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T H E 2 01 5
RUSH NEUROSCIENCE REVIEW
In memory of
Leyla deToledo Morrell, PhD
1941 – 2015
A leader in the field of Alzheimer’s disease research,
Leyla deToledo Morrell was a part of the Rush family for
more than 35 years. She was among the first to use
modern imaging techniques to report that shrinkage in
the medial temporal lobe marks the transition from
prodromal to Alzheimer’s disease. Medial temporal lobe
atrophy is now a major biomarker for the disease.
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RUSH NEUROSCIENCE REVIEW
Faculty editors
Richard Byrne, MD
Aimee Szewka, MD
CHAIRMEN’S LETTER
2
NEUROSCIENCES AT RUSH: AT A GLANCE
4
PRIMARY AND ASSOCIATED FACULTY
Department of Neurological Sciences
6
Department of Neurological Surgery
9
RESIDENTS AND FELLOWS
Department of Neurological Sciences
10
Department of Neurological Surgery
11
SELECT ARTICLES
The Evolution of Neurocritical Care
12
Georgia Korbakis, MD; Thomas Bleck, MD, MCCM, FNCS
Surgical Management of Low-Grade Gliomas
22
Carter Gerard, MD; David Straus, MD; Richard W. Byrne, MD
Visuoperceptive Region Atrophy Independent of Cognitive Status in Parkinson’s Disease Hallucinators
30
Jennifer G. Goldman, MD, MS; Glenn T. Stebbins, PhD; Vy Dinh, BA; Bryan Bernard, PhD; Doug Merkitch, BA;
Leyla deToledo-Morrell, PhD; Christopher G. Goetz, MD
Clinical and Radiographic Analysis of an Artificial Cervical Disc:
7-Year Follow-Up From the Prestige Prospective Randomized Controlled Clinical Trial
43
J. Kenneth Burkus, MD; Vincent C. Traynelis, MD; Regis W. Haid Jr, MD; Praveen V. Mummaneni, MD
PUBLICATIONS
58
RESEARCH GRANTS
72
VOLUME AND QUALITY DATA
Volumes, neurology and neurological surgery
74
Mortality, neurology and neurological surgery
75
Quality indicators, stroke
75
NEUROLOGICAL SPINE SURGERY ROUNDTABLE:
On the planning, execution and future of spine surgery
76
Vincent Traynelis, MD, director of spine neurosurgery at Rush, and colleagues Richard Fessler, MD, PhD,
John O’Toole, MD, MS, Ricardo Fontes, MD, PhD, and Harel Deutsch, MD, talk spine surgery
To view The 2015 Rush Neuroscience Review online, visit www.rush.edu/neurosciencereview.
Chairmen’s Letter
As we look back over the last year, one research
study in particular—the SWIFT-PRIME stroke
trial—demonstrates the multidisciplinary approach
to achieving clinical excellence that is the hallmark
of our two departments. Rush was one of 39
centers in the U.S. and Canada that participated
in the SWIFT-PRIME trial, the results of which
appeared this summer, coauthored by our faculty,
in the New England Journal of Medicine.
The results showed significantly higher functional
outcomes in stroke patients who received IV tPA
plus mechanical thrombectomy vs. IV tPA alone,
the current standard. We hope that these findings
serve as a foundation for nationwide changes in
the way stroke patients receive emergency care—
changes that could one day lead to less patient
disability from stroke.
And we are particularly gratified by the recognition
our stroke team received for the way they
routinely deliver this improved level of care:
• Of all the participating sites in the SWIFT-PRIME
trial, Rush had the fastest times from
patient arrival to insertion of the catheter
(door to groin).
• Rush also had the fastest initiation of the
procedure to restoration of blood flow
(groin to recanalization).
• The Rush team was recognized for having the
best workflow among a larger group of 203
sites in the U.S., Australia, Canada, and Europe
that participated in SWIFT-PRIME and two
other affiliated stroke studies.
In addition to the above, we are pleased to
share highlights from the last year that further
exemplify multidisciplinary approaches to
providing excellent care:
Alzheimer’s disease protection research:
Drawing on years of prior nutrition and
Alzheimer’s research, clinicians at Rush developed
the Mediterranean-DASH Intervention for
2
THE 2015 RUSH NEUROSCIENCE REVIEW
Neurodegenerative Delay, or MIND, diet. The
MIND diet is a hybrid of the Mediterranean and
DASH (Dietary Approaches to Stop Hypertension)
diets, both of which have been found to reduce
the risk of cardiovascular conditions.
Researchers at Rush compared the MIND diet with
Mediterranean and DASH diets. While people
with high adherence to either the DASH or the
Mediterranean diet had reductions in their risk
of developing Alzheimer’s, those who moderately
adhered had negligible benefits. However, the
MIND diet lowered Alzheimer’s risk by as much
as 53 percent for those who had high adherence
and by about 35 percent in those who followed it
only moderately well.
Improving access for movement disorders:
Physicians from our movement disorders program
are piloting a way to make follow-up visits easier
for select patients who live outside the Chicago
area. The physicians can now “see” a patient in
his or her own home—or in some cases a remote
provider clinic—using special monitors. On their
end, patients will use their MyChart accounts to
access the appropriate software to make the
telemedicine process possible.
Huntington’s Disease Center of Excellence:
The Huntington’s Disease Society of America
named Rush one of 29 Centers of Excellence for
2015. Facilities that receive the designation must
demonstrate a team approach to Huntington’s
disease care and research driven by “expert
neurologists, psychiatrists, therapists, counselors,
and other professionals who have deep experience”
working with families affected by the disease.
New developmental synaptopathies
consortium: Rush is a founding member of the
new Developmental Synaptopathies Consortium,
which aims to deepen researchers’ understanding
of rare genetic diseases that disrupt synapse
formation and can cause autism spectrum disorder
and intellectual disability. As part of this aim, the
consortium will launch a five-year study at 10
medical centers, enlisting children ages 3 to 21
for the purpose of tracing the “natural history”
of the progression of tuberous sclerosis complex,
Phelan-McDermid syndrome, and PTEN-associated
autism and hamartoma tumor syndrome. The National
Institutes of Health has pledged $6 million to the
consortium and will also participate as a member.
In addition to the above achievements, our faculty
were lauded for their contributions to our field.
We are proud to share with you a few of these
honors from the last year:
• Orthopedics This Week named Vincent
Traynelis, MD, to its list of 18 of the best
North American spine surgeons for 2014.
• Thomas Bleck, MD, was named a Master of
Critical Care Medicine by the Society of Critical
Care Medicine and the American College of
Critical Care Medicine.
• Thompson Reuters named David Bennett,
MD, and Julie Schneider, MD, of the Rush
Alzheimer’s Disease Center, among the most
influential researchers in the world.
• Neuropsychologist Christopher Grote, PhD,
was elected as president of the Association of
Postdoctoral Programs in clinical neuropsychology.
• Christopher Goetz, MD, received the
Movement Disorders Research Award from the
American Academy of Neurology.
• Spine neurosurgeon Richard Fessler, MD,
PhD, received the 2015 Neurosurgical Society
of America Meritorious Service Medal for
contributions that have significantly changed
the field of neurosurgery.
We invite you to read on to learn more about our
faculty’s robust research and clinical contributions
to the neurosciences.
Regards,
Richard Byrne, MD
Jacob Fox, MD
Chairperson, Department of Neurological Surgery
Chairperson, Department of Neurological Sciences
The Roger C. Bone, MD, Presidential Chair
The Joseph and Florence Manaster Foundation Professor
of Multiple Sclerosis
Chairmen’s Letter
3
Neurosciences at Rush: At a Glance
Department of Neurological Sciences
•Rush Alzheimer’s Disease Center
•Section of Cerebrovascular Disease
• Section of Clinical Neurophysiology and Epilepsy
•Section of Cognitive Neurosciences
•Section of Critical Care Neurology
•Section of General Neurology
•Section of Movement Disorders
•Rush Multiple Sclerosis Center
•Section of Pediatric Neurology
•Section of Neuromuscular Diseases
•Section of Neuro-oncology
•Neuro-ophthalmology Service
Department of Neurological Surgery
•Neuroendovascular Surgery Center
28 986
•Skull Base and Pituitary Surgery Center
Neurology
outpatient visits
•Spine and Back Care
2 528
Neurology
inpatient discharges
3 420
Neurological surgery
outpatient visits (brain)
5 086
Neurological surgery
outpatient visits (spine)
For additional volume and quality data, see pages 66-67.
Beds
Faculty physicians and
researchers
120
Residents and fellows
32
28
67
General
neurology
Neuro
ICU
Psychiatric Rehabilitation
Inpatient Facilities
4
54
THE 2015 RUSH NEUROSCIENCE REVIEW
10
51
Epilepsy
(adult)
Advanced practice nurses
and physician assistants
24
In 2014, Rush received the University HealthSystem Consortium’s
Quality Leadership Award, ranking fifth among more than 100
academic medical centers.
The Rush stroke program is certified
by the Joint Commission as a
comprehensive stroke center.
Rush has earned
Magnet status—
the highest honor
in nursing—three
times from the
American Nurses
Credentialing
Center.
Rush’s rehabilitation program,
including general inpatient and stroke
specialty rehab, is fully accredited by
the Commission on Accreditation of
Rehabilitation Facilities.
The Rush Alzheimer's Disease Center is a designated
Alzheimer's disease research center, funded by the
National Institute on Aging of the U.S. National Institutes
of Health.
Rush’s research program is fully accredited by
the Association for the Accreditation of Human
Research Protection Programs.
Neurosciences at Rush: At a Glance
5
Primary and Associated Faculty (2014)
Department of Neurological Sciences
Chairperson: Jacob Fox, MD
Alzheimer’s disease
Neelum Aggarwal, MD
Konstantinos Arfanakis, PhD
Zoe Arvanitakis, MD
Lisa Barnes, PhD
David Bennett, MD
Patricia Boyle, PhD
Aron Buchman, MD
Ana Capuano, PhD
Robert Dawe, PhD
Debra Fleischman, PhD
S. Duke Han, PhD
Bryan James, PhD
Sue Leurgans, PhD
Sukriti Nag, MD, PhD
Julie Schneider, MD
Raj Shah, MD
Rita Shapiro, DO
Robert Wilson, PhD
Shawna Cutting, MD
Michael Kelly, MD
Vivien Lee, MD
Sarah Song, MD
Not pictured:
Denis Evans, MD
Christopher Gaiteri, PhD
Jingyun Yang, PhD
Lei Yu, PhD
Cerebrovascular disease
Laurel Cherian, MD
James Conners, MD, MS
Clinical neurophysiology and epilepsy
Antoaneta Balabanov, MD
Donna Bergen, MD
Lawrence Bernstein, MD Adriana Bermeo-Ovalle, MD Thomas Hoeppner, PhD
Not pictured:
Esmeralda Park, MD
Michael Stein, MD
Travis Stoub, PhD
Serge Pierre-Louis, MD
6
Marvin Rossi, MD, PhD
Michael Smith, MD
THE 2015 RUSH NEUROSCIENCE REVIEW
Maggie McNulty, MD
Cognitive neurosciences
Not pictured:
Mehul Trivedi, PhD
Christopher Grote, PhD
Richard Peach, PhD
Critical care neurology
Thomas Bleck, MD
George Lopez, MD, PhD
Torrey Boland, MD
Katharina Busl, MD
Rajeev Garg, MD
Diana Goodman, MD
Laura Jawidzik, MD
Steven Lewis, MD
Megan Shanks, MD
Sayona John, MD
Sebastian Pollandt, MD
General neurology
Jonathan Cheponis, MD
Jacob Fox, MD
Jordan Topel, MD
Not pictured:
Margaret Park, MD
Robert Wright, MD
Allison Weathers, MD
Movement disorders
Brandon Barton, MD, MS
Bryan Bernard, PhD
Cynthia Comella, MD
Christopher Goetz, MD Jennifer Goldman, MD, MS Deborah Hall, MD, PhD
Not pictured:
Melany Danehy, MD
Bichun Ouyang, PhD
Aikaterini Kompoliti, MD
Gian Pal, MD, MS
Kathleen Shannon, MD
Glenn Stebbins, PhD
Leonard Verhagen, MD, PhD
Primary and Associated Faculty (2014)
7
Multiple sclerosis
Not pictured:
Michael Ko, MD
Roumen Balabanov, MD Rajendra Goswami, PhD
Dusan Stefoski, MD
James Stewart, PhD
Neurobiology
Not pictured:
Malabendu Jana, PhD
Elliott Mufson, PhD
Dan Nicholson, PhD
Avik Roy, PhD
Dustin Wakeman, PhD
Yaping Chu, PhD
Bin He, PhD
Jeffrey Kordower, PhD
Kalipada Pahan, PhD
Irwin Siegel, MD
Madhu Soni, MD
Neuromuscular disease
Rabia Malik, MD
Matthew Meriggioli, MD
Neuro-oncology
Robert Aiken, MD
Nina Paleologos, MD
Neuro-ophthalmology
Thomas Mizen, MD
Aimee Szewka, MD
Pediatric neurology
Not pictured:
Lubov Romantseva, MD
Elizabeth Berry-Kravis, MD, PhD Peter Heydemann, MD
8
THE 2015 RUSH NEUROSCIENCE REVIEW
Meryl Lipton, MD
Sylvia Perez, PhD
Primary and Associated Faculty (2014)
Department of Neurological Surgery
Chairperson: Richard Byrne, MD
Richard Byrne, MD
Roham Moftakhar, MD
Michael Chen, MD
Harel Deutsch, MD
Richard Fessler, MD, PhD
Ricardo Fontes, MD, PhD
Lorenzo Muñoz, MD
John O’Toole, MD, MS
Sepehr Sani, MD
Vincent Traynelis, MD
Terry Lichtor, MD, PhD
Richard Penn, MD
Demetrius Lopes, MD
Research faculty
Roberta Glick, MD
Associated faculty at Rush University Medical Center
Not pictured:
David Rothenberg, MD, anesthesiology
Mary Sturaitis, MD, anesthesiology
Pete Batra, MD
Otorhinolaryngology
Aidnag Diaz, MD, MPH
Radiation oncology
Sheila Dugan, MD
Physical medicine
and rehabilitation
R. Mark Wiet, MD
Neurotology
Associated clinical faculty*
Jerry Bauer, MD
Martin Herman, MD, PhD
Patricia Raksin, MD
Tibor Boco, MD
Juan Jimenez, MD
John Ruge, MD
George Bovis, MD
Martin Luken, MD
Andrew Zelby, MD
*Primary appointment is not at Rush University Medical Center
Primary and Associated Faculty (2014)
9
Residents and Fellows (2014)
Department of Neurological Sciences
Residents
Anik Amin, MD
Benjamin Savage, DO
Medical school: Baylor College of Medicine
Medical school: Chicago College of Osteopathic Medicine,
Midwestern University
Stuart Bergman-Bock, MD
Medical school: University of Louisville School of Medicine
Ankush Bhatia, MD
Medical school: Rush Medical College
Michael Boffa, MD
Medical school: New York University School of Medicine
Hunan Chaudhry, MD
Medical school: Rush Medical College
Arun Chhabra, MD
Medical school: Eastern Virginia Medical School
Christine Chuck, MD
Medical school: Indiana University School of Medicine
Kathryn Ess, MD
Medical school: University of Oklahoma College of Medicine
Jaspreet Thiara, MD
Medical school: Rush Medical College
Ruby Upadhyay, MD
Medical school: Rush Medical College
David Whitney, MD
Medical school: Temple University School of Medicine
Fellows
Ameer Al Wafai, MD
Medical school: Beirut Arab University
Residency: University of Tennessee Health Science Center
Medical school: Indiana University School of Medicine
Ian Bledsoe, MD
Avram Fraint, MD
Medical school: Rush Medical College
Medical school: Stanford University School of Medicine
Residency: Stanford Hospital and Clinics
Michael Gibbs, MD
Kyle Carpenter, DO
Medical school: Northwestern University Feinberg School of
Medicine
Medical school: Des Moines University
Residency: University of Kansas Medical Center
Sabreena Gillow, MD
Elizabeth Flaherty, MD
Medical school: University of Colorado School of Medicine
Medical school: Rush Medical College
Residency: Rush University Medical Center
Breyanna Grays, MD
Medical school: Indiana University School of Medicine
Joseph Kipta, MD
Christian Hernandez, MD
Medical school: New York Medical College
Residency: McGaw Medical Center of Northwestern University
Medical school: Louisiana State University School of Medicine in
New Orleans
Zehra Husain, MD
Medical school: Wayne State University School of Medicine
Samantha LoRusso, MD
Medical school: Wake Forest School of Medicine
Brian Marcus, MD
Medical school: Medical College of Wisconsin
Melissa Mercado, MD
Medical school: Boston University School of Medicine
Residency: Boston University Medical Center
Matthew Raday, MD
Medical school: Rush Medical College
Residency: Rush University Medical Center
Rochelle Sweis, DO
Medical school: University of Florida College of Medicine
Medical school: Chicago College of Osteopathic Medicine,
Midwestern University
Residency: Froedtert Memorial Lutheran Hospital
Michael Mercurio, MD
Padmaja Vittal, MD
Medical school: State University of New York Upstate Medical
University College of Medicine
Medical school: M.S. Ramaiah Medical College, India
Residency: Tulane University School of Medicine
Nicholas Osteraas, MD
Jessica Walter, MD
Medical school: George Washington University School of
Medicine and Health Sciences
Medical school: Georgetown University School of Medicine
Residency: Mount Sinai Hospital, New York
Colin McLeod, MD
10
Sarah Sung, MD
THE 2015 RUSH NEUROSCIENCE REVIEW
Department of Neurological Surgery
Residents
Sumeet Kumar Ahuja, MD
Medical school: Indiana University School of Medicine
Daniel Eddelman, MD
Medical school: Indiana University School of Medicine
Ricardo Fontes, MD, PhD
Medical school: University of Sao Paulo School of Medicine
Carter Gerard, MD
Medical school: University of Louisville School of Medicine
Manish Kasliwal, MD
Medical school: All India Institute of Medical Sciences
Rob Kellogg, MD
Medical school: Indiana University School of Medicine
Mena Kerolus, MD
Medical school: University of Missouri-Kansas City School of
Medicine
Ryan Kochanski, MD
Medical school: Wayne State University School of Medicine
Joseph Molenda, MD
Medical school: Johns Hopkins University School of Medicine
Stephan Munich, MD
Medical school: University at Buffalo School of Medicine and
Biomedical Sciences
David Straus, MD
Medical school: University of Chicago Pritzker School of Medicine
Lee Tan, MD
Medical school: Indiana University School of Medicine
David Wallace, MD
Medical school: Rush Medical College
Joshua Wewel, MD
Medical school: University of Nebraska College of Medicine
Fellows
Christopher Gillis, MD
Medical school: Schulich School of Medicine and Dentistry,
University of Western Ontario, Canada
Residency: University of British Columbia Faculty of Medicine,
Canada
Andrew Johnson, MD
Medical school: Columbia University College of Physicians and
Surgeons
Residency: Rush University Medical Center
Erwin Mangubat, MD
Medical school: University of Illinois College of Medicine at
Chicago
Residency: Rush University Medical Center
Residents and Fellows (2014)
11
THE EVOLUTION OF NEUROCRITICAL CARE
Georgia Korbakis, MD; Thomas Bleck, MD, MCCM, FNCS
Author Affiliations: Department of Neurological Sciences (Dr Korbakis)
and Departments of Neurological Sciences, Neurological Surgery,
Anesthesiology, and Internal Medicine (Dr Bleck), Rush University Medical
Center, Chicago, Illinois.
Corresponding Author: Georgia Korbakis, MD, Department of
Neurological Sciences, Rush University Medical Center, 600 S Paulina St,
Chicago, IL 60612 ([email protected]).
Previous Publication: This article was previously published in Crit Care
Clin 2014;30(4):657-671. Minor edits have been made.
Key Points
1. Head trauma is a major aspect of neurocritical care, and
the management of cranial injuries can be traced back to
2000 BC.
2. The first contemporary neurointensive care units using
mechanical ventilation developed after the poliomyelitis
epidemic of the 1920s.
3. Modern neurointensive care units use multiple modalities
to monitor a diverse patient population.
4. The Neurocritical Care Society was founded in 2002
and is a multidisciplinary organization dedicated to
progress in the field of neurocritical care and improvement
in patient outcomes.
Historical Aspects
The history of neurocritical care begins in antiquity, as
documented in the Edwin Smith surgical papyrus. This text,
named for a 19th-century Egyptologist who purchased the
document in Luxor or Thebes in 1862, is an unfinished
textbook on bodily injuries written circa 1700 BC. It is
believed to be a copy of an original manuscript written 1000
years prior and describes 48 case reports, including 27 head
injuries and 6 spinal cord injuries, many with documented
interventions by the investigator. The Edwin Smith papyrus
is remarkable in that it not only gives the first anatomical
description of the brain, cerebrospinal fluid, and meninges
but also describes conditions such as tetanus and aphasia.1,2
Although this extraordinary work gives us a view of ancient
medical practices, it does not mention the earliest known
12
THE 2015 RUSH NEUROSCIENCE REVIEW
neurosurgical procedure of
trepanation, which appears to
have originated in the Neolithic
Era after the discovery of a
trephinated skull dating back
to 10 000 BC. Hippocrates,
frequently hailed as the
“father of medicine,” clearly
documented and advocated
trepanation as a management
for certain head injuries
including skull fractures and
contusions. He also documented
neuroanatomical observations,
categorized different skull
fractures, suggested treatment
for such injuries, and recognized
deleterious complications such
Example of an ancient tumi
as fever and inflammation.3
used for skull trepanation
About 300 years later, Aulus
(Aurelius) Cornelius Celsus of
Alexandria promoted the work of Hippocrates, but
additionally described epidural and subdural hematoma
evacuation via trepanation. In the 2nd century AD, another
titan in the field of medicine, Galen of Pergamon, further
expanded on the technique of trepanation and described
innovative new tools.4 This ancient era also heralded the
initial management for spinal cord injury, and Hippocrates is
credited for one of these early treatments: traction. By using
an extension bench he was able to reduce spinal deformities.
Celsus and Galen further advanced the understanding of the
pathophysiology of spinal cord injury by recognizing that
damage to the “spinal marrow” or cord, and not the
vertebrae, leads to deficits.5
The medieval times following the flourishing of science and
medicine in the Greco-Roman epoch lacked major advances,
excepting those described by one famous Persian intellectual,
Avicenna. His Canon of Medicine was used as a medical text
throughout Europe up until the 18th century,6 and he may
have been the first to realize that stroke was due to blockage
of the cerebral vessels, offering remedies for management of
acute stroke including venesection.7
Mechanical Ventilation and the Birth of
Critical Care Medicine
A complete discussion of the history of mechanical
ventilation is beyond the scope of this article; however, many
key elements in the development of artificial respiration are
relevant to critical care medicine as a subspecialty, and
particularly neurocritical care. Galen first described using a
bellows to ventilate a dead animal artificially through the
trachea; later, the Renaissance physician Andreas Vesalius
documented the use of a tracheostomy with artificial
respiration by inserting a reed tube into the trachea of
animals and blowing in air to observe the heart and thoracic
cavity during vivisection.8 More than a century later, in
1744, the first report of positive pressure ventilation by
mouth-to-mouth resuscitation was described by the surgeon
William Tossach during the successful revival of a suffocated
miner.9 Around the same time, several methods regarding
the resuscitation of humans were in practice, including
insufflating tobacco smoke through the anus, and rolling
a barrel against a victim’s thorax.10,11
The next great stride was in respiratory physiology with
the discovery of carbon dioxide by Joseph Black. He
demonstrated that carbon dioxide was the product of
respiration through experiments with caustic alkali.12 The
discovery of oxygen by Joseph Priestley and Carl Wilhelm
Sheele soon followed through tests involving heating
mercuric oxide.13 Antoine-Laurent de Lavoisier repeated
these experiments and named the gas “oxygen.” He also
realized that oxygen was necessary for respiration or “internal
combustion.”14 By the end of the 18th century, bellows and
pistons were favored over mouth-to-mouth resuscitation for
both aesthetic reasons and concern over lack of effectiveness
when using expired air containing carbon dioxide.11 Despite
this trend, positive pressure ventilation was strongly criticized
after experiments on drowned animals in the 1800s
demonstrated emphysema when the lungs were inflated
forcibly, and thus this practice fell out of favor.9,15
In the early 19th century, attention was directed toward
negative pressure ventilation. Dr Dalziel introduced the tank
respirator, which enclosed the patient in a cylindrical tube
and used bellows to reduce the pressure within the tank to
subatmospheric levels.15 In 1929, Drinker and Shaw
published their work on a new tank respirator that used
electrically operated pumps to create negative and positive
pressure within the tank.16 This respirator became known as
the “iron lung” and was used extensively throughout the
United States to provide ventilatory support for respiratory
paralysis during the poliomyelitis epidemic of the late 1940s.17
The poliomyelitis epidemic in Copenhagen in 1952 prompted
the use of intermittent positive pressure ventilation.
Copenhagen was overwhelmed by a large number of bulbar
cases of poliomyelitis with a mortality rate of 80%.18,19
A polio patient inside an “iron lung” machine, circa 1960 (courtesy of CDC)
Primary credit is given to anesthesiologist Bjørn Ibsen, who
treated a patient with tracheotomy followed by manual
positive pressure bag ventilation using humidified oxygen.
This technique was applied to several patients, and a large
staff, including 250 medical students, worked in relays to
provide uninterrupted ventilation for patients. The mortality
rate in Copenhagen was cut to 39%.18 Knowledge spread
throughout Europe, and quickly intermittent positive pressure
ventilation became standard practice.17,20
The Copenhagen poliomyelitis epidemic provided the
catalyst for the development of dedicated respiratory care
units—the first true intensive care units (ICUs)—to treat
patients with respiratory failure of various etiologies, although
Florence Nightingale is customarily regarded as the first to
have established an ICU during the Crimean War.
Nightingale clustered the sicker patients in a “monitoring
unit.” Dr Dandy Walker created a specialized unit for his
postoperative neurosurgical patients at the Johns Hopkins
Hospital in 1929.21
With the subsequent development of respiratory and cardiac
ICUs, a decrease in mortality rate between mechanically
ventilated patients treated in traditional general hospitals
compared to those in new ICUs was quickly identified and
provided convincing evidence for the establishment of these
units, despite higher costs.22 In 1971, the Society of Critical
Care Medicine was founded to promote the field and define
core competencies. The three founding physicians came from
different medical specialties: cardiology, anesthesiology, and
trauma surgery.21 ICUs today remain diverse, and neurocritical
care units represent yet another important subspecialty linking
the care of the damaged nervous system to other organs.
The Evolution of Neurocritical Care
13
Present day neurosurgery at Rush University Medical Center
Head Trauma
Traumatic brain injury (TBI) has gained much attention in
the news recently, especially regarding sports-related injuries;
however, severe TBI due to injuries sustained during periods
of war has been a topic of study since antiquity. One of the
main indications for trepanation is thought to have been
TBI. Trepanation could be performed by scraping, grooving,
or boring and cutting, as was performed by the Greeks, using
an instrument called a trypanon. Interestingly, many of the
ancient skulls discovered showed postoperative changes in
the bone, indicating survival after the procedure. Hippocrates
was the first to systematically document skull fractures and
emphasized the importance of history taking and careful
physical examination.23 Rhazes, a Muslim physician
practicing in the 9th century, was the first to define concussion
in the modern sense, recognizing that brain injury could
occur without skull fracture. In the 14th century, Guy de
Chauliac further elaborated this concept. He described the
term commotio cerebri, a transient cerebral dysfunction caused
by the brain being shaken and not necessarily related to
structural pathology.24 The next great work regarding head
trauma, Tractatus de Fractura Calvae sive Cranei (Treatise
on Fractures of the Calvaria or Cranium) was written by
Berengario da Carpi in the 16th century. He noted the
difference between injuries involving the dura mater, as
opposed to the pia mater (the latter also involving the
underlying brain parenchyma), and described surgical
treatments for head trauma including a description of
contemporary instruments.25
The prevalence of wars in the next few centuries along with
the increased use of firearms during warfare ushered in a new
era of TBI medicine. The American Civil War (1861-1865)
saw a great deal of head injury, but unfortunately, because of
14
THE 2015 RUSH NEUROSCIENCE REVIEW
lack of aseptic technique, surgery frequently met with
significant infection and subsequent mortality. The medical
“pocket manuals” of the time served as guides for military
doctors. They classified injuries into blunt or penetrating
wounds and distinguished between immediate concussion
and delayed compression, now recognized as herniation.
Advances in anesthesia, such as the use of ether, allowed
advances in surgery as well.26 World War I (1914-1918)
advanced the treatment of brain wounds as both the Allied
and Central powers dealt with trench warfare and focal brain
injury due to smaller ammunition. The English neurosurgeon
Percy Sargent and neurologist Gordon Holmes emphasized
the importance of a detailed neurologic examination prior to
operation, gave indications for different procedures, and
described rises in intracranial pressure (ICP) as well as the
underlying causes and treatment.27 The topic of increased
ICP was further expanded on by Harvey Cushing, who went
to France in 1917 as part of the war effort. Dr Cushing’s
experiences in Europe rapidly advanced the field of
neurosurgery and the treatment of TBI by addressing
hemostasis and aseptic technique. Additionally, his
contributions regarding the use of radiographs and the RivaRocci pneumatic device for recording blood pressure during
anesthesia were particularly valuable.28 George Tabuteau was
a proponent of the then-controversial issue of opening the
dura to remove clot, which subsequently lowered infection
rates and improved outcomes.29 Robert Bárány, a surgeon in
the Austro-Hungarian army, described the importance of
primary wound closure after thorough débridement to prevent
infection.30 Over the remainder of the 20th century, advances
in evacuation times from the battlefield and improvement in
our understanding of the pathophysiology and monitoring of
TBI decreased the mortality rates of head wounds from 74%
in the Crimean War to 10% in the Korean and Vietnam wars.23
TBI in the civilian population remains a serious
epidemiological issue with an annual incidence of 1.7
million and a mortality rate of 52 000 per year.31 In 1996, the
Brain Trauma Foundation published the first set of guidelines
for the management of severe TBI. These guidelines were
most recently revised in 2007. Current recommendations
focus on avoiding hypotension and hypoxia while managing
ICP and maintaining cerebral perfusion and oxygenation.32
Adherence to these guidelines significantly improves survival
among TBI patients.33,34
Intracranial Pressure
Assessment and management of ICP remains one of the main
responsibilities of neurointensivists practicing today. In 1901,
Cushing published a landmark study demonstrating the
“Cushing response”: a triad of hypertension, bradycardia, and
irregular respirations related to intracranial hypertension.
Increasing ICP in dogs via infusion of a salt solution directly
into the subdural space and recording several physiologic
measures, Cushing noted a direct correlation of the rise in
arterial blood pressure with ICP elevation and determined
this was a regulatory mechanism to maintain perfusion to the
brainstem. The recognition of this triad of symptoms remains
crucial to clinical intensive care.35
Evaluation of elevated ICP was traditionally assessed by
clinical examination, measurement of vitals, and inference
from lumbar puncture. In 1953, Ryder et al36 published a case
series recording cerebrospinal fluid pressure continuously in a
few patients following acute brain injury, and in 1965 Lundberg
et al37 published the first report of continuous ICP monitoring
using ventricular cannula in patients with TBI and
nontraumatic cases of intracranial hypertension.38 This article
demonstrated the variations in ICP following head injury and
provided a targeted approach for the management of elevated
ICP. Continuous ICP monitoring remains an integral aspect
in the care of the critically ill neurologic patient, extending
beyond traumatic injuries, and is discussed in a later section.
Although identification of elevated ICP is critical, treatment
options are scarce and reveal the tremendous gaps in our
current knowledge of the pathophysiology and management
of intracranial hypertension. Cushing was truly a pioneer in
this field and was the first to describe palliative subtemporal
decompression to relieve elevated ICP prior to brain tumor
resection, thus lowering the risk of herniation during the
resection.39 Decompressive hemicraniectomy remains one of
the few tools to definitively manage elevated ICP. A modern
application of this concept frequently encountered in
neurologic ICUs today is evident in the recent publications
of 3 randomized controlled trials from Europe (HAMLET,
DESTINY, and DECIMAL) showing that early
decompressive hemicraniectomy reduces mortality in patients
with large hemispheric ischemic stroke.40
The use of chemical agents to lower elevated ICP was
developed in the early 20th century. In 1919, Weed and
McKibben41 published a study on ICP changes following
intravenous injection of solutions with varying
concentrations. They recorded cerebrospinal fluid (CSF)
pressures in cats and demonstrated a sustained elevation
following infusion of hypotonic distilled water and conversely
a marked and rapid decrease in ICP with administration of
hypertonic saline and other highly concentrated salt
solutions. Fremont-Smith and Forbes42 found that hypertonic
urea lowered ICP in animals. Initially used in humans in the
1950s, urea soon fell out of favor because of difficulties in
preparation.43 Mannitol was first studied in dogs in 1961;
subsequently, Wise and Chater44 published their report of
lowering CSF pressure in 24 patients with various causes of
intracranial hypertension using mannitol. In the 1990s, there
was a resurgence of interest in other hypertonic solutions
after several studies demonstrated improved survival in
patients treated with hypertonic saline mixed with dextran
for hemorrhagic shock following trauma, termed “small
volume resuscitation.” Some investigators deemed the
improvement to be due to rapid increase in systemic arterial
pressure and reduction in cerebral edema, with subsequent
increase in cerebral perfusion.45,46 The use of hyperosmolar
agents either as continuous infusions or as boluses is still in
practice today in the management of elevated ICP.
Since the 1930s, the correlation between barbiturates and
lowered ICP has been identified, by their effect on reducing
cerebral metabolism.47 Their use, however, was limited
because of side effects of hypovolemia and respiratory
depression. In 1988, Eisenberg et al48 compared patients with
elevated ICP receiving conventional therapy (hyperventilation,
neuromuscular junction blockade, sedation, mannitol, and
ventricular drainage) to those receiving conventional therapy
plus pentobarbital and found high-dose pentobarbital to be
an effective adjunctive therapy for elevated ICP. Currently,
high-dose barbiturates used to achieve a burst-suppression
pattern on continuous electroencephalography (EEG) are
used to lower ICP in medically refractory cases.
Therapeutic hypothermia has also been used for the management
of elevated ICP. The most evidence comes from TBI studies
where it is used in medically refractory cases.49 It has also
been effective at controlling ICP in acute hepatic failure.50
Neuromonitoring
The field of neurocritical care is relatively young but has
quickly evolved over the last 30 years to involve a
multidisciplinary approach to the management of acute
neurologic injury. The term multimodal monitoring refers to
measuring and recording neurospecific variables in real time,
in addition to the patient’s cardiac and pulmonary status.
The oldest and most dependable of these variables is the
neurologic examination. Vigilant bedside monitoring for
neurologic deterioration is difficult but remains vital in the
care of the neurologically ill patient. Serial clinical
neurologic examinations remain crucial in the ICU.
Although several coma scales have been documented,51 the
Glasgow coma scale is one of the most commonly used tools
in the neurologic ICU. Introduced in 1974 by Teasdale and
Jennett, it is extensively used worldwide to classify the level
of consciousness. Clinical parameters measure the best motor,
verbal, and eye opening responses; a summed score of 8 or less
suggests coma and the need for intubation.52 This scale has
become increasingly useful in communication during patient
transfer (eg, from a community hospital to a tertiary care center).53
More recently, the FOUR (Full Outline UnResponsiveness)
score was developed by Wijdicks et al,54 assigning a score from
1 to 4 to each of 4 components: eye response, motor response,
The Evolution of Neurocritical Care
15
brainstem reflexes, and respiration. This score was validated
in 2005 and allows for greater neurologic detail during
evaluation, remaining testable in intubated patients as well.
Monitoring and measuring changes in ICP are crucial parts
of neurocritical care and are fundamental in the management
of patients with subarachnoid hemorrhage (SAH), TBI,
hydrocephalus, stroke, central nervous system infection, and
hepatic failure. The importance of ICP was recognized more
than 2 centuries ago by Alexander Monro, and advances in
monitoring and managing ICP and related measures are in
continuous evolution.55 Claude-Nicolas Le Cat first documented
the placement of an external ventricular drain after specially
devising a cannula with a stopple that was placed in the
lateral ventricle and used to drain small volumes of CSF in
an infant with hydrocephalus.56 William Williams Keen,
Emil Theodor Kocher, and Hermann Tillmanns made
significant advances in approach and aseptic technique.57
Throughout the 20th century, advances in materials proved
most noteworthy, from horsehairs and catgut to metals and
modern plastic catheters. However, as mentioned previously,
Lundberg was one of the first physicians to continuously
measure and document ICP using a ventricular catheter.
This procedure continues to be used in neurologic ICUs
today.37 This device is easily placed at the bedside using
anatomic landmarks and has the added benefit of being able
to treat elevations in ICP via drainage of CSF. The most
significant complications include malposition, occlusion,
hemorrhage, and infection. Current studies examine the use
of silver or antibiotic-coated catheters to reduce the risk of
ventriculitis, but a consensus has yet to be determined.58,59
Fiberoptic, transducer-tipped monitors were developed in the
1980s, and experience with these devices continues to build.
Again, the device is easily inserted at the bedside and can be
left in place for continuous ICP measurement. The
intraparenchymal monitors have lower complication rates,
but major issues include transducer disconnection and drift.60
Additionally, a significant fraction of patients with an
intraparenchymal monitor will require external ventricular
drainage placement to treat elevated ICP.61
Several other modalities have been developed to continuously
monitor the neurologically ill patient. EEG, traditionally used
for the analysis of seizures, provides a continuous, noninvasive
approach to determine brain function, specifically cerebral
ischemia. In the 1970s, changes in cerebral blood flow during
carotid endarterectomy were noted to correlate with EEG
changes, specifically a replacement of faster alpha range
frequencies for slower theta and delta range components.62
Quantitative EEG transforms EEG waves into numerical
values that are compressed over a large period of time to form
visual graphs, allowing the reader to compare one cerebral
hemisphere to the other. This technique has been
increasingly used in the management of SAH to detect
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THE 2015 RUSH NEUROSCIENCE REVIEW
delayed cerebral ischemia in the comatose patient and has
shown accuracy in predicting ischemia prior to clinical or
radiographic changes.63,64 It provides the added benefit of
continuous monitoring, rather than the routine daily
transcranial Doppler ultrasounds, which provide data for only
one time point. Quantitative EEG continues to be limited by
artifact and requires an experienced electroencephalographer
to interpret. Use of intracortical EEG via a depth electrode
has recently been documented in 5 poor-grade SAH patients
and shows some promise in detecting ischemia by reducing
EEG artifact.65
Several new methods for measuring cerebral oxygenation are
available, and a few are discussed here. Near-infrared spectroscopy
was described in the 1970s and was clinically used to monitor
cerebral ischemia during carotid and cardiac surgery. The
device measures the transmission and absorption of nearinfrared-frequency light and is used as an indirect measure of
oxygenation. The monitor is noninvasive, and although it
has been used with increasing frequency in SAH and TBI
patients, the research is limited66 and sometimes contradictory.67
Jugular venous bulb oximetry has been used to measure
jugular venous oxygen saturation, which is the result of
oxygen delivery to the brain minus the cerebral metabolic
rate of oxygen. It has mainly been applied to comatose
patients following TBI to identify global cerebral ischemia,
and desaturations have been associated with poor neurologic
outcome.68 The use of jugular venous bulb oximetry has several
risks, including insertion complications and low sensitivity.69
Brain tissue oxygen monitors were first used in the 1990s and
involve insertion of a small catheter directly into the brain
parenchyma. Benefits of these monitors include that they can
be placed in an area of interest to determine regional
ischemia. They have been studied mainly in TBI, SAH, and
large hemispheric infarctions and offer real-time information
that can guide management of these patients.70
Since 1992, cerebral microdialysis, a technique for continuous
monitoring of cerebral chemistry and metabolism, has been
used in neurologic ICUs. A thin catheter with a semipermeable
membrane is inserted into the brain parenchyma, and perfusate
is infused. Chemicals from the interstitial space diffuse through
the membrane, and the fluid is collected and analyzed. The
main markers investigated are glucose, lactate, pyruvate, and
glutamate.71 Levels and ratios of these metabolic substances
have been studied, and correlation with outcomes after severe
TBI has been identified. Additionally, changes in these values
have been shown to be early predictors of vasospasm in
SAH.72 Microdialysis has furthered our understanding of
brain energy metabolism following severe neurologic injury
and may be used as a tool in the future for the direct delivery
of substances to damaged tissue or for measuring drug
concentrations in brain tissue.73
Brain Death
With the increasing use of mechanical ventilation in the
1950s, patients who would have previously died from
respiratory arrest were being kept alive in ICUs around the
world. This situation resulted in a widely cited French study
on coma dépassé (a state beyond coma, or irreversible coma)
by Mollaret and Goulon published in 1959.74 This study
documented 23 patients who lost consciousness and other
brainstem function and reflexes but maintained a heartbeat
while being kept on mechanical ventilation. This finding
later prompted an ad hoc committee of anesthesiologists,
neurologists, neurosurgeons, ethicists, public health and
biochemistry professors, and transplant surgeons to convene
at Harvard Medical School and define criteria for what was
then termed brain death.75 The clinical criteria included
unresponsivity, absence of movement and brainstem reflexes,
areflexia, and apnea in the context of an identified cause for
coma.76 In 1976, the Conference of Medical Royal Colleges
and their Faculties in the United Kingdom issued a statement
defining brain death as the loss of all brainstem reflexes.77
Shortly thereafter, the President’s Commission for the Study
of Ethical Problems in Medicine and Biomedical and
Behavioral Research published the Uniform Determination
of Death Act providing either cardiopulmonary or neurologic
criteria for the legal determination of death.78
The American Academy of Neurology conducted an
evidence-based review and published guidelines defining
death by neurologic criteria in 1995 focusing on the clinical
examination and apnea testing.79 Although all 50 states have
adopted the Uniform Determination of Death Act, there
remains great variability among different states and different
institutions regarding the guidelines for diagnosing brain
death.80 This variability holds true regarding the diagnostic
criteria for brain death worldwide as well.81 Ancillary testing
such as cerebral angiography, EEG, transcranial Doppler
sonography, and nuclear imaging are available, but there are
no clear guidelines regarding their use.
This concept of brain death remains controversial. Some
have argued that the Harvard report was devised as a way to
ensure organ donors in the new era of transplant medicine.
Others have taken a more philosophic approach and have
promoted the term total brain failure instead.82
Cardiopulmonary Resuscitation and
Hypothermia for Cardiac Arrest
A synopsis regarding the evolution of critical care medicine
as a specialty would not be complete without a discussion of
cardiopulmonary resuscitation (CPR). Details regarding
positive pressure ventilation were discussed earlier. Peter
Safar, an anesthesiologist named the “father of CPR,” first
introduced the concept of mouth-to-mouth resuscitation with
the head-tilt-chin-lift method to open the patient’s airway,
publishing his work in a landmark study in the Journal of the
American Medical Association in 1958.83 Combining the
findings of closed-chest cardiac massage by W. B. Kouwenhoven,
James Jude, and G. Guy Knickerbocker, which showed that a
pulse could be generated on dogs by external chest compressions,84
Safar united this information and came up with the “ABCs”
of basic life support. Safar realized that patients surviving
cardiac arrest and his own postoperative patients needed
closer monitoring and thus established the first multidisciplinary
physician-staffed ICU in the United States at Baltimore City
Hospital in 1958.85 Dr Safar’s attention then turned toward
cerebral resuscitation following cardiopulmonary arrest and
included investigations into hypothermia.17
Hypothermia had been used in the 1940s to reduce cerebral
edema during neurosurgery, and it was around that time that
interest began to build regarding the use of hypothermia
following cardiac arrest, with case series publishing successful
outcomes in patients who were cooled.86 In February 2002,
two studies published in the New England Journal of Medicine
demonstrated improved neurologic outcomes in patients
treated with hypothermia shortly after cardiac arrest.87,88
The 2010 practice guidelines for advanced cardiac life
support include induced hypothermia to a temperature
of 32°C to 34°C for 12 or 24 hours in the algorithm for
post-cardiac arrest care in a patient who does not follow
commands following return of spontaneous circulation.89
In many institutions, the neurocritical care team is responsible
for therapeutic hypothermia following cardiac arrest.
Future Direction
Since its inception, the field of neurocritical care has grown
dramatically. Much of this article has focused on TBI and
multimodal monitoring where the goal is to prevent
secondary injury. An emerging specialty, neurocritical care
bioinformatics, attempts to use all the data gathered through
multimodal monitoring and analyze these parameters at the
bedside in real time to aid in decision making for complicated
cases.90 This specialty may prove to be an exciting new
development as we continue to understand the complex
physiologic relationships following brain injury.
Although over the last several years we have learned that
oxygen free radicals are a common pathway leading to
neuronal dysfunction, further research is needed to identify
targets to prevent cerebral reperfusion injury. One such target
includes modulation of the mitochondrial permeability
transition pore.91 More practical studies are currently
underway as well. For example, the ATACH II study is
designed to determine the ideal systolic blood pressure goal
for patients experiencing acute intracranial hemorrhage.92
The Evolution of Neurocritical Care
17
Bickerstaff’s encephalitis. The two syndromes are now felt to
represent a spectrum of the same disease process.98
Emergency stroke response at Rush University Medical Center
Several advances have been made in ischemic stroke in the
last few decades. The major advance to date was in 1995 with
the publication of the National Institute of Neurological
Disorders and Stroke rt-PA trial supporting the use of
intravenous tissue plasminogen activator (t-PA) for ischemic
strokes, which demonstrated improved clinical outcomes in
treated patients at 3 months.93 A major role of the neurocritical
care unit now is to admit patients who have received rt-PA
for close monitoring for at least 24 hours given the risk of
bleeding. With the invention of several clot retrieval devices,
endovascular treatment of stroke in addition to t-PA was
becoming popular; recently, however, 3 studies (MR
RESCUE, IMS III, SYNTHESIS Expansion) have not shown
any benefit in clinical outcomes for ischemic stroke patients
undergoing endovascular treatment with or without rt-PA.
Nevertheless, further studies are in process to identify stroke
patients who may benefit from endovascular therapies.94
Patients in the neurologic ICU also have fascinating
nonvascular pathologies, particularly the immune-mediated
disorders. Guillain-Barré syndrome or acute inflammatory
demyelinating polyneuropathy is perhaps one of the more
common immune-mediated disorders requiring ICU
admission when neuromuscular respiratory failure or
autonomic instability occurs. Intravenous immunoglobin or
plasmapheresis is the preferred treatment.95 An interesting
variant, the Miller-Fisher syndrome, was described in the
1950s as a triad of ophthalmoplegia, ataxia, and areflexia.96
Around the same time, Bickerstaff proposed a brainstem
encephalitis with patients experiencing ophthalmoplegia,
ataxia, and impaired consciousness.97 Both diseases tended to
occur after an infection, and later the anti-ganglioside antibody
GQ1b was discovered in both Miller-Fisher syndrome and
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THE 2015 RUSH NEUROSCIENCE REVIEW
Another great stride in antibody-mediated diseases is seen
with the paraneoplastic syndromes. Onconeural antibodies
were first discovered in the 1980s, and some classic examples
include Lambert-Eaton myasthenic syndrome, subacute
cerebellar degeneration, and dermatomyositis. These
syndromes are believed to be caused by an immune response
directed against neuronal proteins expressed by a malignant
tumor.99 Recently, the anti-N-methyl-D-aspartate receptor
antibody was discovered in young women presenting with
prominent psychiatric symptoms, seizures, orofacial
dyskinesias, dysautonomia, and decreased level of
consciousness, who were later found to have ovarian
teratomas. Although this condition can be lethal, several
patients who required ventilatory support, immunotherapy,
and tumor resection survived with marked neurologic
improvement.100 Several antibodies against neuronal antigens
continue to be discovered, and prompt identification and
tumor screening are crucial.
Conclusion
Neurocritical care is a diverse and fascinating field that has
quickly blossomed from a small group of interested physicians
in the 1980s to an established subspecialty encompassing
doctors trained in neurology, neurosurgery, internal medicine,
and emergency medicine. In 2002 the Neurocritical Care
Society was founded in San Francisco, California, by a small
group of neurointensivists; the group held its inaugural
meeting in Phoenix, Arizona, in 2003. The United Council
of Neurological Subspecialties, founded in 2005, formally
recognized neurocritical care as a subspecialty fellowship.101
As diagnostic and therapeutic modalities continue to be
developed, highly trained individuals with a profound
understanding of cerebral physiology and metabolism are
crucial. Neurologic ICUs are now present in most major
medical centers across the United States, and several studies
have demonstrated improved outcomes when neurologically
ill patients are cared for by specially trained staff.102,103 As the
field continues to grow, and with the support of an established
professional society, advances will hopefully continue along
with development of new technologies and improved clinical
trial design. However, the roots of neurocritical care—mainly
improving outcomes in disorders of the nervous system—can
be traced back for thousands of years.
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The Evolution of Neurocritical Care
21
SURGICAL MANAGEMENT OF LOW-GRADE GLIOMAS
Carter Gerard, MD; David Straus, MD; Richard W. Byrne, MD
Author Affiliation: Department of Neurological Surgery, Rush University
Medical Center, Chicago, Illinois.
Corresponding Author: Carter Gerard, MD, Department of Neurological
Surgery, Rush University Medical Center, 1725 W Harrison St, Professional
Building Suite 855, Chicago, IL 60612 ([email protected]).
Previous Publication: This article was previously published in Semin Oncol
2014;41(4):458-467. Minor edits have been made.
Low-grade gliomas represent a wide spectrum of intra-axial
brain tumors with diverse presentations, radiographic and
surgical appearances, and prognoses. By necessity, the goals of
surgical treatment of low-grade gliomas are correspondingly
wide, ranging from simple biopsy for diagnosis, to subtotal
resection for relief of presenting symptoms, to attempted
surgical cure. We review the indications for surgery, surgical
Tumor Classifications and Epidemiology
Gliomas are intrinsic brain tumors arising from the glial cell
lines, including astrocytes, ependymal cells, and
oligodendrocytes. The current World Health Organization
(WHO) classification1 uses histology to classify tumors and
determine grade. The tumors are grouped by the most
commonly encountered cell type and graded by the presence
Nonenhancing, T1, T2 Typical, MRS Suggestive
SURGERY
Symptomatic
Asymptomatic
Mass Effect
No Mass Effect
Younger
Older
Patient Informed
Healthy
Unclear Imaging
techniques, adjuncts, and surgical goals and limitations.
As with most neurosurgical procedures, a judicious balancing
of potential risks and benefits is necessary, and involvement
of the patient in the process is appropriate (Figure 1).
Poor Medical
Condition
Mutual Decision
Large
Small
Compact, WellDefined Borders
Noneloquent
Cortex
Diffuse
Eloquent Cortex
Surgery
Periodic MRI
With and Without Gadolinium
Clinical Observation
Resection + Biopsy
Progression
Questionable Diagnosis
No Progression
Biopsy
Anatomic + Functional Imaging
Noneloquent Location
Likely Eloquent Language Location
Likely Eloquent Motor Location
Awake Intraoperative CS Mapping
Awake or Asleep
Intraoperative Mapping
± Intraoperative Imaging
(CSM, SSEP, MEP, Image Guidance)
New Intraoperative Deficit
No New Deficit
No New Deficit
or Changes in Monitoring
Changes in Monitoring
Stop Resection
Gross Total Resection
Gross Total Resection
Stop Resection
Gross Total Resection
Continue Observation
New Intraoperative Deficit
Figure 1. Decision algorithm for surgical intervention in low-grade gliomas. Abbreviations: CS, cortical stimulation; CSM, cortical stimulation mapping; MEP,
motor-evoked potential; MRI, magnetic resonance imaging; MRS, magnetic resonance spectroscopy, SSEP, somatosensory-evoked potential.
22
THE 2015 RUSH NEUROSCIENCE REVIEW
or absence of necrosis, mitotic activity, nuclear atypia, and
endothelial cell proliferation. Low-grade gliomas are classified
as WHO grade I or II. Although WHO grades I and II are
both considered low grade, the natural history and, therefore,
the management of each group of lesions varies greatly.
Intracranial WHO grade I gliomas include pilocytic
astrocytomas, subependymal giant cell astrocytomas,
gangliogliomas, and subependymomas. These lesions may
be diffuse but are usually well defined with a benign clinical
course. Patients with these lesions are often cured with a
successful resection alone. We will focus primarily on the
management of WHO grade II astrocytomas, pleomorphic
xanthoastrocytomas, oligodendrogliomas, and oligoastrocytomas
because these tumors are common in adults and present the
greatest clinical challenges.
WHO grade II gliomas have an incidence of 1 to 2 per
100 000 people per year and are most likely to affect young
adults.2-4 The vast majority of patients, up to 80%, present
with seizures.5 Lesions may be either well defined, involving
two or fewer lobes with clear margins on fluid-attenuated
inversion recovery (FLAIR), or diffuse, with poorly defined
FLAIR borders or involving more than two lobes.
Surgical Indications for Biopsy
When a patient is found to have a lesion consistent with a
low-grade glioma, a decision must be made between surgical
intervention and observation. In cases where a tissue
diagnosis is thought to be useful to direct therapy, stereotactic
or open biopsy may be performed. As more and more
evidence argues for resection first, biopsy of low-grade gliomas
is used in limited scenarios such as when a tumor is
inaccessible or diffuse, or when there is a poor functional
status or uncertain pathology. Open biopsy with image
guidance is appropriate in cases where the lesion approaches
or reaches the cortical surface in a safe, accessible area.
Stereotactic biopsy is most appropriate for deep-seated or
small lesions (Figure 2). Depending on the surgeon’s
A
B
experience and comfort with each technique, frame-based or
frameless stereotactic biopsy can be performed. Frameless
stereotaxy has gained popularity as its reliability has been
shown in large series.6-8
Technical Aspects of Stereotactic and
Open Biopsy
The goal of a biopsy is to acquire sufficient tissue to obtain a
diagnosis while minimizing the risk to the patient. Prior to
any biopsy, imaging is obtained for use in neuronavigation
and the stereotactic targeting system in the operating room.
The most common study is magnetic resonance imaging
(MRI; T2-weighted images and T1-weighted with contrast)
1-mm slices; thin-cut computed tomography (CT) with
contrast may be used if MRI cannot be used. Once the
patient is sedated and positioned, the tumor is localized using
neuronavigation and cranial landmarks. Lesions that arrive
at or are close to the surface of the cortex can be accessed
with a single 1-cm burr hole or with a small craniotomy.
Once the dura is opened, the cortex is inspected for abnormal
appearance, and biopsies are taken, then sent for frozen and
permanent pathology. If the surgeon is satisfied with the
tissue sample, the surgery is complete and the wound is
closed. Although the goals of a stereotactic biopsy are the
same, the technique requires some additional planning.
Prior to incision, a plan is defined in the neuronavigation
computer, including the entry point and the trajectory of the
needle to the target. Several general principles are used when
making any stereotactic plan, whether for stereotactic biopsy
or deep brain stimulator lead placement. The trajectory
should avoid sulci in order to prevent vascular injury and
should try not to pass through the ventricle because of the
risk of intraventricular hemorrhage and subsequent
hydrocephalus. Generally, lesions involving the basal ganglia
are approached with a frontal entry point; the precentral
gyrus can be avoided by placing the burr hole anterior to its
location. Brainstem lesions, such as pontine gliomas, can be
accessed with a burr hole in the suboccipital area, with a
Figure 2. A, A lesion involving the midbrain
and pons. This deep-seated lesion involving
multiple eloquent structures is an ideal
candidate for stereotactic needle biopsy. B, A
superficial lesion involving bilateral frontal lobes,
more so on the left. This lesion involves the
cortex and is easily accessed via an open biopsy.
Surgical Management of Low-Grade Gliomas
23
trajectory that passes through the cerebellar peduncle.
Another strategy used to increase the chance of an accurate
diagnosis includes targeting areas of enhancement to obtain
any tissue that may be high grade. Because of the heterogeneous
nature of gliomas and the limited sample provided from a
biopsy, there is a real chance of undergrading tumors.9 Some
studies have reported improved accuracy by using positron
emission tomography and hydrogen magnet resonance
spectroscopy to target areas that are likely to be high grade.10-13
Once the entry site and trajectory is defined, a 1-cm burr
hole is made, the dura is opened, and the underlying
arachnoid is coagulated. A small docking port is placed
over the burr hole and secured to the patient’s skull with
temporary screws. A guide tube is placed in the docking port
and the trajectory is matched to the predetermined plan.
Stereotactic biopsies often use a blunt cannulated needle
that is 1 mm wide with an 8-mm side port, which will
produce 1×8-mm tissue cores. Once the needle has been
registered with the intraoperative neuronavigation system, it
is placed into the guide and advanced to the target. When
the needle is at target, the side port is opened for a few
seconds while slow steady suction is applied. The inner stylet
is then removed with the tissue core. The process is then
repeated after changing the orientation of the side port with
needle rotation or depth. When sufficient tissue has been
obtained, the needle and docking port are removed and the
wound is closed. The most common complications
encountered with this procedure include new neurological
deficit due to hemorrhage or cerebral edema. The
complication rate for stereotactic biopsies has repeatedly been
quoted with a morbidity rate of 2.4% to 6% and mortality of
0.6% to 1.2%.7,14,15 A series of 270 consecutive stereotactic
biopsies of varying pathologies reported by McGirt et al
demonstrated 5% morbidity and 1% mortality with a
diagnostic accuracy of 93%.8
Surgical Indications for Resection
The indications for surgical resection include diagnosis, relief
of neurological deficits, medically uncontrolled epilepsy, relief
of mass effect, and possibly improvement in progression-free
survival (PFS) or overall survival (OS). The usefulness of
surgical resection for diagnosis and relief of mass effect are
self-evident. If mass effect is causing neurological deficits,
removing the majority of the mass is likely to aid in relief of
neurological deficits. If the tumor is infiltrative of demonstrably
functional areas, but does not cause mass effect, surgical
resection is unlikely to relieve symptoms and may bring a
high risk of postoperative deficit. Surgical resection of a
low-grade glioma in a patient who has medically intractable
epilepsy related to the glioma is a common indication for
surgery. In patients with low-grade glioma-associated seizures,
surgical resection results in seizure improvements in almost
24
THE 2015 RUSH NEUROSCIENCE REVIEW
all patients: Engel class 1 outcome (seizure-free) in 67% to
70% of patients and improvement in seizure frequency in
another 20% to 25%.16-19 Moreover, increased extent of tumor
resection was found to be an important factor in multivariate
analysis of seizure outcome in low-grade glioma.16-18
There has been significant historical discussion regarding the
influence of the extent of resection (EOR) and overall survival
in the treatment of low-grade gliomas.20 Arguments for biopsy
alone or radiographic monitoring have been purported since
the advent of CT and MRI technologies. Similarly, as our
ability to detect these lesions has grown with increasingly
sensitive neuroimaging modalities, we have been forced to
scrutinize our management approaches to these lesions. Our
diagnostic and surgical treatment algorithm has been outlined
above. Older retrospective studies comparing subjective EOR
parameters (eg, “gross total resection” vs “subtotal resection”
vs “biopsy”) have yielded variable results.20,21 However, recent
literature examining volumetric EOR data has identified
consistent associations between increased EOR and increased
patient PFS and OS.22-27 On the basis of these data, a growing
number of surgeons pursue a maximal resection of low-grade
gliomas. In cases without mass effect and where the expected
volumetric resection of tumor is less than 50%, it may be
appropriate to consider biopsy or radiologic monitoring as
outlined above.23,24 Although minor transient deficits are
common after surgery for eloquent low-grade glioma,25,28-30
most resolve over the first several months postoperatively and
thus yield a low rate of permanent neurologic morbidity and
consequent functional impairment.28
Preoperative Evaluation of the Surgical
Patient
The most critical factor in surgical planning for resective
surgery in low-grade gliomas is the neuroanatomic milieu
within which the neoplastic lesion exists. The intuitively
obvious evidence of this fact has been demonstrated in
numerous large case series,23-25,30-32 each of which has shown
the prognostic importance of the anatomic location of lowgrade gliomas. Preoperative MRI (T2-weighted images and
T1-weighted with contrast) with 1-mm (or smaller) slices is
used to evaluate and categorize lesions into 3 groups:
presumed eloquent location, near-eloquent location, and
noneloquent location. Our definition of topographic regions
of the brain with presumed eloquence is in line with
previously published studies30,33 and includes the primary
sensorimotor cortex of the precentral and postcentral gyri,
the Wernicke area (posterior portion of the superior temporal
gyrus and the inferior parietal lobule), the Broca area
(inferior dominant frontal lobe), the calcarine visual cortex,
the basal ganglia, the internal capsule, the thalamus, and the
white matter paths of each. If any part of the lesion is found
to infiltrate these regions, it is regarded as being located in
A
B
Figure 3. A, Functional
magnetic resonance imaging
of a patient with a lesion in the
left frontal parietal operculum.
Language activity can be seen
in the Broca area, the Wernicke
area, and the supramarginal
gyrus. B, Motor mapping of
the same patient. While the
patient is speaking, motor
activity of tongue is evaluated.
The study shows that the
tumor has altered the normal
anatomy and shows tongue
activity displaced to the superior
margin of the tumor.
presumed eloquent brain; if it approaches but does not clearly
involve these regions, it is considered near eloquent; and if it
is situated in a separate anatomic location, it is considered
noneloquent. The preoperative MRI also is used to identify
functionally important vessels that will be encountered and
must be spared during the operation.
the most dangerous regions of the tumor with regard to
neurological morbidity and to estimate the extent of safe
resection prior to the operation, further informing discussions
with both the patient and multidisciplinary care providers
considering adjuvant and neoadjuvant treatment options.
The classification of a lesion as located in eloquent, neareloquent, or noneloquent brain has ramifications for the
operative strategy used. Although lesions distant from
eloquent anatomic structures do not require further
preoperative investigation, it may be prudent to pursue
preoperative functional imaging in lesions involving eloquent
and near-eloquent brain to help define the critical structures
within the proposed operative field. This imaging includes
diffusion tensor tractography to define white matter tracts
(eg, the posterior limb of the internal capsule), and
functional MRI (fMRI) to localize primary speech and motor
cortices (Figure 3, A and B). While the use of fMRI allows
the surgeon to better assess the relationship of a lesion to
eloquent cortex, there are considerable limitations, especially
when mapping language areas. Multiple recent studies have
shown relatively reliable motor mapping when compared to
intraoperative stimulation.34-37 However, while fMRI largely
has replaced the Wada test for language lateralization, fMRI
does not allow for precise localization of language, which is
reflected by the wide range of reported results in the
literature. A review of 5 studies showed language mapping
sensitivity from 59% to 100% and specificity from 0% to
97% when compared to intraoperative stimulation.38,39
Various authors have used newer noninvasive technologies
for anatomic mapping such as magnetoencephalography and
transcranial magnetic stimulation.40,41 Advanced preoperative
functional imaging may serve two important purposes:
(1) neuroplasticity may induce migration of functional activity
to other neighboring regions in tumor-infiltrated brain, thus
providing a better understanding of the true functional
eloquence of the anatomically eloquent region under
investigation; and (2) it enables the surgeon to understand
Intraoperative Monitoring and Cortical
Stimulation
The paradigm of noneloquent versus eloquent and neareloquent lesions is also used to define the extent of
intraoperative monitoring and mapping required to safely
perform a maximal resection of low-grade gliomas. In
noneloquent lesions, the low risk of surgical trauma to
anatomically eloquent regions of the brain and the low
likelihood of aberrant relocation of functional neural tissue
enables a lower level of intraoperative monitoring. In the
noneloquent cases no physiologic monitoring may be
necessary. In other cases, somatosensory-evoked potentials
and/or motor-evoked potentials are used and the operation
is performed with the patient under general anesthesia.
Conversely, in eloquent and near-eloquent lesions the
potential for neurologic injury is magnified. To maximize safe
resection in these cases, awake craniotomy may be employed
if the patient is cooperative and capable of tolerating such a
procedure.29,30,42,43 This method enables active monitoring of
the functional neural tissue in the operative bed and enables
intraoperative mapping of functional tissue. Addressing the
eloquent region of tumor as the final step of the surgical
resection and using cortical and subcortical stimulation to
map the eloquent region of tumor during surgery allows a
safe, maximal tumor resection. A member of the mapping
team is appointed to continuously monitor speech and motor
function during the resection. Bipolar electrodes (Integra) are
used starting at an amplitude of 2 mA (pulse frequency 60 Hz
and 2-3 seconds duration). The surgical team notes where
stimulation produces motor reaction, sensory reaction, or
speech arrest.28,44 Stimulation levels are raised until a
Surgical Management of Low-Grade Gliomas
25
physiological response is noted or until an after discharge is
noted on electroencephalogram (Figure 4). A stimulation site
is considered positive if the response is clear and
reproducible. Resection of tumor comes no closer than 1 cm
from a positive stimulation site, and the vascular supply to
the area must be preserved.45,46 In a patient with a neareloquent lesion who is unable to tolerate awake craniotomy,
phase reversal of electrocorticography using subdural
electrodes may be used to identify the central sulcus and
perirolandic gyri.47 Cortical stimulation at increased
amplitudes also may be used in the sleeping patient to induce
motor activity and to identify motor cortex. During
stimulation it is important to be prepared for an induced
seizure, the anesthesia team must be informed of stimulation,
and cold saline irrigation48 should be immediately available to
help abort stimulation-induced seizures. The anesthetic
course for awake craniotomy with intraoperative mapping
involves generous application of local anesthetic to achieve a
complete scalp block. During pinning and surgical opening
the patient is heavily sedated, typically with propofol and
remifentanil.28,30,42,44 After exposure is complete, the sedation
is lightened to enable patient participation during mapping
and tumor resection. Finally the patient is resedated after the
tumor resection is completed for final closure.
Surgical Technique
should begin at the least eloquent areas and end at the most
eloquent areas. The corticotomy is made through
noneloquent tissue, with attention to surrounding vascular
structures. A sufficient biopsy of the lesion is performed and
sent for pathology; care should be taken to obtain tissue from
different regions of the lesion and to include samples of any
enhancing or visually atypical areas to minimize the risk of
misdiagnosing a higher-grade lesion due to sampling error.
After sufficient tissue is obtained for pathology, tumor
resection is performed with the aide of suction, bipolar
electrocautery, and ultrasonic surgical aspirator. The surgeon
uses color, firmness, and texture to follow the tumor from
sulcus to sulcus. In eloquent and near-eloquent lesions,
subcortical mapping is used to define the resection margin
and avoid functionally eloquent white matter structures. At
the border of the lesion, distinguishing between normal tissue
and tumor may become quite difficult. A combination of
neuronavigation, visual cues (typical metallic-gray
discoloration of the tissue49), various tumor-staining dyes such
as 5-aminolevulinic acid,50 and intraoperative imaging
(ultrasound,51 CT,52,53 and MRI54) are employed to define the
precise margins of resection. Multiple studies have reported
increased extent of resection with the use of intraoperative
MRI.55-60 However, the increased operative times, narrow
applicability, and high cost make this technology far from
ideal. Intraoperative ultrasound fused with preoperative MRI
has been described in the neurosurgical literature and may be
beneficial.61 Another technique, based on observations in
diffuse tumors that abnormal cells can be found up to 20 mm
beyond any MRI abnormalities,62 is the “supratotal” resection.
This technique involves extending the resection around a
tumor beyond abnormalities seen on imaging until eloquent
areas are localized.43 The surgery is ended when maximal
resection of the lesion is complete, when there is a new
deficit, or when changes in monitoring are noted.
Surgical exposure depends on the anatomic location and size
of the lesion. Intraoperative stereotactic navigation is useful
to plan the craniotomy site and dimension. Positioning, skin
incision, and type of craniotomy are performed in a manner
similar to the treatment of other intracranial lesions. After
the craniotomy has been performed and the dural opening
made, the next steps in surgical treatment involve localization
of the lesion within the surgical field. The margins of the
tumor are mapped with the aide
of stereotactic neuronavigation,
A
B
which also provides visual cues
to abnormal tissue (edematous
regions, grayish discoloration,
and increased vascularity)
(Figure 5). The borders of the
tumor can be defined with
surface and depth markers; once
resection has begun, the brain
can shift, rendering
neuronavigation less reliable.
For eloquent and near-eloquent
lesions, cortical mapping is
performed (as described above)
to provide an outline of the
Figure 4. A, Cortical mapping with a bipolar stimulator. When eloquent areas are identified, they are marked with
resection margins and to
the white surface marker that is seen on the field. During stimulation, the electroencephalogram is monitored.
B, The recording shows the effect of induced regional activation and not focal activation between the bipolar
identify functionally critical
stimulator probes. This induced activation may lead to both false positive localization and generalized seizures.
cortical regions. Resection
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THE 2015 RUSH NEUROSCIENCE REVIEW
A
B
C
Figure 5. Low-grade glioma. A, Preoperative magnetic resonance imaging (MRI) shows a left insular glioma that extends to the frontal and temporal
operculum. B, On gross inspection, the tumor can initially be identified as a gray discoloration of the cortex. Resection is then started with ultrasonic
aspiration and bipolar cautery. C, The postoperative MRI shows the resection cavity with decreased mass effect on surrounding structures.
The goals of surgery must always remain in the forefront of
the surgeon’s mind during the preoperative and operative
phases of treating patients with low-grade gliomas. Along
these lines, surgical intervention can offer a number of
benefits to patients with low-grade gliomas. First, the most
modest, but critical, function of surgery is to obtain tissue
to provide the patient and oncology team with a definitive
histopathologic and molecular diagnosis of the lesion. This
diagnosis is critical in planning subsequent chemotherapy or
radiotherapy where appropriate and also may help to guide
further surgical decision making in the event of recurrence
or of residual tumor. Second, resection of tumor provides the
additional benefits of removing any mass effect resulting from
the tumor’s growth and also achieving a critical cytoreduction
of neoplastic cells as the first step in treatment of these
lesions. Finally, in patients with resectable lesions, total
excision of the tumor may result in long-term oncologic
control.63 In all cases, the goal is to achieve the surgical goals
without causing new neurological deficits. Thus, the ideal
surgery will achieve a tissue diagnosis along with total excision
of the lesion and cause no additional neurologic morbidity.
However, certain tumors, particularly those located in
functionally eloquent regions, may not permit all of these
goals to be achieved, and it is here that surgical judgment
of the value of further resection at the risk of neurologic
morbidity is most critical. In many cases, taking the resection
to the extreme margins of functional tissue with the aid of
intraoperative cortical/subcortical mapping will allow for a
maximal resection but may induce transient partial neurologic
deficits. Depending on the goals of the procedure, specific
surgical endpoints may include adequate biopsy; sufficient
debulking to remove mass effect from tumor; resection of
tumor to eloquent tissue as determined by either anatomic
topography, functional imaging, intraoperative monitoring,
cortical/subcortical mapping, or neurologic deficit during
awake craniotomy; or gross total resection of tumor.
Postoperative Management
After surgery, the patient is awoken from anesthesia and
admitted to the intensive care unit overnight for neurological
monitoring. The patient’s neurologic status is monitored,
normotension is maintained, and medication for seizure
prophylaxis is continued. If the patient had no seizure
activity prior to surgery, the surgeon may choose to place
the patient on a short course of seizure prophylaxis.64
Although perioperative antiepileptic medication is
commonly administered for tumors, a recent prospective
study has demonstrated a perioperative clinical seizure rate
of only 3%, which calls into question the need for
prophylactic medications for this population.65 The following
day, the patient is transitioned out to a general floor or even
home depending on the patient’s functional status. MRI with
and without contrast is done prior to 72 hours after surgery to
detect residual tumor. The patient will return to the clinic
10 to 14 days later for inspection of the wound and removal
of staples or sutures. The initiation of chemotherapy or
radiation is often delayed for 2 weeks or more from surgery,
if possible, to limit the effects on wound healing.
Conclusion
A growing body of evidence shows that aggressive surgical
resection of low-grade gliomas may improve symptoms, extend
PFS, and even cure a select few patients. With the application
of preoperative functional imaging, intraoperative navigation,
and cortical stimulation, neurosurgeons are able to perform
more complete resections while limiting the risk to patients.
Although the treatment paradigm has moved away from biopsy
and observation, that approach still has a role when the patient
has a poor status or when the tumor is unresectable.
Surgical Management of Low-Grade Gliomas
27
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Surgical Management of Low-Grade Gliomas
29
VISUOPERCEPTIVE REGION ATROPHY
INDEPENDENT OF COGNITIVE STATUS IN
PARKINSON’S DISEASE HALLUCINATORS
Jennifer G. Goldman, MD, MS; Glenn T. Stebbins, PhD; Vy Dinh, BA; Bryan Bernard, PhD;
Doug Merkitch, BA; Leyla deToledo-Morrell, PhD; Christopher G. Goetz, MD
Author Affiliations: Department of Neurological Sciences, Rush University
Medical Center, Chicago, Illinois (Drs Goldman, Stebbins, Bernard,
deToledo-Morrell, and Goetz and Mr Merkitch); and School of Medicine
and Public Health, University of Wisconsin, Madison (Ms Dinh).
Corresponding Author: Jennifer G. Goldman, MD, MS, Department of
Neurological Sciences, Rush University Medical Center, 1725 W Harrison St,
Suite 755, Chicago, IL 60612 ([email protected]).
Previous Publication: This article was previously published in Brain
2014;137(pt 3):849-859. Minor edits have been made.
Introduction
Psychosis in Parkinson’s disease clinically ranges from
illusions to hallucinations and delusions, with visual
hallucinations being the most frequent form.1-3 Visual
hallucinations develop in more than 50% of Parkinson’s
disease patients and, once present, are progressive, chronic,4,5
and associated with increased nursing home placement,
morbidity, and mortality.6,7 Risk factors for hallucinations in
Parkinson’s disease patients include older age, advanced
disease, cognitive impairment, depression, and sleep
disturbances.2 Although dopaminergic medications play a
role in the pathophysiology of Parkinson’s disease
hallucinations, the development of the hallucinations
extends beyond mesolimbic dopaminergic receptor
hypersensitivity or stimulation. At present, however, their
exact mechanisms and neurobiological substrates are not fully
known. Current evidence favors multiple levels of cerebral
dysfunction including aberrant “bottom-up” and “top-down”
visual processing, with faulty input from the visual system and
brainstem to higher cortical visual areas (eg, occipitaltemporal and occipital-parietal lobes) and altered cortical
integration from orbitofrontal and dorsolateral prefrontal
cortex to cortical visual regions.8-11 Furthermore, these visual
processing aberrations invoke the ventral “what” and dorsal
“where” streams, which are responsible for object recognition
and spatial location, respectively.12,13 Visual hallucinations
experienced by Parkinson’s disease patients may reflect
disturbances in the brain’s ability to attend to and process
30
THE 2015 RUSH NEUROSCIENCE REVIEW
these visual stimuli, integrate sensory information and prior
expectations, and generate correct interpretations of visual
input, thereby integrating elements of attentional, cognitive,
emotional, and visuoperceptive processes.10,11,14
Neuroimaging studies using structural, metabolic, and functional
techniques permit in vivo investigations of underlying brain
abnormalities in Parkinson’s disease patients with hallucinations.
Metabolic and functional neuroimaging studies in Parkinson’s
disease visual hallucinators, compared to nonhallucinators,
frequently reveal dysfunction in brain regions involved in
visuoperception, namely the occipital, temporal, and parietal
lobes, and thus suggest that the culprit may be primarily
aberrant visual processing.15-20 This decreased activation in
the visual “what” and “where” regions of the brain in hallucinators
has been coupled in some studies with increased activation of
frontal or subcortical regions in response to functional MRI
visual stimulation paradigms18 or hyperperfusion of temporal,
precentral,20 or frontal regions17 on metabolic imaging studies.
Other functional MRI studies, however, reveal decreased
activation in frontal regions in hallucinators just prior to
image recognition19 or decreased activation in fronto-parietal
networks.21 Although these somewhat differing results of
metabolic and functional neuroimaging studies do not resolve
the debate of “bottom-up” or “top-down” processing, they are
united by the shared theme of disrupted posterior and
anterior brain regions. Collectively, they suggest a role of
attentional, cognitive, emotional, and visuoperceptive
processes, individually or in combination, in the clinical
manifestation of visual hallucinations.
Despite the predominant decreased activation in the
posterior visuoperceptive brain regions found in many of the
metabolic and functional neuroimaging studies, it is
surprising that, to date, only one structural brain MRI study
using an automated, unbiased analytic technique of wholebrain voxel-based morphometry (VBM) to compare
Parkinson’s disease visual hallucinators to nonhallucinators
has revealed gray matter atrophy in these areas (ie, lingual
Multidisciplinary Parkinson’s disease care lead by Christopher Goetz, MD (right)
gyrus, superior parietal lobule).22 Most other structural MRI
studies using VBM analyses demonstrate predominantly
decreased gray matter volumes in hippocampal, limbic,
paralimbic, and neocortical regions in Parkinson’s disease
hallucinators, compared to nonhallucinators.21,23-25 These
brain regions, particularly the mesial temporal lobe, however,
are also implicated in memory and cognitive functions26 and
exhibit atrophy on structural MRI scans in Parkinson’s
disease dementia patients.27 Thus, the co-occurrence of
cognitive impairment or dementia in Parkinson’s disease
hallucinators potentially confounds our interpretation of
these MRI findings as representing neuroanatomical
substrates specifically associated with hallucinations in
Parkinson’s disease. Moreover, in several MRI studies, even
those hallucinating Parkinson’s disease patients classified as
without dementia frequently exhibited significantly worse
performance on global cognitive function, memory, and
executive function tests, compared to nonhallucinating
Parkinson’s disease patients without dementia,24,25 thereby
indicating that the examined groups were not truly of
comparable cognitive abilities.
Although the pathophysiology of hallucinations may be
linked to impaired attentional and visuoperceptive
processing, and although their presence has been considered
an important predictor of dementia,28 we hypothesize that
these two behavioral abnormalities, namely hallucinations
and dementia, may have distinct and independent
neurobiological substrates. The identification of structural
MRI differences in Parkinson’s disease hallucinators,
independent of cognitive deficits, would be clinically
important not only for more accurate establishment of
underlying neurobiological mechanisms, but also for the
development of novel therapies targeting Parkinson’s disease
hallucinations and visuoperceptive functions. Thus, it is
important to examine Parkinson’s disease hallucinators and
nonhallucinators of comparable cognitive function to identify
neuroanatomical contributions that are specific to Parkinson’s
disease hallucinations. Accordingly, the aim of our study was
to use structural MRI whole-brain VBM analyses to identify
changes in gray matter in Parkinson’s disease participants
with current and chronic visual hallucinations where
dementia was controlled for, that is, where participants were
matched for cognitive status (with/without dementia) to
Parkinson’s disease patients without visual hallucinations.
Materials and Methods
Participants
Parkinson’s disease participants were recruited from the Rush
University Medical Center movement disorders clinic as part
of an ongoing study of clinical and neuroimaging markers of
Parkinson’s disease-related cognitive and behavioral problems.29
From a cohort of 100 Parkinson’s disease participants, we
Visuoperceptive Region Atrophy in Parkinson’s Disease Hallucinators
31
identified 25 with current and chronic visual hallucinations.
From the remaining 75 nonhallucinators, we selected 25 who
were matched to the hallucinator group on cognitive status
and age. All Parkinson’s disease participants were examined
by a movement disorders neurologist (J.G.G.) and met United
Kingdom Parkinson’s Disease Society Brain Bank criteria.30
Parkinson’s disease participants had disease durations of ≥ 4
years and were on stable medication regimens. Exclusionary
criteria were (1) atypical or secondary forms of parkinsonism
(eg, dementia with Lewy bodies, multiple system atrophy,
progressive supranuclear palsy, corticobasal degeneration, or
parkinsonism due to neuroleptic exposure, cerebrovascular
disease, or known structural causes); (2) severe or unstable
depression; (3) anticholinergic medications (eg, trihexyphenidyl,
benztropine, tricyclic antidepressants); (4) other medical or
neurological reasons for cognitive impairment (eg, seizures,
strokes, head trauma, significant vision or hearing deficits);
or (5) contraindications to MRI (eg, cardiac pacemaker/
defibrillator, surgical clips, foreign metallic implants). In
Parkinson’s disease participants with dementia, all had motor
symptoms for at least 1 year prior to dementia onset. The study
was approved by the Institutional Review Board of Rush
University Medical Center in Chicago, Illinois; participants
gave written informed consent to participate in the study.
Parkinson’s disease participants were classified as current and
chronic hallucinators if they met the following criteria: (1)
current hallucinations: a score ≥ 1 on the Movement
Disorder Society Unified Parkinson’s Disease Rating Scale
(MDS-UPDRS) Part I question 1.2, “Hallucinations and
Psychosis,”31 which determines whether the patient has seen,
heard, smelled, or felt things that were not really there over
the past week (the question is scored as follows: 0: normal,
no hallucinations or psychotic behavior; 1: slight illusions
or nonformed hallucinations, but patient recognizes them
without loss of insight; 2: mild, formed hallucinations
independent of environmental stimuli, no loss of insight; 3:
moderate, formed hallucinations with loss of insight; 4:
severe, patient has delusions or paranoia); and (2) chronic
hallucinations: the presence of psychotic symptoms,
occurring for at least 1 month, and fulfilling diagnostic
criteria for Parkinson’s disease-associated psychosis proposed
by the National Institutes of Health/National Institute of
Table 1. Clinical Features of the Parkinson’s Disease Cohorta
Parkinson’s Disease
Nonhallucinators
(n = 25)
Parkinson’s Disease
Hallucinators
(n = 25)
P Value
Age, y
75.4 (6.1)
74.8 (6.0)
0.73
Male, n (%)
18 (51.4)
17 (48.6)
0.76
Education, y
15.7 (2.9)
15.4 (3.3)
0.75
Disease duration, y
10.8 (4.4)
13.1 (4.6)
0.08
MMSE
25.1 (4.4)
23.9 (5.4)
0.38
CDR Global Score, median (range)
0.5 (0-2)
0.5 (0-2)
0.46
CDR Sum of Boxes
3.2 (3.2)
3.5 (3.1)
0.72
43.5 (13.2)
39.0 (13.8)
0.24
3 (2-5)
3 (2-5)
0.85
787.8 (356.9)
808.3 (329.5)
0.83
7 (14%)
8 (16%)
0.76
Antipsychotic use, n (%)
3 (12.0%)
6 (24.0%)
0.27
CPZ equivalent dose, mg/d
12.0 (37.1)
13.3 (27.6)
0.33
Cognitive medication, n (%)
7 (28.0%)
7 (28.0%)
1.0
Demographics
Cognition
Motor
MDS-UPDRS total motor score
MDS-UPDRS Hoehn and Yahr, median (range)
Medications
LEDD, mg/d
Dopamine agonist use, n (%)
Abbreviations: CDR, Clinical Dementia Rating; CPZ, chlorpromazine; LEDD, levodopa equivalent daily dose; MDS-UPDRS, Movement Disorder
Society Unified Parkinson’s Disease Rating Scale; MMSE, Mini-Mental State Examination.
a
Data presented as mean (SD) unless otherwise noted.
32
THE 2015 RUSH NEUROSCIENCE REVIEW
Mental Health (NIH/NIMH) Work Group.1 All Parkinson’s
disease hallucinators had visual hallucinations, though
participants with hallucinations in other sensory modalities
(eg, auditory, olfactory, tactile) were included in this group if
these hallucinations occurred in addition to visual
hallucinations. Parkinson’s disease participants without
hallucinations had a score of 0 (“normal”) on the MDSUPDRS “Hallucinations and Psychosis” question and did not
meet the NIH/NIMH Work Group criteria for Parkinson’s
disease-associated psychosis.
The Parkinson’s disease participants were matched by their
cognitive status, defined as either with or without dementia,
so that the hallucinator and nonhallucinator groups had
equal numbers of participants with dementia. Dementia was
defined by MDS Parkinson’s disease dementia (PDD)
criteria32 and determined in a consensus conference involving
a neurologist specializing in movement disorders and
neuropsychiatry (J.G.G.) and 2 senior neuropsychologists
(G.T.S., B.B.), using the clinical and neuropsychological data
described below and previously published methods.29 The
Parkinson’s disease participant groups were also matched by
age (± 3 years).
Evaluations
Clinical evaluations included assessments of demographics,
medications, and disease-related features including the MDSUPDRS and Hoehn and Yahr stage.31 Dopaminergic
medications for Parkinson’s disease were converted to
levodopa equivalent daily doses.33 Antipsychotic medications
were converted to chlorpromazine equivalents.34 Parkinson’s
disease participants underwent comprehensive cognitive
evaluations including (1) Mini-Mental State Examination
(MMSE),35 (2) Clinical Dementia Rating (CDR) scale,36 and
(3) individual neuropsychological tests representing 5
cognitive domains (attention/working memory, executive
function, language, declarative memory, and visuospatial
function) as recommended by a Movement Disorder Society
Task Force,37 which were used to determine cognitive status.
The neuropsychological battery included the following: (1)
attention and working memory (Digit Span Backwards and
Letter Number Sequencing from the Wechsler Adult
Intelligence Scale-III [WAIS-III], Trail Making Test-A); (2)
executive function (Controlled Oral Word Association Test,
Goodglass and Kaplan Clock Drawing Test); (3) language
(Boston Naming Test, WAIS-III Similarities); (4) memory
(3 trials of word list learning and delayed recall from the
Consortium to Establish a Registry for Alzheimer’s Disease,
Logical Memory I and II prose passages); and (5) visuospatial
function (Benton Judgment of Line Orientation, Goodglass and
Kaplan Clock Copying Test). Raw scores for neuropsychological
tests were transformed to z scores based on normative data
from healthy, cognitively normal controls at our center.38
Cognitive domain scores were calculated by averaging z
scores for neuropsychological tests within specific domains.
Magnetic Resonance Imaging Acquisition and
Processing
Magnetic resonance images were acquired on a 1.5-T Signa
scanner (GE Healthcare). Participants underwent a
3-dimensional MRI with a T1-weighted magnetizationprepared rapid acquisition with gradient echo scan
(MPRAGE) sequence with the following parameters: 166
contiguous sagittal images, 1.2 mm thick, matrix = 192×192,
field of view = 24 cm, echo time = minimum full, repetition
time = 1000 ms, flip angle = 8°, NEX 1, phase field of view 1,
and band width 15.63 Hz.39
Structural imaging data were preprocessed and analyzed using
statistical parametric mapping 8 (SPM8) (http://www.fil.ion.
ucl.ac.uk/spm) implemented in Matlab 7.4a (MathWorks).
The VBM8 toolbox was used to perform the following steps
on the raw images: segmentation into gray matter, white
matter, and cerebrospinal fluid based on tissue probability
maps; and using DARTEL processing techniques, which
provide an algorithm for accurate diffeomorphic image
registration; normalization of gray matter segments to a gray
matter template in Montreal Neurological Institute (MNI)
space; modulation of the normalized gray matter images with
the Jacobian determinants; and smoothing of images with
a 3-dimensional Gaussian filter of 8 mm full width at half
maximum (FWHM).40,41 An estimation of total intracranial
volume was calculated from the addition of global gray,
white, and cerebrospinal fluid volume carried out by SPM8 as
part of the standard processing stream and was included as a
covariate in the analysis of covariance when comparing gray
matter volumes between the Parkinson’s disease hallucinator
and nonhallucinator groups. Voxels that demonstrated
significant group differences between Parkinson’s disease
hallucinators and nonhallucinators were used to create
regions of interest and extract volume measurements
using the statistical parametric mapping sample volume
function. Multiple linear regression models were used to
examine the relationship between the gray matter volumes
for these regions (ie, independent variable) and severity
of hallucinations as measured by the MDS-UPDRS Part I
question 1.2. Neuroanatomical regions of significance were
identified with the statistical parametric mapping glassbrain32
program, which names the MNI coordinates used in statistical
parametric mapping and adds corresponding Talairach
coordinates based on the Wake Forest University PickAtlas
database (fmri.wfubmc.edu/software/PickAtlas). Corresponding
Brodmann areas for neuroanatomical regions of significance
were identified using Talairach Daemon (www.talairach.org).
All MRI processing and analyses were performed blinded to
participant identity and clinical diagnosis.
Visuoperceptive Region Atrophy in Parkinson’s Disease Hallucinators
33
Table 2. Cognitive Domain z Scores in the Parkinson’s Disease Cohort a
Parkinson’s Disease
Nonhallucinators
(n = 25)
Parkinson’s Disease
Hallucinators
(n = 25)
P Value
Attention/working memory
–2.13 (1.6)
–2.01 (1.5)
0.78
Executive function
–2.2 (1.2)
–2.0 (1.3)
0.55
Language
–1.2 (1.4)
–1.1 (1.3)
0.80
Memory
–2.2 (1.4)
–1.8 (1.5)
0.37
Visuospatial function
–2.1 (2.0)
–2.8 (1.9)
0.19
Domain
a
Data presented as mean (SD).
Statistical Analyses
Statistical analyses for demographic and disease-related
variables were performed with SPSS 18.0 for Mac (PASW 19;
SPSS Inc) using 2-tailed t tests or chi-squared tests as appropriate.
Statistical significance for these analyses was set at P < .05.
For image analyses, between-group voxel-wise comparisons
were conducted with the general linear model within SPM8.
Group differences were tested using a whole-brain approach.
The significance threshold for differences on image analyses
was set at P < .01, uncorrected, with a cluster extent threshold,
k = 10. Relationships between gray matter volumes extracted
from the regions that significantly differed between groups
and the hallucination severity, as measured by the MDSUPDRS “Hallucinations and Psychosis” item, were examined
in the Parkinson’s disease hallucinators using the SPM8
multiple regression (correlation) module with the same
statistical and cluster thresholds as the whole-brain analysis.
A
Results
C
B
Clinical Characteristics
Twenty-five Parkinson’s disease participants with current and
chronic hallucinations were compared to 25 Parkinson’s
disease participants without hallucinations. All hallucinators
had visual hallucinations as their primary modality;
additional auditory hallucinations were present in 6 of 25
hallucinators. Of the hallucinations, the median score for the
MDS-UPDRS question on hallucinations and psychosis was
2 (range, 1-4), with 10 participants (40%) with illusions or
nonformed hallucinations (score 1); 11 participants (44%)
with mild, formed hallucinations with insight (score 2);
2 participants (8%) with moderate, formed hallucinations
without insight (score 3); and 2 participants (8%) with
delusions (score 4). There were no significant differences
between the hallucinator and nonhallucinator participants
in age, gender, education, or duration of Parkinson’s disease
(Table 1). The two Parkinson’s disease groups were matched
34
THE 2015 RUSH NEUROSCIENCE REVIEW
Figure 1. Location of significant clusters of gray matter volume loss
in Parkinson’s disease participants with hallucinations compared to
Parkinson’s disease participants without hallucinations. Results overlapped
on a T1-weighted image of healthy, control brain. Yellow color indicates
significantly different areas involving cuneus, fusiform, lingual, middle
occipital and cingulate gyri, inferior parietal lobules, and precentral gyrus
(A, sagittal; B, coronal; C, axial slices). P < .01, uncorrected.
Table 3. Anatomical Location of Areas Showing Significant Differences in Gray Matter Volume Between Parkinson’s Disease Participants With Hallucinations
and Without Hallucinations
Cluster Size
(mm3)
Cluster
Significance
T value
Z value
Talairach
Coordinates
(x, y, z)
Right cuneus (BA 18)
482
0.001
3.16
2.99
1, –72, 19
Right fusiform gyrus (BA 20)
335
0.001
3.43
3.23
43, –5, –22
Left inferior parietal lobule (BA 40)
187
0.001
3.37
3.17
–39, –51, 38
Left precentral gyrus (BA 6)
169
0.001
3.21
3.04
–61, –11, 39
Right middle occipital gyrus (BA 18)
140
0.005
2.68
2.58
9, –97, 15
Right middle occipital gyrus (BA 19)
140
0.001
3.46
3.25
36, –75, 7
Left cuneus (BA 17)
139
0.002
3.07
2.92
–18, –78, 5
Right lingual gyrus (BA 19)
113
0.003
2.94
2.8
19, –64, 3
Right inferior parietal lobule (BA 40)
105
0.001
3.15
2.98
40, –53, 43
Right cingulate gyrus (BA 24)
89
0.001
3.54
3.32
9, 0, 29
Left/right cingulate gyrus (BA 24)
53
0.002
3.07
2.92
0, 5, 40
Left fusiform/subgyral gyrus (BA 20)
39
0.003
2.87
2.74
–43, –13, –20
Left paracentral lobule (BA 5)
38
0.006
2.64
2.53
–16, –42, 55
Left middle occipital gyrus (BA 18)
37
0.001
3.03
3.03
–30, –80, 1
Left cingulate gyrus (BA 31)
23
0.003
2.92
2.78
–15, –36, 36
Left middle occipital gyrus (BA 19)
21
0.006
2.64
2.54
–52, –78, 5
Right precentral gyrus (BA 6)
18
0.004
2.73
2.62
65, 6, 19
Right lingual gyrus (BA 18)
17
0.007
2.55
2.46
6, –83, –5
Region (BA)
Abbreviation: BA, Brodmann area.
in terms of their cognitive status with 12 participants with
dementia and 13 participants without dementia per group.
There were no significant differences between the hallucinator
and nonhallucinator groups in global cognitive measures,
namely mean MMSE scores, CDR global scores, or CDR sum
of boxes scores. Also, the groups did not significantly differ in
their performance across the 5 cognitive domains, depicted as
mean z scores of neuropsychological tests in the domains of
attention/working memory, executive function, language,
memory, and visuospatial functions (Table 2). Finally, the
Parkinson’s disease groups did not differ significantly in motor
severity scores, measured by the MDS-UPDRS part III motor
score and Hoehn and Yahr stage, or dopaminergic
medications for Parkinson’s disease, including levodopa
equivalent doses and use of dopamine agonists. Cognitive
medications (ie, cholinesterase inhibitors or memantine)
were used by 7 participants in each Parkinson’s disease group.
Antipsychotic medications (ie, quetiapine) were used by 6
hallucinators and 3 nonhallucinators; the nonhallucinators,
however, were taking low-dose quetiapine for problems with
sleep and impulsivity rather than hallucinations.
Image Analyses
On whole-brain VBM analyses, the Parkinson’s disease
hallucinators exhibited significant clusters of reduced gray
matter volume compared to the nonhallucinators. The
regions where the hallucinators exhibited reduced gray matter
volumes included the bilateral cunei, fusiform, middle
occipital, precentral, and cingulate gyri and inferior parietal
lobules; right lingual gyrus; and left paracentral gyrus (Figure
1, Table 3). We did not detect any gray matter volume
differences between the two groups in the mesial temporal
lobe, insula, or brainstem, which were regions specifically
examined given findings in previous studies. There were no
cerebral areas where the nonhallucinators had significantly
greater gray matter volume loss than hallucinators.
There was a significant relationship between the gray matter
volumes, calculated for those regions in which the hallucinating
participants demonstrated reduced gray matter, and the
severity of hallucinations, measured by the MDS-UPDRS
“Hallucination and Psychosis” item. Four of the 18 regions
that had reduced gray matter volumes on VBM analysis in
Visuoperceptive Region Atrophy in Parkinson’s Disease Hallucinators
35
Table 4. Anatomical Location of Areas Showing a Significant Relationship to Hallucination Severity
Cluster
Size (mm3)
Cluster Significance
T value
Z value
Talairach
Coordinates
(x, y, z)
Left inferior parietal lobule (BA 40)
62
0.001
4.11
3.52
–37, –53, 44
Left cuneus (BA 18)
22
0.001
3.56
3.15
–4, –82, 17
Right lingual gyrus (BA 19)
22
0.003
3.08
2.79
18, –68, 5
Right precentral gyrus (BA 6)
15
0.001
3.41
3.04
64, 4, 22
Region (BA)
Abbreviation: BA, Brodmann area.
the hallucinating patients significantly contributed to the
regression model (P = .027): left inferior parietal lobule, left
cuneus, right lingual gyrus, and right precentral gyrus (Table 4).
To further explore the potential dissociation of neuroanatomical
regions involved in hallucinations and dementia, we
compared Parkinson’s disease participants with and without
dementia, controlling for hallucination status, on wholebrain VBM analyses using a 2 (with versus without dementia)
by 2 (hallucinator versus nonhallucinator) factorial design
(Figure 2, Table 5). In this analysis, participants with dementia
had significantly reduced gray matter volumes in predominantly
frontal and temporal regions, including bilateral
parahippocampal gyri; inferior frontal, medial frontal, and
middle frontal gyri; superior temporal gyri; and insula; right
uncus, amygdala; and left claustrum and hippocampus,
compared to participants without dementia (P < .01
uncorrected, k = 10). However, we did not detect gray matter
atrophy in the occipital-temporal-parietal regions that are
typically associated with visuoperceptive functions and were
found in our hallucinator versus nonhallucinator comparison.
Discussion
Our study has several key findings. Compared to Parkinson’s
disease participants without hallucinations, Parkinson’s
disease participants with current and chronic visual
hallucinations exhibit reduced gray matter volume on
structural brain MRI in regions specifically associated with
visuoperceptual function, independent of cognitive status.
These regions of gray matter atrophy in the hallucinators
correspond selectively and neuroanatomically to brain areas
associated with visuoperceptual processing and include the
ventral “what” and dorsal “where” visual streams. These
regions, frequently implicated in theories of visual
hallucinations in Parkinson’s disease (discussed below), have
been shown to exhibit decreased perfusion or activation in
metabolic or functional neuroimaging studies of Parkinson’s
disease patients with hallucinations, but have not previously
demonstrated atrophy in most structural MRI studies, possibly
because of confounds of comorbid cognitive impairment. In
36
THE 2015 RUSH NEUROSCIENCE REVIEW
contrast to several structural MRI studies, we did not detect
gray matter volume loss in the hallucinators in brain regions
that are frequently associated with cognitive impairment and
dementia in Parkinson’s disease such as mesial temporal,
insular, limbic, or frontal lobe regions. Conversely, when
controlling for hallucinations, we demonstrated atrophy
in these frontal, insular, limbic, and temporal regions in
Parkinson’s disease participants with dementia but not in
the posterior occipital-temporal-parietal regions. Thus, our
structural MRI findings of highly localized structural brain
abnormalities in the visuoperceptive system and the fact
that the hallucinations experienced by Parkinson’s disease
participants are predominantly visual ones suggest that specific
brain and behavior relationships underlie hallucinations in
Parkinson’s disease. Our findings also suggest that the
neuroanatomical substrates involved in visual hallucinations
in Parkinson’s disease are distinct from those typically found
on structural MRI analyses in cognitive impairment or
dementia in Parkinson’s disease, a dissociation that has not
previously been shown.
The gray matter atrophy in the Parkinson’s disease hallucinator
participants found in our study is of particular interest in
terms of clinico-anatomical correlations, because the affected
regions play essential roles in primary and secondary visual
processing and visuoperceptual functions.13 Specifically, the
brain regions exhibiting atrophy selectively involve (1) areas
responsible for determining patterns, light intensity, colors,
shapes, words, visual memory, and primary visual processing
(ie, the middle occipital gyrus, lingual gyrus, and cuneus); (2)
areas responsible for recognizing faces and body regions (ie,
the fusiform gyrus, which forms part of the visuoperceptive
ventral “what” stream); and (3) areas responsible for
multimodal processing and network connections among areas
involved in motor, sensory, emotional, language, cognitive,
attentional, and visuospatial functions (ie, inferior parietal
lobule and cingulate gyrus). These clinico-anatomical
correlations may even help explain why the majority of
hallucinations in Parkinson’s disease are visual ones, manifesting
as misperceptions of still or moving objects, or as hallucinations
of altered faces or figures, and frequently invoking heightened
emotions.2,3 Furthermore, it is interesting to note that similar
clinico-anatomical correlates have been detected in VBM
studies of schizophrenia. For example, participants with
schizophrenia experiencing auditory verbal hallucinations
demonstrate reduced gray matter volume in the bilateral
superior temporal gyrus including the Heschl gyri,42 an area
involved in auditory processing. These findings of brainbehavior correlates in schizophrenic participants, as well as
in our study of Parkinson’s disease hallucinators, support a
model of aberrant neural system processing at different levels
of sensory processing.
Our findings of gray matter atrophy in predominantly
visuoperceptive regions in the hallucinating Parkinson’s
disease participants differ from findings of several other
structural MRI studies in which the Parkinson’s disease
hallucinators exhibited primarily hippocampal or
temporal,23-25 insular,21 frontal,23,25,43 or thalamic or
pedunculopontine atrophy,25,44 compared to Parkinson’s
disease nonhallucinators. Several differences in clinical and
imaging methodologies between those studies and ours could
account for these differences. One key difference is our
careful control of cognitive abilities when comparing
Parkinson’s disease hallucinators and nonhallucinators.
The two groups in our study had comparable numbers of
participants with and without dementia in each group and
did not differ significantly on scores of the 5 cognitive
domains tested. In several other studies, in contrast, the
Parkinson’s disease hallucinators had greater cognitive
impairment than the nonhallucinators. In addition, studies
have varied with regard to the definitions of Parkinson’s
disease dementia (eg, MMSE scores < 24; Diagnostic and
Statistical Manual of Mental Disorders, Fourth Edition, Text
Revision [DSM-IV-TR] criteria; or MDS PDD criteria)24,25,44,45
that were used as criteria either to include participants or to
exclude participants if the study focused on Parkinson’s
disease without dementia. The tendency toward worse
cognitive function in Parkinson’s disease participants with
hallucinations could lead to greater detection of atrophy on
structural MRI in mesial temporal lobe, limbic, and
neocortical regions. Gray matter atrophy in these areas has
been detected in Parkinson’s disease patients with cognitive
impairment and dementia in several structural MRI studies.27
Furthermore, greater amnestic deficits in those hallucinating
Parkinson’s disease participants classified as having dementia
by DSM-IV-TR criteria, which require memory impairment
by definition, could also contribute to gray matter atrophy in
the mesial temporal lobe on MRI, an area implicated in
declarative memory function.26 Even when Parkinson’s
disease hallucinators were considered to be without dementia
in many of these studies, they performed worse on tests of
global cognitive function and on multiple cognitive domains
compared to Parkinson’s disease nonhallucinators. The
hallucinators had worse scores on (1) the MMSE22,24; (2)
memory on verbal list learning and recall tests22,24; (3) visual
memory25; (4) attention and executive function on tests of
fluency, set shifting, and interference21,23,25; and (5)
visuospatial function with facial recognition tasks.22,23 Other
important differences among structural MRI studies include
various definitions of visual hallucinations (eg, frequency,
severity, and/or rating scales used), sample sizes (eg, ranging
from 8 to 46 Parkinson’s disease hallucinators in studies), and
imaging methods (eg, MRI scanners, SPM versions, wholebrain VBM or selective region of interest approaches, choices
in smoothing kernels, cluster threshold significance, and
corrections for multiple comparisons used). An additional
consideration is that in other studies, the Parkinson’s disease
hallucinators compared to the nonhallucinators had worse
motor impairment,22,24,44 longer disease duration,43,44 and
greater depressed mood on standard rating scales.22,24 Our
matching for cognitive status and age, along with the lack of
significant between-group differences in Parkinson’s disease
duration, motor severity, or depression, in the hallucinators
and nonhallucinators represents a major strength of our study
and thus allows for the first time a clinico-anatomical analysis
that separates the regions associated with hallucinations from
those associated with dementia as two distinct, but sometimes
overlapping, clinical problems.
To the best of our knowledge, only one other structural MRI
study has detected greater gray matter atrophy in regions
associated with visual processing in Parkinson’s disease
hallucinators compared to nonhallucinators.22 Our findings
further extend this work, which demonstrated gray matter
atrophy in three regions, the left lingual gyrus and bilateral
superior parietal lobes, in Parkinson’s disease hallucinator
participants. The structural MRI findings of gray matter
atrophy in visuoperceptive regions in Parkinson’s disease
hallucinators complement previous metabolic and functional
neuroimaging studies, which reveal that similar regions are
affected. These studies show decreased cerebral perfusion or
glucose metabolism in posterior (ie, occipital, parietal, and
temporal) regions, and decreased activation of similar regions
in functional MRI visual stimulation paradigms.15-19 Together,
these neuroimaging studies suggest that structural
abnormalities in the brain’s visual processing areas may not
only form the basis for these abnormally decreased metabolic
or cortical activation patterns, but also might even explain
the clinical presentation of visual rather than nonvisual
hallucinations. The exact mechanisms by which these
structural, metabolic, or functional aberrations relate to the
severity of visual hallucinations in Parkinson’s disease are not
fully elucidated. In our study, 4 of the 18 identified regions of
gray matter atrophy in the Parkinson’s disease hallucinators
(ie, left inferior parietal lobule, left cuneus, right lingual
gyrus, and right precentral gyrus) showed the greatest
relationship to hallucination severity scores. The majority of
these areas perform different roles in the visuoperceptive
system, ranging from processing of visual stimuli (eg, cuneus
and lingual gyrus) to integrating multimodal information.
Visuoperceptive Region Atrophy in Parkinson’s Disease Hallucinators
37
The inferior parietal lobule, in particular, may play a pivotal
role in the presence and severity of visual hallucinations in
Parkinson’s disease due to its connectivity to multiple other
brain regions involved in a wide array of motor, sensory,
language, and visual functions.46 It is not known, however,
whether gray matter atrophy in visuoperceptive regions could
be the consequence (rather than the cause) of long-standing
visual hallucinations in Parkinson’s disease patients.
Multimodal neuroimaging studies performed at the same time
point in hallucinators may help answer questions regarding
the temporal relationship of structural changes to metabolic
and functional abnormalities (ie, do the decreased perfusion
or activation patterns result from structural atrophy or might
they occur at an early disease stage, prior to structural changes?).
Several theoretical explanations for visual hallucinations
have been proposed. These include impairment in the visual
system from the retina to higher-order visual processing;
cortical release phenomena due to sensory deafferentation
such as in the Charles Bonnet syndrome; cortical irritation or
excitability; abnormalities in various perceptual, attentional,
arousal, or cognitive processes; or dysregulation of external
perception and internal image production across the visual
system, brainstem, and subcortical and cortical regions.8,11,14,47
Deficits in the primary visual system due to dopamine cell loss
in the retina or structural changes in retinal thickness in
Parkinson’s disease may contribute to hallucinations,48-50 and
hallucinators exhibit reduced contrast sensitivity, color
discrimination, and visual acuity compared to
nonhallucinators.51 Hallucinations may result from either
increased misperceptions of visual stimuli in a visually
deprived environment or by the chronic deafferentation of
higher-order visual regions. This chronic denervation could
be hypothesized to lead to subsequent brain atrophy
selectively in visuoperceptive regions. Other theories of
hallucinations emphasize impairment in cognitive,
attentional, and visuoperceptive processes, spanning the
neuroanatomical levels of the brainstem and the subcortical
and cortical regions. Each theory focuses on the relationship
of hallucinations to distinct elements such as impaired
arousal or vigilance, sleep-wake disturbances or dream
intrusions, altered attention and/or specific cognitive
processes (eg, set-shifting, executive functions, or visuospatial
abilities), abnormal inference and modulation of internal and
external perceptions, or altered higher-order visuoperceptive
processing.8,10,11,14 Our structural MRI findings, with
abnormalities in primarily “what” and “where”
visuoperceptive regions, best fit with the “bottom-up” model
of altered visuoperceptive processing but also share features of
impaired attentional models of Parkinson’s disease
hallucinations. Regional atrophy also occurred in the inferior
parietal lobule and cingulate gyrus, which are two areas
implicated in visuoperceptive processing, visuospatial
orientation, and visual memory but also multisensory
38
THE 2015 RUSH NEUROSCIENCE REVIEW
A
B
C
Figure 2. Location of significant clusters of gray matter volume loss in
Parkinson’s disease participants with dementia compared to Parkinson’s
disease participants without dementia. Results overlapped on a T1-weighted
image of healthy, control brain. Yellow color indicates significantly different
areas involving inferior frontal, medial frontal, and middle frontal and superior
temporal gyri; parahippocampal gyrus; hippocampus; amygdala; insula; uncus;
and claustrum (A, sagittal; B, coronal; C, axial slices). P < .01, uncorrected.
integration, attentional, and emotional processes. Structural
abnormalities in the visuoperceptive pathways and “hub”
regions suggest that there may be a “disconnection” between
posterior and anterior parts of the brain in hallucinators, as
seen in several metabolic and functional neuroimaging
studies. Future integrated studies using multimodal structural,
functional, and metabolic neuroimaging techniques;
physiological measures of vision and sleep/arousal; and
experimental attentional, cognitive, and visuoperceptive
tasks may provide insights into how these various theories
contribute to the development of hallucinations in
Parkinson’s disease.
To date, there have been few neuropathological studies of
Parkinson’s disease participants with hallucinations. In those
clinico-pathological studies that were carried out, Lewy
Table 5. Anatomical Location of Areas Showing Significant Differences in Gray Matter Volume Between Parkinson’s Disease Participants With and Without Dementia
Cluster
Size (mm3)
Cluster Significance
T value
Z value
Talairach
Coordinates
(x, y, z)
Left parahippocampal gyrus, hippocampus
(BA 35, 28)
1222
0.001
3.41
3.2
–19, –21, –15
Right inferior frontal gyrus, parahippocampal
gyrus, amygdala (BA 47)
1038
0.001
3.46
3.24
25, 15, –23
Right middle frontal gyrus (BA 8, 9)
503
0.001
3.33
3.13
28, 31, 34
Left medial frontal gyrus (BA 11)
469
0.001
3.6
3.35
–7, 27, –13
Right middle frontal gyrus (BA 6, 10)
376
0.001
3.51
3.28
36, 40, 12
Right middle frontal gyrus (BA 6)
341
0.001
3.75
3.47
31, 1, 44
Left claustrum
260
0.005
2.72
2.6
–31, 3, 1
Left middle frontal gyrus (BA 10, 46)
255
0.001
3.38
3.17
–34, 40, 9
Right medial frontal gyrus (BA 11)
234
0.001
3.16
2.98
1, 57, –18
Right superior temporal lobe (BA 21)
178
0.003
2.95
2.81
56, 2, –10
Left insula (BA 13)
166
0.001
3.23
3.04
–37, –21, 22
Right inferior frontal gyrus (BA 9)
130
0.001
3.2
3.02
34, 11, 23
Right inferior frontal gyrus (BA 6)
111
0.001
3.44
3.22
19, –2, 54
Right temporal gyrus (BA 21)
109
0.003
2.9
2.76
46, –11, –8
Left medial frontal gyrus (BA 9)
105
0.001
3.69
3.42
–21, 26, 30
Right inferior frontal gyrus (BA 11)
103
0.005
2.72
2.6
24, 36, –18
Left superior temporal gyrus (BA 22)
76
0.002
3.04
2.88
–67, –37, 14
Left insula (BA 13)
70
0.005
2.71
2.59
–40, –32, 21
Left inferior frontal gyrus (BA 47)
66
0.004
2.75
2.63
–21, 31, –22
Right insula (BA 13)
60
0.005
2.7
2.58
39, –28, 19
Left superior temporal gyrus (BA 13)
54
0.001
3.12
2.95
–50, –46, 20
Left parahippocampal gyrus (BA 19)
53
0.004
2.78
2.65
–19, –44, –2
Region (BA)
Left inferior frontal gyrus (BA 9)
48
0.003
2.9
2.75
–36, 10, 23
Left superior temporal gyrus (BA 22)
41
0.006
2.64
2.53
–59, –26, 3
Right uncus (BA 28)
35
0.005
2.66
2.55
22, –15, –35
Left superior temporal gyrus (BA 22)
29
0.006
2.64
2.53
–48, –26, 3
Right superior temporal gyrus (BA 38)
21
0.006
2.61
2.5
42, –1, –18
Left inferior frontal gyrus (BA 47)
20
0.008
2.49
2.4
–31, 18, –21
Abbreviation: BA, Brodmann area.
bodies were reported in the amygdala, parahippocampus,
frontal and parietal lobes, and inferior temporal cortex in
Parkinson’s disease hallucinators.52,53 Interestingly, the
inferior temporal cortex comprises part of the ventral stream
visuoperceptive pathway responsible for representation of
complex object features and facial perception. However, Lewy
bodies were negligible in the occipital lobe in one study52 and
not examined in the other.53 Small sample sizes, presence of
cognitive deficits or dementia in the hallucinators, and
overall more advanced disease at death, however, pose
challenges for parsing out neuropathological changes specific
to hallucinations. These findings also suggest that other
neuropathologies, neurochemical alterations (ie, abnormal
serotonergic54,55 or cholinergic receptor binding56), or
Visuoperceptive Region Atrophy in Parkinson’s Disease Hallucinators
39
disrupted white matter pathways (ie, inferior longitudinal
fasciculus)57 may play a role in the atrophy in occipital and
related visuoperceptive regions found on structural MRI of
Parkinson’s disease hallucinators.
In our study, in addition to gray matter volume loss
predominantly in visuoperceptive areas in the hallucinators
compared to the nonhallucinators, we also detected reduced
gray matter volume in the precentral gyrus (premotor cortex).
Although the two Parkinson’s disease groups did not differ
significantly in motor scores (as measured by the MDSUPDRS part III and by Hoehn and Yahr stage) or in disease
duration, the hallucinators had slightly longer disease
durations (mean 13.1 ± 4.6 years versus 10.8 ± 4.4 years).
Considering clinico-anatomical correlates, we hypothesize
that the greater precentral gyrus atrophy in the hallucinator
group might possibly relate to their slightly longer disease
course or to a greater degree of motor dysfunction that was
not captured by the demographic or disease-related variables
of interest in our study.
We acknowledge that this study has some limitations,
including a relatively small sample size, which although
smaller than in one study25 is larger than in several previously
published structural MRI studies.22-24,44 Even so, larger sample
sizes of cognitively well-matched hallucinators and
nonhallucinators are needed to validate these gray matter
atrophy results with more stringent statistical corrections,
which minimize potential false positives. Our findings of
distinct structural MRI brain-behavior correlates for
hallucinations and dementia, however, may generate
hypotheses and new models regarding these two frequent and
disabling complications in Parkinson’s disease. At present, we
cannot establish the underlying neuropathology associated
with the gray matter atrophy detected on MRI, but future
postmortem studies will be informative. Although the
Parkinson’s disease groups were matched on cognitive deficits
and age, they were not matched for use of antipsychotic
40
THE 2015 RUSH NEUROSCIENCE REVIEW
medications. It is notable that even when some of the
hallucinators were treated for the condition, the underlying
structural abnormalities were evident. Whether antipsychotic
treatment per se can produce structural changes on brain
MRI remains a question for future studies of Parkinson’s
disease hallucinators. Lastly, we cannot confirm that the
Parkinson’s disease nonhallucinators will never become
hallucinators. Planned longitudinal follow-up studies with
careful monitoring will permit assessment of “conversion”
and clinical and neuroimaging risk factors.
In conclusion, the structural abnormalities detected in
participants with Parkinson’s disease with current and
chronic visual hallucinations suggest that there are distinct
regional patterns of gray matter atrophy associated with visual
hallucinations in Parkinson’s disease, independent of
cognitive impairment or dementia. Reduced gray matter in
these brain regions that subserve visuoperceptive functions
may contribute to aberrant processing of visual input,
especially in the ventral “what” and dorsal “where” visual
streams, and thus lead to the clinical manifestations of visual
hallucinatory phenomena in Parkinson’s disease. These
neuroanatomical findings provide the basis for future studies
investigating the role of neural network dysfunction in visual
hallucinations in Parkinson’s disease and ultimately providing
patients with novel therapies that target hallucinations and
visuoperceptive dysfunction.
Funding
K23NS060949 (J.G.G.). The Rush University Section of
Parkinson Disease and Movement Disorders is supported by a
center grant from the Parkinson’s Disease Foundation.
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42
THE 2015 RUSH NEUROSCIENCE REVIEW
CLINICAL AND RADIOGRAPHIC ANALYSIS
OF AN ARTIFICIAL CERVICAL DISC:
7-Year Follow-Up From the Prestige Prospective
Randomized Controlled Clinical Trial
J. Kenneth Burkus, MD; Vincent C. Traynelis, MD; Regis W. Haid Jr, MD; Praveen V. Mummaneni, MD
Author Affiliations: Wilderness Spine Services, Columbus, Georgia (Dr
Burkus); Department of Neurological Surgery, Rush University Medical
Center, Chicago, Illinois (Dr Traynelis); Atlanta Brain and Spine Care,
Atlanta, Georgia (Dr Haid); and Department of Neurological Surgery,
University of California, San Francisco (Dr Mummaneni).
Corresponding Author: J. Kenneth Burkus, MD, The Hughston Clinic,
6262 Veterans Pkwy, Columbus, GA 31908-9517 ([email protected]).
Previous Publication: This article was previously published in J Neurosurg
Spine 2014;21(4):516-528. Minor edits have been made.
Introduction
Clinical and radiographic outcomes have been reported from
several prospective studies of patients undergoing cervical
disc replacement with a metal-on-metal implant.1-4 An early
clinical prospective observational cohort study of 15 patients
reported successful clinical and radiographic outcomes in
the treatment of symptomatic cervical radiculopathy.5
An optimized ball-and-trough-designed implant (Prestige
Cervical Disc, Medtronic) was then developed and used in
a prospective randomized trial.3 Fifty-five patients were
enrolled in this pilot study at 4 investigational sites. At
24-month follow-up, Neck Disability Index (NDI) scores
showed improvement that favored the disc replacement group
over the control group, and motion was maintained at the
treated level. In 2002, a large-scale, prospective, randomized,
multicenter study was initiated in which this metal-on-metal
disc prosthesis was compared with anterior cervical
discectomy and fusion in patients who had symptomatic
single-level cervical degenerative disc disease.6 Investigators
reported the interim data from this randomized controlled
trial (RCT) in previous publications.6,7 These early clinical
reports have shown that the prosthesis maintained segmental
spinal motion and was associated with improved neurological
success, clinical outcomes, and reduced secondary surgical
procedures when compared with anterior cervical discectomy
and fusion. These improvements in outcomes were similar to
other early clinical and radiographic findings for the Bryan
Cervical Disc (Medtronic),8 the ProDisc-C (Synthes, Inc),9
Kineflex|C (SpinalMotion),1 and the Mobi-C (LDR)10,11
devices. At 24 months in these cervical disc replacement
RCTs, the postoperative data showed improvement in
all clinical outcome measures, and patients treated
with the artificial disc had a statistically greater overall
success rate.12,13
The safety and efficacy of cervical disc prostheses beyond the
initial 24-month follow-up has not been as widely reported.
Reports from RCTs with 4 years of follow-up have been
published for the Bryan Disc14 and with 5 years of follow-up
for the ProDisc-C.15 The final 2-year and interim 5-year data
from the Prestige disc RCT have been published.6,7 The
purpose of this article is to report the final 7-year clinical and
radiographic outcomes from the Prestige disc RCT.
Materials and Methods
Study Design
This prospective, randomized, nonblinded study was
conducted under an approved investigational device
exemption (IDE). Patients in the IDE trial were followed in
this Food and Drug Administration (FDA)-regulated
postapproval study for an additional 5 years, resulting in a
total of 7 years of follow-up. Institutional review board
approval was obtained from all participating centers, and
informed consent was obtained for all patients enrolled in the
follow-up studies. The clinical trial registration number for
this study is NCT00642876 (http://www.ClinicalTrials.gov).
Between October 2002 and August 2004, 541 patients were
enrolled at 31 investigational sites and underwent surgery.
The patients were randomly assigned to 1 of 2 treatment
groups: the investigational group received the Prestige
disc, and the control group underwent an interbody
fusion using allograft with plate fixation. Data were
Seven-Year Outcomes of Prestige Cervical Disc Replacement
43
collected preoperatively, intraoperatively, and at 1.5, 3,
6, 12, 24, 36, 60, and 84 months postoperatively. Adverse
events and secondary surgeries were recorded at each
follow-up visit.
Patient Demographics
The 2 treatment groups were similar demographically, and
there were no statistically significant differences (P < .05) for
the variables of age, sex, smoking, or work status (Table 1).
All patients were between the ages of 22 and 73 years and
had symptomatic degenerative cervical disc disease at the
C3-C4 or C6-C7 levels. For at least 6 weeks before their
surgery, all patients had neck and arm pain that was
recalcitrant to nonoperative treatment modalities, such as
physical therapy, reduced activities, and anti-inflammatory
medications.
Patient Follow-Up
A total of 541 patients were treated in the RCT; 276 patients
were assigned to the investigational group, and 265 patients
were assigned to the control treatment group (Figure 1).
One center declined to participate in the long-term follow-up
study after the initial 24-month evaluation period was
completed. As a result of the nonparticipating site, 8 patients
(4 each in the investigational group and control group) were
excluded from this study, leaving 533 patients who were
eligible for the FDA postapproval follow-up.
Clinical Outcome Measures
All patients were considered candidates for a single-level
anterior cervical decompression and interbody fusion and had
plain radiographic findings that documented single-level
cervical disc disease and at least one additional confirmatory
neuroradiographic study, such as magnetic resonance imaging
or computed tomography-enhanced myelography that was
consistent with clinical findings and complaints.
Overall success was the primary clinical outcome measure for
this clinical trial. A patient’s outcome was considered an
overall success if all of the following conditions were met: (1)
postoperative NDI score improvement of at least a 15-point
increase from preoperative score; (2) maintenance or
improvement in neurological status; (3) disc height success
(the functional spinal unit [FSU] was measured to assess for
any loss of disc height due to subsidence); (4) no serious
adverse event classified as implant associated or implant/
surgical procedure associated; and (5) no additional surgical
procedure classified as a “failure.”
Patients were excluded from the study if they had cervical
spinal conditions other than single-level symptomatic
degenerative disc disease or evidence of instability. Other
exclusion criteria were symptomatic disc disease at level
C2-C3 or C7-T1, a history of discitis, or a medical condition
that required medication, such as steroids or nonsteroidal
anti-inflammatory medications that could interfere with fusion.
When overall success was assessed, it was apparent that in
some instances the radiographic images did not allow clear
visualization of the FSU, and, therefore, adequate disc height
measurements were unobtainable. For this reason, overall success
rates were computed with and without inclusion of disc height
success as a component of overall success. When disc height
success was included as a component of overall success,
Table 1. Patient Demographic Data
Variable
Control Group
276
265
Age, y
mean
range
43.3
25-72
43.9
22-73
.435
Mean weight, lb
181.7
184.7
.389
Male, %
46.4
46.0
1.000
Workers’ compensation, %
11.6
13.2
.603
Litigation, %
10.9
12.1
.687
Alcohol use, %
43.5
53.2
.025
Tobacco use, %
34.4
34.7
.000
Work status, %
65.9
62.6
.473
No. of patients
a
44
P Valuea
Investigational Group
For continuous variables, P values are from analysis of variance, and for categorical variables, they are from the Fisher’s exact test.
THE 2015 RUSH NEUROSCIENCE REVIEW
Randomized and Treated
(n = 541)
SURGERY
Symptomatic
Investigational
(n = 276)*
Control
(n = 265)*
60-month Follow-up
Deaths through 60 months (n = 2)
Deaths through 60 months (n = 5)
Withdrawn through 60 months (n = 5)
Withdrawn through 60 months (n = 13)
Lost to follow-up (n = 49)
Lost to follow-up (n = 57)
Analyzed (n = 220)†
Analyzed (n = 190)†
84-month Follow-up
Deaths through 84 months (n = 2)
Deaths through 84 months (n = 5)
Withdrawn through 84 months (n = 5)
Withdrawn through 84 months (n = 14)
Lost to follow-up (n = 57)
Lost to follow-up (n = 63)
Analyzed (n = 212)†
Analyzed (n = 183)†
Figure 1. Flowchart of participants throughout the 7-year study. *Cumulative adverse event rates include adverse events from patients who withdrew from
the study. † Patients had at least 1 complete outcome measure.
patients in whom the radiographic images did not permit disc
height measurement were excluded from the analysis.
Secondary and additional clinical outcome measures included
the Physical Component Summary (PCS) of the 36-Item
Short Form Health Survey (SF-36), neck and arm pain scores
(100-point scale, which was the product of duration [1- to
10-point scale] multiplied by intensity [1- to 10-point scale]),
and return-to-work status.
Radiographic Assessments
Plain radiographic studies were obtained preoperatively,
intraoperatively, and at 1.5, 3, 6, 12, 24, 36, 60, and 84
months postoperatively. Neutral anteroposterior and lateral
radiographs and dynamic flexion-extension lateral
radiographs were obtained at each study point. Sagittal
plane angulation motion was measured on dynamic lateral
radiographs using the Cobb technique. Subsidence was
measured by comparing the FSU height from 1.5 months
after surgery. This calculation required that the entire
vertebral body above and below the index surgical level
could be visualized. For centralization of assessments and
measurements, radiographs taken at each investigational
site were evaluated at the same core-imaging laboratory
(SYNARC) through all study periods. Two independent
radiographic reviewers and an adjudicator determined
radiographic findings in both treatment groups. Some
radiographs could not be interpreted by radiologists because
the prominent shoulders obscured critical portions of the
radiographic images. For these reasons, the numbers of
complete radiographic assessments varied from the numbers
of clinical assessments at each of the study’s follow-up intervals.
Adverse Events
An adverse event was defined as any clinically adverse sign,
symptom, syndrome, or illness that occurred or worsened
during either the operative or postoperative observation
periods, regardless of causality, that was not being measured
otherwise in the study. The adverse event information
recorded was based on the following: (1) signs or symptoms
detected during the physical examination, (2) the clinical
evaluation of the participant, (3) the participant interview,
and (4) the medical charts monitored during the study. Adverse
events were collected for the duration of the entire study.
Secondary Surgical Procedures
Secondary surgical procedures at the level of the index
procedure were classified according to the IDE trial protocol
as revisions, removals, supplemental fixations, or reoperations.
In this investigation, a revision surgery was defined as any
procedure that adjusts or modifies the original implant
configuration (implant repositioning). A removal surgery was
defined as a procedure in which 1 or more components of the
original implant was removed and replaced with a different
type of implant. For example, removal of the Prestige implant
and replacement with an interbody cage and anterior plate
would be classified as a removal surgery. A supplemental
Seven-Year Outcomes of Prestige Cervical Disc Replacement
45
fixation procedure, such as posterior wiring or plating,
provided additional stabilization to the index surgical site.
This definition included the application of an external bone
growth stimulator as a supplemental fixation procedure;
however, data are summarized separately in this article.
A secondary surgical procedure was classified as a reoperation
if the procedure was carried out at the index level and was
not classified as a revision, removal, or supplemental fixation.
An example of a reoperation would be a posterior foraminotomy
to relieve persistent nerve root pressure at the index surgical level.
Statistical Analysis
Statistical comparisons were based primarily on the observed
and recorded follow-up data. Missing values for patients who
were lost to follow-up were not imputed. For outcomes of the
patients requiring an additional surgical procedure that was
classified as a failure (removal, revision, or supplemental
fixation), the observations immediately before the second
surgery were carried over for all future evaluation periods.
For statistical comparisons of demographic differences
between the groups, analysis of variance was used for
continuous variables, and Fisher’s exact test was used for
categorical data. Assessment of the statistical significance of
postoperative improvement from preoperative values within
each treatment group was performed using a paired t test.
For the binary outcome variables, such as overall success,
the success rate of the investigational group and the control
group were compared using a z test with the standard
Table 2. Comparisons of Functional, Pain, and Quality of Life Outcomes
Variable
Investigational Group
No. of Patients
Mean ± SD
Control Group
No. of Patients
Mean ± SD
P Valuea
NDI
Preoperative
276
55.7 ± 14.8
264
56.4 ± 15.9
24 mo
253
20.0 ± 21.4
220
22.4 ± 21.5
.140
36 mo
197
18.9 ± 21.5
160
24.0 ± 20.4
.008
60 mo
219
17.5 ± 20.4
188
21.7 ± 20.7
.014
84 mo
211
18.1 ± 20.0
181
23.8 ± 21.6
.002
Preoperative
276
59.1 ± 29.4
264
62.4 ± 28.5
24 mo
253
13.9 ± 24.6
220
14.2 ± 24.3
.521
36 mo
197
12.9 ± 24.4
161
15.6 ± 23.1
.141
60 mo
218
10.6 ± 21.5
189
13.6 ± 23.5
.092
84 mo
210
12.7 ± 24.1
181
15.0 ± 24.9
.174
Preoperative
276
68.2 ± 22.7
264
69.3 ± 21.5
24 mo
253
15.6 ± 24.4
220
16.6 ± 1.62
.368
36 mo
197
14.2 ± 23.0
161
19.6 ± 26.1
.018
60 mo
217
12.7 ± 22.4
189
16.9 ± 24.4
.033
84 mo
210
13.1 ± 23.3
181
19.4 ± 24.8
.004
Preoperative
275
31.9 ± 7.0
263
32.0 ± 7.5
24 mo
248
44.6 ± 12.2
218
44.4 ± 12.0
.277
36 mo
197
45.6 ± 11.9
160
43.7 ± 11.5
.032
60 mo
217
45.8 ± 11.7
187
44.7 ± 11.9
.098
84 mo
209
45.1 ± 12.0
179
43.2 ± 12.1
.017
Arm pain
Neck pain
SF-36 PCS
Abbreviations: NDI, Neck Disability Index; SF-36 PCS, 36-Item Short Form Health Survey Physical Component Summary.
a
The P values are for comparisons between the treatment groups from the analysis of covariance with preoperative score as the covariate.
46
THE 2015 RUSH NEUROSCIENCE REVIEW
A
P = .002
P = .026
P = .129
P = .010
B
80.0
70.0
60.0
50.0
40.0
30.0
20.0
10.0
0.0
P = .008
P = .005
P = .069
P = .008
24 months
36 months
60 months
84 months
90.0
Overall Success Rate Without FSU (%)
Overall Success Rate With FSU (%)
90.0
24 months
36 months
60 months
80.0
70.0
60.0
50.0
40.0
30.0
20.0
10.0
0.0
84 months
Investigational
Control
Figure 2. Overall success with (A) and without (B) disc height. FSU, functional spinal unit.
deviation derived using the Farrington-Manning16 method.
Analysis of covariance was used with the preoperative score
as the covariate for comparing postoperative continuous
measurements and improvements such as NDI. One-sided
P values were reported for most clinical outcomes, except for
additional surgical procedures and adverse events. Time-toevent analysis was performed for comparing adverse events
between the treatment groups, and the log-rank test was used
to determine statistical significance. A P value < .05 was used
to evaluate statistical significance without adjusting for
multiple comparisons. The primary study objective for the
postapproval study was to assess noninferiority (with a
10% margin) in overall success at 7 years comparing the
investigational group to the control group. If noninferiority
was established, superiority was also assessed. Noninferiority
P values are not presented in this article.
confirmed. At 60 months, the overall success rates with the
FSU measure were 71.3% for the investigational group and
65.2% for the control group, a 6.1% difference that was not
statistically significant (P = .129) (Figure 2). When the FSU
measure was excluded, the overall success rates at 60 months
were 78.2% and 71.8% for the investigational and control
groups, respectively, a 6.4% difference that was also not
statistically significant (P = .069). However, at 84 months the
overall success rates with and without the FSU measure were
both significantly higher in the investigational group. Overall
success rates with the FSU measure were 72.6% and 60.0%
for the investigational and control groups, respectively (P = .010),
and were 75.0% and 63.7% without the FSU measure for the
investigational and control groups, respectively (P = .008).
Results
The NDI questionnaire measures the level of pain and
disability associated with various activities. The NDI scores
improved significantly in both groups from the preoperative
scores by 1.5 months, and these improvements were
maintained through 7 years (P < .001). For the investigational
group, average NDI scores improved 37.6 points at 84 months
from a mean preoperative score of 55.7. For the control group,
average NDI scores improved 32.6 points at 84 months from
a mean preoperative score of 56.4. These improvements were
similar to those at 60 months, which were 38.2 points and
34.7 points for the investigational and control groups,
respectively. At both the 60-month and 84-month periods,
there were significant between-group differences in favor of
arthroplasty (P = .014 and .002, respectively) (Table 2).
Follow-up rates at 60 and 84 months were 79.7% and 76.8%,
respectively, for the investigational group and 71.7% and
69.1%, respectively, for the control group (Figure 1). The
overall follow-up rate at 84 months was 73% (395 of 541
patients). There were 212 patients in the investigational
group and 183 in the control group. Follow-up rates were
based on the number of patients who had at least 1 complete
outcome measure at that interval. Note that more patients
reached the 60-month follow-up time point by 2012 than
reported in our previous publication.7
Overall Success
At 60 and 84 months, noninferiority in overall success
comparing the investigational and control groups was
NDI Scores
The NDI success criterion is based on the preoperative NDI
score. A 15-point or greater NDI score improvement after
Seven-Year Outcomes of Prestige Cervical Disc Replacement
47
surgery was required to be considered a successful outcome.
The 2 groups demonstrated similar rates of NDI success at
60 and 84 months, which were 85.4% and 83.4%,
respectively, for the investigational group and 84.8% and
80.1%, respectively, for the control group. There were no
significant between-group differences in NDI success rates
at 60 months (P = .293) or at 84 months (P = .109).
Arm Pain
Arm pain scores improved significantly in all groups from the
preoperative scores by 1.5 months, and these improvements
were maintained through 7 years (P < .001). For the
investigational group, average arm pain scores improved
46.4 points at 84 months, from a mean preoperative score
of 59.1. The control group showed comparable improvement
in arm pain scores, improving an average of 47.4 points from
a preoperative score of 62.4. There were no significant
between-group differences in arm pain scores at 60 months
(P = .092) or at 84 months (P = .174) (Table 2).
months in the investigational group (12.7) than in the
control group (16.9), and was also significantly lower (P =
.004) at 84 months in the investigational group (13.1) than
in the control group (19.4) (Table 2).
SF-36 PCS
The SF-36 measures specific health concepts related to
physical functioning, social functioning, and health
perceptions. SF-36 PCS scores improved significantly in both
groups from preoperative scores by 6 months (P < .001),
which was the first postoperative period for SF-36 evaluation,
and these improvements were maintained through 7 years.
There were no significant between-group differences in SF-36
PCS at 60 months (45.8 points and 44.7 points for the
investigational and control groups, respectively) (P = .098).
At 84 months, the SF-36 PCS score for the investigational
group was 45.1 points compared with 43.2 points in the
control group (P = .017) (Table 2).
Neurological Success
Neck Pain
Neck pain scores improved significantly in both groups
from the preoperative scores by 1.5 months, and these
improvements were maintained through 7 years (P < .001).
For the investigational group, average neck pain scores
improved 55.1 points at 84 months, from a mean preoperative
score of 68.2. For the control group, average neck pain scores
improved 49.9 points at 84 months, from a preoperative score
of 69.3. Neck pain was significantly lower (P = .033) at 60
Neurological status of the patients was determined by
measuring 3 objective clinical findings: motor function,
sensory function, and deep tendon reflexes. Neurological
success for each of these 3 objective findings was based on
postoperative maintenance or improvement in condition
compared with preoperative status. Overall neurological
status success was determined by maintenance or
improvement in all 3 clinical findings.
P = .166
P = .045
P = .146
P = .006
P = .004
P = .004
P = .017
P = .011
1.5 months
3 months
6 months
12 months
24 months
36 months
60 months
84 months
Investigational
Control
100
Neurological Success Rate (%)
90
80
70
60
50
40
30
20
10
0
Figure 3. Neurological success rates in the investigational group and control group. The P values are 1-sided from normal approximation with standard
error derived from the Farrington-Manning method.
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THE 2015 RUSH NEUROSCIENCE REVIEW
Table 3. Comparison of Observed Neurological Success Ratesa
Period
24 mo
60 mo
84 mo
Neurological Success Determination
Neurological Success, %
Investigational
Control
Observed
91.6
83.6
Imputing LTFU as failures
83.3
69.4
Observed
92.2
85.7
Imputing LTFU as failures
73.2
61.1
Observed
88.2
79.7
Imputing LTFU as failures
67.4
54.7
Abbreviation: LTFU, lost to follow-up.
a
Rates were calculated by imputing patients who were lost to follow-up as failures.
In the investigational group, overall neurological success
(maintenance or improvement) rates were high, exceeding
88% at all follow-up intervals (Figure 3). The overall success
rates of neurological status in the investigational group were
92.2% and 88.2%, respectively, at 60 and 84 months, compared
with 85.7% and 79.7% in the control group (P = .017 and
.011, respectively). The neurological success rate may have
been influenced by the difference in surgical technique between
the study groups. The arthroplasty surgical technique required
an extensive posterior and posterolateral decompression across
the disc space. In the arthroplasty group, the entire posterior
annulus and posterior longitudinal ligament was resected.
Uncovertebral joints were partially removed, enlarging the
neuroforamina. This extensive dissection and decompression
was not required in the fusion control group. Indirect enlargement
of the neuroforamina through intradiscal distraction was
permitted in the control group. Assuming missing-equalsfailure for patients lost to follow-up, the differences between
the treatment groups in neurological success remain in favor
of the investigational arthroplasty group (Table 3).
Work Status
Before surgery, 65.9% of the investigational group was working
compared with 62.6% of the control group. At 84 months, the
percentage of working patients was 73.9% in the investigational
group and 73.1% in the control group, reflecting no difference
between the groups. Statistical tests were not done at each
follow-up interval to determine if differences in working rates
were statistically significant; instead, time to return to work
was compared between the 2 treatment groups using the
Kaplan-Meier approach. The difference in days after surgery
for return to work between the two groups (P = .022; Wilcoxon
test) favored an earlier return to work in the investigational
group. A Cox proportional hazard model, adjusting for
preoperative work status, was also used to evaluate differences
in days for return to work and again demonstrated an earlier
return to work in the disc arthroplasty group (P = .033).
Radiographic Outcomes
The radiographic outcomes were based on measurements
recorded by 2 independent radiologists. In the control group,
sagittal angular motion was restricted after surgery. The fusion
success rate was 97.8% (131 of 133) at 60 months and 96.9%
(127 of 131) at 84 months.
In the investigational group, the Prestige implant effectively
maintained sagittal angular motion averaging 6.67° at 60
months and 6.75° at 84 months after surgery (Figures 4 and
5). Preoperatively, sagittal angulation at the target disc space
averaged 7.55°. Sagittal angular motion greater than 4° and
less than or equal to 20° was seen in 70.5% (146 of 207) of
patients at 60 months and in 68.8% (141 of 205) of patients
at 84 months (Figures 6 and 7). In the investigational
patients, bridging bone was observed in 13 of 209 patients
(6.2%) with complete radiographic follow-up at 60 months
and in 20 of 201 patients (10.0%) at 84 months, as compared
to 2 of 250 patients (0.8%) at 24 months.
FSU failure, a surrogate measure of subsidence, was defined as
a decrease of more than 2 mm in FSU height from 1.5
months after surgery. This calculation required that the entire
vertebral body above and below the index surgical level be
able to be visualized, which was not possible in all of the
patients with complete sets of radiographs. In those patients
with adequate visualization of the vertebral bodies, FSU
failure was observed in 12 of 165 patients (7.3%) at 60
months and 7 of 166 patients (4.2%) at 84 months. As a
comparison, the corresponding FSU failure rates in the control
group were 6 of 134 patients (4.5%) at 60 months and 4 of
127 patients (3.1%) at 84 months. There was no statistically
significant difference in those rates between the 2 treatment
groups at 60 months (P = .844) or 84 months (P = .683).
At the 84-month follow-up examination, 1 of 204 patients
(0.5%) showed radiographic evidence of disc implant
Seven-Year Outcomes of Prestige Cervical Disc Replacement
49
8
7.87
7.63
7.16
7.55
7.59
7.73
7.23
7.22
7
6.67
6.75
Degrees
6
5
4
3
2
1
0
0.53
Preop
1.5 months
0.33
0.31
0.33
0.35
0.45
0.45
0.48
3 months
6 months
12 months
24 months
36 months
60 months
84 months
Investigational
Control
Figure 4. Mean angular motion at the index surgical level in the investigational group and control group.
Adjacent-Segment Angular Motion
A
6°-7°
B
Figure 5. A, Range of motion in flexion and extension of the cervical spine
with the Prestige ST implant in place. The arthroplasty maintained a mean
of 6° to 7° at 84 months. B, An anterior cervical fusion with allograft and
plate fixation with no segmental motion.
migration. No disc migrations were observed at any previous
follow-up interval. At 84 months, 5 of 204 patients (2.4%)
showed evidence of a broken or fractured Prestige screw. In
the control group, there was no evidence of graft migration
and no evidence of broken or fractured implants or screws.
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THE 2015 RUSH NEUROSCIENCE REVIEW
Adjacent-level disc degeneration and ossification were not
specific data points captured in this study; however, the
independent radiologists reviewed adjacent-segment angular
motion patterns. At 6 weeks postoperatively, motion at the
superior adjacent segment was 10.6° and 9.7° for the
investigational and control groups respectively (P = .041).
There were no other significant between-group differences in
motion at adjacent levels at any other time point (P > .097).
In the investigational group, at the adjacent disc spaces,
sagittal angular motion was effectively maintained above the
implant, averaging 10.7° at 60 months (208 patients) and
11.4° at 84 months after surgery (206 patients). In the
control group, similar motion patterns were seen at the
superior disc space averaging 10.7° at 60 months (179
patients) and remained unchanged at 10.7° at 84 months
after surgery (170 patients). At the disc space level below the
index surgery, in the investigational group, sagittal angular
motion averaged 8.0° at 60 months (126 patients) and 7.7° at
84 months after surgery (134 patients). In the control group,
sagittal angular motion averaged 8.4° at 60 months (111
patients) and 8.5° at 84 months (113 patients) after surgery.
Adverse Events
Adverse events reported by both groups are included in Table
4. There were 259 of 276 (97.7%) investigational group
patients and 232 of 265 (94.5%) control group patients who
reported at least 1 adverse event (P = .958) through
completion of the study. Excluding nonunion, there were
only 2 categories of adverse event in which the occurrence
rates differed between the treatment groups. Investigational
patients reported fewer spinal events than control patients
(20.9% vs 38.9%, P < .001), whereas the control patients
reported fewer urogenital events than the investigational
patients (20.1% vs 12.2%, P = .024).
Dysphagia and Dysphonia
Complaints of dysphagia and dysphonia were identified and
recorded as adverse events in both treatment groups. At
84-month follow-up, the cumulative rate for the control
group was 10.5% compared with a cumulative rate of 11.5%
for the investigational group. There was no statistically
significant difference between the groups.
Secondary Surgical Procedures
Secondary surgical procedures performed after the index operation
occurred in both the investigational and the control treatment
groups (Table 5). At 84 months of follow-up, 11 patients in the
investigational disc arthroplasty group had secondary surgeries
(cumulative rate 4.8%) performed at the initial treatment level;
29 patients in the fusion control group had second surgeries
(cumulative rate 13.7%) performed at the index level (P < .001).
Revision Surgery
There were no (0%) revision surgeries, defined as any
procedure that adjusted or modified the original implant
Table 4. Summary and Comparison of All Adverse Events Based on Life-Table Method
24-Mo Follow-Up Window (911 days)
Investigational
(n = 276)
Adverse Event Category
Patients with any adverse events
b
Investigational
(n = 276)
Control
(n = 265)
No. of Patients
No. of Patients
No. of Patients
No. of Patients
(Cumulative Rate %)a (Cumulative Rate %)a (Cumulative Rate %)a (Cumulative Rate %)a P Valueb
235 (86.4)
219 (87.5)
259 (97.7)
232 (94.5)
.958
Anatomic technical difficulty
1 (0.4)
0 (0.0)
1 (0.4)
0 (0.0)
.327
Cancer
5 (1.9)
2 (0.8)
12 (5.2)
5 (2.4)
.148
Cardiovascular
18 (6.8)
13 (5.5)
39 (17.8)
31 (15.5)
.601
Carpal tunnel syndrome
18 (6.8)
7 (2.9)
24 (10.6)
12 (6.0)
.076
Death
0 (0.0)
3 (1.3)
2 (0.9)
5 (2.2)
.197
Dysphagia/dysphonia
24 (8.7)
22 (8.4)
29 (11.5)
26 (10.5)
.868
Gastrointestinal
30 (11.2)
30 (12.5)
56 (24.7)
51 (24.9)
.915
2 (0.8)
5 (2.1)
6 (3.1)
7 (3.1)
.623
Infection
32 (11.9)
24 (10.0)
62 (27.0)
41 (20.5)
.091
Neck or arm pain
145 (53.8)
121 (48.8)
178 (70.2)
148 (64.8)
.094
Neurological
68 (25.2)
60 (24.6)
99 (42.5)
87 (41.5)
.79
Nonunion
0 (0.0)
9 (3.6)
0 (0.0)
9 (3.6)
.002
Nonunion (outcome pending)
0 (0.0)
21 (8.9)
0 (0.0)
22 (10.0)
<.001
Other
81 (30.2)
85 (35.0)
137 (57.2)
127 (57.1)
.637
Other pain
82 (31.1)
64 (26.3)
137 (58.7)
107 (50.1)
.081
Respiratory
10 (3.8)
8 (3.4)
22 (9.7)
19 (10.1)
.897
Spinal event
23 (8.6)
50 (20.6)
45 (20.9)
82 (38.9)
<.001
Subsidence
1 (0.4)
0 (0.0)
3 (2.3)
0 (0.0)
.087
Trauma
72 (27.2)
50 (20.8)
107 (44.9)
93 (44.9)
.688
Urogenital
20 (7.7)
8 (3.3)
44 (20.1)
23 (12.2)
.024
Intraoperative vascular injury
5 (1.8)
2 (0.8)
6 (2.2)
3 (1.3)
.36
Implant displacement/loosening
a
Control
(n = 265)
Cumulative Through Study Completion
Cumulative rates include adverse events from patients who withdrew from the study.
The P values are from log-rank test for time-to-event analysis.
Seven-Year Outcomes of Prestige Cervical Disc Replacement
51
Table 5. Summary of Secondary Surgeries at the Treated Level Based on the Life-Table Method
24-Mo Follow-Up Window (911 days)
Investigational
(n = 276)
Surgerya
Secondary surgery at
treated level
Control
(n = 265)
Cumulative Through Study Completion
Investigational
(n = 276)
Control
(n = 265)
No. of Patients
No. of Patients
No. of Patients
No. of Patients
(Cumulative Rate %) (Cumulative Rate %) (Cumulative Rate %) (Cumulative Rate %)
P Valueb
9 (3.4)
19 (7.9)
11 (4.8)
29 (13.7)
<.001
Revision
0 (0.0)
4 (1.6)
0 (0.0)
5 (2.1)
.019
Removal
6 (2.3)
8 (3.3)
8 (3.6)
8 (3.3)
.808
Elective removal
0 (0.0)
4 (1.7)
0 (0.0)
13 (7.0)
<.001
Supplemental fixation
0 (0.0)
3 (1.3)
0 (0.0)
5 (2.3)
.017
Reoperation
4 (1.5)
2 (0.8)
4 (1.5)
4 (3.0)
.894
0 (0.0)
6 (2.5)
0 (0.0)
7 (3.0)
.006
Supplemental fixation: BGSc
Abbreviation: BGS, external bone growth stimulator.
a
Some patients had more than 1 secondary procedure.
b
The P value is for between-group comparisons through study completion from the log-rank test.
c
BGS is not included in the total number of secondary surgeries at the treated level.
configuration, in the investigational group compared with
5 revision surgeries in 5 control patients (2.1%), which
resulted in a significant between-group difference (P = .019).
Supplemental Fixation
Procedures that provided additional stabilization at the
index surgical site were considered supplemental fixation
procedures. In the IDE trial protocol, use of an external
bone growth stimulator was also considered as supplemental
fixation. In the control group, 5 patients (2.3%) underwent
supplemental posterior spinal fixation surgeries, compared
with no investigational patients (P = .017), and 7 patients
(3.0%) had application of an external bone graft stimulator
to treat suspected symptomatic nonunion arising from
the index fusion procedures, whereas no investigational
patients underwent application of a bone growth stimulator
(P = .005). The use of bone growth stimulators is not
included in the comparison of surgical procedures in this
article because bone growth stimulators were used only in
the control group.
Implant Removal
Eight nonelective implant removals occurred in both
treatment groups (P = .808). All patients underwent removal
of the disc implant and interbody fusion because of persistent
radicular pain. No disc arthroplasty implants were electively
removed; in the control group, 13 patients (7.0%) underwent
elective removal.
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THE 2015 RUSH NEUROSCIENCE REVIEW
Reoperation
Reoperations occurred in both treatment groups at similar
rates. The investigational group had a reoperation rate of
1.5% (4 patients) compared with 3.0% (4 patients) in the
control group.
Secondary Surgery at Adjacent Levels
Secondary surgeries at adjacent cervical levels occurred as
stand-alone procedures and also involved revision surgery
at the initial index surgical level. Secondary surgery that
involved only an adjacent level occurred in 8 patients (3.9%)
in the investigational group and 10 patients (5.4%) in the
control group (P = .451). The cumulative rates are calculated
from the log-rank test.
Through 84 months, 11 investigational patients (4.6%) and
24 control patients (11.9%) underwent secondary surgeries
that involved adjacent levels (P = .008) (Figure 8).
Discussion
A large-scale, prospective, randomized, multicenter study in
which the Prestige disc was compared with anterior cervical
discectomy and fusion was initiated in 2002.6 Investigators
reported the interim data from this study as patients enrolled
in the study began their 24-, 36-, and 60-month evaluations.7
In this article, we report the final 60- and 84-month
outcomes from this study.
With the use of the Prestige disc implant in patients with
single-level cervical degenerative disc disease, sustained
clinical and radiographic improvements in validated clinical
outcome measurements were maintained at 84 months
following surgery. A slightly earlier return to work was seen in
the disc replacement group.6,17 The Prestige disc maintained
physiologic segmental motion after implantation at the index
surgical level; motion was also maintained at both adjacentlevel disc spaces. Preservation of segmental motion may be
related to a reduction in degenerative radiographic findings in
adjacent segments in patients treated with arthroplasty.18-21 In
addition, there was only 1 implant migration through 84
months and low rates of bridging bone at the implant site.
Similar outcomes were reported with the Bryan disc in an
RCT at 12- and 24-month follow-up.8,22 The postoperative
data from that study showed improvement in all clinical
A
B
outcome measures by 12 months; at 24 months after surgery,
the disc replacement group had a statistically greater
improvement in the primary outcome variables, including
NDI score and overall success, than the fusion group. These
clinical and radiographic improvements were maintained out
to 4 years.14 Outcomes at 2 and 5 years have been reported for
the ProDisc-C cervical disc replacement.9,15 In an RCT
evaluating the surgical treatment of single-level cervical disc
disease, investigators reported that in the ProDisc-C
treatment group there was a statistically and clinically
significant improvement at 2 and 5 years compared to
baseline. At 5 years, ProDisc-C patients had statistically
significantly less neck pain intensity and frequency compared
with the fusion control group.
In a different RCT of a metal-on-metal cervical disc
replacement (Kineflex|C) in patients with 24 months of
C
Figure 6. A, Preoperative lateral radiograph showing disc space narrowing and radial osteophyte formation at the C5-C6 level. B, Lateral extension radiograph
shows 8° of lordosis across the C5-C6 interspace. C, Lateral flexion radiograph shows that the C5-C6 interspace only flexes to 0°.
A
B
C
Figure 7. A, Postoperative lateral radiograph obtained at 84 months, showing the disc prosthesis in place at the C5-C6 level. B, Lateral extension radiograph
showing 4° of lordosis at the C5-C6 interspace. C, Lateral flexion radiograph showing an increase to 5° of kyphosis at the interspace.
Seven-Year Outcomes of Prestige Cervical Disc Replacement
53
Percentage of Patients Who Had Secondary Surgeries Involved With Adjacent Levels
30
Treatment Group
Investigational
Control
25
20
15
10
Logrank = .008
5
0
0
6
12
18
24
30
36
42
48
54
60
66
72
78
84
90
96
Months From Index Surgery to Secondary Surgery
Figure 8. Second surgeries that involved adjacent levels were those at adjacent levels only or those that involved both adjacent and index levels.
follow-up, investigators reported similar outcomes to the
Prestige disc. Mean NDI and visual analog pain scores
improved significantly by 6 weeks after surgery and remained
significantly improved throughout the 24-month follow-up
period.1 The overall success rate was significantly greater
in the disc replacement group when compared with the
fusion group.
Dysphagia is a common occurrence after anterior cervical
spinal procedures.23 Surgical level, number of levels,
instrumentation, and operative time have been associated
with its occurrence. In addition, a correlation between
intraoperative pharynx/esophagus retraction and
postoperative swallowing disturbances has been established.24
There were no differences in the incidence of dysphagia or
dysphonia between the two groups at any of the time frames
studied. The incidence of postoperative dysphagia and the
long-term resolution of the dysphagia were similar in a
previously reported RCT.25
The Prestige disc is able to maintain sagittal angular motion
throughout 7 years postoperatively at the index surgical site.
In addition, the superior and inferior adjacent levels to the
index surgery showed similar motion preservation for
54
THE 2015 RUSH NEUROSCIENCE REVIEW
preoperative measurements. Motion preservation after
cervical disc replacement is affected by spontaneous fusion
and the development of heterotopic ossification. Differences
in occurrence rate of heterotopic ossification are, in part,
related to the prosthesis type.26,27 The Prestige disc has the
lowest rate of heterotopic ossification formation reported
among contemporary RCTs for cervical disc replacements.
Conclusions
Cervical disc arthroplasty has the potential for preserving
motion at the operated level while providing biomechanical
stability and global neck mobility and may result in a
reduction in adjacent-segment degeneration. The Prestige
disc maintains improved clinical outcomes and segmental
motion after implantation at 7 years of follow-up.
Acknowledgments
The authors thank Medtronic biostatisticians Guorong Ma,
PhD, Feng Tang, PhD, and Youjun Zhu, MS, for providing
data analysis and statistical review of the manuscript. David
Wootten, PhD, also an employee of Medtronic, assisted with
manuscript review and editing. The authors also acknowledge
the following investigators: Perry J. Argires, MD; Hyun Bae,
MD; David Benglis, MD; Paul A. Broadstone, MD; Wade M.
Ceola, MD; Johnny Delashaw, MD; Kevin Foley, MD; Jose
Garcia-Corrada, MD; Douglas Geiger, MD; Matthew F.
Gornet, MD; Joseph Grant, MD; Jeremy Greenlee, MD;
Jason Highsmith, MD; Jason R. Hubbard, MD; Jorge E. Isaza,
MD; Theodore Jacobs, MD; Ross Jenkins, MD; Kee D. Kim,
MD; Thomas Kopitnik, MD; Jeffrey Lewis, MD; R. Dean
Martz, MD; Bruce Mathern, MD; Hallett Mathews, MD;
Matthew T. Mayr, MD; Lloyd Mobley, MD; Robert Narotzky,
MD; Russell P. Nockels, MD; Charles C. Park, MD; Joel
Pickett, MD; Ralph F. Reeder, MD; Joseph Riina, MD; James
Robinson, MD; Patrick Ryan, MD; Timothy Ryken, MD; Paul
Sawin, MD; David D. Schwartz, MD; Joseph Sramek, MD;
Rebecca E. Stachniak, MD; Ann Stroink, MD; Steven E.
Swanson, MD; Brian Wieder, MD; Charles Winters, MD; and
Thomas A. Zdeblick, MD.
Disclosures
Author 1 (corresponding author) has received reportable
payments for consulting fees and royalty payments from
Medtronic, Inc. Author 1 has no proprietary interest, such as
a patent, trademark, or copyright ownership or a licensing
relationship, with regard to the product under investigation.
Since the commencement of the clinical study, author 1 has
not had an equity interest (such as ownership, stock, or stock
options) in Medtronic, Inc. Since the commencement of the
clinical study, author 1 has not received compensation in
which the value of compensation could be affected by study
outcome, such as a royalty interest.
Author 2 is a consultant to and receives royalties and
institutional research support from Medtronic. Author
2 receives institutional research support from NIH and
institutional fellowship support from Globus.
Author 3 receives royalties from Medtronic and Globus and is
a consultant for Nuvasive and Piedmont Healthcare. Author
3 serves on the Medical Board of Directors for Globus and has
stock in Nuvasive, Globus, Spinewave, and Vertical Health.
Author 4 is not a consultant for nor has he received payments
from Medtronic, the manufacturer of the PRESTIGE
implant. Author 4 has received honoraria from Globus and
DePuy Spine and has received a royalty from DePuy Spine
related to thoracolumbar instrumentation but not related to
any cervical implant.
Seven-Year Outcomes of Prestige Cervical Disc Replacement
55
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Scheer JK, Harvey MJ, Dahdaleh NS, Smith ZA, Fessler RG.
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Serrano GE, Sabbagh MN, Sue LI, Hidalgo JA, Schneider JA,
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Shah RC, Matthews DC, Andrews RD, Capuano AW,
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Sherva R, Tripodis Y, Bennett DA, Chibnik LB, Crane PK, de
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Shulman JM, Yu L, Buchman AS, Evans DA, Schneider JA,
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Skovrlj B, Gologorsky Y, Haque R, Fessler RG, Qureshi SA.
Complications, outcomes, and need for fusion after minimally
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Spine J. 2014;14(10):2405-2411.
Smith ZA, Fessler RG. Minimally invasive spine surgery. Preface.
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Smith ZA, Fessler RG. Nonexpandable tubular retractors and
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Smith ZA, Lawton CD, Wong AP, Dahdaleh NS, Nixon AT, Ganju
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Smith ZA, Sugimoto K, Lawton CD, Fessler RG. Incidence
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Smith ZA, Vastardis GA, Carandang G, Havey RM, Hannon
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THE 2015 RUSH NEUROSCIENCE REVIEW
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Kanter AS, La Marca F, Fessler R, Uribe J, Shaffrey CI, Lafage V,
Haque RM, Deviren V, Mundis GM Jr; Minimally Invasive Surgery
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Select Publications
71
Select Research Grants (2014)
Department of Neurological Sciences
Neelum Aggarwal, MD
Deborah Hall, MD, PhD
• Effect of Passive Immunization on the Progression of Mild
Alzheimer’s Disease
• Adult Neurological Phenotypes of Fragile X Gray Zone Expansion
• Dose Study in Patients with Mild-Moderate Alzheimer’s Disease
• Exploratory Study of Different Doses of Endurance Exercise in
People with Parkinson’s Disease
• Anti-Amyloid Treatment in Asymptomatic Alzheimer’s Disease
S. Duke Han, PhD
• Community-Based End-of-Life Intervention for AfricanAmerican Dementia Caregivers
• Neural Correlates of Impaired Financial and Health Care
Decision-Making in Old Age
Zoe Arvanatakis, MD, MS
Aikaterini Kompoliti, MD
• Vascular Cognitive and Motor Decline: Impact of aPL
Roumen Balabanov, MD
• Oral Treatment for Subjects with Moderate to Severe
Parkinson’s Disease
• Dosage Study in Subjects with Relapsing Remitting Multiple
Sclerosis
• Assess Sustained Effects of Droxidopa Therapy in Patients
with Neurogenic Hypotension
Lisa Barnes, PhD
George Lopez, MD, PhD
• Risk Factors for Cognitive Decline in African Americans
• Minimally Invasive Surgery Plus rtPA in the Treatment of
Intracerebral Hemorrhage
• Rush Center of Excellence on Disparities in HIV and Aging
David Bennett, MD
• Role of Genetic Variations in Age Dependent Risk of
Alzheimer’s Disease
• National Alzheimer’s Coordinating Center (NACC)
• Role of the Innate Immune System in Aging and
Development of Alzheimer’s Disease
• Chronic Effects of Neurotrauma Consortium Award
• Cellular and Molecular Medial Temporal Lobe Pathology in
Elderly Pre-Mild Cognitive Impairment Subjects
• Neurobiology of Mild Cognitive Impairment in the Elderly
Dan Nicholson, PhD
• Development of Lewy Bodies Biofluid Signatures by Targeted
Proteomics
• Proteomic Reconstructive Microscopy of Healthy and
Diseased Dendrites
• Pathway Discover, Validation, and Compound Identification
for Alzheimer’s Disease
Kalipada Pahan, PhD
• Epidemiologic Study of Neural Reserve and Neurobiology of Aging
• Experimental Autoimmune Encephalomyelitis Study in
Animal Cellular/Biochemical Assays
• Risk Factors, Pathology, and Clinical Expressions of
Alzheimer’s Disease
• Cinnamon, Ciliary Neurotrophic Factor (CNTF), and
Experimental Autoimmune Encephalomyelitis (EAE)
Patricia Boyle, PhD
• RANTES and Eotaxin: New Players in Parkinson’s Disease
Progression
• Two Preclinical Latent Scores to Predict Occurrence of
Dementia of Alzheimer’s Type
• Epidemiologic Study of Impaired Decision-Making in
Preclinical Alzheimer’s Disease
• Characterizing the Behavior Profile of Healthy Cognitive Aging
Nina Paleologos, MD
• Trial for Seizure Prophylaxis in Patients with Malignant Gliomas
Julie Schneider, MD
Aron Buchman, MD
• Epidemiologic Study of TDP-43 Pathology in Aging and
Dementia
• Identifying Genetic Determinants of Human Sleep and
Circadian Rhythms
Raj Shah, MD
• Brain and Spinal Cord Microvascular Pathology in Late-Life
Motor Impairment
• The Clinical Profile of Parkinson’s Disease Pathology
Laurel Cherian, MD
• Study to Prevent Major Vascular Events in Patients with Acute
Ischemic Stroke
Cynthia Comella, MD
• Evaluation of Dysport in Adults with Cervical Dystonia
• Assess Safety of Dysport in Adults with Cervical Dystonia
James Conners, MD, MS
• Stroke Trials Network-Regional Coordinating Stroke Centers
72
Elliott Mufson, PhD
THE 2015 RUSH NEUROSCIENCE REVIEW
• Long-Term Safety Extension of Studies with Mild to Moderate
Alzheimer’s Disease
• Study for Detection of Cerebral ß-Amyloid Compared to
Postmortem Histopathology
• ß-Amyloid Imaging with Positron Emission Tomography in
Prediction Progression in Alzheimer’s Disease
• Biomarker Algorithm for Prognosis of Risk of Developing
Mild Cognitive Impairment in Alzheimer’s Disease
• Study in Subjects with Amnestic Mild Cognitive Impairment
Due to Alzheimer’s Disease
• Integrated Inpatient/Outpatient Care for Patients at High Risk
of Hospitalization
• CAPriCORN
Glenn Stebbins, PhD
Leonard Verhagen, MD, PhD
• A New Rating Scale for Focal Task-Specific Dystonia of the
Musician’s Hand
• Treatment of Levodopa-Induced Dyskinesia in Parkinson’s
Disease Patients
• FuRST 2.0 Rating Scale
Robert Wilson, PhD
Dusan Stefoski, MD
• BAILA: Being Active, Increasing Latinos’ Healthy Aging
• John Cunningham Virus (JCV) Antibody Program in Patients
with Relapsing Multiple Sclerosis
Lei Yu, PhD
• Role of Impaired Cognitive States and Risk Factors in
Conversion to Mixed Dementia
Department of Neurological Surgery
Richard Byrne, MD
Demetrius Lopes, MD
• Methylation Patterns of DNA in Epilepsy
• The Effect of Blood Pressure on the Outcome of Elective
Endovascular Neurointerventions for Cerebral Aneurysms
• Neuronal Changes in Intractable Epilepsy
• Molecular Biology of Epileptogenesis
• Sensitivity of Glioma Cell Line to New Chemotherapeutic
Agents
• Cellular Substrates of Hyperexcitability in Temporal
Lobe Epilepsy
Michael Chen, MD
• WEAVE Trial: Wingspan Stent System Post-Market
Surveillance Study
• LVIS: Pivotal Study of MicroVention, Inc. Neurovascular
Self-Expanding Retrievable Stent System in the Treatment
of Wide-Necked Intracranial Artery Aneurysms
• FRED: Pivotal Study of the MicroVention Flow Re-Direction
Endoluminal Device Stent System in the Treatment of
Intracranial Aneurysms
• SWIFT-PRIME: Solitaire FR with the Intention for Thrombectomy
as Primary Endovascular Treatment for Acute Ischemic Stroke
• Prospective Analysis of Aneurysm Management by Dual
Trained Neurosurgeons
• Treatment of Symptomatic Intracranial Stenosis with
Submaximal Angioplasty
• BEACH: Boston Scientific EPI: A Carotid Stenting Trial for
High-Risk Surgical Patients
• COCOA: Complete Occlusion of Coilable Aneurysms Using
Pipeline Embolization Device
• Outcomes of Cranial Neuropathy After Treatment of
Intracranial Aneurysms with Flow Diverters
Roham Moftakhar, MD
• ASPIRE: Aneurysm Study of Pipeline in an Observational Registry
• Modern Clinical Indications and Cost-Effectiveness of
Catheter Cerebral Angiography
Lorenzo Muñoz, MD
Harel Deutsch, MD
• Identification and Modification of Developmental Genes in
Adult Primary Brain Tumors
• Activ-L Lumbar Artificial Disc
• Safety and Efficacy of Staphylococcus Aureus Vaccine in
Adults Undergoing Elective Posterior Instrumented Lumbar
Spinal Fusion Procedures
Richard Fessler, MD, PhD
• Minimally Invasive Surgery for the Treatment of Adult
Deformity: A Multicenter Retrospective Study
• The Relationship Between Patient Expectations and
Outcomes in Minimally Invasive Surgery vs. Open Lumbar
Surgical Procedures
• Methylation Patterns of DNA in Neoplasms of the Brain
• Surgery and Stereotactic Radiosurgery for Brain Metastases
John O’Toole, MD, MS
• Validation of the Visual Analog Motion Scale
• Os Odontoideum in the Adult
Sepehr Sani, MD
• Reclaim Deep Brain Stimulation for Obsessive Compulsive
Disorder (OCD) Therapy
Vincent Traynelis, MD
• Intubation Mechanics of the Stable and Unstable Cervical Spine
• Critical Analysis of Extubation Parameters for Patients
Undergoing Combined Anterior Posterior Cervical Fusion
• Efficacy of Riluzole in Patients with Cervical Spondylotic
Myelopathy Undergoing Surgical Treatment %
Select Research Grants
73
Volume and Quality Data
Volumes, neurology and neurological surgery
3 000
2 500
2 000
1 500
1 000
500
0
2 133
2010
2 186
2011
2 398
2012
2 589
2013
Neurology outpatient visits, fiscal years 2010-2014
Outpatient visits
Number of discharges
Neurology volumes*, fiscal years 2010-2014
2 528
2014
30 000
25 000
20 000
15 000
10 000
5 000
0
21 104
22 736
25 162
26 937
28 986
2010
2011
2012
2013
2014
Year
Year
*Includes neuro-oncology discharges
Rush had the highest volume of general neurology discharges in the Chicago region for fiscal year 2014.
Outpatient visits
6 000
5 000
4 375
4 000
3 000
2 000
1 000
3 101
1 305
2010
3 222
4 345
3 666
5 086
3 420
2 258
1 599
2011
2012
2013
2014
Volume of patients monitored for epilepsy,
calendar years 2010-2014
Cases of video EEG
monitoring for seizure
classification or localization
Neurological surgery outpatient visits, fiscal years
2010-2014
1 200
1 000
800
600
400
200
0
667
894
1009
834
1091
2010
2011
2012
2013
2014
Year
Spine
Year
Brain*
*Includes all non-spine procedures
Neurological surgery volume of major cases by area, fiscal year 2014
Epilepsy and movement disorders
51
(1.89%)
184
(6.82%)
Trauma
79
(2.93%)
Open cerebrovascular
44
(1.63%)
Functional
110
(4.08%)
Brain tumor
334 (12.38%)
Spine and nerves
977 (36.21%)
Other
160
Neuroendovascular-diagnostic
450 (16.68%)
Neuroendovascular-interventional
309 (11.45%)
Cerebrospinal fluid treatments
Total:
2 698
Surgeries
(5.93%)
Rush had the highest volume of neurosurgical discharges in the Chicago region for fiscal years 2011-2014.
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THE 2015 RUSH NEUROSCIENCE REVIEW
Mortality, neurology and neurological surgery
Neurological surgery mortality o/e, fiscal years
2010-2014
Neurology mortality o/e, fiscal years 2010-2014
1.0
0.8
Mortality index
Mortality index
1.0
0.6
0.4
0.2
0.0
1.02
0.56
0.71
0.60
0.79
2010
2011
2012
2013
2014
0.8
0.6
0.4
0.2
0.0
0.72
0.87
0.75
0.77
0.95
2010
2011
2012
2013
2014
Year
Year
Source: University HealthSystem Consortium clinical database
Source: University HealthSystem Consortium clinical database
Quality indicators, stroke
Median times to endovascular
recanalization treatment at Rush
Stroke IV tPA rate %,
fiscal year 2014
Stroke inpatient mortality %, fiscal year 2014
25
40
20
32
15
42 min.
32 min.
10
5
24
22.47
16
12.21
8
0
Door to
groin time
Groin to
recanalization time
Source: Data from SWIFT-PRIME trial
0
5.96 4.38
Ischemic
stroke
Ischemic stroke1
Rush
U.S. Hospitals2
19.16 22.25
1
2
Intracerebral
hemorrhage
12.95 16.84
Subarachnoid
hemorrhage
Administered at Rush and outside hospitals combined
Includes all U.S. Hospitals participating in Get With the Guidelines stroke data registry
Source: Get With the Guidelines stroke registry
Rush had the fastest door to groin and groin to recanalization times of any participating SWIFT-PRIME trial sites.
See page 2 for more information about the trial.
Stroke case volumes, fiscal year 2014
Total:
965
Cases
Subarachnoid hemorrhage
139 (14.40%)
Intracerebral hemorrhage
261 (27.05%)
Ischemic stroke
503 (52.12%)
Transient ischemic attack (<24 hours)
62
(6.43%)
Volume and Quality Data
75
NEUROLOGICAL SPINE SURGERY ROUNDTABLE:
On the planning, execution, and future of spine surgery
Left to right: Harel Deutsch, MD; Richard Fessler, MD, PhD; John O’Toole, MD, MS; Vincent Traynelis, MD; Ricardo Fontes, MD, PhD
From a beloved Disney mascot to professional athletes to patients of all ages with scoliosis, neurological spine
surgeons at Rush have treated patients with the full gamut of spine conditions. Together, these physicians have
more than 75 years of experience. During that time, they have pioneered several minimally invasive techniques,
including minimally invasive decompression of cervical and lumbar stenosis and unilateral transforaminal lumbar
interbody fusion.
Here, Vincent Traynelis, MD, director of spine neurosurgery at Rush, sits down with colleagues Richard Fessler, MD, PhD,
John O’Toole, MD, MS, Ricardo Fontes, MD, PhD, and Harel Deutsch, MD, to discuss the future of spine surgery and
the importance of finding the right treatment for each patient—and what goes into that decision-making process.
On recent advances in spine surgery
Traynelis: Let’s start with discussing advances that have
changed spine surgery.
Fontes: We understand spinal deformity a lot better than we
did ten years ago. It’s opened up a number of new treatments
for patients who would otherwise be relegated to palliative
treatment like morphine pumps and spinal cord stimulators.
The big national and international registries that we
participate in have shown that surgery can effectively treat
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THE 2015 RUSH NEUROSCIENCE REVIEW
quality of life in these patients with adult spinal deformity,
such as from scoliosis, and that nonoperative treatments
actually are not as effective.
At Rush we have a whole team of surgeons who are able
to address that through minimally invasive and open
techniques, and a lot of other specialists—ICU, rehab
physicians—are involved in the care as well.
Traynelis: While adolescent idiopathic scoliosis is a
prominent disease, the aging population of our country has
resulted in a large number of patients with scoliosis from
degenerative processes. So, now degenerative deformity has
become a huge issue in spinal surgery, at least in terms of the
magnitude of patient numbers.
More is understood about deformity and there are newer
techniques, yet a great deal of thought must be given to each
patient in terms of how much intervention is enough and
how much is too much. And interventions must be planned
not only with an eye to what will address the current
problem, but also what will minimize the potential for further
trouble in the future.
Fontes: For those of us who treat adult deformity, I think the
most obvious example of progress is people who have a lot of
back and leg pain because of disc degeneration and prior
surgeries. And because of this, they’re considerably bent forward.
That’s a problem we understand a lot better now. We’re able
to correct it much better using minimally invasive techniques
and, when necessary, we can use more conventional open
techniques. We can make a difference with these patients,
who otherwise in the past would have been considered to
have huge problems and not be candidates for surgery.
Now we can offer something for them, and it’s been shown
extensively that it improves their quality of life.
Traynelis: And these patients, the degenerative deformity
patients who are generally in their 60s and 70s, they still have
a lot of things they want to do. They’ve given up everything
because their quality of life is so bad.
O’Toole: That’s right; they are baseline very active people
who have essentially developed these deformities that are
disabling. I had a patient who was an instructor for chefs,
and he would have to stand at the teaching kitchen all day.
He just progressively got more and more deformity and just
couldn’t work anymore.
A few months after surgery, he was already back at work and
upright and feeling good. Same thing with the patients who
like to work in their gardens.
Traynelis: They’re approaching retirement and all of a
sudden in their golden years…
O’Toole: Right, and their recreational activity is golf…
Traynelis: And they can’t do anything but just sit in a chair
because they’re miserable.
O’Toole: And these types of operative interventions can get
these people back to those activities.
Fontes: Those are really some of the happiest patients we
have. It’s truly impressive.
Fessler: Yes, I can give you an extreme scoliosis example.
I had a patient with adult degenerative scoliosis. His passion
was playing basketball. Not only could he not play basketball,
but he was having difficulty walking down the block. We
corrected his scoliosis using minimally invasive technique.
He is now playing basketball every week.
Traynelis: And of course along with these advances, there’s
fusion, which is a critically important part of treating many
patients with spine problems, and progress in terms of
improvements in instrumentation and the way we place
instrumentation, such as with navigation.
O’Toole: Yes, but I think more important is the research
that Drs Traynelis and Deutsch have done in non-fusion
technology: specifically total disc replacement and
arthroplasty: Dr Traynelis has been a leader in cervical
arthroplasty research, and Dr Deutsch has been a leader in
lumbar arthroplasty research.
Fusion is not necessarily the answer to all problems. It’s the
answer to many problems, but we’re constantly looking for
new and different solutions, and we here at Rush are actively
involved in research efforts to make that happen.
Traynelis: For arthroplasty there are now quality data going
out seven years that show that this, for the proper patient, is a
durable treatment. In fact, that’s one of the articles in this
publication. And, the results are better than those with
fusion. But it has to be noted that arthroplasty is not for
everyone. For a certain select group of patients, it is the better
choice. The key is always to select the right treatment for the
clinical problem.
Deutsch: Many people know that when you have a fusion,
the levels adjacent to that fusion may be affected, and the
arthroplasty potentially prevents that. That’s especially
important in younger patients.
For instance, I’ve had a lot of success with artificial discs in
police officers. They’re highly motivated to go back to work,
and the perceived restrictions they would have if they had a
fusion deter them from having one. And then they end up
having artificial discs, and they can return to work.
Fontes: Of course it’s also important to mention that
through the use of minimally invasive techniques, typically
we can achieve a fusion pretty successfully without the need
for a huge operation.
Fessler: The other impact that the minimally invasive
scoliosis surgery has is that we’ve reduced blood loss from
liters to literally 100 to 200 cc. Most patients don’t require
transfusions, and we’ve reduced complications from 70% to
10%, comparing open to minimally invasive techniques.
Neurological Spine Surgery Roundtable
77
O’Toole: I think that gets to the deformity part of it too, as
you think about big fusion operations and what people go
through in terms of complications following surgery. Many
of us are trying to apply more minimally invasive techniques
to reduce complication rates, reduce recovery times and
ultimately still produce similar excellent outcomes for what
is a very challenging disease and patient population. That’s
where a lot of the current research is focusing.
available, and the collective experience of the surgeons is
very broad and deep.
On finding the right procedure for the
right patient
Moreover, when you’re talking about spine surgery, you’re
talking about at least two different organ systems: the
musculoskeletal system and the nervous system. A lot goes
into determining which aspects of the patient’s problems are
related to one thing or another, the extent of your treatment,
the consequences of this treatment, as well as the patient’s wishes.
Traynelis: It is important to first correctly diagnose the
factors creating the problem after which one is able to
determine the possible interventions. As with artificial discs,
it’s about appropriate patient selection and the thought that
goes into deciding which procedure is right for each patient.
A previously operated patient with extensive instrumentation
may not be a candidate for minimally invasive. It’s a great
option for people, but, again, the value of the Rush
neurosurgery spine program is that all of these techniques are
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THE 2015 RUSH NEUROSCIENCE REVIEW
O’Toole: Among surgery disciplines, clinical decision making
in spine surgery is one of the most complicated there is, I
think. And it’s largely due to the fact that, although there are
clinical practice guidelines that exist for what we do, many of
the patients we see don’t fit nicely into the categories that
some of those guidelines dictate.
So, a lot of these elements have to factor into those decisions.
That’s where having colleagues like you guys around is such a
huge advantage, because we’re able to bounce off different
ideas and think about all these issues that are rarely simple in
many of these patients.
Traynelis: There are two things that contribute to a good
patient outcome—and they’re equally important. The first
is the planning: If you have a bad plan and you choose the
wrong thing to do, no matter how well you do it, it won’t
work. We have the ability to talk to each other and create
the right plan. Almost always there are at least two of us in
clinic at any time. This facilitates immediate discussion when
an unusual or challenging case arises. We also have a regular
spine conference where cases can be reviewed.
The planning is just as hard as executing it, which is the
second phase: executing the surgery properly. Before entering
the operating room, especially for these bigger cases, hours
have been spent studying anatomy, measuring angles and
discussing options amongst ourselves, and explaining all to
the patient. Both the planning and execution are critical to
having a good outcome.
On limiting radiation exposure
Fontes: In addition to surgical outcomes, another quality
issue we’re examining is radiation, particularly in deformity.
Radiation exposure is a big concern for patients, especially for
patients with scoliosis who get repeat tests over time, such as
the pediatric and adolescent population. So, we’re aware of
that and are continuing to look at ways to address this issue.
O’Toole: Ricardo [Fontes] and I have been working on this
issue quite a bit. We’re looking at intraoperative radiation
exposures, so we extensively use image-guided navigation in
the operating room. Basically it involves an intraoperative
CT-type machine that acquires images and allows us to then
use 3-D navigation with a computerized system to work in the
spine that ordinarily would require a lot of intraoperative
X-ray or fluoroscopy. We’ve demonstrated substantial
reductions in radiation exposures using this kind of technology.
Traynelis: To the patient and the team?
O’Toole: Yes, to everyone involved.
Fontes: That’s huge, especially from the patient safety
standpoint. And, in addition to reducing radiation exposure,
with this technology the placement of implants is much more
accurate and leads to fewer revisions.
Traynelis: Each year we are more cognizant of the potential
deleterious effects of X-rays, and the images ordered are
limited without compromising care. For instance, instead
of automatically getting the standard six views of the spine,
if really two will show what is of concern, only two views
are ordered.
O’Toole: Yes, and along those lines, a lot of what’s changed
spinal cancer care both in terms of what we do on a day-to-
day basis and in improving care for patients is the role of
stereotactic radiosurgery—particularly in the treatment of
metastatic disease to the spine. We’re now able to perform
surgeries that are somewhat less morbid or fraught with
complications because we can apply this more powerful
radiation technique to get better control.
So, the paradigm has shifted in terms of care of these patients
and what we can do. We’re able to do more for patients with
metastatic disease in terms of achieving pain relief,
neurological preservation of function, and spinal stability.
Traynelis: Yes, that’s important because some of the
techniques that have changed—for both radiation and
surgery—result in quicker recoveries. For people whose time
is more limited, that’s important. It gets them out of the
hospital, functioning and doing what they want to do.
On measuring—and learning from—
outcomes data
O’Toole: And with regard to function, a big quality focus for
us recently has been collecting patient-reported outcome
measures, which is really the standard of care now for spine
surgery in general. Wouldn’t you guys agree? We utilize a
number of different outcome measures that let us know how
patients are doing through a digital online platform that
patients use to fill out various questionnaires both before
surgery and after surgery.
We’re able now to trend these kinds of changes over time,
which allows us to focus specifically on how we’re doing
with quality in the care of these patients. That’s been a
groundbreaking thing for us in that we’re getting real-time
responses from patients about how they’re doing. This has
allowed us to transform the way that we’re doing our own
quality assurance measures.
Traynelis: Our plan going forward is to examine these data
at regular intervals, see what our results are and look at other
benchmarks. Each time we look at the data, we want the
numbers to be better. So, we continually ask, “What can we
do to improve this outcome?”
On the importance of collaboration
O’Toole: Our collaborations with colleagues throughout
Rush help in this regard as well. For instance, you see the
advantages of working in an institution like Rush clearly in
cancer because what has happened with spinal oncology is a
turn towards interdisciplinary care. We run a comprehensive
spine tumor clinic through the Rush University Cancer
Center. It’s co-directed by myself and Aidnag Diaz [MD,
MPH], one of the radiation oncologists here.
Neurological Spine Surgery Roundtable
79
The idea is that for patients with metastatic cancer to the
spine, in particular, that’s not their only disease problem.
So we take the view that we’re trying to look at the patient
in a holistic way, at their overall cancer care: What are the
goals for this patient in light of the extent of their disease,
and what can we do for the spinal component of the problem?
In some cases, that means radiation alone, sometimes it
means surgery, and sometimes it means both or neither. All
of this is done under the aegis of the medical oncologist and
the patient’s other care providers, so that we are all providing
a comprehensive treatment plan.
Traynelis: Yes, an advantage of practicing at Rush is that
you’re part of a team—you have a group of highly skilled
partners and each of them, although they all are excellent
general spine surgeons, each person has some extra area of
focus. That helps us as a group, and it’s also to the advantage
of the patient. If a patient comes to me with a problem that’s
not something I manage regularly, then I can send that
person to one of my colleagues.
O’Toole: In addition, we have the advantage of collaborative
relationships with the excellent departments here that are
associated with the spine. For example, as I noted earlier, the
medical and radiation oncology departments, and the
partnerships we have with them with working with patients
with spinal tumors. And the movement disorders group is a
big part of what affects us in spine surgery because Parkinson’s
disease patients often will have a lot of spinal issues. And
they’re a fantastic group, as are our other neurology colleagues.
We also work with the folks in physical medicine and
rehabilitation…
Traynelis: Yes, and our rehabilitation center.
O’Toole: We have a strong group here. So, it’s these other
service lines that intersect with spine surgery and the high
quality that’s present in those other groups as well that
elevates the work we do.
On the future of spinal surgery
Traynelis: So looking forward, what’s next for spinal surgery?
Dr Fontes, you’ve done key basic research investigating disc
degeneration in the laboratory and how and where this
occurs. These results certainly represent new knowledge and
may lead to improved outcomes at some point in the future.
Fontes: Well, as you know, it’s all very experimental at
this point. But, at some point, the future of spinal surgery
will involve manipulating discs. There’s a lot of data from
the laboratory, and we understand this process a lot better
now. Dr Fessler, would you want to speak more about
disc regeneration?
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THE 2015 RUSH NEUROSCIENCE REVIEW
Fessler: Yes, it is experimental, but we are able to do it in
smaller animals. It’s a question of time until we can do that in
larger animals. And then the question is how we actually
implement that in humans, whether it’s going to be an
injection to regrow within the disc or whether we grow the
disc outside and then implant an entire disc. Those answers
are still in the future.
Traynelis: Yes, the exciting point is that even though this is
down the road, we have people here participating in what the
future will be. So, it is a futuristic idea. But smartphones once
were futuristic.
Fessler: The other futuristic thing we’ve got going on is that
we’re just starting to enroll in the next spinal cord stem cell
transplantation study for cervical spinal cord injury.
This is actually the third trial that I’ve been involved in
personally. The first was in the mid-90s of transplantation
of human embryonic spinal cord. The second was in the
mid-2000s for stem cell transplantation into individuals with
thoracic-level spinal cord injuries.
This is the first study that will be done in subacute spinal cord
injury in the cervical spinal cord. We are much more hopeful
in achieving some kind of a functional effect because the
length that the cells have to grow is much shorter than the
mid-thoracic spinal cord. If we can grow 2 cm, we might be
able to return some hand function, for example. It’s a very
exciting study.
Deutsch: We’re also involved in a trial of a vaccine against
staph, which is the most common cause of surgical infections,
and the main risk for complications in spine surgery,
especially open surgery. The hope is that future patients may
get a vaccine a week before they have surgery, and that may
reduce infection rates significantly. It’s going to be a
randomized study where people get the vaccine or placebo.
Traynelis: If it works, then the vaccine could be offered to all
patients who have surgery, which would be a great advance. %
For a patient consultation or referral to
a neurologist at Rush, please call (312) 942-4500.
For a neurosurgeon at Rush, call (312) 942-6644.
RUSH’S HOSPITAL: DESIGNED AROUND THE PATIENT
Rush’s hospital transforms medicine by focusing on one key element: quality patient care. That's why hundreds of doctors, nurses and other
clinicians, with input from patients and families, worked with architects to design our state-of-the-art hospital Tower. One of the nation's most advanced
hospitals, the hospital houses acute and critical care patients, as well as technologically sophisticated surgical, diagnostic, and therapeutic services.
Rush is a not-for-profit health care, education and research enterprise comprising
Rush University Medical Center, Rush University, Rush Oak Park Hospital and Rush Health.
PLEASE NOTE: All physicians featured in this publication are on the medical faculty of Rush University Medical Center. Some of the
physicians featured are in private practice and, as independent practitioners, are not agents or employees of Rush University Medical Center.
Rush University Medical Center
1653 W. Congress Pkwy.
Chicago, IL 60612
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