complex regional pain syndrome, causalgia, and arachnoiditis. SCS
was FDA approved as a treatment method in 1989 [2].

HISTORICAL DEVELOPMENT
The earliest record of neurostimulation for pain relief occurred in 40 AD, when
Scribonius Largus first used electricity for medicinal purposes; including relief from
headaches and gout pain. In ancient Greece, Egypt and Rome, electric eels and torpedo fish
were used to treat migraines and epilepsy. The fish was either applied directly or indirectly
*

Corresponding Author: Kelsey T. Vander Werff, Ph.D. Department of Neurological Surgery, Rutgers New Jersey
Medical School 90 Bergen Street, Suite 8100 Newark NJ, 07103,


2

Kelsey T. Vander Werff and Nitin Agarwal

via a pool of water. Scribonius Largus stated ―For any sort of foot gout, when the pain comes
on it is good to put a living black torpedo fish under his feet while standing at the beach, not
dry but one on which the sea washes, until he feels that his whole foot and ankle are numb up
to the knees‖ [3].
In the 1780‘s, Luigi Galvani explored ―animal electricity‖ incidentally, while dissecting a

frog leg and noting muscle contractions when the scalpel touched the muscle. Later, Galvani
noted muscle contractions in the eyes, jaws and extremities in newly deceased prisoners [4].
The Galvanic experiments led to years of future research in the area of electrophysiology.
Charles Bell, renowned neurophysiologist, in 1811 published his experimental results with
German pointer dogs demonstrating divisions of brain – cerebrum connects to the anterior
roots and cerebellum the posterior roots [4]. Later, building on Bell‘s discoveries, Francois
Magendie revealed the true difference between anterior and posterior roots [5]. The BellMagendie Law (1822) was named after both Charles Bell and Francois Magendie after
discovering the separate entities of sensory and motor roots of the medulla – anterior
influences muscular contractility, while posterior nerve roots control sensory [6]. Hall (1833)
further added to spinal discoveries by determining the distinct function of the spinal cord and
medulla oblongata. Furthermore the reflex system was described, which is separate from the
sensory and motor system noted by Bell and Magendie [7].
Giannuzzi (1863) was a pioneer in the therapeutic use of neurostimulation. He was best
known for stimulating the spinal cord in dogs; experimenting with hypogastric and pelvic
nerves to regulate bladder function in the hope of treating chronic urinary retention [8, 9].
Budge (1872) added to this by proposing that two sets of nerve roots innervate the bladder:
motor fibers from anterior roots of S1, 2, 3 as well as sensory fibers from the hypo gastric
plexus.

THE MODERN ERA
In the early 20th century major advances occurred in the development of electric
oscillators, stimulators, and amplifiers for various therapeutic treatments [9]. These
advancements greatly improved the understanding of nerve impulses, synaptic transmission,
and nervous system function. The Electreat, appeared around the beginning of the 20th
century with the promise of relieving pain among other physical conditions. Of note, this
battery operated device has been cited for its resemblance to the modern date transcutaneous
electrical nerve stimulation (TENS) unit [10].
Over the years leading up to the development of spinal cord stimulation, various portable
implants have been invented to modulate a variety of organs. As early as 1960, cardiac
stimulators were being fully implanted. Advances included, for example, radio-frequency

cardiac stimulation developed by Glenn and Mauro. Their method of long-term externally
applied cardiac stimulation was further refined by creating a small, compact, and portable
transmitter [11]. The use of radio-frequency based stimulation later was applied as a
therapeutic strategy for primary hypoventilation syndrome with electrophrenic respiration
[12]. Meanwhile, as early as in the 1960s, instruments for neuromodulation were also being
advanced. For instance the first cochlear implant was placed in 1961 by House and Doyle


History of Spinal Cord Stimulation

3

[13]. The modern era of neuromodulation has been suggested to begin as the early 1960s,
initially with deep brain stimulation followed soon thereafter by spinal cord stimulation in
1967. In 1967, Norman Shealy et al. documented the initial concept of a spinal cord
stimulator [10]. Commercial spinal cord simulators became available by 1968 and were
initially, and continue to be, indicated as an appropriate therapeutic strategy for the relief of
neuropathic pain syndromes, such as: refractory failed back surgery syndrome and complex
regional pain syndrome Type I [11].
Although initially developed for pain relief, spinal cord stimulation has been noted to
have wide ranging effects on human physiology, with effects on spasticity, and blood flow, in
addition to pain relief. In 1976, Cook and Dooley helped patients with multiple sclerosis
improve their spasticity with implanted stimulators [12,13]. In 1987, Murphy and Giles found
that dorsal column stimulation of the spinal cord helped to alleviate pain from intractable
angina pectoris [14]. Finally, in 1996, Hautvast documented protection against ischemia
which was associated with the increase of myocardial perfusion during spinal cord
stimulation [15]. Spinal cord stimulators gained approval from the United States Food and
Drug Administration to relieve neuropathic pain in 1989.
Over the past twenty years, spinal cord stimulation has evolved from single channel
systems, which required laminectomies, to multichannel systems utilizing percutaneous leads

[16]. The stimulator works by sending mild electrical impulses to the spine to block pain
signals. The pulse generator sends low current electricity through extension wires into the
leads tunneled into the spine. The electrical current from delivered via the leads creates
paresthesia sensations which disguises the pain signal that travels to the brain. Technical
improvements in multi-contact percutaneous leads may have improved clinical results by
increasing SCS coverage areas and decreasing overall pain [17].
The earliest SCS involved electrode placement in the epidural or subarachnoid space and
subsequently required laminectomy [10]. Electrodes used for SCS can be categorized as
follows: percutaneous leads, inserted through a needle, or insulated arrays, requiring surgical
exposure of the epidural space [18]. Original electrode placement was the level above the
pathological segment, however over time evolved to include the painful segment. The overall
invasiveness of the implantation is a SCS has decreased and trials have been implemented in
order to predict if implantation of the device would successful [18]. Percutaneous leads were
originally developed for temporary placement of SCS, mostly used for trials, later was
adapted as a permanent implanted device [19]. Electrode migration and malposition were
common errors related to using percutaneous leads. In order to account for this common
issue, the development of electrode arrays with multiple contacts allowing for optimal
implantation was developed. Later, multicontact arrays were complemented by programmable
implantable pulse generators. As a result, surgical revisions related to SCS decreased [17]. An
advantage of utilizing percutaneous leads is that it allows for placement without general
anesthesia and therefore the patient can provide direct feedback as to the paresthesia coverage
areas targeted during the implantation procedure [20].
Within the last twenty years, implanted pulse generators, using pacemaker technology,
involving an internal battery have been developed and commonly used. Implanted pulse
generators include external powered, radiofrequency coupled, and internally powered systems
with primary cells [18]. Internally powered systems make the device more conducive to use
in patient, not having to wear a bulky external device. Therefore, patient compliance has


4


Kelsey T. Vander Werff and Nitin Agarwal

improved and long term usage has enhanced. Programmable implantable devices also allow
for selection of anodes and cathodes from the array of multiple contacts [18].

CONCLUSION
The use of electrical stimulation for the treatment of human disease, and for the relief of
suffering has a long history. As our understanding of human physiology, and electrical
engineering continued to advance in parallel, over the centuries, an assortment of
neuromodulation devices and indications have emerged. Spinal cord stimulation grew out of
this tradition, and helped to usher in the era of modern neuromodulation devices, along with
deep brain stimulators, and cochlear implants. SCS technology continues to evolve, as do the
indications for its use. These topics will be covered in detail in later chapters in the book.

REFERENCES
[1]
[2]
[3]
[4]
[5]
[6]
[7]
[8]
[9]
[10]

[11]

[12]


[13]

Melzack R, Wall PD. Pain mechanisms: a new theory. Science. Nov 19
1965;150(3699):971-979.
Kumar K, Rizvi S. Historical and present state of neuromodulation in chronic pain.
Current pain and headache reports. Jan 2014;18(1):387.
Moller E. Review: Electric Fish. Bioscience. 1991;41:794-796.
van Gijn J. Charles Bell (1774-1842). Journal of neurology. Jun 2011;258(6):11891190.
Cranefield PF. The way in and the way out: Franocis Magendie, Charles Bell and the
roots of the Spinal Nerves. 1 ed. New York: Futura Publishing Company; 1974.
Bell C. Idea of New Anatomy of the Brain-submitted for the observations of his friends.
London: Strahan and Preston; 1811.
Hall M. On the reflex function of the Medulla oblong-gata and medulla spinalis.
Philisophical Transaction. 1833;123:635-665.
Nashold BS, Jr., Friedman H, Boyarsky S. Electrical activation of micturition by spinal
cord stimulation. The Journal of surgical research. Mar 1971;11(3):144-147.
Tanagho EA. Neuromodulation and neurostimulation: Overview and future potential.
Translational Androlology and Urology 2012;1:44-49.
Shealy CN, Mortimer JT, Reswick JB. Electrical inhibition of pain by stimulation of
the dorsal columns: preliminary clinical report. Anesthesia and analgesia. Jul-Aug
1967;46(4):489-491.
Taylor RS, Van Buyten JP, Buchser E. Spinal cord stimulation for complex regional
pain syndrome: a systematic review of the clinical and cost-effectiveness literature and
assessment of prognostic factors. European journal of pain. Feb 2006;10(2):91-101.
Dooley DM, Kasprak M, Stibitz M. Electrical stimulation of the spinal cord in patients
with demyelinating and degenerative diseases of the central nervous system. The
Journal of the Florida Medical Association. Nov 1976;63(11):906-909.
Dooley DM. Spinal cord stimulation. AORN journal. Jun 1976;23(7):1209-1212.



History of Spinal Cord Stimulation

5

[14] Murphy DF, Giles KE. Dorsal column stimulation for pain relief from intractable
angina pectoris. Pain. Mar 1987;28(3):365-368.
[15] Hautvast RW, Blanksma PK, DeJongste MJ, et al. Effect of spinal cord stimulation on
myocardial blood flow assessed by positron emission tomography in patients with
refractory angina pectoris. The American journal of cardiology. Mar 1 1996;77(7):462467.
[16] North RB, Kidd DH, Zahurak M, James CS, Long DM. Spinal cord stimulation for
chronic, intractable pain: experience over two decades. Neurosurgery. Mar
1993;32(3):384-394; discussion 394-385.
[17] North RB, Ewend MG, Lawton MT, Piantadosi S. Spinal cord stimulation for chronic,
intractable pain: superiority of "multi-channel" devices. Pain. Feb 1991;44(2):119-130.
[18] North RB, Guarino AH. Spinal cord stimulation for failed back surgery syndrome:
technical advances, patient selection and outcome. Neuromodulation: journal of the
International Neuromodulation Society. Jul 1999;2(3):171-178.
[19] Hosobuchi Y, Adams JE, Weinstein PR. Preliminary percutaneous dorsal column
stimulation prior to permanent implantation. Technical note. Journal of neurosurgery.
Aug 1972;37(2):242-245.
[20] North RB, Ewend MG, Lawton MT, Kidd DH, Piantadosi S. Failed back surgery
syndrome: 5-year follow-up after spinal cord stimulator implantation. Neurosurgery.
May 1991;28(5):692-699.



In: Spinal Cord Stimulation
Editor: Antonios Mammis


ISBN: 978-1-63484-098-9
© 2016 Nova Science Publishers, Inc.

Chapter 2

INDICATIONS AND PATIENT SELECTION
Andrew Kaufman*, MD, and Rita Shankar Shah, MD
Department of Anesthesiology, Rutgers New Jersey Medical School,
Newark, New Jersey, US

INTRODUCTION
During the 20th century, electricity began to emerge as an analgesic modality. Shealy et
al. introduced dorsal column stimulation into the neuromodulatory pain world but quickly
suffered from setbacks secondary to device failures, poor patient selection, and lead fractures
[1]. Aside from technological advancements, precise indications and patient selection
improved spinal cord stimulation (SCS) during the modern era. Appropriate patient selection
for SCS requires identification of diagnoses amenable to treatment and thorough assessment
of patient characteristics, such as failure with conservative therapy, psychological evaluation,
medical evaluation, and a SCS trial demonstrating pain relief [2]. Patients with appropriate
diagnoses and characteristics are more likely to predict success with spinal cord stimulation in
chronic, intractable pain.

Keywords: indications, patient selection, spinal cord stimulation, failed back surgery
syndrome, chronic pain regional syndrome

INDICATIONS
While SCS mainly treats neuropathic pain, it is not contraindicated in somatic pain. Both
definite and relative indications for spinal cord stimulation have been studied. Patients
exhibiting neuropathic pain should have a MRI prior to SCS to rule out surgically curable
pain etiologies, i.e., spinal canal compression [3]. In the United States, Failed Back Surgery

*

Corresponding Author: Andrew Kaufman, M.D. Department of Anesthesiology, Rutgers New Jersey Medical
School 90 Bergen Street, Suite 3400 Newark, NJ, 07103,


8

Andrew Kaufman and Rita Shankar Shah

Syndrome (FBSS) or post laminectomy pain syndrome is the most common use for SCS (See
Chapter 3) [3]. The Prospective Randomized Controlled Multicenter Trial of the
Effectiveness of Spinal Cord Stimulation (PROCESS) studied 100 FBSS patients with
neuropathic radicular pain, who were randomized into groups with spinal cord stimulation
and conventional medical management, and another with conventional medical management
alone. The results illustrated significantly improved pain relief, quality of life, and ability to
engage in daily living activities with SCS [4].
Complex regional pain syndrome (CRPS), for both Types I (Reflex Sympathetic
Dystrophy) and II (Causalgia), is the second most common indication for SCS in the United
States [3] (See Chapter 4). SCS can be considered in CRPS patients after failed conservative
medical management, rehabilitation, or sympathetic blocks [5]. The International Association
for Study Pain or IASP recommends early introduction of SCS within 12-16 weeks after
failed conventional therapy [6]. In a randomized, controlled study comparing SCS plus
physical therapy to physical therapy alone, Kemler et al. showed that 24 out of 36 patients
who received successful trial stimulation at six months showed a mean reduction of 2.4cm as
per the visual analog scale while an increase 0.2cm was noted to the latter group [7]; during
the two year follow-up period, the former group showed improvements in pain intensity and
health-related quality of life [8]. At five years, both groups showed similar results but 95% of
patients with implants would repeat the treatment to achieve the same outcomes [9].
Spinal cord stimulation has also shown to have favorable outcomes in the treatment of

chronic ischemic states, specifically in angina pectoris and peripheral vascular disease.
Mannheimer et al. indicate that SCS decreases angina and ischemia via decreased myocardial
oxygen consumption [10]. As per the European Society of Cardiology, SCS is considered a
first-line treatment in refractory angina pectoris with anti-ischemic effects and strong
evidence showing decreased anginal episodes, better quality of life, and functional status.
Moreover, it has also proven to be economically effective after 15-16 months of failed
conservative medical management [11]. In the United States, SCS has been linked to
improved New York Heart Association functional class, exercise capacity, and quality of life.
In addition, it was associated with decreased pain, nitrate requirements, and hospitalizations.
In the United States, SCS use for angina is not widely practiced as it can mask ischemic
symptoms, potentially resulting in silent infarctions [3]. The Electrical Stimulation versus
Coronary Artery Bypass Surgery or ESBY study randomized 104 patients with severe angina
and increased surgical risks to CABG vs SCS, and showed no difference between both groups
in survival or quality of life [12]. Therefore, high risk surgical candidates with severe, stable
angina and a poor quality of life can have favorable outcomes with SCS. Patients who have
valve defects, unstable angina, or cardiac pacemakers are generally not candidates for SCS
due to hardware interference [3].
When revascularization is not an option for peripheral vascular disease (PVD), patients
should be considered for SCS. Patients who demonstrate severe ischemic pain at rest, no
tissue involvement, and good collateral blood flow can strongly benefit from SCS [3]. In
2003, the European Peripheral Vascular Disease Outcome Study, a prospective multicenter
study, showed that SCS treatment on non-reconstructable critical leg ischemia had better limb
survival rates compared to conservative management [13]. A meta-analysis conducted the
year after further proved that a combined approach of SCS and conservative treatment for
inoperable chronic critical leg ischemia decreased pain and improved limb survival and
overall clinical outcomes [14].


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