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CMEinfo presents a definitive multimedia course

NEUROSURGERY —
A COMPREHENSIVE
REVIEW
directed by Ian F. Dunn, MD, FAANS
BRIGHAM AND WOMEN’S HOSPITAL
Neurosurgery –
A Comprehensive Review
Provided By:

Oakstone Publishing, LLC

WARNING:
The copyright proprietor has licensed the picture
contained on this recording for private home use only
and prohibits any other use, copying, reproduction, or
performance in public, in whole or in part (Title 17 USC
Section 501 506).

© 2016 Ebix, Inc. DBA Oakstone Publishing. LLC.


CMEinfo is a registered trademark of Oakstone Publishing, LLC.
CMEinfo is not responsible in any way for the accuracy,
medical or legal content of this recording. You should be
aware that substantive developments in the medical field
covered by this recording may have occurred since the
date of original release.

Date of Original Release: June 15, 2016


Date Credits Expire: June 15, 2019

This activity was planned for Neurosurgeons in practice,


Neurosurgery Fellows and Residents, Nurse Practitioners
and Physician Assistants working in Neurosurgery.

It is estimate that it should take the average learner 35.00


hours to complete the activity.
ACCREDITATION
Oakstone Publishing, LLC is accredited by the
Accreditation Council for Continuing Medical Education
(ACCME) to provide continuing medical education for
physicians.

DESIGNATION
Oakstone Publishing, LLC designates this enduring
material for a maximum of 35.00 AMA PRA Category 1
Credits™. Physicians should claim only the credit
commensurate with the extent of their participation in
the activity.
DISCLOSURE
Oakstone Publishing, LLC has assessed conflict of interest
with its faculty, authors, editors, and any individuals who
were in a position to control the content of this CME activity.
Any identified relevant conflicts of interest were resolved for
fair balance and scientific objectivity of studies utilized in
this activity. Oakstone Publishing’s planners, medical
reviewers, and editorial staff disclose no relevant financial
relationships with commercial interests.

The following content contributors report:


Course Director Ossama Al-Mefty, MD, FACS
Ian F. Dunn, MD, FAANS Director of Skull Base Surgery,
Department of Neurosurgery, Brigham and Brigham and Women’s Hospital;
Women’s Hospital, Harvard Medical Harvard Medical School,
School, Boston, MA Boston, MA
Reports no commercial interest Reports no commercial interest

Faculty Rocco A. Armonda, MD


Tord D. Alden, MD Director, Neuroendovascular Surgery, Co-
Attending Neurosurgeon, Chief Medical Director, Neuro-ICU, MedStar Georgetown
Informatics Officer, Ann & Robert H. Lurie University Hospital and Washington
Children’s Hospital of Chicago; Assistant Hospital Center, Washington, DC
Professor, Northwestern University The Reports no commercial interest
Feinberg School of Medicine, Chicago, IL
Reports no commercial interest
The following content contributors report:
Ashok Asthagiri, MD John H. Chi, MD, MPH
Associate Professor, Assistant Professor, Director of
Department of Neurosurgery, Neurosurgical Spine Oncology,
University of Virginia School of Medicine, Brigham and Women’s Hospital,
Charlottesville, VA Dana-Farber Cancer Institute,
Reports no commercial interest Harvard Medical School,
Boston, MA
Jeffrey N. Bruce, MD, FACS Reports no commercial interest
Vice-Chairman, Edgar M. Housepian
Professor of Neurological Surgery,
Department of Neurological Surgery,
Columbia University College of Physicians
and Surgeons, New York, NY
Reports no commercial interest

The following content contributors report:


Charles S. Cobbs, MD Rose Du MD, PhD
Director, Ivy Center for Advanced Brain Associate Professor,
Tumor Treatment, Department of Neurosurgery,
Swedish Neuroscience Institute, Brigham and Women’s Hospital,
Seattle, WA Harvard Medical School,
Reports no commercial interest Boston, MA
Reports no commercial interest
Garth Rees Cosgrove, MD, FRCSC
Director, Epilepsy and Functional
Neurosurgery, Brigham and Women’s
Hospital, Harvard Medical School, Boston,
MA
Reports no commercial interest
The following content contributors report:
Michael W. Groff, MD Edward Laws, MD
Director of Spinal Neurosurgery, Brigham Professor of Neurosurgery,
and Women’s Hospital, Boston, MA Harvard Medical School,
Reports Research Grants: Neurosurgical Boston, MA
Research and Education Fund Reports no commercial interest
Advisory Role: Biomet Spine, Depuy Spine
Independent Contractor: BestDoctors, Inc

Adam S. Kanter, MD
Chief of Spine Services,
Associate Professor of Neurological
Services,
University of Pittsburgh Medical Center,
Pittsburgh, PA
Reports no commercial interest

The following content contributors report:


Christopher Loftus, MD Susan E. Mackinnon, MD
Chair, AANS International Programs; Schoenberg Professor of Plastic and
Treasurer, WFNS; Reconstructive Surgery, Chief, Division of
Professor and Chairman, Department of Plastic and Reconstructive Surgery,
Neurosurgery, Professor of Neurology, Washington University School of Medicine
Loyola University Stritch School of in St. Louis, Barnes-Jewish Hospital, St.
Medicine, Louis, MO
Maywood, IL Reports no commercial interest
Reports Advisory Role: 3M, Portola
Honoraria: Scanlan
The following content contributors report:
Paul McCormick, MD, MPH Praveen Mummaneni, MD
Gallen Professor of Neurological Surgery, Professor and Vice Chairman,
Columbia University College of Physicians Department of Neurosurgery,
and Surgeons, University of California, San Francisco,
New York, NY School of Medicine,
Reports no commercial interest San Francisco, CA
Reports Research Grants: AO spine
Advisory Role: Depuy Spine
Board Membership: SRS, CNS, AANS/CNS
Spine Section
Honoraria: AO spine
Ownership Interests:
Spinicity/ISD

The following content contributors report:


Nelson M. Oyesiku, MD, PhD, FACS Allan Ropper, MD
Al Lerner Chair and Vice-Chairman, Raymond D. Adams Master Clinician and
Neurosurgery, Professor, Neurosurgery and Executive Vice Chair,
Medicine (Endocrinology), Department of Neurology,
Emory University School of Medicine; Brigham and Women’s Hospital;
Co-Director, Emory Pituitary Center, Professor of Neurology,
Atlanta, GA Harvard Medical School,
Reports no commercial interest Boston, MA
Reports no commercial interest
Kalmon D. Post, MD
Chairman Emeritus, Department of
Neurosurgery,
Professor, Neurosurgery and Medicine,
Icahn School of Medicine at Mount Sinai,
New York, NY
Reports no commercial interest
The following content contributors report:
Nader Sanai, MD, FAANS, FACS Robert Michael Scott, MD
Associate Professor of Neurological Fellows Family Chair in Pediatric
Surgery, Director, Division of Neurosurgical Neurosurgery,
Oncology, Barrow Neurological Institute, Emeritus Neurosurgeon-in-Chief,
Phoenix, AZ Boston Children’s Hospital;
Reports no commercial interest Professor of Neurosurgery,
Harvard Medical School,
Charles A. Sansur, MD, MHSc Boston, MA
Associate Professor of Neurosurgery, Reports no commercial interest
Director of Spine Surgery, Department of
Neurosurgery, University of Maryland
School of Medicine, Baltimore, MD
Reports Advisory Role: Medtronic,
DepuySynthes, Stryker, Globus

The following content contributors report:


Jason Sheehan, MD Gary K. Steinberg, MD, PhD
Harrison Distinguished Professor and Vice Bernard and Ronni Lacroute-William
Chair, Department of Neurological Surgery, Randolph Hearst Professor of Neurosurgery
University of Virginia School of Medicine, and the Neurosciences, Department of
Charlottesville, VA Neurosurgery, Stanford University School of
Reports no commercial interest Medicine; Chief of Neurosurgery, Stanford
Health Care, Stanford University, Stanford,
Robert Spinner, MD CA
Chair, Department of Neurologic Surgery, Reports Advisory Role: Medtronic,Qool
Burton M. Onofrio, MD, Professor of Therapeutics, Peter Lazic US, Inc.
Neurosurgery, Professor of Orthopedics and
Anatomy,
Mayo Clinic, Rochester, MN
Reports no commercial interest
The following content contributors report:
Jamie S. Ullman, MD
Associate Professor, Department of
Neurosurgery, Hofstra Northwell School of
Medicine, Hampstead, NY; Director of
Neurotrauma, North Shore University
Hospital, Manhasset, NY
Reports no commercial interest

Henrikas Vaitkevicius, MD
Instructor in Neurology, Brigham and
Women’s Hospital, Harvard Medical
School, Boston, MA
Reports no commercial interest

LEARNING OBJECTIVES
After viewing this program, participants will be better able to:
• Evaluate the most current neurosurgical techniques available in
order to treat patients with neurosurgical problems.
• Analyze recent literature and data regarding clinical trials relevant to
the practice of neurosurgery.
• Describe best practices in the management of patients requiring
surgery for vascular disorders.
• Explain the latest techniques used in functional neurosurgery.
LEARNING OBJECTIVES
After viewing this program, participants will be better able to:
• Differentiate among the techniques used for spine surgery.
• Discuss the most appropriate procedures for the management of
brain tumors and spinal tumors.
• Identify the most optimal methods for nerve injury and tumors.
• Assess the best neurosurgical treatment plans for pituitary
disorders.

THE OAKSTONE PLEDGE


While we provide a vast array of continuing medical education materials, it is
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We strive to work with highly experienced clinicians and experts in their fields
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Our reputation depends on it.
800.633.4743 | Oakstone.com

© 2016 Ebix, Inc. DBA Oakstone Publishing, LLC.


CMEinfo is a registered trademark of Oakstone Publishing, LLC.
Oakstone Publishing, LLC
Neurosurgery - A Comprehensive Review
June 15, 2016

Topic/Speaker Book Page #


Vascular
Ischemic and Hemorrhagic Stroke
1
Henrikas Vaitkevicius, MD
Intracranial Aneurysms
62
Rose Du, MD, PhD
Vascular Malformations and Moyamoya Disease
111
Gary K. Steinberg, MD, PhD
Extracranial Carotid Artery Disease
179
Christopher M. Loftus, MD, Dr.h.c. (Hon), FAANS
Head Injury/ Craniocerebral Trauma
Closed Head Injury/Concussion and Head Injury in Sports
258
Ian F. Dunn, MD, FAANS
Skull and Facial Fractures/Paranasal Sinus and Skull Base Trauma
316
Col. Rocco A. Armonda, MD
Subdural Hematoma
368
Col. Rocco A. Armonda, MD
Decompressive Craniectomy
413
Jamie S. Ullman, MD
Spinal Surgery
Cervical Spine Trauma
456
John H. Chi, MD, MPH
Thoraco-Lumbar Fractures
482
Charles A. Sansur, MD, MHSc
Disc Herniations: Cervical, Lumbar and Thoracic
526
Charles A. Sansur, MD, MHSc
Lateral Access to the Spine
550
Adam S. Kanter, MD
Minimally Invasive Spine Surgery
603
Praveen V. Mummaneni, MD
Hydromyelia/Syringomyelia
673
Charles A. Sansur, MD, MHSc
Peripheral Nerves
Acute Nerve Injury and Repair
693
Susan E. Mackinnon, MD
Peripheral Nerve Tumors
744
Robert J. Spinner, MD
Brachial Plexus Lesions
803
Susan E. Mackinnon, MD
Oakstone Publishing, LLC
Neurosurgery - A Comprehensive Review
June 15, 2016

Topic/Speaker Book Page #


Peripheral Nerves
Compression Neuropathy
829
Susan E. Mackinnon, MD
Nerve Transfers for Shoulder and Elbow
938
Susan E. Mackinnon, MD
Nerve Transfers for the Hand
992
Susan E. Mackinnon, MD
Brain Tumors
Metastatic Brain Tumors
1093
Charles S. Cobbs, MD
Malignant Gliomas
1129
Charles S. Cobbs, MD
Meningiomas
1177
Ossama Al-Mefty, MD, FACS
Low Grade Gliomas
1334
Nader Sanai, MD, FAANS, FACS
Pineal Region Tumors
1355
Jeffrey N. Bruce, MD, FACS
Posterior Fossa Tumors of Childhood
1391
Tord D. Alden, MD
Vestibular Schwannomas and Other Cerebello-Pontine Angle Tumors
1450
Kalmon D. Post, MD
Radiosurgery for Brain Tumors, Arteriovenous Malformations, and Trigeminal Neuralgia
1573
Jason Sheehan, MD, PhD, FACS

Spine and Spinal Cord Tumors


Metastatic Tumors of the Spine
1621
Michael W. Groff, MD
Spinal Cord Tumor Management
1662
Paul C. McCormick, MD, MPH
Skull Base Lesion
Meningiomas of the Skull Base and Other Skull Base Lesions
1715
Ian F. Dunn, MD, FAANS
Pituitary Tumors and Craniopharyngiomas
Non-Functioning and Functioning Pituitary Tumors
1768
Nelson M. Oyesiku, MD, PhD, FACS
Transsphenoidal Endoscopy
1807
Edward R. Laws, MD
Oakstone Publishing, LLC
Neurosurgery - A Comprehensive Review
June 15, 2016

Topic/Speaker Book Page #


Pituitary Tumors and Craniopharyngiomas
Craniopharyngiomas
1837
R. Michael Scott, MD
Hydrocephalus/Cysts/Infection
Hydrocephalus and Congenital Cysts
1864
Tord D. Alden, MD
Functional Neurosurgery
Functional Neurosurgery
1898
Garth Rees Cosgrove, MD
Special Topics
Neurofibromatosis and von Hippel-Lindau Disease
1924
Ashok R. Asthagiri, MD
Coma and Brain Death
1967
Allan H. Ropper, MD
Anticoagulation, Reversal, and Hemostasis in Neurosurgery
1980
Christopher M. Loftus, MD, Drhc, FAANS
Copyright © Oakstone Publishing, LLC, 2016. All Rights Reserved.

Ischemic and
Hemorrhagic Stroke
Henri Vaitkevicius MD.
Brigham and Women’s Hospital
Harvard Medical School
Date: May 19, 2016

Disclosures

Consultant for SAGE Therapeutics and Principal


Investigator for a study evaluating neurosteroid use
in status epilepticus

1
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Objectives

Follow a clinical case


Introduce clinically relevant decision points
Introduce the evidence for these decisions
Intended audience:
-clinicians on Neurosurgical services

Public Health

Stroke is leading cause of disability


795,000 strokes/yr
4th leading cause of death
31% went to skilled nursing home
Cost in US: $36.5 billion in 2010

Circulation. 2014 Jan 21;129(3):399-410

2
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63 year old man …

Last seen well 35 minutes ago


NIHSS 21
SBP 215

63 year old man …

Last seen well 35 minutes ago


NIHSS 21
SBP 215

3
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63 year old man …

Last seen well 35 minutes ago


NIHSS 21
SBP 215

63 year old man …

Last seen well 35 minutes ago


NIHSS 21
SBP 215

4
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Ischemic Pneumbra

Cerebrovasc Dis 2011;32:307–320


http://www.radiologyassistant.nl/

Revascularization

Outcome

Mortality

Stroke. 2007;38:967-973.

5
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Revascularization

Outcome

Mortality

Stroke. 2007;38:967-973.

TPA

0-3 h

3-4.5 h

Saver JL Arch Neurol 2004;61:1066-70


Stroke. 2010; 41: 2381-2390

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TPA

0-3 h

3-4.5 h

# needed to treat for MRS 0-2 = 8


# needed to benefit = 3
# needed to harm = 30

Saver JL Arch Neurol 2004;61:1066-70


Stroke. 2010; 41: 2381-2390

We have time …. ????


Door to needle time < 60min

Acute Stroke
Time from ED arrival to TPA treatment (min)

180
TPA Response Times

150

120
Door to needle

90

60

30

0
0 30 60 90 120 150 180
Time from stroke onset to ED arrival (min)
Modified from Albers JAMA 2000;283:1147

LSN

7
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Time = brain

Stroke.2006;37:263-266.

TPA (NINDS, ECASS)

Estimated Odd Ratio for a Favorable Outcome at 3 Months


in rt-PA Patients Compared to Controls

4.0

3.5 n = 2775
Adjusted Odds Ratio

3.0

2.5

2.0

1.5

1.0

0.5

60 90 120 150 180 210 240 270 300 330 360

Minutes
Lancet 2004;363:768-74

8
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Who do we give TPA to?

Age > 18
Brain trauma/stroke/surgery > 3 months
Major surgery > 2 weeks
GI hemorrhage > 3 weeks
Plt > 100K; INR < 1.7
SBP <185/110

Bad candidates

Any history of ICH


Aneurysm, AVM, intracranial neoplasm

9
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Unique aspects for 4.5 h


Age < 80
History of stroke AND diabetes
Any use of anticoagulants
NIHSS < 25

NIHSS

1A Wakefulness (3)
1B Month and Age (2)
-1 if intubated
1C commands (2)

10
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NIHSS

2 Gaze (2)
3 Fields (3)
4 Face (3)
5 Motor arms (10s) (4) Drift / hit bed / gravity / none
6 Motor legs (5s) (4) Amputation?

NIHSS

7 Ataxia (2)
8 Sensation (2)
9 Language (3)
10 Dysarthria (2)
Intubated (UN)
11 Extinction (2)

11
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NIHSS

Big picture

Score Stroke severity Relevance

POINT,
0-3 Mild
CHANCE

4-7 Moderate TPA alone

8-21 Severe TPA/IA

>21 Catastrophic TPA/IA

Now what ????

Telestroke
Received TPA in < 90min
Arrives to our hospital < 180min
No change in exam

12
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Now what ????

Telestroke
Received TPA in < 90min
Arrives at BWH < 180min

Who benefits most from TPA?

NIHSS 0-5 6-10 11-15 16-20 >20

OR 0.8 2.6 2.4 1.6 2.6

95% CI 0.2-3.6 1.3-5.1 1.1-5.2 0.7-3.5 0.6-10.8

Stroke. 2004;35:2418-2424

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Who benefits most from TPA?

NIHSS 0-5 6-10 11-15 16-20 >20

OR 0.8 2.6 2.4 1.6 2.6

95% CI 0.2-3.6 1.3-5.1 1.1-5.2 0.7-3.5 0.6-10.8

Stroke. 2004;35:2418-2424

Who benefits most from TPA?

NIHSS 0-5 6-10 11-15 16-20 >20

OR 0.8 2.6 2.4 1.6 2.6

95% CI 0.2-3.6 1.3-5.1 1.1-5.2 0.7-3.5 0.6-10.8

Stroke. 2004;35:2418-2424

14
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PROACT II (IA r-proUK)

Median baseline NIHSS = 17


Median time treatment = 5.3 hr

JAMA 1999;282:2003

PROACT II (IA r-proUK)

Median baseline NIHSS = 17 Revascularization


Median time treatment = 5.3 hr • Control = 18%
• Pro UK = 66%
JAMA 1999;282:2003

15
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Revascularization

Stroke. 2009;40:2761-2768

Revascularization

Stroke. 2009;40:2761-2768

16
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Better device …

MR CLEAN

500 patients
195/233 mechanical interventions

N Engl J Med 2015;372:11-20

17
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Recanalization

MR RESCUE

SYNTHESIS
IMS III
MR CLEAN

Neurology 2009;73:1066–1072

Recanalization

MR RESCUE

SYNTHESIS
IMS III
MR CLEAN

Neurology 2009;73:1066–1072

18
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Recanalization

MR RESCUE

SYNTHESIS
IMS III
MR CLEAN

Neurology 2009;73:1066–1072

Recanalization

MR RESCUE

SYNTHESIS
IMS III
MR CLEAN

Neurology 2009;73:1066–1072

19
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Recanalization

MR RESCUE

SYNTHESIS
IMS III
MR CLEAN

Neurology 2009;73:1066–1072

Recanalization

MR RESCUE

ESCAPE
Extend-IA
SYNTHESIS Swift Prime
REVASCAT
IMS III
MR CLEAN

Neurology 2009;73:1066–1072

20
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Successful trials

ESCAPE
(n = 316)

EXTEND-IA
(n = 70)

SWIFT-PRIME
(n = 196)

REVASCAT
(n = 193)

N Engl J Med. 2015 Feb 11


N Engl J Med. 2015 Apr 17.

Successful trials

ESCAPE
(n = 316)
3 4
2

EXTEND-IA
(n = 70)
1
SWIFT-PRIME
(n = 196) 1

REVASCAT 2
(n = 193)

N Engl J Med. 2015 Feb 11


N Engl J Med. 2015 Apr 17.

21
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Primary Outcomes

Study Control Intervention NNT


MR CLEAN 19% 33% 7
ESCAPE 29% 53% 4
EXTEND-IA 40% 71% 3
SWIFT PRIME 35% 60% 4
REVASCAT 28% 44% 6

N Engl J Med. 2015 Feb 11


N Engl J Med. 2015 Apr 17.

Complications

Study Hemorrhage Mortality

MR CLEAN 6.4 / 7.7 % 22 / 21 %

ESCAPE 2.7 / 3.6 % 19 / 10 %

EXTEND-IA 6/0% 20 / 9 %
SWIFT PRIME 3/0% 12 /9 %
REVASCAT 1.9 / 1.9% 16 / 18 %

N Engl J Med. 2015 Feb 11


N Engl J Med. 2015 Apr 17.

22
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Unique

Study Country Key features Time NIHSS IV-TPA N


MR CLEAN Netherlands Completed 6h 17 90% 500
ESCAPE CA, US, Korea, UK Collaterals 12h 16 76% 311
EXTEND-IA Australia, New Zealand Perfusion, TPA 6h 17 100% 70
SWIFT PRIME USA , Europe Solitaire, 6h 17 98% 196
Perfusion
REVASCAT Spain ASPECTS > 7 8h 17 73% 206

N Engl J Med. 2015 Feb 11


N Engl J Med. 2015 Apr 17.

Back to the patient

23
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Outcome at 60 days

Word finding difficulty


Independent

Few definitions …

ASPECTS SCORE
-normal = 10

TICI score
-normal = 3 Score
0
Definition
No flow
1 < 20%, flow limiting
2a 20-50%, 2/3 territory
2b 50-99%, delayed
3 Normal

24
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Bottom line:

Multidisciplinary team work


- ED, nursing, medflight, neuoICU, endovascular team

Speed
- Decision to TPA
- Decision to transfer
- Decision to intervene
- IA team mobilization

Follow up
- Multidisciplinary stroke service
- Feedback to the teams

What if things do not go well?


Malignant MCA infarct
-80% mortality French (DECIMAL)
-Max edema 2-5d German (DESTINY)
Life saving surgery Dutch (HAMLET)
-NNT = 2

Lancet Neurol 2007; 6: 215–


22

25
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A few details about hemicraniectomy

Timing within 48 hours


-Before herniation
Population
-18-60 yr
-NIHSS > 15
-decreased consciousness
-Infarct volume >145 cc
-(or >50% of MCA)

J Neurol (2002) 249 : 1183–1190


J Neurol (2009) 256:1126–1133

Next, why did he have the stroke?


CBC, lytes, Glucose, Lipids,
Vascular imaging coags
-CT/CTA -HgA1C
-MRI/MRA
Who gets TTE?
-Carotid Ultrasound
-Cardio embolic stroke
-Trascranial dopplers (TCDs)
-<45 y shunting (PFO)
EKG
Cardiac monitorin

26
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Significance of TOAST

Atherosclerosis (large vessel)


Cardioembolism (embolic)
Small vessel (lacunar)
Other

Vascular imaging

CTA (Dynamic?) CT/Angio contrast


-Luminal outline -Allergy
Angio -Nephrotoxicity

-Luminal outline MRI contrast

US
-Velocity and direction
MRI/MRA
-Velocity and direction
TCDs
-Velocity and particulates

27
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28
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29
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30
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Treatment

Antiplatelets Cholesterol
-Aspirin/dipyridamole -LDL < 100 (70)
-Clopidogrel Blood pressure
Full anticoagulation -7-14 days
CEA/CAS -ACE/HCTZ
-140/90 (130/80)
Intracranial bypass
Glucose
Intracranial stenting
Smoking, BMI, Physical activity,
Hormones

Major anti-platelets trials


Strokes Bld.
Trial Pts. Y. ASA+
Plac. ASA ASA+D Clop
C
AICLA (1983) 604 3y 31 17 (RR 18 (RR
42%) 42%)
ESPS (1990) 2,500 2y 184 114 (RR
38%)
PRoFESS 2.5 y

CAPRIE (1996) 19,185 1.9 y 1,021 939


(5.3%) (4.9%)
MATCH (2004) 7,599 1.5 y 9% 9% +1.3
%
CHARISMA 15, 603 2y 7% 6% +0.8
(2006) %

• SAMMPRIS: ASA + Plavix for 90 day benefit


-Carotid disease
• Idea for CHANCE and POINT

31
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BMJ 2002;324:71–86
Stroke. 2008;39:1358-1363

CHANCE (POINT pending)

• NIHSS < 3
• Clopidogrel 90 d.
+ASA 21 d.
• Aspirin 90 d.

NEJM 2013; 369(1): 11

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Lipids (SPARCL)

4731 patients (TIA and Stroke)


LDL 100-190
Atorvastatin 80mg QD

N Engl J Med 2006;355:549-59.

Blood pressure

Autoregulation (24h)
Decrease by 10/5
Goal 120/80
? 140/90
Diuretics
ACEI

Stroke. 2003;34:2741-2748

33
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Risk factor modification

Glycemic control
-What is HgA1C target ?
Smoking
-Must stop
Alcohol
-1-2 drinks per day
Physical activity
-sweat or rise in HR
-1-3x per week

Carotid disease

Strokes
Trial Pts. Yr. Stenosis
Med CEA CAS

Symptomatic

NASCET 2267 2y 30-99% (70- 26% 9%


(1991) 99%)
5y 22% 16%

ECST (1998) 3024 3y 0-100% (80- 27% 15%


99%)
CREST 2502 2.5 y 50-99% 6.8% 7.2%

Gender differences Not symptomatic


Surgical risk and the ACAS (1995) 4657 5y 60-99% 11% 5%
risk of MI ACST (2003) 3120 5y 60-99% 12% 6%

VA 444 8y 50-99% 26% 8%

Catheter Cardiovasc Interv. 2013 Jan 1;81(1):E76-123

34
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ACTS (Not symptomatic)

Lancet 2010; 376: 1074–84

Approach to Carotid disease

Symptomatic (6 months) Asymptomatic


Territory threatened 70% - 99%
< 2 weeks - Consider CEA/CAS
Life expectancy > 5 years
- <3% complication
- Life expectancy > 5 years
70 % - 99%
- Women?
- consider CEA/CAS
- TCD hits?
- <6% complication
<70%
>50% - 70%
-Follow
-TCDs with HITs
-TCD hits?
-Women?
<50%
-Follow

35
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Carotid intervention details

Timing: 2 weeks
High surgical risk = CAS
-High riding bifurcation (C3)
-History of radiation
-Significant CAD
Intervention threshold
>70% on US = >50% on angio

Stroke. 2014; 45:2160-2236

Case (continued)

After CEA patient has been doing well


Now he 72 and develops atrial fibrillation

36
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Risk scales

CHADS2 Score CHA2DS2-VASc Score

CHEST 2008; 133:546S–592S


The American Journal of Medicine (2012) 125, 603.e1-603.e6

Cardioembolic

Age CHADS2 score

Ann Intern Med. 2009;151:297-305.

37
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Risk of stroke in Afib

The American Journal of Medicine (2012) 125, 603.e1-603.e6

Anticoagulation for Atrial Fibrillation

Incidence of stroke
Rivaroxaban

Dabigatran
Edoxaban
Apixaban
Warfarin
Placebo

ASA

Trial
150 mg
110 mg

AFASAK 4.2 2
BAATAF 3.0 0.4
SPAF 7.0 2.3
CAFA 3.8 2.6
VA 4.3 0.9
EAFT 12.3 3.9
Lancet. 1989 Jan 28;1(8631):175-9
RE-LY 1.7 1.5 1.1 Am Heart J. 1992 Dec;124(6):1567-73
J Am Coll Cardiol. 1991 Aug;18(2):349-55
Rocket AF 2.2 1.7
Am J Cardiol. 1996 Jan 25;77(3):38A-44A
ARISTOTLE 1.6 1.3 Circulation. 1995 Oct 15;92(8):2178-82
J Med. 2010 Nov 4;363(19):1877
AVERROES 3.7 1.6 N Engl J Med. 2011 Sep 8;365(10):883-91
N Engl J Med 2013;369:2093-104
ENGAGE AF 1.5 1.2 Stroke. 2012 Dec;43(12):3291-7

38
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Anticoagulation

Warfarin
Direct thrombin inhibitors
Factor Xa inhibitors

NOAC Dose T 1/2 Test Reversal


Dabigatran 150mg Q12h 12-17h Dilute TT Idarucizumab
Rivaroxaban 20mg QD 7-17h PTT, anti-Xa Andexanet
Apixaban 5mg Q12h 5-9h Anti-Xa Andexanet
Edoxaban 60mg QD 6-11h Anti-Xa Andexanet

N Engl J Med. 2005;353(10):1028


Eur Heart J. 2008;29(2):155.
Thromb Res. 2011 Jun;127(6):497-504
J Am Coll Cardiol 2012

Efficacy (stroke)
Dabigatran Apixaban

Rivaroxaban Edoxaban

39
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Risk (bleeding)

Rivaroxaban
Dabigatran

Edoxaban
Apixaban
Warfarin
ASA

Trial

150 mg
110 mg

RE-LY 3.4 2.7 3.1 Incidence of major


Rocket AF
ARISTOTLE
5.4
3.1
5.6
2.1
bleed per year
AVERROES 3.8 4.5
ENGAGE AF 3.4 2.8 Circulation. 1995 Oct 15;92(8):2178-82
J Med. 2010 Nov 4;363(19):1877
N Engl J Med. 2011 Sep 8;365(10):883-91
N Engl J Med 2013;369:2093-104
Stroke. 2012 Dec;43(12):3291-7

Comparisons to Warfarin

Bleeding risks
-13 trials
-102,707 patients

NOACs Warfarin
Fatality 7.6% 11%
Major bleeding 0.16 per 100 pt-years 0.32 per 100 pt-years
Fatal bleeding RR 0.53
Mortality RR 0.91
Blood. 2012;119(13):3016
Ann Intern Med 2015; 163:382
Mayo Clin Proc 2014; 89:896
J Thromb Haemost 2015; 13:2012
JAMDA 16 (2015) 1103.e1e1103.e19.

40
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Case (continued)

Patient was anticoagulated


Presents with acute left sided weakness

Epidemiology

10-30% of all strokes


30 day mortality 40%
1 year mortality 64%
>60% of survivors severely disabled

Stroke. 2015;46:2032-2060

41
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How to treat?

Some data
Expert opinions / guidelines
(AHA and ASA)

Stroke. 2015;46:2032-2060

Mortality – ICH Score

Stroke. 2007;38:1641-1644

42
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Mortality – ICH Score

Stroke. 2007;38:1641-1644

Functional outcome - FUNC

Stroke. 2008;39:2304-2309

43
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Functional outcome - FUNC

Stroke. 2008;39:2304-2309

Who provides care better?

1,038 US patients
Mortality rates

Crit Care Med. 2001;29:635–640

44
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What are they doing differently?

1696 patients in Australia


Acute Stroke Units

Glucose 6.8-7.0 mmol/L = 122-126mg/dL

Lancet 2011; 378: 1699–706

DNR: self-fulfilling prophecy

Effect of early DNR (24h)


8233 patients across 234 hospitals

Stroke. 2004;35:1130-1134

45
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DNR: self-fulfilling prophecy

Effect of early DNR (24h)


8233 patients across 234 hospitals

Stroke. 2004;35:1130-1134

Hematoma Expansion

46
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Hematoma Expansion

Coagulopathy Summary
Anticoagulant Agent Dose
INR >6 → 50 IU/kg
4 factor PCC
INR >4 → 35 IU/kg
(heparin) INR < 4 → 25 IU/kg

Warfarin Vitamin K 10mg IV over 10min


INR >4 → 50 IU/kg
or Profilnine SD INR < 4 → 25 IU/kg Agent t½ Target
or FFP 2-6 units Dabigatran 12-17h IIa
fibrinogen > 150 → 2 vials Rivaroxaban 7-17h Xa
RiaSTAP fibrinogen < 150 → 2+2 vials
TPA Apixaban 5-9 hours Xa
fibrinogen < 150 → 20+20 units
or Cryoprecipitate fibrinogen > 150 → 20 units Edoxaban 6-11 Xa
Heparin Protamine 1mg/100 heparin units over the last 4 h
Protamine If <8h → 1mg/mg of enoxiparin
Enoxaparin (Lovenox)* If > 8h → 0.5mg/mg of enoxiparin
Andexanet
Aspirin* Platelets 6 pack
ddAVP 0.3 µg/kg over 30 min
Plavix*
Platelets 6 pack
Idarucizumab
Dabigatran (Thrombin)* 100 units/kg
FEIBA
*Note: These are
Rivazoxaban, Apixaban, 4 factor PCC
Edoxaban, (factor Xa)* Andexanet
35 IU/kg possible reversal
Uremia* ddAVP 0.3 µg/kg over 30 min agents that are
Fondaparinux* Factor VIIa 90 µg/kg being tried and may
ddAVP 0.3 µg/kg over 30 min not be effective.
Argatroban*
Cryoprecipitate 10 units

47
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Reversing Warfarin
Vitamin K (2 hours)
FFP

N Engl J Med 2005;352:777-85


Circulation. 2013;128:1234-1243

Reversing Warfarin
Vitamin K (2 hours)
FFP
NOVO VII
-399 patients
-4 hours
-7% MI or CVA

N Engl J Med 2005;352:777-85


Circulation. 2013;128:1234-1243

48
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Reversing Warfarin
Vitamin K (2 hours)
FFP
NOVO VII
-399 patients
-4 hours
-7% MI or CVA
3/4 factor PCC
(II,IX,X) /(II,IX,X,VII)

N Engl J Med 2005;352:777-85


Circulation. 2013;128:1234-1243

Platelets

CHANT trial
-NXY-059
Creutzfeldt et al
-368 patients
-Identical ICH volume, MRS, Mortality
Ducruet et al
-66 patients
-No difference in ICH

Neurology® 2009;72:1397–1402
J Stroke Cerebrovasc Dis. 2009;18:221-228
Neurol Res. 2010;32:706-710
Neurocrit Care (2012) 16:82–87
BMC Neurology 2010, 10:19

49
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Platelets

CHANT trial
-NXY-059
Creutzfeldt et al
-368 patients
-Identical ICH volume, MRS, Mortality
Ducruet et al
-66 patients
-No difference in ICH
Naidech et al
-44 patients
- <12h to receive platelets
-activity 472±50 -> 561±92 ARU Neurology® 2009;72:1397–1402
J Stroke Cerebrovasc Dis. 2009;18:221-228
Neurol Res. 2010;32:706-710
Neurocrit Care (2012) 16:82–87
BMC Neurology 2010, 10:19

Platelets

CHANT trial
-NXY-059
Creutzfeldt et al
-368 patients
-Identical ICH volume, MRS, Mortality
Ducruet et al
-66 patients
-No difference in ICH
Naidech et al
-44 patients
- <12h to receive platelets
-activity 472±50 -> 561±92 ARU Neurology® 2009;72:1397–1402
J Stroke Cerebrovasc Dis. 2009;18:221-228
PATCH trial Neurol Res. 2010;32:706-710
-Netherlands Neurocrit Care (2012) 16:82–87
-190 patients BMC Neurology 2010, 10:19

-6 hours

50
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Blood Pressure and Hematoma Size

INTERACT 2 (6 hours)
2839 patient
SBP <140 vs. <180
Primary outcome:
MRS > 2: OR 0.87; p = 0.06
Secondary outcome:
Improved MRS: OR 0.87; p = 0.04
Small bleeds (<20cc)
Slow to reach target SBP

N Engl J Med 2013;368:2355-65

Blood Pressure and Hematoma Size

INTERACT 2 (6 hours)
2839 patient
SBP <140 vs. <180
Primary outcome:
MRS > 2: OR 0.87; p = 0.06
Secondary outcome:
Improved MRS: OR 0.87; p = 0.04
Small bleeds (<20cc)
Slow to reach target SBP

N Engl J Med 2013;368:2355-65

51
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Blood Pressure Goals?

ATACH (6 hours)
60 patients IPH Expansion
SBP 110-139
SBP 140-169
SBP 170-199

ATACH 2 (3 hours)
1280 Patients (stopped at 1000 this fall)
SBP <140 v.s. <180
MRS > 3
Arch Neurol. 2010;67(5):570-576

Steroids

93 patients
Stopped early

N Engl J Med. 1987 May 14;316(20):1229-33

52
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Steroids

93 patients
Stopped early

N Engl J Med. 1987 May 14;316(20):1229-33

Seizure Prophylaxis

CHANT Trial
295 Patients
1.7% seizures

Neurocrit Care (2009) 11:38–44

53
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Seizure Prophylaxis

CHANT Trial
295 Patients
1.7% seizures

Neurocrit Care (2009) 11:38–44

Seizure Prophylaxis

Retrospective review 1,182 patients


543 on AEDs
Phenytoin (68%)
Leviteracetam (30%)
No effect on mortality or MRS

Neurocrit Care. 2012 December ; 17(3): 361–366

54
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Ventricular TPA

Gaberel T et al. Stroke 2011;42:2776-2781

Stroke 2011; 42:3009-3016


Gaberel T et al. Stroke 2011;42:2776-2781

Ventricular TPA

Gaberel T et al. Stroke 2011;42:2776-2781

Stroke 2011; 42:3009-3016


Gaberel T et al. Stroke 2011;42:2776-2781

55
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Clot Evacuation STICH 2005

1,033 patients
Early < 24h
Mortality
Functional outcome

Lancet 2005; 365: 387–97

Clot Evacuation STICH 2005

1,033 patients
Early < 24h
Mortality
Functional outcome
26% surgery

GCS < 8 is BAD

Lancet 2005; 365: 387–97

56
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Clot Evacuation STICH II


601 patients
<1cm depth
Functional outcome
Mortality

Lancet 2013; 382: 397–408

Clot Evacuation STICH II


601 patients
<1cm depth
Functional outcome
Mortality

21% surgery

Lancet 2013; 382: 397–408

57
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Clot Evacuation STICH+

15 trials
3,366 patients

Lancet 2013; 382: 397–408

Hemicraniectomy

9 studies
226 cases
GCS < 8 and ICH > 60cc
May be safe
Improves mortality and functional outcome

Neurosurg Focus. 2013 May;34(5):E5

58
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Clot Evacuation Posterior Fossa


205 patients
Mortality 38%
Obliterated 4th ventricle
Intraventricular blood

Neurol Res. 1984 Sep;6(3):145-51


Neurosurgery. 1994 Feb;34(2):246-50

Clot Evacuation Posterior Fossa


205 patients 101 patients (49 and 52)
Mortality 38% GCS > 14 or ∅ < 4cm → conservative
Obliterated 4th ventricle GCS < 14 or ∅ > 4cm → surgical
Intraventricular blood No brainstem reflexes → non surgical

Patients who violated the rules


>70 year old
Hydrocephalus with ∅ < 4cm

Neurol Res. 1984 Sep;6(3):145-51


Neurosurgery. 1994 Feb;34(2):246-50

59
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Minimally Invasive Evacuation

Expert Rev. Neurother. 15(8), 919–933 (2015)

Summary for IPH

Specialized ICU IT TPA - safe


DNR risks Posterior fossa; ∅ > 3cm
Reverse anticoagulants Surgery
Platelet transfusion -May be beneficial
-No benefit for early surgery
SBP goal <140 or <160
-Minimally invasive strategies
AEDs? No phenytoin
No steroids

60
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Thank You

Special thanks to:


Steve Feske, MD
NeuroICU staff

61
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screening is recommended, repeat at least every 10 years if
negative (Bor et al., Lancet Neurology, 2014)

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rate of aneurysm formation 1-2% a year, should be screened

66
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Treatment of Aneurysms

Endovascular Microsurgery
(coiling, stent- (clipping, clip
assisted coiling, reconstruction,
flow diversion, bypass)
WEB)

72
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73
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endovascular* surgery

ISUIA ISAT ISAT BRAT ISAT** ISAT BNI BRAT


2003 2005 2009 2015 2005 2009 1999 2015

complete 55% 66% 48% 82% 91.8% 96%

neck remnant 24% 26% 12% 5.5%

significant 18% 8% 6% 2.7%


residual
rebleeding 0.7% 0.13%‡ 0.1% 0.02%‡

retreatment 16.4% 4.6%

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74
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78
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79
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./)/>*$'$)"$)-2+/2-)2-6.(.

• 
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$(+4$%0(>; ;OMNP

80
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Microsurgical Treatment

•  (%,,%*#
•  (%,.+*/0.41+*
•  8,//

Surgical Techniques

Avoidance of injury to brain


•  Brain relaxation
•  Skull base exposure
•  Neurophysiologic monitoring
•  Burst suppression
•  Management of intraoperative rupture

Preservation of parent vessels and perforators


•  Intraoperative angiography
•  Indocyanine green videoangiography

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Brain Relaxation

•  mannitol

•  drainage of CSF
•  from Sylvian fissure or basal cistern
•  ventriculostomy or lumbar drain

•  positioning
•  avoid impairing venous return
•  head elevation

2-*+#6.$*'*"$ *)$/*-$)"
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/(%*6%0$%*SM)%*40/

82
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92
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94
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95
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96
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)"()/*
2-#)*$ (*--#"

Hunt and Hess Grading Scale for SAH

Grade Description

1 Asymptomatic or minimal headache and


slight nuchal rigidity
2 Moderate to severe headache, nuchal
rigidity, no neurologic deficit except cranial
nerve palsy
3 Lethargy, confusion, or mild focal deficit

4 Stupor, moderate to severe hemiparesis,


early decerebrate rigidity and vegetative
disturbances
5 Deep coma, decerebrate rigidity, moribund
appearance

+++40+)0S)+*0$/
.Q=RQY
.R=OQY

+470(>; ;NVVS

97
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$.#--.






$.#-- .-$+0*)
N +(+++*
O %4/+.5.1((8.\N))0$%'

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0$%'
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 6%0$+.6%0$+40

%/$.0(>;4.+/4.#.8;NVUM

Hydrocephalus
•  Acute hydrocephalus in 20-27%, chronic in 14-23%
•  More frequent in poor grade patients
•  Ventriculostomy for patients with Hunt and Hess grade 3 or higher
•  50-80% of patients improve neurologically after EVD placement
•  Caveat: sudden and large release of CSF may precipitate
rebleeding
•  Complications: hemorrhage, infection

Grade # patients % with


hydrocephalus

1 30 3

2 44 5

3 98 30

4 19 42

5 19 26
Milhorat, Neurosurgery, 1987

98
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Other Initial Management


•  seizure prophylaxis/management: Dilantin or Keppra

•  management of high intracranial pressure: mannitol

•  management of hypertension:
•  Recommend nicardipine
•  Nitroglycerin and other vasodilators are
contraindicated in patients with cerebral edema
(Cottrell et al., JNS, 1980)
•  Caveat: only use for extreme hypertension to
avoid reducing cerebral perfusion prior to
placement of EVD

Neurogenic Stunned Myocardium


•  EKG changes and arrhythmia in >50%
•  troponin leak in 20-40%
•  looks like MI on EKG but lower troponin
levels
•  regional wall motion abnormality has
apical-sparing pattern
•  occurs 2 days - 2 weeks after SAH. Most
likely in first 2 days, decreasing over 3-8
days
•  usually resolves within 5 days
•  possible mechanism: release of
catecholamines by myocardial sympathetic
nerves which could damage both myocytes
and nerve terminals
•  No difference in cardiac morbidity between
surgical and endovascular therapy
•  Risk factors: higher Hunt and Hess grade,
older age, smoking (Malik et al., World
Neurosurgery, 2015)

99
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2.*/#)$.$'$/6/J(*)/#.

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•  )%.+)+(%00%*TMY+,1*0/6%0$ 5%F0%*;
4.+/4.#.8;OMMSG

• 
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102
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$.&/*-.*-.*.+.(

E )+4*0+(++
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•  %/$..P=OPBOQ,1*0/5(+,/5.
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E )+'%*#
E  8,.0*/%+*
E +/0.%+.%.4(1+**4.8/);,.%((+/(.0.8
*4.8/)/

Fisher et al., Neurosurgery, 1980


Abla et al., JNS, 2014

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103
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•  NMCNO)) #
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•  8/0+(%(++,.//4.NSMCOMM)) #

104
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110
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Moyamoya Disease

Gary K. Steinberg, M.D., Ph.D.


Bernard and Ronni Lacroute-William Randolph Hearst Professor of
Neurosurgery and the Neurosciences

Chairman, Department of Neurosurgery

Co-Director, Stanford Stroke Center

Stanford University School of Medicine

Disclosure Statement

Advisory Role: Medtronic,Qool


Therapeutics, Peter Lazic US, Inc.

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Moyamoya Disease

• Progressive occlusion of terminal Internal Carotid Artery


(sometimes MCA, ACA, PCA)
→ lack of brain blood flow
Unknown cause: not atherosclerotic, non-inflammatory

• Compensatory enlargement of perforating arteries


– Moyamoya (“puff of smoke”) vessels in the deep brain
→ hemorrhage

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Proliferative angiopathy
MMD control Takagi, Y., K. Kikuta, et al. (2007).
Neurol Med Chir (Tokyo) 47(1): 1-4.

Fibrocellular intimal thickening


control
Proliferation and hyperplasia of
smooth muscle (intima)

Disrupted internal elastic lamina


MMD
Intraluminal thrombosis
MMD MMD control

B,D, G from control patients


All arrows point to internal elastic lamina

Moyamoya Disease
• Initially identified in Japan, 1950’s
• Felt to be a disease affecting Asian population
• Prevalence: 6-10/100,000 (Asia)

• Incidence: 0.54/100,000/yr (Asia, 2003)


0.94/100,000/yr (Asia, 2006)
0.086/100,000/yr (US, 2005)
0.57/100,000/yr (US, 2012)

• Bimodal onset:
1st decade, 3rd-4th decades

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Stages of Moyamoya

Suzuki J, Takaku Arch Neurol 20:288-299, 1969

Moyamoya Stage 6
4 5 “bottleneck sign”

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72 y.o. female, 15 mos hx of multiple TIAs:


Aphasia and Rt Upper Extremity weakness

Atherosclerotic arterial occlusive disease


(Non-Moyamoya)

Moyamoya Disease
Treatments
• Medical (not effective)
– Antiplatelet agents, coumadin, steroids, vasodilators, mannitol
– Ca++ antagonists
• Surgical
– Cervical sympathectomy (not effective)
– Extracranial-intracranial grafts

• Revascularization: rationale
– improves cerebral perfusion
→ prevent ischemia
– reduces stress on collateral vessels
→ prevent hemorrhage

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Moyamoya Disease
Treatments
Revascularization techniques (↑ CBF)
– Direct
• STA-MCA anastomosis

– Indirect
• Encephalo-duro-arterio-synangiosis (EDAS)
• Encephalo-myo-synangiosis (EMS)
• Encephalo-duro-arterio-myo-synangiosis (EDAMS)
• Omental transposition
• Burr holes

Alaska
1 Moyamoya State Distribution
(47 states, District of Columbia, Puerto Rico, and U.S. Virgin Islands)

Washington 2 New Hampshire Maine


Vermont
21 Montana North Dakota

4 Minnesota Massachusetts 4
3
New
Oregon
Idaho
4 Wisconsin York
12 South Dakota
Michigan
25 Rhode Island 3
3 1 19 Connecticut 7
Wyoming 25 Pennsylvania
2 Nebraska
Iowa
19 New Jersey 11
Delaware
4 Indiana Ohio
Nevada 3 Illinois
18 1 Maryland 10
Utah
31 10 West
Virginia
13 Colorado Virginia District of Columbia 1
California 6 Kansas Missouri Kentucky 20
23 12 12 8 North
292 10 12 Carolina
Tennessee
Oklahoma 4 South
Arkansas Carolina
Arizona
New Mexico 8
5 4 Alabama
Guam 2 5
Georgia

15 9
Texas 16 Mississippi

1 35 Louisiana

Florida

29
Hawaii
51
2
866 patients
Puerto Rico
U.S. Virgin
Islands 1
1389 revascularization procedures

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Moyamoya World Distribution


(17 countries)
Norway
2
Netherlands
Canada 1
5 Germany
Ireland
3
2
United States Japan 1
of America 838 Israel China
3 Kuwait 2

Saudi 1 Korea 1
Arabia
1
Qatar
1 1
Vietnam

1
Australia
South 2
Argentina
Africa
1

Annualized Moyamoya Surgeries


1991-2016

12/04 started collecting blood, CSF, STA and M4 MCA *annualized from 4 mos

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Moyamoya Adults vs Pediatrics


Surgery Cases

Pediatrics, 350,
25%

Adults
Pediatrics

Adults, 1039,
75%

Moyamoya Age of Presentation


10 year interval
250

200
Number of patients

201

150
184

100 123
119
115
50
101

23
0
9

9
0-

-1

-2

-3

-4

-5

-6
10

20

30

40

50

60

Age group

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Moyamoya Gender & Ethnicity


Hispanic, 62,
7% Other, 26, 3%
Asian, 282,
32%

Male, 251,
29%
Asian
Black
Caucasian
Hispanic
Other
Female,
615, 71%
Black, 40, 5%

Caucasian,
456, 53%
Male
Female

Current total number of patients: 866

Moyamoya Angiopathy
1. Moyamoya Disease – isolated disorder ( 755 pts )

2. Associated with other disorders (Quasi-Moyamoya Disease)


( 111 pts )

- Neurofibromatosis - Leptospirosis
- Sickle cell disease - Connective tissue defect
- Post-irradiation - Marfan’s syndrome
- TB - Tuberous sclerosis
- Pyogenic meningitis - Pseudoxanthoma elesticum
- Fanconi’s anemia - Apert’s syndrome
- Glycogen storage disease - Coarctation of the aorta
- Down syndrome - Hemocystinuria
- Sneddon’s syndrome - Vasculitis
- Alagille syndrome - Primordial dwarfism
- Graves disease

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Primordial Dwarfism
(MOPD II) and
Moyamoya Syndrome
Pericentrin gene mutation

Unrelated 17 yo and 14 yo boys

Presenting symptoms in Peds

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Presenting symptoms in adult patients

The Neurologist 2012;18:398–403

11 patients misdiagnosed with multiple sclerosis


(2 mos-19 years; median 4 yrs)
1991: 26 yo physiatrist progressive episodic weakness alternating
between all 4 limbs, dyphasia, numbness in extremeties

Treated for MS with corticosteroid (no benefit)

19 years later finally had MRA and then angio: MMD; bypassed 2010
2003 2010 2010

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Superficial
temporal artery

Temporalis
muscle

Craniotomy site Sylvian fissure

Line of incision

Superficial
temporal artery

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Reflected
temporalis muscle

Dural incision

Superficial
temporal artery

Superficial
Reflected dura and temporal artery
temporalis muscle

Temporal lobe

M4 branch of middle
cerebral artery

Frontal lobe

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Superficial temporal artery

M4 branch of middle
cerebral artery

Completed STA-MCA
anastomosis

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Moyamoya Disease
Intraoperative Management
• Normocapnia (end tidal CO2 35mm Hg)
• MAP: nl to high range
• Mild hypothermia (33°C)
• Monitor EEG (don’t monitor SEPs, MEPs)
• Thiopental/Propofol for occlusion
• Quantitative CBF (Transonic Flowmeter)
(M4, STA) pre- & post-bypass

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127
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Adult and Pediatric Vessel Size

1.5 1.4 1.4


† * 1.3 Adult
1.1
Pediatric
Diameter (mm)

1.0

0.5
† P<0.0001

* P=0.0056
0.0
STA MCA STA MCA

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Occlusion Time Distribution


(1991-2000)
8

7
Frequency(# of surgeries)

0
9 16 23 30 37 44 51 58 65 72 79 86
Minutes

Occlusion Time Distribution


(2006-2009)
40

35 Shortest: 9.5 min


Frequency(# of surgeries)

30

25 2015: 11-22 min


20

15

10

0
9 16 23 30 37 44 51 58 65 72 79 86
Minutes

130
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STA-MCA bypass: Post-anastomosis video angiography with


IndoCyanine Green (ICG)

Moyamoya Disease
Post-operative F/U

• Post-op MR scan
• 6 month, 3 yr, 10 yr, 20 yr F/U
Clinical
Angiography, MR
CBF studies
– MR perfusion, Xenon CT, SPECT (+/- Diamox)

Neuropsychological testing

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STA size

Pre-op 6 months s/p STA- 3 years s/p STA-


MCA bypass MCA bypass
(6/28/05)
(1/31/06) (10/29/08)

62 yo female, bilateral strokes, slowed mentation


Lt ICA Rt ICA

Lt ICA Rt ICA

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2 mos s/p bilateral


STA-MCA bypasses
Rt STA

Rt STA Lt STA Lt STA

Indirect revascularization

Matsushima Y. et al. Surg. Neurol. 15:313-320, 1981

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2 yo, neurofibromatosis, L focal sz, L face/arm weakness

ADC Ax Diff

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Pre-Operative Lt ICA
Rt ICA Rt ICA

4 Months s/p EDAS (indirect graft)


Rt ICA Rt ICA Rt ICA

5 yo boy, MMD, bilateral hemisphere TIAs


4 mos post-op

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1993
Xenon CT
Pre-operative Post-operative
(4 mos)

2012
Pre-Diamox

2014
Post-Diamox

5 yo boy, Moyamoya Disease


Pre-Op 4 mos Post-Op

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Intraoperative blood flow analysis of direct


revascularization procedures in patients with moyamoya disease

Marco Lee, Raphael Guzman, Teresa Bell-Stephens and Gary K Steinberg

Journal of Cerebral Blood Flow & Metabolism 31:262-274, 2011

* 22.2
25
* p<0.0001
20
Normal MCA flow:
10-20 ml/min
ml/min

15

10
4.4
5

0
Pre-anastomosis Post-anastomosis
Total MCA Flow Before & After Bypass Surgery

Correlation of STA Size & Post-anastomosis


Proximal MCA Flow

75
R2=0.11
P<0.0001
Proximal MCA
flow (ml/min)

50

25

0
0 1 2 3
STA diameter (mm)

138
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Failure of Primary Percutaneous Angioplasty and Stenting in the


Prevention of Ischemia in Moyamoya Angiopathy

Nadia Khan, Robert Dodd, Michael P. Marks, Teresa Bell-Stephens, Joli Vavao,
Gary K. Steinberg

Cerebrovascular Diseases 31:147-153, 2011

• 5 patients
• Angioplasty: 1
• Angioplasty/stenting: 4

• Recurrent ischemic symptoms and re-stenosis:


1 day- 4 months after treatment

16 yo male MOPD II, hemorrhage from ruptured aneurysm


Rt carotid Lt carotid

vertebrobasilar

Rt carotid: 2 y post-bypass Lt carotid: 2 y post bypass


vertebrobasilar: post clipping

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17 yo male, MOPD II with 2 ½ y later, SAH


moyamoya, bilateral EDAS

Small P1-P2 aneurysm


s/p stent assisted coiling

Natural History of MMD


• Inevitable disease progression in majority of patients

• Variable course: slow or rapid neurologic decline

• 2/3 patient have symptomatic progression over 5 yrs;


outcome poor without tx (Choi, 1997; Kurokawa, 1985; Kuroda, 2005)

• “Asymptomatic” MMD misnomer (Kuroda, 2007)


(20% silent infarcts; 3.2%/yr stroke risk)

With surgical tx (meta-analysis 1156 pts <21 yo):


2.7% symptomatic progression (mean f/u 4.5 yrs) (Fung, 2005)

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Natural history of adult MMD with medical management


No. of No. of Pediatric Follow-Up
Authors & Year Stroke Recurrence
Patients Patients Duration
Chiu et al., 1998 35 7 40 ± 31 mos Stroke: 10.3%/person-yr
(bleed, 1.7%; ischemia, 8.6%)
Gross & Du, 2013 42 0 Mean 2.9 yrs Stroke: 13.3%/person-yr;
bleed: 1.7%/person-yr
Hallemeier et al., 34 0 Median 5.1 yrs 5-yr Stroke: 65%
2006
Kobayashi et al., 42 1 Mean 80.6 mos Hemorrhage: 7.1%/person-yr
2000
Kuroda et al., 2007 40 1 Mean 43.7 mos Stroke: 3.2%/person-yr
(bleed, 2.4%; infarction, 0.8%)
Morioka et al., 2003 36 2 or 3 12.7 ± 7.1 yrs Hemorrhage: 29 rebleeds in 21
patients (61.1%)
Cho et al., 2015 241 0 82.5 ± 62.9 mos Stroke: 4.5%/person-yr
(bleed, 2.3%; ischemia, 2.2%)
Starke et al., 2009 19 0 Mean 41 mos 5-yr Stroke: 64%
hemispheres

Stroke Rate: 3-15%/yr 5 yr Stroke Rate: 15-75%

Stanford Moyamoya Disease


Long Term Results

• 265 patients undergoing 450


revascularization procedures
• mean follow up of 4.7 years
(0.5-16.8 years, median 3.2 years)

J Neurosurg, 111:927-935, 2009

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Natural History
Washington Univ (St. Louis)
Medical Treatment
5-year risk of recurrent
ipsilateral stroke of 65%
after the initial symptom
(17% after revascularization)

Stanford series:
5-yr risk of having a stroke (any Hallemeier CL, et al Stroke 2006
distribution) after revascularization
surgery was 5.5%

Clinical outcome
(modified Rankin scale)

P<0.0001 0: no symptoms
2 1: symptoms, no disability
2: slight disability
MRS

1 3: moderate disability
4: mod-severe disability
5: severe disability
0
Pre MRS Post MRS 6: dead

90% of the patients had a mRS 0-2 (mean follow-up: 4.1 years)

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Persistent TIA at follow-up


(171 patients presenting with TIA)

15.3%
% of patients with
post-OP TIA within 1st
TIA 1st month month
% of patients TIA free
84.7% within 1st month

8.8%
% of patients with
post-op TIA after 1st
year
TIA after 1st year % of patients TIA free
after 1st year
91.2%

Moyamoya Disease
Long Term Outcome 1991-2007

• 2 new ischemic strokes


– 1 pt: 3 mos post op; VF deficit; PCA territory
– 1 pt: 2 yrs post op; died

• 2 patients recurrent bleed from moyamoya vessels


9 mos and 9 yrs after STA-MCA
1 recovered completely; 1 recovered to baseline deficits

• 98% graft patency (angiography) F/U (0.5-9.5 yrs)


high long term patency over 1-23 years
(doppler, MRA, CTA, DSA)

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Stanford Moyamoya Series


Surgical Morbidity and Mortality (≤ 30 d)
Morbidity:
12 patients undergoing 13 procedures
(7 ischemic strokes, 6 hemorrhages)
2.8% of procedures; 4.5% of patients

Mortality:
3 patients (2 bleeds, 1 multiple strokes- MELAS)
0.7% of procedures; 1.1% of patients

Major Morbidity/Mortality:
5.7% per patient; 3.6% per procedure

42 yo female, R-sided weakness, aphasia

Pre-op

Pre-op 1 day s/p Lt STA-MCA bypass


(new Lt weakness, LE>UE)

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6 yo female with progressively frequent and severe Lt


hemisphere TIAs
Pre-op Intraop hemorrhage
(MAP ↑ to 130)

Rt hemiparesis,
expressive
aphasia

5 mos later,
complete
recovery

Markedly impaired Lt hemisphere


hemodynamic reserve pre-op
(SPECT/Diamox)

Intraoperative Flow Measurements for


Moyamoya Disease

Can intraoperative flow measurements help predict:

● Patency of grafts

● Perioperative complications
stroke, hemorrhage, transient neurologic deficits

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Higher Total MCA flows correlate with post-op complications

Complications: ischemic stroke, hemorrhage


Lee, et al: JCBFM 31:262-74, 2011

Stanford Moyamoya Series (1991-2007)


Transient Neurologic Deficits (TND)

Transient (but prolonged) new deficits (9 pts)


Delayed 1-2 d post-op; Mainly left hemisphere

• 8 patients aphasia or oro-bulbar apraxia, 1 pt arm weakness


• MRs normal; TCDs nl; Xenon CT unchanged (1 pt), ↓ CBF (1 pt )
• Symptoms resolved after 2 days - 2 weeks
• 3.3% patients; 2.0% procedures (1991-2015: 15% procedures)

• ? Hyperperfusion ? Hypoperfusion
Treat by ↓ or ↑ BP?

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TNDs due to Hyperperfusion


SPECT and PET imaging

STA flow post-anastomosis & post-op TND

35 * 28.8
30
25
20
ml/min

20
15
10
5
0
Control TND
* P=0.036

Lee, et al: JCBFM 31:262-74, 2011

147
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40 yo male, progressive headaches & right visual field loss


Pre-op

2 days post-op:
Mild expressive aphasia.
Resolved over next 11 days

Delayed TND

Xenon CT (delayed TND)


Baseline Post-Diamox
57.3 42.2 45.7
64

71.1 27.1
Pre-op 83.8 28.7

34.8 14 59.5 24.8

36.3 32.2 57.5 46.1

42.8 17.8 Post-op 69.1 24.1


day 6
40.3 14.4 68.5 19.2

63.5 61.1 62.2 51.6

71.5 35 Post-op 66.2 29.7


day 9
40.5 24.9 24.9 9.2

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Hemedex Bowman CBF (thermal diffusion blood flow probe)

Moving average plot of pooled median perfusion by time


Left TND group (n=7) Left No TND group (n=19)

Right No TND group (n=25)


Onset neurologic deficit Improving symptoms
(12-25 hrs) (48 hrs)

TND group flows start higher


More variable
Significant drop at TND onset

Local Hypoperfusion

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Conclusions
Transient Neurologic Deficits following STA-MCA bypass for
MMD is due to local relative hypoperfusion (flows initially higher)

Possibly related to competing flows between the native circulation


and the graft

Background of impaired autoregulation and fluctuating flows

Treatment: Maintain ↑ BP

Acute Pre-operative Infarcts and Poor Cerebrovascular Reserve are


Independent Risk Factors for Severe Ischemic Complications Following
Direct Extracranial-Intracranial Bypass for Moyamoya Disease
M Antonucci, T M Pulling, T Burns, J Rosenberg, M Marks, G Steinberg, G Zaharchuk

AJNR (2015)
• Retrospective, case-control
• Included all adult cases 2005-2011
• Separated into 2 groups
Index cases – large territorial strokes (>15 ml volume)
• 6 patients with 9 operated hemispheres
• Mean Age (Range): 44 (27-67) yrs; 4 female
• Mean DWI Lesion size (SD): 95±55 ml
Controls – no post-op DWI lesions, no post-op symptoms (even
transient)
• 25 patients with 36 operated hemispheres
• Mean Age (Range): 38 (18-59) yrs; 18 female

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Results: Pre-op acute infarcts

Pre-operative acute
infarcts (DWI +)
– Patients with poor
outcomes 4/6 (66%)
(another pt subacute infarct:
DWI+/ADC-) (5/6; 83%)

– Patients with good


outcomes 0/25 (0%)

Results: Cerebrovascular Reserve


Percent change

P=0.0004

• Preop Augmentation was significantly lower in the anterior


circulation in stroke patients, sometimes with steal

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43 year-old woman with bilateral Moyamoya

Pre-diamox (Baseline)

Post-ACZ

43 year-old woman with bilateral Moyamoya


Pre-op

Post left EC-IC bypass

New post-op large infarct not always in same hemisphere as pre-op infarct

Multivariate analysis: Preop acute infarcts (p=.02) and impaired CVR


are independent risk factors for post bypass large infarcts (p<.001)

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Stanford Moyamoya 1991-2015

57 patients underwent 76 repeat revascularization procedures


17 patients/hemispheres initially Stanford (1.3% /hemisphere)

36 adult, 21 peds; 39F, 18 M

Indications: persistant TIAs (3); strokes (13); sz/new cognitive deficits


(3); TIAs/choreiform movements (1); new MR infarcts/CVR steal (1)

All inadequate angiographic filling & perfusion deficits (CBF studies)


>50% impaired hemodynamic reserve after diamox

67% (38) had failed indirect procedures; 56% (32) pediatric

Right Left

After EDAS

After additional
STA-MCA grafts

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46 yo female,
Moyamoya Disease

s/p Bilateral EDAS

Bilateral
Hemisphere TIAs

Right Hemisphere
Left EC-MCA TIAs
Vein Graft

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1996

1996

155
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10 Days Post-Op

8 yo ♀ MMD, Failed prior


EDAS and multiple burr
holes

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Omental-Cerebral
Transposition

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Free Omental Graft

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Omental-Cerebral Transposition
21 for Moyamoya disease

1991-2000: 9
2011-2016: 12, laparoscopic harvesting

12 pedicled grafts, 6 free grafts


Ramon Navarro MD
Kevin Chao MD
Peter A. Gooderham MD
Matias Bruzoni MD
Sanjeev Dutta MD
Less-Invasive Pedicled Omental–Cranial Transposition in Gary K. Steinberg MD, PhD
Pediatric Patients with Moyamoya Disease and Failed Prior Departments of Neurosurgery, and
Stanford Stroke Center and Pediatric
Revascularization Surgery
Stanford University School of
Medicine and Lucile Packard
Children’s Hospital, Stanford, CA

ONS: OPERATIVE TECHNIQUE


NEUROSURGERY, Mar 2014: Suppl 1:1-14

Rt ECA injection after STA-MCA 7 yo ♀, bilat STA-MCA


after Lt stroke

Asymp for 5 yrs

New Rt hemisphere
motor TIAs & Lt sided
choreiform movements
Rt hemisphere

Rt gastroepiploic artery
injection

6 mos s/p omental


transposition

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Immediate post-op
6 mos Post-Op: Improved CBF and reserve

6 mos post-op

4 yrs post omental transposition


Rt ECA

Gastroduodenal artery

Gastroduodenal artery

Gastroduodenal artery

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5 yo ♀, s/p bilat STA-MCAs and EDAMS, Persistent disabling bilat


motor & sensory TIAs, New MR infarcts, ↓ CBF

Lt ECA

Rt ECA

Bilateral Omental- Cerebral Transposition


(laparascopic omental harvest)

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6 mos s/p bilateral omental graft


Resolution of TIAs

Rt gastroepiploic artery injection

3 ½ yrs post op

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Repeat Revascularization for MMD

57 patients

1 perioperative bleed (died); 1 perioperative stroke

F/U: 6 mos- 21 years (mean 4.8 yrs)

81% free of TIAs, choreiform movements, no further strokes


(1 pt required a 3rd revascularization procedure)

19% occasional TIAs

Conclusions
Repeat revascularization is safe and effective in preventing future
ischemic events in patients with failed prior revascularization
procedures

At Stanford, initial indirect bypass has a higher rate of requiring repeat


revascularization c/w direct bypass

17 initial surgery Stanford:


4% (5/137) indirect; 1% (12/1107) direct (p=.03)

58% of repeat revascularizations were achieved with direct bypass


(STA-MCA, OA-MCA, Saph Vein-MCA)

42% indirect (EMS, EDAS, EDAMS, omental transposition, bur holes)

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Moyamoya Genetics

1. Familial in 10-15% of patients

2. Incidence of MMD in both monozygotic twins is 80%

3. Sib recurrence rate ↑44x and relative incidence rate in


offspring ↑34x compared with general population

4. MM angiopathy sometimes associated with other


genetic diseases (NF1, Down syndrome, Marfan’s syndrome,
Alagille syndrome, MOPDII)

Moyamoya Genetics

• Inheritance: autosomal dominant with incomplete


penetrance or polygenic

• Prior linkage studies (mainly in siblings)


Several candidate MMD-associated loci:
3p24.2-p26; 6q25; 8q23; 12p12; 17q25

• Until recently, no single gene mutation identified as


increasing the susceptibility to MMD

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Moyamoya Genetics
• RNF213 (MIM 613768), gene at 17q25, encodes a ring finger
protein, is a MMD susceptibility gene
(polymorphism c.1457G>A in 95% familial & 75% sporadic MMD,
in 1% Japanese population)

Gain or loss function?

? (Kamada et al, J Hum Genet 56:34–40, 2011)

Depletion of RNF213 causes Mouse RNF213 KO: no abnormalities


abnormal vessel sprouting in (Sonobe, et al. Brain Res 1552:64–71, 2014)
Zebrafish

Stanford familial Moyamoya patients

Family 8: X-linked recessive


(Elisabeth Tournier-Lasserve, PhD)

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Loss of BRCC3 Deubiquitinating Enzyme Leads to Abnormal


Angiogenesis and Is Associated with Syndromic Moyamoya

Miskinyte S, Butler MG, Herve´ D,Sarret C, Nicolino M, Petralia JD, Bergametti F,


Arnould M, Pham VN, Gore AV, Spengos K, Gazal S, Woimant F, Steinberg GK,
Weinstein BM, Tournier-Lasserve E Am J Hum Genet 88(6):718-28 , 2011

3 unrelated families X-linked moyamoya syndrome

Moyamoya angiopathy, short stature, stereotyped facial dysmorphism

Deletion of Xq28 results in loss of


BRCC3, a deubiquitinating enzyme

BRCC3 deletion in zebrafish


results in defects in angiogenesis

6 familial carriers with


MMD (5 strokes)

Smooth muscle α-actin

ACTA2 carrriers with mutations in


R258 have >25% incidence of early
stroke
(R149, R118 >25% premature CAD)

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ACTA 2 mutations lead to increased SMC and myofibroblast


proliferation in vivo and in vitro
coronary arteries in 28 yo ♂ myocardial arteries in 50 yo ♂ and 53 yo ♀

Large Scale Exome Sequencing Effort


in Diverse MMD Population (Stanford)
•Efficient alternative to whole genome
(Illumina HiSeq2000, 60X coverage)

•Focus on nonsynonymous in/dels and SNVs (single nucleotide variations)

•117 MMD patients

•Ethnicity included: Asian (n=36), Caucasians (n=71)

•Appropriate matched control data from 1000 Genomes, but now have
in-house control data

•Unique bioinformatics/analytical pipeline (Personalis Inc.)


Personalis Inc.

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Key Preliminary Findings


Exome Sequencing Effort in Diverse MMD Population
Asian Population: Caucasian Population:

• Confirmation of RNF213 • Identification of a novel


mutation haplotype block (Chr 10)
which includes 4 protein-
• RNF213 mutation not coding genes
present in ANY Caucasian
or African MMD patients • Haplotype block not
present in ANY Asian
• Additional gene mutation MMD patients
candidate (a membrane
Sex Differences:
transport protein) may be
associated with Southeast
• There were no significant
Asian/Pacific Islander
variants or genes in
MMD patients
male/female subgroups
Personalis Inc.

Genetics of Moyamoya
Certain gene mutations may predispose to MMD

Presence of these mutations plus second environmental insult may


cause dysfunction in angiogenesis or vascular smooth muscle

Leads to stenosis/occlusion Circle of Wills arteries

Important implications for clinical management of patients/families

According to the testing, my sister and I have the mutated RNF213 gene. My mom
does not. Miya does not have the mutated gene. SUCH wonderful news! We were
told this "drastically reduces her chance of developing Moyamoya", although the
genetics of MM is not completely clear, so it is not with certainty, of course.

Important for elucidating the pathomechanisms underlying MMD and


other vascular diseases

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Array Tomography Reveals Aberrant Vascular


Architecture (Middle Cerebral Artery, M4)
Control Moyamoya

Lumen
Lumen

Smooth Muscle Actin (green) •Intimal thickening


Elastin (red) •Proliferation and hyperplasia of smooth
Nuclei (blue) muscle cells (intima)
•Disrupted internal elastic lamina

Unresolved Questions
Is Indirect bypass as effective/safe as Direct bypass for adults?

Starke, Connolly et al, J Neurosurg, 111:936-942, 2009


EDAS in 67 hemispheres (43 pts)
Peri-op infarct rate 3%/hemisphere (2/67)
5 yr ipsilateral stroke rate 6% c/w 64% in contralat, non-operated side

Dusick, Gonzalez, Martin Neurosurgery 68:34-43, 2011


63 EDAS hemispheres, 58 burr hole hemispheres (Adults: 46 hemispheres)
f/u 0-211 mos; median 14 mos
1 yr 10/11 (91%) adults no ischemic symptoms
6.3% perioperative cx: 2 subdural hematomas, 2 new ischemic events

Agarwalla, Ogilvy, et al, J Neurosurg 121:1394-1400, 2014


52 EDAS hemispheres (37 pts) f/u mean 38.2 mos
↓ in TIAs, ischemic stroke, hemorrhage from 1.7/pt to 0.14/pt

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Direct v Indirect Bypass for Moyamoya


Paper Year Journal Country No. of pts Conclusion
Adult

Arias et al 2015 J Stroke USA, 15 pts Direct bypass provides more consistent &
Cerebrovas Dis Missouri complete cerebral revascularization
Kazumata 2014 JNS 121: 432- Japan, 2032 direct, 4171 Direct bypass: higher extent of angiographic
et al 440 Sapporo indirect revascularization. Comparable postop stroke
Systematic review risk in direct and indirect group (5.4% v
5.5%) Recurrent stroke risk is higher in
indirect bypass group
Abla et al 2013 NeuroSx 73: USA, 39 indirect Direct bypass: Significantly greater
430-439 BNI 29 direct improvement in symptoms. Both direct &
indirect equally effective in preventing stroke
Bang et al 2012 NeuroSx 70: Korea, 65 pts, 75 bypasses Direct bypass: greater extent of angiographic
625-633 Seoul revascularization at 6 months
Czabanka 2011 Cerebrovasc Germany 24 patients STA-MCA/EMS: superior to single EMS in
et al Dis 32: 361- Berlin 24 direct, 24 restoring CVRC. Better angiographic
369 indirect collateralization

Kawaguchi 2000 JNS 93: 397- Japan, 22 patients Direct bypass significantly reduce the risk of
et al 401 Nara 11 cons, 6 direct recurrent hemorrhage. Direct bypass
bypass, 5 EDAS significantly reduce the risk of recurrent
ischemic events
Houkin et 2000 Acta Neurochir Japan, 85 pts Direct bypass useful in over 90% of adult
al 142: 269-276 Sapporo 22 sides in adult cases
cases assessed Poorer rate of neo-angiogenesis by indirect
bypass in adults

Advantages of Direct Bypass vs Indirect Bypass for Adult MMD


Immediate increase in CBF

Better angiographic revascularization

Better improvement in hemodynamic reserve

Better long term clinical outcomes (ischemic/hemorrhagic)

Lower rate of repeat revascularization


Disadvantages of Direct Bypass vs Indirect Bypass for Adult MMD
Technically more demanding (not an issue with experience)

Higher risk of perioperative delayed transient neurologic deficits

[No higher perioperative stroke (ischemic/hemorrhagic) rate]

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Unresolved Question until recently


Efficacy of bypass surgery for hemorrhagic MMD

Surgical revascularization might reduce the incidence of


rebleeding to 12.5–20% (from the estimated 30–65%)
(Kobayashi, 2000, Yoshida, 1999, Fujii, 1997, Morioka, 2003)

•Kobayashi, 2000; 42 patients, f/u 6 ¾ yrs (mean)


33% rebleed rate (good recovery 21%; mortality 29%)
1st bleed (good recovery 46%; mortality 7%)

However, the evidence levels of these studies were not high


(Houkin, 1996, Yoshida, 1999, Okada, 1998, Wanifuchi, 1993)

Effects of Extracranial–Intracranial Bypass for Patients With


Hemorrhagic Moyamoya Disease
Results of the Japan Adult Moyamoya Trial
Susumu Miyamoto, Takashi Yoshimoto, Nobuo Hashimoto, Yasushi Okada, Ichiro Tsuji, Teiji
Tominaga, Jyoji Nakagawara, Jun C. Takahashi on behalf of the JAM Trial Investigators
Stroke 45(5):1415-1421, 2014

No antiplatelet agents

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Kaplan–Meier cumulative curves for end point


(All morbidity) (Bleeds)

Bypass reduces bleeding and improves outcome !!


Stanford hemorrhagic pts (85): 1.9%/yr rebleed after direct bypass
2.7%/yr all morbidity

Unresolved Questions

What about pts with intractable headaches or cognitive


deficits?

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Neurocognitive Impairment in Adults with Moyamoya Disease


without Stroke
Neurosurgery 70:634-8, 2012
Karzmark P, Zeifert PD, Bell-Stephens TE, Steinberg GK, Dorfman LJ

Neuropsych assessment in 30 MMD adults; no MRI evidence of stroke


or hemorrhage

7 (23%) had significant cognitive impairment


Executive functioning, mental efficiency, word-finding impaired
Memory (intellect) relatively intact

Significant emotional distress (depression /anxiety) in 11 (37%) patients

Can earlier surgical revascularization prevent cognitive impairment?

Unresolved Questions
Are CBF studies useful in deciding when to revascularize an
asymptomatic hemisphere?

Is Moyamoya Disease a spectrum of cerebral vasculopathies?

What can we learn from new genetic data and how to


correlate with the phenotype?

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Which patients should have revascularization surgery?

Symptomatic patients
usually with prior MR watershed infarcts
usually with poor angiographic filling
& impaired hemodynamic reserve

Minimally symptomatic and asymptomatic patients with


prior MR watershed infarcts and impaired hemodynamic reserve

Who not to operate on

Asymptomatic patients with normal hemodynamic reserve

Patients with recent stroke (DWI +), esp with cerebrovascular steal

Older patients (> 60 yo)

? Patients with other vascular risk factors


(hypertension, diabetes, hyperlipedemia, coronary artery disease)

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Stanford Moyamoya Center 2016


Cerebrovascular Surgery Neuro ICU
Gary Steinberg, MD, PhD Anna Finley, MD
Neuroradiology Chitra Venkat, MD
Michael Marks, MD Marion Buckwalter, MD, PhD
Huy Do, MD Karen Hirsch, MD
Rob Dodd, MD, PhD Neuroanesthesiology
Greg Zaharchuk, MD Richard Jaffe, MD, PhD
David Drover, MD
Clinical Fellows Michael Chen, MD
Raphael Guzman, MD (2006-7)
Marco Lee, MD, PhD (2007-8) Neuropsychology
Nadia Khan, MD (2008-10) Peter Karzmark, PhD
Paritosh Pandey, MD (2009-10) Penelope Zeifert, PhD
Peter Gooderham, MD (2011-12) Leslie Dorfman, MD
Ramon Navarro, MD (2011-12) Nurse Coordinators
Nitin Mukerji, MD (2012-13) Teresa Bell-Stephens, RN
DJ Cook, MD, PhD (2012-13) Joli Vavao, RN, NP
Sunil Furtado, MD (2013-14) Melissa Lewis, RN, NP
Jeremiah Johnson, MD (2014-15) Mary Marcellus, RN
Mario Teo, MD (2014-16) JJ Baumann, RN
Venkat Madhugiri, MD (2015-16)
Research Staff
Stroke Neurology Lori Shoemaker, PhD
Greg Albers, MD Maria Coburn, BS
Neil Schwartz, MD, PhD Jeanne Gu, BS
Ami Tai, MD Jill MacInnes, BA

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Stanford Moyamoya Center Annual Reunion


June 2014

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17 yo male, MOPD II, moyamoya disease


10 months s/p clipping ruptured L vertebral-PICA aneurysm and
bilateral EDAS

Courtesy of Gary Parker Photography

17 yo male, MOPD II, moyamoya disease


10 months s/p clipping ruptured L vertebral-PICA aneurysm and
bilateral EDAS

Courtesy of Gary Parker Photography

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Stanford University

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Evidence-Based Evaluation and


Treatment of Carotid Stenosis

Christopher M. Loftus MD, Dr. h.c., FAANS


Professor and Chairman
Department of Neurosurgery
Loyola University Stritch School of Medicine
Maywood, IL, USA
Treasurer – WFNS
Chair, International Programs – AANS
Oakstone Publications Video Lecture
April, 2016

Disclosure Statement

Advisory Role: 3M, Portola


Honoraria: Scanlan

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2nd Edition here!!


Publication: July 2006

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Imagine my
surprise!

What do we know about CEA?

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The data can be confusing…

Fundamental Questions for 2016

• Is CEA superior to medical therapy?


• Is CEA superior to CAS-P?
• How can we make treatment as safe
and effective as possible?

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Asymptomatic Trials

• MACE - No benefit (except for aspirin!)


• CASANOVA - No benefit
• VA CSP167 - Surgery prevents TIA’s
• ACAS - Surgery prevents stroke
• ACST - Surgery prevents stroke

Symptomatic Trials

• ECST - Surgery prevents stroke


• VA CSP 309 - Surgery prevents stroke
• NASCET - Surgery prevents stroke

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CML Current Practice

• Asymptomatic (ACAS)
– >60 % - surgery
• Symptomatic (NASCET, ECST, VASST)
– >50 % - surgery (NASCET final data)
– <50 % - best medical management

50% Ulcerated stenosis/TIA’s

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What do we know about CAS?

CEA/CAS summary 2016


• Historical trials favored CEA
• Randomized contemporary trials
– SAPPHIRE –high risk equipoise CEA/CAS
– SPACE – favors CEA
– EVA-3S – favors CEA
– CREST – statistical equipoise, 30 day data
favors CEA
– ICSS/CAVATAS 2 – strongly favors CEA

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Cases I Have Sent for Stenting

• Carotid dissection
• High cervical carotid aneurysms
• Extreme high exposures
• Medically unstable cases
• Fibromuscular dysplasia
• Second side cases with CN palsy
• Patient choice by CMS criteria

Pseudoaneurysm 4 years post CEA

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M.S. 62 female CVA, DWI, ADC, T2

RICA AP and lateral

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LICA

RICA post-stent

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AT Carotid Blowout 2015

Left AP Left Lateral Right AP Right Lateral

August 2015 – 71 year old Cath Lab Tech


Left handed tingling spells for 6 months

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R.J.
61y.o. female
TIA’s

STENT

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What’s Coming Next?

• ACST – 2: Rudarakanchana N, Dialynas M,


Halliday A. Asymptomatic Carotid Surgery Trial-
2 (ACST-2): rationale for a randomised clinical
trial comparing carotid endarterectomy with
carotid artery stenting in patients with
asymptomatic carotid artery stenosis. Eur J Vasc
Endovasc Surg. 2009 Aug;38(2):239-42

What’s Coming Next?

• SPACE2 - a three-arm randomised-


controlled clinical trial.
The control groups in the large trials for asymptomatic carotid artery disease (ACAS
and ACST) originate from more than a decade ago and, for the most part, have not
received a medical primary prevention strategy that would now be considered the
standard according to current national and international guidelines. For this reason,
a three-arm trial (SPACE2; http://www.space-2.de) with a hierarchical design and a
recruitment target of 3640 patients is chosen. Firstly, a superior trial of
intervention (carotid artery stenting or carotid endarterectomy) vs. state-of-
the-art conservative treatment is designed. In case of superiority of the
interventions, a noninferiority end-point will be tested between carotid artery
stenting and carotid endarterectomy. This trial is registered at Current Controlled
Trials ISRCTN 78592017.

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CREST 2
• Carotid revascularization for primary prevention of stroke
(CREST-2) is two independent multicenter, randomized
controlled trials of carotid revascularization and intensive
medical management versus medical management alone in
patients with asymptomatic high-grade carotid stenosis.
One trial will randomize patients in a 1:1 ratio to
endarterectomy versus no endarterectomy and another will
randomize patients in a 1:1 ratio to carotid stenting with
embolic protection versus no stenting. Medical
management will be uniform for all randomized treatment
groups and will be centrally directed.

So what about CAS in 2016?


• CEA Superior:
– SPACE
– EVA-3S
– ICSS/CAVATAS 2
• CAS Equivalent
– SAPPHIRE (high-risk)
– CREST (maybe)
• CAS Superior
– Nothing
• Serious questions about emboli and cognitive
deficits with CAS-P
• CEA remains my primary choice!

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Fundamental Questions for 2016

• Is CEA superior to medical therapy?


– YES
• Is CEA superior to CAS-P?
– YES
• How can we make CEA as safe and
effective as possible?

#1 – Get the Imaging Right

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Preoperative

• Ultrasound ☹
• MRA
• CTA
• Catheter Angiography

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CTA Left
Carotid
(Asymptomatic)

CTA read as 60% Stenosis!

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Watch out for CTA!

“Trust Your Instincts”

CVA patient
Duplex 70-
79%
NASCET 13%
Wisp of ulcer

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Angio/Plaque Mismatch 2012

#2 - Know the Equipment

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Scanlan
“Loftus”
carotid
set

Loftus Shunt
Clamps for
ICA

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#3 - Look for Strange Anatomy

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Pre-Op R CEA

Post-Op

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Pre-Op R CEA

Post-Op

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Unstable Recanalized Occlusion/CVA

1+coumadin =

3
4

Unstable Recanalized Occlusion/CVA

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#4 - Always plan for high exposure

No Go

Slow Go

E-Z Go

Low Go

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How Can We Measure High Exposure?

• Spine anatomy
• ECA branches on lateral A/G
• Color change in vessel
• Hard or soft digital feel
• Doppler auscultation of ICA

C2 Body

Top of
Marker ICA
branch on plaque
ECA

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Sternomastoid Muscle

Common Facial Vein

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Plowing the road – a big


lymph node obscures the
ICA

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Hypoglossal
Sternomastoid Nerve
Artery

Cut Edge of Digastric Muscle

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#5 - Understand/respect the nerve


anatomy

Avoidance of nerve injury


• Vagus (CCA cross-clamp)
(gentle retraction)
• Laryngeal nerves
– no deep medial retraction
– no circumferential dissection
• Accessory nerve
• Ansa hypoglossi

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Nerve Sparing February 2013

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#6 - Protect the ICA at all times

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Why would someone have a stroke?

• There’s not enough blood flow


• A piece of debris or air goes to the
brain
• The vessel occludes postop

Protect the brain from ICA emboli!

• Give the Heparin bolus early


• Minimal manipulation of the
CCA / ICA
• High/low exposure (digastric
/ omohyoid)
• Expose the ICA well above
the plaque!!

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Anticoagulants in CEA
• Stop plavix/ticlid/coumadin 1 week
preop
• Continue ASA throughout
surgery/restart plavix later
• Heparin common - no problem
• Check ACT in heparinized patients
– Most often surprisingly low
• Heparin bolus 5000U or weight-based

Final dissection of carotid


• External identified and secured
• Superior thyroid secured
• Potential back-bleeders isolated
• Distal ICA controlled above plaque
• Shunt clamps fitted
• Shunt reviewed

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Doppler for ICA Distal Endpoint

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Arteriotomy
• EEG notified
• Clamps applied (ICA, ECA, CCA)
• Arteriotomy with #11 blade and
Pott’s scissors
• Shunt if required

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Is a Shunt Needed?
• Awake: deficit • TCD: MCAV 0-15%
within 60 seconds pre-clamp
• Stump: CSP • EEG:
<50mmHg – unilateral attenuation 8-
• CPP: stump-IJP 15hz fast
<18mmHg – 2x increase 1hz delta
• rCBF: 18- • SSEP:
20ml/100g/min – 50% amplitude decrease
– 5% latency increase in
CCT (Kearse 20%)

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Isolated M-1 Segment needs Shunt!!

Right

Left

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Insertion of Shunt
• Total exposure above plaque
• Shunt in CCA first
• Evacuation of shunt
• Gentle ICA insertion
– Backbleeding
– Shunt open to distend ICA lumen
• Doppler of shunt
• Monitoring must return

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Shunt in L CEA 2014

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Difficult ICA insertion (loop)

Is the Shunt Working?

• Functional
– recovery of EEG or SSEP
• Vascular
– Return of MCAV by TCD
– Ocular plethysmography
– Return of rCBF
– Doppler of shunt

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Doppler Auscultation of Shunt

Plaque removal
• Plane developed at lateral edge
• Feathered edge in ICA
• Sharp dissection in CCA
• Marsupialized in ECA/ opened
PRN
• Tacking sutures in ICA 40% of
cases
• Careful attention to retained
fragments

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Heavily Calcified Carotid

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Clean Break in ICA

Inadequate ICA endpoint

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Placing the Tacking Sutures

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Tacking Down the CCA

#7 - Ensure a widely patent repair


(patch)

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Stay Sutures for Patch 2013

Stay Sutures for Patch 2013

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Stay Sutures for Patch 2013

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Completion of arterial repair

• Small opening in lateral wall


• All vessels back-bled
• Shunt clamped and removed
• Vessel filled while knot thrown
• Clamps released in sequence
• Leaks - pressure, occasional stitch
• Doppler of all vessels

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CML Technique of Shunt Removal

Backbleeding Check

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Stubborn External

235
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Declamping Sequence
(Flushing step)

• External carotid
• Common carotid
• WAIT 10 seconds
• Internal carotid

236
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Poke and Stitch It

237
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Rip-Stop Medial Side 2014

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Rip-Stop x 3

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Doppler of Completed Repair

Immersion Test for Bleeding

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Wound Closure

• Hemovac placed in carotid sheath


• Sheath closed with 3-0 vicryl
• Platysma closed with 3-0 vicryl
• Skin stapled or running 4-0 vicryl
• No reversal of heparin

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Let’s Talk about


Complications

Complications in CEA

• Principle – the surgery should


benefit the patient!
• Small risks are inevitable
• There should be no doubt that
benefits exceed risks…..

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The things I worry about…

• Medical complications
• Cranial nerve injuries
• Stroke
• Wound problems, residual stenosis,
and vessel integrity

The things I worry about…

• Medical complications
• Cranial nerve injuries
• Stroke
• Wound problems, residual stenosis,
and vessel integrity

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Complications - Medical

• Choose the right patient


• Do the proper preop workup
• Have a skilled anesthetist
• Use the ICU postop

Complications - Medical

• Chose the right patient


• Do the proper preop workup
• Have a skilled anesthetist
• Use the ICU postop

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Dysautoregulated
Hypertensive
Patient on
Heparin Postop

The things I worry about…

• Medical complications
• Cranial nerve injuries
• Stroke
• Wound problems, residual stenosis,
and vessel integrity

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Complications – Nerve Injury

• Understand the anatomy


• Work through windows
• Minimize retractor injury
• Fast and slow
• Keep the field dry

Fixed
Retractors,
the old way

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N.B. - Fish-
hooks, the
new way

Lone Star +

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The things I worry about…

• Medical complications
• Cranial nerve injuries
• Stroke
• Wound problems, residual stenosis,
and vessel integrity

Why would someone have a stroke?

• There’s not enough blood flow


• A piece of debris or air goes to the
brain
• The vessel occludes postop

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Complications - Stroke

• Protect the ICA at all times


• Maintain critical perfusion
• Assure short and long term patency

What would you do?

Monitoring
changes 43
minutes in
while sewing
up the lateral
wall of the
repair….

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1 2

Red =
Baselin
3
e

Complications - Stroke

• Protect the ICA at all times


• Maintain critical perfusion
• Assure short and long term patency

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Assure Patency

• Universal Patch Graft


• Short and Long Term occlusion rate -
Zero

The things I worry about…

• Medical complications
• Cranial nerve injuries
• Stroke
• Wound problems, residual stenosis,
and vessel integrity

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JD0229406

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Neck mass 2 weeks post CEA

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Neck Mass 5 days postop

Copy me to hi-risk when done

Pseudoaneurysm 4 years post CEA

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Trust Your Instincts


Postop!

Strive for continuous self-improvement!

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Loftus - Conventional and


Hemashield Patch Angioplasty
• 1110 cases
• Symptomatic 89%, asymptomatic 11%
• Shunt rate (EEG) 15.7%
• All stroke 1.8%
– major 0.72%
• Mortality 0.4%
– myocardial infarct 1
– ARDS 1
• Wound hematoma 0.4%

Many thanks for your attention!

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Closed Head Injury


Concussion
Head Injury in Sports

Ian F. Dunn, MD
Associate Professor of Neurosurgery
Department of Neurosurgery
Brigham and Women’s Hospital
Boston, MA

Disclosure Statement

Reports no commercial interest

258
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Outline
• Epidemiology

• Definition of TBI
• Assessment

• Management principles and considerations

• Concussion

• Head injury in sports

TBI
• Who gets it?

TBI:
– Young men, age 15 – 20s (MVAs) and those older than
65 (falls)
– 1.7million TBIs; >75% mild; about 10% severe
– 52,000 deaths/year

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Epidemiology
• The numbers:
• 2 million people per year (1% of all injuries presenting to ER)
• 250,000 hospitalized per year
• 75,000 die
• 50% of trauma deaths

• Who’s at risk:
• men
• 2 peaks: 15-30yo, >75yo. Mortality also highest in these groups.

• Mechanism of injury:
• MVA: most common cause of TBI (about 50%)
• Firearms: account for largest proportion of deaths from TBI nationwide
• Age:
• Young and elderly: falls are most common cause of TBI

Closed head injury Penetrating head injury

Contact:
Epidural hematoma*
Subdural hematoma*
Skull fracture
Coup contusion

Inertial injuries:
Translational acceleration:
Contracoup contusion
Intracerebral hematoma
Subdural hematoma
Rotational acceleration (+ angular)
Concussion
Diffuse Axonal Injury (DAI)*
Subarachnoid hemorrhage (SAH)*
Intraventricular hemorrhage (IVH)
Gliding contusion
Tissue tear hemorrhage

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Epidural/subdural
Epidural
hematomas
Subdural

• EPIdural space • SUBdural space


• 9% severe head injuries • 30% severe head injuries
• rupture of MMA (80%);
90% associated with skull • rupture of bridging veins;
fx associated DAI
• classic “lucid” interval isn’t • presentation likely due to
so classic—12-25%
• Watch very closely in ED high ICP/associated
with serial neurological injuries—no “lucid interval”
exams • Evacuate:
• Evacuate: – high ICP
–high ICP
– neurologic signs
–neurologic signs
–midline shift on CT (>5mm!) – midline shift on CT (>5mm!)
• Mortality: 10%
• Mortality: 40-90%

Orrison, W. Neuroimaging

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Closed head injury: Contact and


inertial
EDH SDH

Rotational Acceleration Injury Spectrum


Concussion

Tissue tear contusion


Gliding contusion

Marion, DW. Traumatic Brain Injury.

Diffuse Axonal Injury (DAI)

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Diffuse Axonal Injury (DAI)


• Prolonged post-traumatic coma that is not due to mass lesion/CVA

• Caused by: Angular acceleration +/- contact force


• Centripetal nature of the rotational force correlation with depth of injury

• Injury:
• Differences in density between gray/white matter
• Not just axonal!
• MICROscopic findings are pathognomonic
• CT may dramatically underestimate injury—look for small hemorrhagic foci. MRI may
show more due to edema collection.

• Presentation: LOC on impact contrast with traumatic mass lesion


• Comatose. Posturing (decorticate/decerebrate).

• Prognosis: can be devastating.


• “6 month window”

Diffuse Axonal Injury (DAI): Radiology

•classically underestimates extent of neurological injury


•maybe: evidence of high ICP; small punctate hemorrhage; IVH.

Gean, A. Imaging of Head Trauma. Image: www.usushs.edu.

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Gean, A. Imaging of Head Trauma. Image: www.usushs.edu.

29M GCS 5T s/p MVA

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ICP rises while closing

Contralateral EDH

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Closed head injury: contact or inertial


Intracerebral hematoma: classic contracoup

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Glasgow Coma Scale 14-15: MILD head injury


9-13: MODERATE head injury
Eye Opening <9: SEVERE head injury
Spontaneous (4)
To speech (3)
To pain (2)
Not open (1)
Verbal Response Mortality
Conversant (5) 3: 100%
Confused (4) 4: 80%
Nonsense (3)
5: 70%
Sounds (2)
Silence (1) 6: 50%
Motor Response 7: 30%
To command (6) 8: 20%
To pain 9-13: 15%
Localizing (5) 14-15: 0
Withdrawal (4)
Arm flexion (3)
Arm extension (2)
No response (1) Teasdale G, Jennett B. Assessment of coma and impaired
consciousness. A practical scale. Lancet 1974;2:81-4.

Management Goals

Treat primary injury

Prevent secondary injury

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Traumatic brain injury

• Primary injury
– The direct injury

• Secondary injury: pathophysiology after


primary injury.
– edema, hypoxia, hypotension
– non-operative management centers around
limiting secondary injury

Management I: Mild Head Injury (GCS 14-15)

•History: mechanism; time of injury; ?LOC; ?amnesia;


H/A; seizures
•Physical: general + neuro
•Imaging: C-spine if indicated; CT
•BAL/urine tox

Observe/Admit Discharge
•Abnormal CT •If doesn’t meet any of admission criteria
•Penetrating injury •“Return to ED STAT if....” be thorough
•LOC/declining MS •F/U in clinic
•EtOH/drugs
•Skull fx
•Amnesia
•Distracting injuries
•Social factors

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Management II: Moderate Head Injury (GCS 9-13)

• Like Mild, but: Admit and CT.

• Re-CT if condition changes

• D/c when appropriate (90%)

• If patient deteriorates (10%): manage as if


severe head injury

Management III: Severe Head Injury (GCS 3-8)

ATLS Trauma evaluation

Intubation
Fluid Resuscitation: LR/NS
Ventilation (PaCO2 = 35-40mmHg)
O2
Sedation +/- pharmacologic paralysis

Herniation? +/- Hyperventilation


Deterioration? +/- Mannitol (1mg/kg IV bolus)

Head CT

ICU
SAH Surgical lesion OR Monitor ICP
Treat IC HTN

Nimodipine: 60mg
q4hrs x 21 days

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Severe TBI: ICP and CPP guidelines

CPP >70mmHg Key stats:


Insert ICP monitor
1. ICP never <20mmHg: 90% mortality
2. CPP <60mmHg: 95-100% mortality
IC HTN?

YES NO Great! OR if surgical


lesion
CSF Drainage

IC HTN? RepeatHead CT

YES
Last resort
Hyperventilate to
PCO2 =30-35mmHg
High dose barbiturates (pentobarbital):
Loading: 10mg/kg over 30 min
IC HTN? 5mg/kg every hour x 3 doses
YES Maintenance: 1mg/kg/hr

+/- Mannitol (0.25-1mg/kg IV bolus)


+/- Lasix 0.3-0.5mg/kg IC HTN? YES

Cornerstones of Severe TBI Management

Recognition of Mass Lesions


Prompt detection
Evacuation

Cerebral Perfusion ICP Management


CPP management Head Positioning
Adequate Oxygenation Sedation/Neuromuscular blockade
Avoidance of Hypotension/Hypoxia CSF drainage
Neuroprotective Strategies Osmotherapy
Barbiturates
Decompressive Craniectomy
Hyperventilation

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Cornerstones of Severe TBI Management

Primary Recognition of Mass Lesions


Prompt detection
Evacuation

Secondary Cerebral Perfusion ICP Management


CPP management Head Positioning
Adequate Oxygenation Sedation/Neuromuscular blockade
Avoidance of Hypotension/Hypoxia CSF drainage
Neuroprotective Strategies Osmotherapy
Barbiturates
Decompressive Craniectomy
Hyperventilation

After dealing with primary injury, goal is to avoid ischemia


by maintaining cerebral perfusion and controlling ICP

Intracranial Pressure Physiology


Quantitative Breakdown

Intracranial Compartment
1,500 ml

Blood (10%) Brain (80%) CSF(10%)


150 ml 120-140 ml

Venous Arterial Ventricular Cranial SA/Cysterns Spinal SA


60-70% 30-40% 40 ml 50-70 ml 30 ml

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ICP-Volume Relationship

ICP

Intracranial reserve exhausted

Imminent
Compensated state herniation

Volume

Elevated ICP: 2 main sequelae

•Herniation of brain structures leading to compression of


brain/nerves/vessels
symptoms follow accordingly

•Decreased Cerebral Perfusion Pressure (CPP)


brain ischemia

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Intracranial Pressure: Herniation

1. Cingulate herniation

2. Uncal herniation

Falx cerebri 3. Central herniation

4. Tonsilar herniation

5. Extracranial

Tentorium cerebelli Foramen magnum

Narayan, R. Neurotrauma.

Ipsilateral blown pupil

Contralateral hemiplegia

III III Ipsilateral hemiplegia

Uncus Uncus Impaired vision

CP CP
Obtundation coma
PCA PCA

Decorticate (bad) Decerebrate


(worse)

RULE OF THUMB:
mass lesion is ipsilateral to dilated
pupil

Images: www.utah.edu: Webpath

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ICP monitoring: Bolt? Drain?


• Why: maintain cerebral perfusion and limit
secondary injury while brain recovers by
monitoring and treating intracranial
hypertension

• Formal guidelines:
– Monitor ICP if GCS 3-8 with abnormal CT OR
– Normal CT and age > 40, posturing, SBP < 90

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Ventriculostomy Anatomy
nasion

10cm

tragus
1-2cm
3cm

Coronal suture
Midline

Mid-pupillary line

Line to ipsilateral medial canthus

Inter-tragal line

ICP control
Elevate head of bed to 30 degrees; head in neutral position;
avoid cervical venous compression

Maintain normocapnia (pCO2 goal 35-40mmHg)

Adequate sedation (eg, Propofol, Morphine, Fentanyl, Versed)

CSF drainage by ventriculostomy

Osmotherapy (Mannitol, Hypertonic Saline)

Neuromuscular paralysis (eg, Atracurium, Vecuronium)

If refractory, consider:

High-dose barbiturate therapy


Hyperventilation (pCO2 goal 30-35mmHg)
Decompressive Hemicraniectomy

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ICP, continued
• ICP control improves outcome
• Highly useful predictor of worsening
underlying surgical pathology
• Can’t measure CPP without measuring ICP

• Management principles:
– Avoid O2 sat < 90, PaO2<60
– Avoid SBP < 90mmHg

• We don’t know exact threshholds or more


precise resuscitative goals
• Best volume expander for the brain?

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Hyperosmolar therapy
• Mannitol: 0.25g/kg – 1g/kg bolus
– “buying time” maneuver vs repeated
administration in the ICU for ICP control
– Rebound effect

• Hypertonic saline (up to 23.4%)


– Pulmonary edema
– No rebound?

Hypothermia?
• There are currently no data to convincingly
suggest that hypothermia improves outcome
in TBI

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CPP-ICP relationship in preserved


autoregulation

Cerebral Perfusion Pressure


• CPP = MAP – ICP
• Critical threshold: 50mmHg
• >70mmHg: significant increase in risk of ARDS
• Current recommendations: CPP 50s-70s, so
we keep 60-70

• Are we really monitoring ischemia?


• PbTiO2, SvjO2

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Sedatives
• Propofol: sedative/hypnotic, rapid
onset/offset of action
– Propofol infusion syndrome: >5mg/kg/h
– Lipemia, metabolic acidosis, etc

Pressure autoregulation

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Normal Physiologic Parameters for the


Brain

PARAMETER RATE
Global CBF ~50 ml/100g/min
CBF (Gray)) ~80 ml/100g/min
CBF (White) ~20 ml/100g/min
CMR oxygen ~3.5 ml/100g/min
CMR glucose ~4.5 ml/100g/min
CBF/CMR oxygen ~15 ml/100g/min
ICP 5-12 mm Hg
Venous PO2 >35 mm Hg

Cerebral Blood Flow (CBF) Thresholds


Ischemic Rate of CBF Neurological
Threshold (ml/100g/min) Manifestations
Normal 50-60. Mean 53 No deficit

First 25-30 Mile-moderate deficit.


Electrical impairment
Second 16-20 Severe deficit.
Electrical failure
Third 10-12 Profound deficit. Pump
failure, cytotoxic
edema
Fourth <10 Impending death.
Metabolic failure

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Intracranial Hypertension: Therapeutic interventions


Ventilation

Hyperventilation:
Intense cerebral vasoconstriction: ischemia
Profound chronic hyperventilation (PCO2 <30
mmHg) contraindicated.
Maintain PCO2 > 35 mmHg

Chronic hyperventilation (PCO2<30)


Requires special monitoring of cerebral ischemia
Only temporary for rapid deterioration

Intracranial Hypertension: Therapeutic interventions


Sedation

• Control Agitation
• Control Ventilation
• Decrease Cerebral Metabolic Rate (CMRO2) and
reduces ischemic threshold

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Intracranial Hypertension: Therapeutic interventions


Fluid Management

Maintain euvolemia
Normal saline
Monitor balance, weight
Avoid:
Dehydration
Free water
Glucose
Hyponatremia

Intracranial Hypertension: Therapeutic interventions


Fluid Management

Use of Mannitol
Mannitol is effective for control of increased ICP in
severe CHI.
Limited data suggests intermittent doses may be
more effective than a continuous infusion
Maintain serum osmol < 320.
AVOID DEHYDRATION

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Intracranial Hypertension: Therapeutic interventions


Fluid Management

Use of Mannitol
One of the few interventions (1 of 6) that achieved the level of use as a
guideline.
There are two Class I studies and one class II studies that support the use of
Mannitol in ICP control.

Intracranial Hypertension: Therapeutic interventions


Fluid Management
Mechanism
1) Immediate plasma expanding effect that
reduces hematocrit, blood viscosity, increases
CBF and cerebral oxygen delivery.
Rheologic effect on ICP most marked with CPP<70
mmHg

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Intracranial Hypertension: Therapeutic interventions


Fluid Management

Mechanism
2) Osmotic effect, delayed for 15-30 minutes
until gradients are established between
plasma and cells.
Reflection coefficient 0.9
(Defined as the ability of BBB to exclude a
compound)

Intracranial Hypertension: Therapeutic interventions


Fluid Management

Mechanism
3) Free radical scavenging,
4) Removal of fluid even from brain tissue in which
the blood-brain barrier is damaged,
5) Reduced volume and rigidity of red blood cells,
6) Compensatory cerebral vasoconstriction in
response to increased cerebral blood flow

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Intracranial Hypertension: Therapeutic interventions


Fluid Management

Mechanism: Precautions
Large continuous levels can cause “opening”
of BBB, where Mannitol and other small
molecules can pass into the interstitium.
Mannitol should be administered as repeated
boluses
Serum osmolality > 320 and hypovolemia
should be avoided, monitor renal function.

Intracranial Hypertension: Therapeutic interventions


Fluid Management

• Hypertonic saline
– Recent interest shows that hypertonic saline is
equivalent to mannitol
– Reflection index of 1.0 in intact BBB.
– Goal to maintain Na+ 145-155 meq
– Non osmotic effects.
– No randomized trials

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Intracranial Hypertension: Therapeutic interventions


Fluid Management

• Initial hyperosmolar treatment in 1919


• Extensive animal research showing benefits in
managing TBI since 1980
• Clinical literature is sparse
– Use in trauma resuscitation
– Case/series reports in TBI
– One prospective study in adults
– Two prospective studies in pediatrics

Intracranial Hypertension: Therapeutic interventions


Fluid Management
Proposed mechanism of action for HTS

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Intracranial Hypertension: Therapeutic interventions


Fluid Management

– Hemodynamic effects
– 1) Improve and maintain MAP
– Plasma volume expansion
– Centrally mediated increases in CO
– 2) Improving CO, brings improvement in CPP and
cerebral oxygen delivery

Intracranial Hypertension: Therapeutic interventions


Fluid Management

– ICP effects
– 1) Ability to dehydrate edematous tissue via
transendothelial gradient
– 2) No osmotic diuretic properties that decrease
circulating volume
– 3) Improvement in restoration of transcellular
cerebral osmolytes by improving cellular
cotransporter systems

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Intracranial Hypertension: Therapeutic interventions


Fluid Management

• Osmolar effects
– Dehydration of brain tissue by creating
transendothelial osmotic gradient

• Reflectance coefficient of 1.0


• (Mannitol 0.9)

– Dehydration of endothelial cells, reducing vascular


resistance

Intracranial Hypertension: Therapeutic interventions


Fluid Management

Immunomodulating effects
1)Decrease leukocyte adherence and migration and
reduce certain prostaglandins and other inflammatory
mediators
2)Increase levels of cortisol and ACTH
3)Reduce neutrophil marginalization and trafficking,
possibly protecting against bacterial infection

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Intracranial Hypertension: Therapeutic interventions


Fluid Management

– Neurochemical effects
– In face of lower Na levels, cell wall polarity is lost
with accumulation of extra cellular excitatory
amino acid, i.e., glutamate.
– HTS reverses these changes and restores cell wall
membrane transport systems.

Intracranial Hypertension: Therapeutic interventions


Fluid Management

Adverse Effects of HTS


• Potential for osmotic demyelinating
syndrome (ODS) or central pontine
myelinolysis (CPM)
• Hyperchloremic metabolic acidosis
• Sever hypernatremia with neurologic
deterioration
• “Opening” of BBB from
hypernatremia/hyperosmolality

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Intracranial Hypertension: Therapeutic interventions


Fluid Management

Adverse Effects of HTS


• Rebound increase ICP, especially in setting of
trauma resuscitation when inadvertent
decrease in osmolality can occur from fluid
administration
• Renal failure
• Diuresis with drop in filling pressures due to
obligate natriuresis from hypernatremia
• Coagulopathy

Intracranial Hypertension: Therapeutic interventions


Hypothermia

• Decrease Cerebral Blood Flow (CBF) coupled with


decrease CMRO2
• Reduces ICP
• Randomized Control Trials
– Failed to show improved outcome in Traumatic Brain Injury
– Other trials are currently ongoing

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Intracranial Hypertension: Therapeutic interventions


Barbituate Coma

• Barbituate coma
– Coupled reduction of CBF/CMRO2 with decrease
ICP
– Significant hemodynamic compromise
– Randomized Controlled Trials show no
improvement in outcome

Intracranial Hypertension: Therapeutic interventions


Decompressive Hemicraniectomy

• Generalized cerebral edema not responding to


medical management
• Consider prior to barbituate coma

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Intracranial Hypertension: Therapeutic interventions


Decompressive Hemicraniectomy
ICP<25 mmHg CPP>60 mmHg

• Stage I • Stage III


– Propofol, fentanyl, atracurium – Inotropes / 5% NaCl /
– 10-15 º head up Mannitol
– PaCO2 4.5-5.0 kPa – PaCO2 4.0 kPa
– SaO2 >97%, PaO2 >11kPa – Temp 35 °C
– Temp < 37 ºC
• Stage IV
• Stage II – Temp 33-34 ºC
– External ventricular drain
• Stage V
– Thiopentone
– Decompressive craniectomy

Intracranial Hypertension: Therapeutic interventions


Decompressive Hemicraniectomy– DECRA

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Standard “trauma flap”

Principles:
• Reverse question mark incision for hemispheric access--muscle
taken anteriorly

• Low temporal decompression to preserve midbrain/PCA

• Maximal decompression while staying away from sagittal sinus and


transverse sinus

• Frontal sinus may be entered anteriorly

Incision

Drawings courtesy of Andrew Rekito, Rekito Visuals

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Sinus proximity

Drawings courtesy of Andrew Rekito, Rekito Visuals

Craniotomy/craniectomy

Drawings courtesy of Andrew Rekito, Rekito Visuals

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Drawings courtesy of Andrew Rekito, Rekito Visuals

Post-craniectomy

Drawings courtesy of Andrew Rekito, Rekito Visuals

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Post-craniectomy

Durotomy
Hematoma evacuation

Some groups do anterior temporal


lobectomy

Duraplasty/Gelatin membrane

Drawings courtesy of Andrew Rekito, Rekito Visuals

Bifrontal

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Initial Grade vs. Outcome


No Intensive Neurological Management
Good/Moderate
GCS Vegetative/Dead
recover

11-15 93% 7%

8-10 59% 41%

3-7 20% 80%

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Initial Grade vs. Outcome


No Intensive Neurological Management
• Patients with a severe head injury and those
with a moderate injury with deterioration
have a 50% chance of poor outcome if they
have no intensive neurological management

• NOTE: Applies to both, patients with operative


and non-operative lesions.

Outcome with or without intensive neurological


management
Without With

Good 31% 56%


recover/Moderate
disability

Severe 19% 10%


Disability/Vegetati
ve
Dead 50% 34%

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Concussion

Head Injury in sports

Defintion

https://myaans.aans.org/en/sitecore/content/MyAANS/Resources/Concussion%20and%20Sports.aspx

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Concussion and sports


1. Why is it hard to predict the clinical course of
a concussion?
2. Do kids fare better or worse than adults after
mild head injuries?
3. What is the role of brain rest?
4. Is neuropsych testing a magic bullet in
diagnosis and management of concussion?
5. Can we prevent concussion and more serious
brain injuries?

Why are these injuries under-reported and ignored?

• There may be no external signs of trauma.


• Coaches, trainers and primary care physicians
may not be completely familiar with the
issues.
• By nature, competitive kids don’t want to be
removed from play.
• There remains a tradition of concussion being
a ‘badge of honor’.

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Specific Considerations in Children vs. Adults


Pediatric Considerations WINNER
Child Adult
Biomechanics -smaller size and strength of athlete means
injury less likely to occur.
-experimental data indicates more force is
required to produce injury in pediatric brain
-however, weaker neck means more force
imparted to head with any given impact

Pathophysiology Pediatric brain seems more susceptible to


swelling once injury does occur (i.e. second
impact syndrome)
Neurobehavioral Immature brain appears more vulnerable to
diffuse injury and recovers more slowly

Environmental Children are still learning. Their brains are


issues required to be more plastic and acquire new
knowledge.

Vulnerability of the Developing Brain


• Concussive injuries seem to have much more
effect on the development of future skills than
they do on already established skills.
• Overall, pediatric patients, by nature of their
immature and developing brain, are more
vulnerable to concussion and should be
treated more conservatively.

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Epidemiology of sports-related concussion

• Recreation sports
– Alpine Skiing
– Cycling
– Equestrian
• Organized Sports
– Football
– Boxing
– Ice hockey
– Rugby
– Soccer

Distribution of sports-related MTBI in athletes

• MTBI represented 5.5-9% of sports related injuries in


teenagers. This extrapolates to at least 62,816 cases of
MTBI annually among high school varsity athletes.
– Football 63% Soccer 11.9%
– Wrestling 10.5% Basketball 9.4%
• Most injuries due to collision.
• Risk generally escalates with age (with the exception of
baseball and golf)
• 6 / 1219 cases represented intracranial hemorrhage
*Powell J, Barber-Foss KD. Traumatic Brain Injury in High School Athletes. JAMA 282:10,
1999.

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What is the role of the physician in sports-


related head injury?
ACUTE SUBACUTE CHRONIC

Identify
immediate Prevent
neurologic catastrophic
emergency Prevent
outcome from
permanent
second impact
brain injury
syndrome
from repeat
concussions

Spectrum of Concussion
• 80-90% of concussions resolve spontaneously
over 3-7 days.
• 10% of concussions have prolonged
symptoms.

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Disclaimer:
“managing the athlete with mild
traumatic brain injury may be more
of an art than a science”

Maroon JC, Lovell MR, Norwig J, Podell K, Powell, JW, Hartle R.


Cerebral concussion in athletes: Evaluation and neuropsychological
testing. Neurosurg, 47:3: 659-672, 2000.

Role of Imaging
• By definition standard imaging should be
normal (ie. concussion is a physiologic
process).
• Functional imaging studies may play a role in
the future, but not of current practical value.
• If symptoms persist or show focality, CT or
MRI should be obtained to be sure that no
brain injury exists.

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Metabolic markers of concussion

• No biomarker has consistently demonstrated


the ability to predict post-concussive
symptoms, so the results must be assessed
judiciously in conjunction with clinical factors
– S100 Protein
• Most widely studied, but results are variable
– Neuro-specific enolase (NSE)
– Cleaved tau protein (CTP)

Concussion Grading Scales

• Over 35 scales have been published since 1973 to


grade concussion. Most scales define 3 grades of
concussion severity, but vary widely in the
definitions and the criteria for return to play.

• No current scale is universally appropriate.


Clinical judgment is still crucial.

• Grading concussions is falling out of favor, as it


imparts a severity of injury at the onset.

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Brain Rest
• Key component of management
– Cognitive rest during symptomatic period
• Medications should be avoided, except to
treat headache
• Consider referral to specialist for prolonged
symptoms.

– Brown NJ, Mannix RC, O'Brien MJ, Gostine D, Collins MW, Meehan WP 3rd. Effect of cognitive
activity level on duration of post-concussion symptoms. Pediatrics. 2014 Feb;133(2)

Role of neuropsychological testing


• Neuropsychological testing seems to provide a
sensitive guide to ongoing and possibly
cumulative problems after athletic MTBI.
• Preseason baseline evaluation is helpful, but not
essential, to assess any potential deficits after
concussion.
• Computerized screening tests have an
expanding role in the management algorithm
for athletes, especially those with prolonged
concussion symptoms, and especially in
teenagers.

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Sports concussion
Graded Exertion Protocol

Exercise Goal
1. No activity –complete rest 1. recovery
2. Light aerobic exercise 2. Increase HR
3. Sport-specific training 3. Add movement
4. Non-contact training drills (may 4. Exercise +
start resistance training) coordination +
5. Full contact practice after thinking
medical clearance
6. Return to play

24 hours per step


If there is recurrence of symptoms at any stage, return to step 1

Athlete with sports concussion

Are there
any indications YES
Initial medical assessment
for neurosurgical
intervention?

Have the symptoms or signs been NO


present for more than 7 days? Acute
neurosurgical
consult
YES NO

Are the symptoms


Consider neuroimaging YES present at rest?
Rest for
48 hours NO
& reassess YES
YES Are the symptoms Are the symptoms
present at rest or after exercise? present after exercise ?
NO NO
YES
IS NP assessment normal? Medical clearance

NO

Sports Stepwise
concussion return to
specialist sport

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Prevention

• Head injury is the leading cause of death and


disability in children.

• CDC estimates:
– 475,000 pediatric TBI occur annually
– 2% of Americans have sequelae of TBI.

What are the obstacles to injury


prevention?

Injury prevention is undervalued in our society

• Poorly funded

• Underappreciated

• Lack of understanding regarding modifiable risk factors

• Difficult to evaluate effectiveness of an intervention

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Many simple but effective preventive measures are


still under-utilized or improperly utilized

Hit Counts
• Does limiting hits to the head prevent long
term problems?

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Pitch Counts

105

Which is More Important?

VS

106

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Reduce Hitting in Practice

game Key Takeaway


We can reduce total brain
trauma by >50% if we
restricted hitting in
practice

Practice

Reduce Hits in Practice


• Football:
– Reduce hitting in practice
• Hitting in practice is not correlated to team success
– Many Youth football programs have virtually eliminated
hitting in practice
• >50% reduction in concussions
• >50% reduction in total brain trauma
• Reduction in overall injuries

• Soccer
– Limit headers, especially for younger players

108

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Rules Changes

Players in U-11 programs and younger shall not


engage in heading, either in practices or in
games.

• Ivy League Limiting Full Contact Practices

What have we done as


neurosurgeons?

• “Clear and visible leadership in the interests of


the public’s health is regarded by many as the
best way for the medical profession to regain
and retain the public trust that has diminished
in recent decades.”
Wynia, et. al. NEJM, 341:21, 1999

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Sports concussions and second impact


syndrome

Second Impact Syndrome

• A catastrophic brain injury which occurs when an


athlete sustains a second head injury before the
symptoms of a prior head injury have cleared.
Thought to be due to loss of autoregulation of
cerebral vasculature.
Saunders RL, Harbaugh RE. Second impact in catastrophic contact sports head
trauma. JAMA252:538, 1984.
• Described in multiple sports, including football,
hockey and skiing.
• Second injury may appear quite mild, but athlete
rapidly loses consciousness, with herniation and
respiratory arrest. Mortality 50%, morbidity 100%.

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Resources
• State laws and education programs
• CDC
– Head’s Up Program
• Online training module
• ACE “acute concussion evaluation” worksheets
• Consensus Conferences
– Publications and forms are widely available.
– “Consensus statement on concussion in sport: the 4th
International Conference on Concussion in Sport held
in Zurich, November 2012”

2012 Zurich Consensus conference

• A standardized method for evaluating an


athlete who has suffered a concussion
• Includes
– SAC (Standardized Assessment of Concussion)
– Symptom score and GCS
– Physical, balance and coordination scores
– Maddock Score

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Pediatric Concussions
• No athlete should be allowed to return
to play while still experiencing signs or
symptoms of a concussion.
• Clinical judgment and graded return to
play criteria are important, but
increasingly science is adding objective
criteria for return to play.
• Concussion prevention must come on
several levels, including science,
education, legislation, and advocacy and
commitment by the medical profession.

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Skull Base Trauma:


Frontal, Sphenoid and Paranasal Sinus
Injury

Rocco A. Armonda, MD
MedStar-Washington Hospital Center &
Georgetown University Hospital
Washington, DC

Disclosure Statement
• Reports no commercial interest

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Mechanism of Trauma
• Blunt
– MVA
• Penetrating
• Blast
– Blunt/Blast Wave/Fragments
• Iatrogenic
– Transphenoidal
– Skull Base Tumor Surgery

Management Algorithm
• Decompress The Brain!
• Stop The Bleeding!
• Restore Anatomic Continuity
• Water-tight Dural Closure
• Frontal Sinus Management and Skull Base
Foundation Re-establish/Orbital Bando to
allow further reconstruction

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T-Bar Incision

Subtemporal
Decompression

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Management Algorithms

Anterior and Lateral Pericranial


Flaps

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Case Presentation
• 25 yo Soldier Struck by roadside explosive
on the passenger side.
• Initially following commands, left side
paretic, intubated for transport
• Right Pupil Traumatic Dilation, with
Suspected Globe Injury
• Open Depressed Contaminated Scalp
Wound

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Roadside Explosive:
Passenger Side Beneath Kevlar

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What is the best treatment?


1.Superficial Debride, Close Scalp, Place a
Monitor/Ventric on the Left?
2.Right Decompressive Craniectomy, with
Right Enucleation?
3.Extended Bicoronal Incision for Right
Hemicraniectomy, Frontal Sinus Exeneration,
Orbital Bando and Orbit Reconstruction?
4.Staged Right Decompression, return for
frontal sinus exeneration, orbit reconstruction,
place left ventric?

Increased ICP, CSF Leak,


Febrile

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3D Reconstructions

Entry Wound

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Maxillofacial Fixation

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Orbit-Reconstruction

Obital Roof-Split Thickness


Bone from Cranial Vault

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Closing the Orbital-bando


Defect

• Identified/Quantifie
s Best Tailored
Surgical Approach
• Based on the
Nasofrontal
Outflow Tract
Plastics and Reconstructive Surgery,
Vol122:1850,2008

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Frontal Sinus Fracture


• Displaced • Nasofrontal
• Nasofrontal Duct Outflow Tract
Injury Disruption
• Cosmetic – Gross Outflow
Tract Obliteration
Deformity
– Frontal Sinus Floor
• CSF Leak Fracture
– Anterior Table-
Medial Wall
Fracture

Frontal Sinus Injury:


Techniques and Complications
• Observation • Obliteration
– Non-displaced, – Burring of Wall of
NFOT intact sinus to Remove
• Reconstruction Mucosa
Invagination
– Duct Mucosa
Preservation – Plugging the
Nasofrontal Duct
– Anterior Wall
Reconstruction – Fill Sinus Cavity

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Frontal Sinus Injury:


Techniques and Complications
• Ablation • Cranialization
– (Exenteration) – Remove Posterior
– Remove Mucosa Table
– Plug the Duct – Burring Mucosa after
stripping especially
– Reidel Procedure Along the diploic veins
• Remove Supra- of Breschet
orbital Rims – Remove the NFOT
– Delayed – Remove the Mucosa
Reconstruction
– Erradicated the Frontal
– Cosmetically Poor Sinus, Incorporated
into the anterior
Cranial Fossa

Frontal Sinus Injury:


Techniques and Complications
• Ablation/Cranializat • Fat Obliteration
ion with
– 9-10% Osteoneogenisis
Complication Rate – Strip Walls of
Mucosa
– Cavity is Preserved
– Ducts Sealed
– 22-42.9%
Complication Rate

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Clinical History
• L hemispheric decompressive craniectomy
• Frontal craniotomy- anterior skull base
mesh/pericranial flap
• Failed cranioplasty X2
– Bone
– PMMA
• CSF leak/ fungal meningitis

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Operative Plan
• Frontal craniotomy/ central bandeau
• Mesh removal
• Obliterate sinuses
• Bone graft reconstruction-anterior cranial
fossa
• Interpose vascularized tissue
– Free flap

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Mesh

Pericranial flap

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Nasofrontal ducts

Cranial bone grafts

ALT Adipofacial Free Flap

Pedicle

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Anterior
ALT flap

Posterior

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Penetrating Frontal Trauma:


GSW Submental through Frontal Sinus
• Open Communication from beneath the
Jaw to the Anterior Cranial Fossa and
Forehead
• Vision Spared
• Emergent Tracheostomy
• Damage Control Cranial Decompression
– Bifrontal Decompressive Craniectomy
– No Repair to Skull Base
– No Frontal Sinus Exeneration

Path Through Hard Palate


Entry Wound

Fragment Path Molded Tract Exit Wound Midline Forehead

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Extent of Bifrontal
Decompression

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BLAST OVERPRESSURE:
EXPANSILE SKULL BASE
FRACTURE

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GSW: Management
• Cerebral Angiogram Assess
Neurovascular Structures
– ICAs, ACA, Venous Sinus
• Combined Neurosurgery/OMFS
Reconstruction
• Frontal Sinus Exeneration
• Skull Base/Orbital Bando Reconstruction
• Dural Repair/Re-inforcement
• OMFS Mandible/Palate Repair

Delayed Complications
• Pneumocephalus
– CSF Leak
• Endoscopic Repair
– Delayed CSF Infection
– Low-Pressure Hydrocephalus
• Skull Base Sealed Second Intracranial
Procedure
• Delayed Bifrontal Cranioplasty 6 months

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Skull Base Fractures and


Vascular Injuries
• Barrow Neurologic Institute (Feiz-Erfan et
al, JNS 107; 364-369,2007)
– 71 Patients with Skull Base Injury and
Neurovascular Imaging
– CTA, MRA, Cerebral Angiography of
Head/Cranio-cervical Junction
– 9/71 (8.5%) With Neurovascular Injuries

Skull Base Fractures and


Vascular Injuries
• Barrow Neurologic Institute (Feiz-Erfan et
al, JNS 107; 364-369,2007)
– Fractures of the Clivus Injuries Most Likely to
Result in Neurovascular Injuries (0.001)
• Majority AVF, Difficult to Identify on CTA best Seen
on DSA
– Fractures of the Sella-Turcica Sphenoid
Sinus Complex High Assoication with
Neurovascular Injury (0.07)

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ENTRY ENTRY

Spherical Ball Bearing PBI Through Maxillary, Ethmoid


and Sphenoid Sinus with Fracture of the Lateral Sinus
Wall and Clivus and Tear of Carotid

Pre-Cavernous Aneurysm
Projecting into Sphenoid
Sinus: Massive Epistaxis

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Neck Remnant:
Reangio/Retreat 4-6 weeks

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Initial CT:GCS4

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5 minutes Later

Post-ICA Occlusion:
Hemicraniectomy

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Conclusions
• Assess Risk for Neurovascular Injury
– DSA may be more Diagnostic than CTA/MRA
• Decompress the CNS
– Brainstem
– Optic Nerve (Anterior Skull Base; Early)
– Facial Nerve (Lateral Skull Base)
• Restore Anatomic Continuity/Separation
with Dural Repair
– Avoids Delayed CSF Leak, Infection,
Encephalocele

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The Management of Subdural


Hematomas
Rocco A. Armonda, MD
MedStar Washington Hospital Center
and Georgetown University Hospital
Washington, DC

Case Presentation
• 58 yo male assaulted at a nightclub several
hours earlier found confused agitated.
• No Medical History, Unknown Meds
• Intubated, Not Following Commands
• Left Hemiparasis, Pupils Asymmetric R>L,
Localizes with Right UE withdraws R LE
• HTN 170/90
• Stat CT Obtained

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Brainstem Compression & Shift

Treatment Decision Points


• 1. Plan Right FTP Craniotomy with ICP
monitor?
• 2. Prepare Right FTP Hemicraniectomy
with/without ICP, Pb02 Monitor?
• 3. ICP Monitor medical therapy in ICU.

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Unknown?
• 1. Coagulation Status and Meds?
• 2. How long since injury?
• 3. Associated Injuries (ie Cspine,
Abdomen,Occult Vascular Injury)?
• 4. What is his best expected outcome?

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What is the likely outcome?


• Timing to Surgery?
• Primary Injury?
• Associated Hypoxia/Hypotension?
• Delayed increased ICP?
• Age, Co-morbidities, Occult Injuries…

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Post-Op Coronal CT

Acute SDH
• 1. In General ASDH worse prognosis than EDH

• 2. Outcome not related to ASDH size but to


underlying brain injury.

• 3. GCS, Cisterns, Shift more predictive of


underlying brain injury than ASDH.

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Spectrum of Injury
• Chronic SDH(After 20 days)
– Older, Brain Atrophy, Anticoagulation, Minor
Trauma, Slow Onset of Symptoms…
• Subacute SDH (4-20 days)
– Usually within a 2-3 week history of minor
trauma, anticoagulation (ASA vs Anticoagulation).
• ASDH (3 days of Trauma)
– Severe Trauma, Significant Underlying Brain Injury
Possible, Diffuse Brain Swelling may be delayed.

8-58/100K >65
3.4/100K<65

7.24/100K US Pop

79.6/100K in VA pop

10.35/100k Japan

SDH for VA Population:


121.4/100K by 2030

17.1/100K Gen US by 2030


Increase from 12 to 20% in cSDH

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Chronic SDH
• Risk Factors
– Age >65
– Hx of Fall
– Anticoagulation
• Warfarin 42.5 X Higher
• Those Anticoagulated
– 750K Acute Coronary Syndromes
– 2.4 Million with Atrial Fibrillation (Increased SDH
Risk)

cSDH: Etiology
• Trauma?
• Neovascular Membranes + More Friable
Subdural Bridging Veins
• Increased Brain Atrophy + Anticoagulation Use
• Alcohol Contributes: Brain Atrophy and
Coagulopathy, Estrogen More Ectatic Blood
Vessels

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Recurrence Rate/Treatments
• Up to 33.3%
• Neovascular Membrance
– High Vascular Endothelia Growth Factor (VEGF)
• Use of ACE-Inhibitors to decrease Recurrence
– Lower VEGF (Vascular Endothelia Growth Factor)
– 5% Recurrence vs 18%
– NNT 8 to see a difference
(Weigel et al NS 61:788-793, 2007)

Non-Operative Treatments
• Tranexamic Acid (TRACS Canadian Trial)
– Background Japanese Study: 21pts 100%
resolution at 28-137 days CT every 3 wks.
Kageyama et al JNS 2013: 119; 332-7
– 750 of TXA q day.
– 130 pts
– Radiologic Resolution by 20 weeks
– Excluded pts with Thromboembolic Risks
– If surgery outer-membrane is sampled

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Non-operative Treatment:
Chronic Subdural Hematomas
• Atorvastatin (ATOCH Trial)
• 25% Recurrence with 11-13.5% Mortality
• Background Study: 23 pts Chronic SDH with
Atorvastatin (J of Neurol Sci. 2014; 336 (1-2):
237-42.
• Mechanism Statin Inhibits: VEGF,
Pseudoenvelope Abnomal Blood Vessels,
Inflammatory Reaction Modulator

Best Treatment Chronic SDH


• Large Recent Lit Review World Neurosurgery
(86; 399-418, Feb 2016)
1.Drain vs No Drain
2.Twist Drill vs Burr Hole
3.Flat vs Elevated
4.Frontal vs Parietal Drain
5.ACE-Inhibitor vs Placebo

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Outcomes Treatment:
World NS Review (86:399-418,Feb 2016)
Drain Lower Recurrence (8 vs 22%; 8 NNT)
evidence quality Moderate
Drain Place Frontal (5% vs 20%) Parietal
Recurrence (evidence quality Low)
Small Difference Twist vs Burr Hole
Evidence quality low
HOB Small Difference (30.6% vs 25% overall
complications flat vs upright)

Outcomes Treatment:
World NS Review (86:399-418,Feb 2016)
• Irrigate with Thrombin Solution vs Saline
– 5.6 % vs 25.6% Recurrence (NNT=5)
– Moderate Grade GRADE Evidence
• ACE-Inhibition vs Placebo Post-Drainage (No
Recurrence either group)
• Twist Drill No Irrigation 48 vs 96 hrs Closed
Drain
– 2.9% vs 23.3% General Complications (NNT=5)

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Middle Meningeal Artery


Embolization
• First Reported by Mandai for a Pt with Liver
Cirrhosis (JNS 2000; 93: 686-8)
• Tanaka MMA in 35 pts diffuse dilation of
vascular network=macrocapillary outer
membrane (No Shinkei Geka, ‘98; 26: 339-47)
• Cerebral Angiography Demonstrated
Abnormal Pattern of Dural Vascular Stain
• Capillary like vessels, Small Veins, Small
Arteries penetrate through dural connect to
MMA

When to Restart
Anticoagulation/Antiplatelets?
• Small Study 12 pts
• After 2 wks for Mechanical Heart Valves
– Neurocritical Care 2013; Aug:19(1):90-94.
– Average 14 days Anticoagulation Held; 9 days
postoperative
– Length of Stay 19 days
– No Deaths nor Thromboembolic Events

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When to Restart
Anticoagulation/Antiplatelets? JNS
124; 750-759, 2016
• 479 Pts Chronic SDH 2007-2012 231 prior AT of which 120
Restart AT with Postop Hemorrhage:
– 14.8 % Major Hemorrhage
– 23% Minor Hemorrhage
– 1.67% Thromboembolism

Conclusions
• Those Restart AT lower ICH risk than those not
restart AT (26.9% vs 2.2.%)
• Prior AT more likely to have Postop Recurrence (19 vs
10%)
• Recommendation Restart AT no earlier than 3 days
due to increased risk of Thromboembolic
Complications
• > 75% Restart by 2 weeks, median 52 days.
JNS 124:750-759, 2016

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JNS 124: 750-759,2016

cSDH: Restart AT/AC

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Delayed ICP and Outcome: SDH

What about timing?

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RESCUE ICP >>>>>>RESCUE ASDH

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What about in austere developing


countries?

Improved outcomes DC early


• Lack of advanced neuromonitoring
• All treated <12 hours
• Surgical Criteria:
– Obliterated Basal Cisterns
– Midline Shift >5mm
– Acute SDH >1 cm
– EDH >30cc
– ICH >50cc

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Results: 2009-2013
106 managed under the protocol/inclusion
•Favorable Outcome 66.1% unfavorable 33.9%
– (p=0.0001)
– Mortality 25.4%, 70.1 deaths with Penetrating TBI
•Factor Poor outcome:
– ISS>35.62, SDH at first CT, Absent Cisterns, Non-
reactive pupils at ER arrival.
•ICU Good vs Bad: 13+/-2.7 vs 27 +/-5 (.0002)
•Hospital Stay: 26.6 +/- 6, 48 +/- 13(p=.0001)

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The “Real World”

• 65 yo AA Obese female fell


onto 14 cement steps prior
anticoagulation for afib,
delayed arrive due to ICE
storm.
• Left Pupil dilated, Left
Hemiparasis
• Already engaged in another
emergent craniotomy

Initial CT

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Post-OP CT

T-Bar Incision

387
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Bifrontal Craniectomy:
Without Falx Release

388
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389
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Fall Intoxicated Delayed


Presentation

• Fall Down 14 steps


• Drunken
• Localizing Not Following Commands
• Pupils Symmetric

390
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Day#4

391
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Delayed SDH Evacuation

392
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Post-Decompression

393
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Post-Decompression

Immediate Imaging

394
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395
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396
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Fall Backwards from a Truck: GCS6

397
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Coronal Demonstrated Hemispheric


Shift

Immediate Post-OP

398
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Delayed Post-OP

PRE/POST

399
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Isodense Subacute SDH

Subacute SDH: 74 yo AA male with


Afib on Coumadin

400
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Post-Op Drain

Postop Drain HOB FLat

401
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Delayed Drain Out

402
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404
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Evolution of Role for Hemicraniectomy:


Rescue ICP Trial for SDH

Acute SDH Role for Hemicraniectomy


• 2/3 of Neurosurgical Patients with severe TBI
have Acute SDH
• Miller et al reported 2/3 patients had elevated
ICP after ASDH evacuated (flap in place).
• 50% of Patients with elevated ICP died with
intractable ICP
• Wilberger 40% of 101 comatose patients had
ICP<20, while 43% ICP>45mmhg
uncontrollable (40 vs 95% Mortality)

405
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Emergent “Inpatient” Consult


• 67 yo wm with complex medical/surgical hx
• 1 month s/p ex-lap for diverticulitus, with sepsis,
endocarditus
• Post op Occipital Right Side Small embolic stroke
• Now at 0200am acutely deteriorated,
unresponsive.

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0700 am

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Post OP Day#1

408
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ASDH and ETOH

Agitated then Deteriorated

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Immediate Post-Op:
Pneumocephalus

Pneumocephalus

410
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Post-OP Day 5

411
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Conclusions
• Acute SDH
– Underlying Brain Injury Dictates Outcome
– Early Decompression when Significant Edema
– Correct Coagulopathy
• Chronic SDH
– Rising Number expected
– Use of Drains, Frontal Placed
– Consider Tranexamic Acid (TXA), ACE-Inhibition,
Statin Adjucts drecrease Recurrence
– Consider Thrombin Irrigation decrease Recurrence

412
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Decompressive Craniectomy
for TBI
Jamie S. Ullman, MD, FACS
Associate Professor
Department of Neurosurgery
Hofstra Northwell School of Medicine
New York

Disclosure Statement
Reports no commercial interest

413
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Severe TBI

414
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Severe TBI
Primary Injury
Moment of Impact
Irreversible
Secondary Injury
Anytime thereafter
Especially first 24 hours
Potentially preventable

Severe TBI
Secondary Injury:
ISCHEMIA
State of oxygen deprivation
Anaerobic metabolism
Lactate production
increased in acidity (decreased pH)
Ischemic cascade

415
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Biochemical Changes in
Ischemia
Ischemic Cascade
1. Influx calcium ions
Decreases transmembrane potentials
increases voltage-dependent Ca++ channels
Decreases transmembrane Na+ gradient
Slows outward transport of Ca++
2. Ca++ release from ER due to decrease in ATP
3. Increase EAA release (glutamate)
increased activation of NMDA receptor-gated
Ca++ channels
EAA- excitatory amino acids NMDA- N-methyl-D-Aspartate

Biochemical Changes in
Ischemia
Increased intracellular calcium
Decreases mitochondrial phosphorylation,
decreases ATP production
Increases membrane permeability/breakdown
Phospholipases
Free fatty acids
Arachadonic acid (cyclooxygenase)
Prostaglandins– edema
Lipooxygenase– edema
Thromboxanes– vasoconstriction, platelet aggregation
Cell Death
Apoptosis

416
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Causes of Ischemia in Head


Injury
Decreased perfusion due to elevated ICP
Hemorrhage
Edema
Hypoxia
Hypotension
Especially with concurrent extracranial injury

ICP Monitoring
Allows for early warning for significant
intracranial developments
Flourishing contusions
Increased brain swelling
Complications after surgery
Enables Cerebral Perfusion Pressure
(CPP) measurement
ICP >40 mm Hg associated with poor
outcome

417
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Severe TBI

Attention to maintaining good oxygen


delivery to the brain cells will go a long way
in preventing or minimizing the
SECONDARY injury which can result in
more brain damage than was originally
caused by the primary impact.

Decompressive Craniectomy:
The Past

418
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DC in Head Injury
Controversial

Biphasic use
1960’s-1970’s
1990’s-2000’s+
Era of Doubt:
April 2011+

DC: The Past


Kocher (1901)
“If there is no CSF pressure, but brain
pressure does exist, pressure relief must
be achieved by opening the skull. Relief of
pressure by trephination is clearly indicated
in all cases of brain pressure.”
“In the late stages, the procedure alone will
be of no further use.”

419
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DC Indications
Trauma
Ischemic stroke
High-grade subarachnoid hemorrhage
Venous sinus thrombosis
Malignant brain tumors
Other neurological conditions
eg. encephalitis

Purpose of DC
Cranial Vault
Closed Cavity
Three components
Brain
Blood
CSF

420
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Monro-Kellie Doctrine

From
Rosner

Purpose of DC
Cranial Vault
Three Components
Brain
Evacuate mass lesion, lobar resection, infarct resection
Blood
Vasoconstriction
CSF
Ventricular drainage

Closed Cavity
Take off bone and dura– protect brainstem

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Monro-Kellie Doctrine

Decompressive Craniectomy
Benefits
Has reduced infarct volume in experimental
models
Increase brain perfusion
Preserve/improve penumbral areas
Reduce need for intensive therapy
Pressors in trauma
Hyperosmolar therapy

422
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Decompressive Craniectomy
Types:
Suboccipital
Unilateral frontotemporoparietal
“Hemicraniectomy” 12-15+ cm in AP direction
+/- Anterior temporal lobar resection
Bifrontal
Subtemporal/ temporal
Cushing (1905): 6x8 cm opening
Stellate dural opening

DC in TBI
Kjellberg and Prieto (JNS 34:488-493, 1971)
73 cases (trauma, tumor, hemorrhage,
encephalopathy, pseudotumor) Mass
General
Last resort therapy
Bifrontal craniectomy
Ligated sinus/cut falx
18% (13) survival
12 TBI, 7 bilat fixed pupil
5 excellent, 4 some deficit, self care

423
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DC in TBI
Ransohoff J, et al. Hemicraniectomy in
the management of acute subdural
hematoma JNS 34:70-76, 1971
35 pts with acute SDH, posturing, uni-or bilateral
pupillary dilation
Post op management with normothermia, no
steroids
Mortality: 60% (vs.>90), 50% independent outcome
among survivors (7 of 14)
9 underwent cranioplasty

DC in TBI

Venes, JL and Collins WF. “Bifrontal


decompressive craniectomy in the
management of head trauma.” JNS 42:429-33,
1975
13 pts
Mortality: 31%
Diffuse injury– poor functional outcomes

424
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DC “Career-ending” trials:
Cooper PR, et al., “Hemicraniectomy in the
treatment of acute subdural hematoma: a
reappraisal.” Surg Neurol 5:25-8, 1976.
Additional 50 patients treated since 1971 report
10% total survival rate
4% functional survival rate
“Operation…should be restricted to those
patients…obtunded but without demonstrable
brain stem dysfunction, only to deteriorate
subsequently because of increased hemispheric
edema and/or subdural clot.”

DC “Career-ending” trials
Cooper PR, et al., “Enhancement of
experimental cerebral edema after
decompressive craniectomy: implications in
the management of severe head injuries.”
Neurosurgery 4:296-300, 1979.
Cryogenic lesions in 10 dogs (5 immediate DC, 5
control), injected with Evans blue dye, sacrificed
after 8 hours. All but one hyperventilated <30
DC: better ICP, higher volume of Evans Blue Staining
around lesion (1.96 vs. 0.27 ml)
IVF: Ringers Lactate

425
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DC “Career-ending” trials
Cooper, et al, 1979.
Conclusion: “Massive bony decompression
effectively controls intracranial pressure, but at the
cost of enhanced edema production. The long-
term complications of this are still unknown.”
? Cryogenic lesion, hypotonic fluids

DC “Career-ending” trials
Cooper, et al, 1979: Comment

“Most Neurosurgeons can remember a case when decompression


for brain swelling probably prevented a disastrous clinical
outcome. And many neurosurgeons will continue to
decompress the brain by craniectomy when intracranial
pressure is out of control, despite the observations reported
here by Dr. Cooper and his colleagues… Whether reduced
cerebral perfusion in an intact skull is better than massive
cerebral edema in an open skull is the question. The answer is
not obvious yet.”
--- JT Hoff, MD

426
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“Traditional” Management of
Severe Head Injury
Hyperventilation to PCO2 = 25 mm Hg
Mannitol
Especially in suspected ICH or herniation
Prophylacitc or routine
Maintain osm 300-320
Fluid restriction
Decadron
Strict BP control
HOB 30 degrees

DC in Head Injury
Literature
Paucity of randomized, control trials
Anecdotal evidence in recent literature
indicates that DC has a role in treating
patients with elevated ICP.

427
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DC in Stroke
Malignant Cerebral Edema
15% of MCA infarctions
80% mortality

DC in Stroke
Three European Randomized Trials

DECIMAL
DESTINY
HAMLET

428
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DC in Stroke
DECIMAL (Stroke 38:2506-17, 2007)
Early DEcompressive Craniectomy in
Malignant Middle Cerebral Artery Infarction
France
Age 18-55
38 pts, stopped by Data Monitoring Committee
58% absolute reduction in mortality with DC
Favorable outcome (6 mo and 1 yr f/u)
Surgery: 25% and 50%
Medical: 5.6% and 22.2%

DC in Stroke
DESTINY
DEcompressive Surgery for the Treatment
of Malignant INfarction of the Middle
Cerebral ArterY (Stroke 38:2518-25, 2008)
Germany
32 pts
Mortality: Surgery (12%) Medical (53%)
Functional Outcome (6 mo and 1 yr f/u)
Surgery: 47%
Medical: 27%

429
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DC in Stroke
HAMLET
Hemicraniectomy After Middle Cerebral
Artery Infarction with Life-threatening
Edema Trial (Lancet 8: 326-33, 2009)
Netherlands 64 pts
Med vs Surg: Mortality 59 vs 22%
32 surgery stratified <48 hrs, 48-96 hrs (11 pts)
Mortality: 19% vs 27
Age <51(N=38) vs 51-60(N=26)
Mortality: 38% vs 6%

DC and Stroke
Pooled Data Analysis of three RCT (Lancet
Neurol 6:215-22, 2007)
Favorable outcome (mRS </=4)
75% (surg) vs. 24%; ARR 51%
mRS </=3
43% vs. 21%; ARR 23%
Survival
78% vs. 29%; ARR 50%
Conclusions: DC within 48 hours reduces
mortality and increases functional outcome
(incl those w/aphasia; younger did better)

430
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DC
Stroke vs. TBI
Continuum
Ischemic Stroke
Univariate: infarct/penumbra
TBI
multivariate- heterogeneous
Hemorrhage, structural damage,
ischemia, penumbra
Can results be more definitive?

DC Present times

Mortality Severe TBI


1970’s: 50%
2000’s: 25%
Less in children

Changes in ICU
management Jennett, et al, JNNSPSY, 40:
CT 291-8, 1977
ICP/CPP
Maintain physiological
parameters

431
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DC in TBI
Questions/Criticisms
Are we accomplishing anything with DC?
Are we reducing mortality at the expense of
increasing incidence of severe disability
and vegetative state?

Ideal world: Every severe TBI patient will


return to full functionality and regain their
ability to contribute to society.

Severe TBI

There is no magic
bullet to completely
reverse the effects of
the primary and
secondary effects of
severe TBI in humans.

432
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Severe TBI
Current Armamentarium
ICP monitoring
Oxygen monitoring
Induced normothermia
Hyperosmolar therapy
Barbiturates
Hypothermia
Decompressive Craniectomy

DC in TBI
Guerra, et al (JNS 90:187-96, 1999)
Resurrected DC
57 pts. prospective series, 1977+
Unilateral DC with focality, bifrontal for diffuse
Not section falx and left bone over sinus
Result: 19% mortality; 58% achieved “social
rehabilitation”
Advocated advancing DC early to 2nd tier therapy
Not indicated with irreversible herniation

433
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DC in TBI
Polin et al (NS 41:84-94, 1997)
35 pts with historical control (92) (TCDB)
Bifrontal, diffuse injury without mass lesion
Poor outcome if ICP>40 and no operation
within 48 hours
6.7% favorable vs 60% without above
Medical management (control)
3.8x risk of unfavorable outcome vs DC
Pediatric: 44% favorable vs 29% adult

DC for TBI
Aarabi et al (JNS 104:469-479, 2006)
50 pts retrospective
DC for malignant swelling
49 pts unilateral
Mortality 28%
51% favorable GOS among survivors

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DC for TBI
Taylor, et al. A randomized trial of very early
decompressive craniectomy in children with traumatic
brain injury and sustained intracranial hypertension.
Child’s Nerv Syst 17:154-162, 2001
27 children, medical vs. early DC, diffuse
Surgery: bitemporal craniectomy, no durotomy
Good outcome 54% vs. 14% (med)
ICP reduction greater in DC
9 mm vs. 3.7 mm HG (P = 0.57)

DC in Head Injury
DC and Therapeutic Intensity
Weiner et al. (Neurosurg 66:111-19, 2010)
10 severe TBI pts with BTPO2 monitoring
DC performed mean 2.8 days post admission
ICP immediately reduced (by ave. 7.8mm Hg)
Therapeutic intensity Level reduction correlated
with ICP reduction
Cumulative ischemic burden as measured by
BTPO2 was reduced.
30-day mortality: 10% (40% were GCS 3 on
admit)

435
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DC in Head Injury
DC and Functional Outcome
Williams, et al. (J. Trauma 66:1570-76, 2009)
171 pt underwent DC for severe head injury
Single institution: Memphis
1-6 yr follow-up
32% mortality, 117 survived with 95% f/u
Good Outcome (GOSE): 82% survivors (56% of
all)
Younger age (26 vs. 43 yrs)
Greater change in ICP (pre DC ICP not diff in survivors
vs. non-survivors)

DC in Head Injury
Whitmore, et al (JNS 116:1106-13, 2012)
Is aggressive treatment of TBI [including DC]
cost-effective

More Cost effective than comfort care


Less costly until age 80
Young patients more given decreased long-
term costs.

436
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DC in Head Injury
Cochrane Review, 2006
Literature analysis
Due to lack of randomized, controlled trials, DC
cannot be recommended for routine use in
adults.
Taylor trial lends to conclusion that DC would be
beneficial in pediatric patients with refractory
ICP

DC in Head Injury
Important questions:
At what stage do we perform DC?
At initial operation for mass lesion when swelling
is encountered or anticipated?
As third tier therapy when all other medical
management has failed?
As second-tier therapy when initial measures
(sedation, ventricular drainage, mannitol) not
effective?
Would you rather use hypothermia/barbiturates
first?

437
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DC in TBI
DECRA (NEJM 364:1493-502,2011)
Early Decompressive Craniectomy in
Patients With Severe Traumatic Brain
Injury
155 pts; DC 73 pts, Standard care 82 pts
Pts with diffuse injury

DECRA
Craniectomy (Bifrontal, Standard Care
falx /SSS intact)
ICP >20 x 15 min in 1 hr First Tier: Sedation
Sedation EVD
EVD Normocapnea
Normocapnia Mannitol
mannitol Second Tier:
Hypothermia
Barbiturates
DC permitted >72 hours
(15 pts total, 4 <72 hrs)

438
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DC in TBI
DECRA
DC group higher incidence of fixed pupils
(27% vs 12%)
DC (35 hrs mean to rand.) Standard Care

ICP (after): 14.4 mm Hg ICP: 19 mm Hg (p < 0.001)


Required fewer interventions
ICU LOS: 13 d ICU LOS: 18 d (p < 0.001)
Ventilator: 11 d Ventilator: 15 d (p < 0.001)
Mortality: 19% Mortality: 18%
*Unfavorable: (6 mo) 70% *Unfavorable: 51% (p < 0.02)
* Not significant after adjustment for pupils

DC in TBI
DECRA
Conclusions:
DC decreased ICP and ICU LOS in patients with
ICP refractory to first tier therapy.

DC Resulted in significantly worse outcomes at 6


months (GOSe)

439
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DC in TBI
DECRA
Critique:
1. ICP threshold for DC (a big procedure)
may be too low- often easy to meet
CPP requirements at this level)
2. More bilaterally fixed pupils in DC
group

DECRA (cont)
3. Corrected analysis of pupils showed no
difference in outcome not carried over to
final conclusions
4. Falx not cut, but ICP still significantly
lower
5. When non-DECRA pts in Australia
analyzed:
Mortality: 18.4%
Favorable outcome: 54% (Honeybul JNT 27:1225-
32, 2010)

440
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DC in TBI
DECRA
Take home message:
Bifrontal craniectomy in pts with diffuse injury
likely has no advantage over continued
medical management early in the post-
injury course.

Ho et al,
Continued improvements in pts upon 18 month
f/u (Crit Care Med 39:2495-2500, 2011)

World Neurosurg. 2015 Dec 27. pii: S1878-8750(15)01748-9. doi:


10.1016/j.wneu.2015.12.044. [Epub ahead of print]
Decompressive Craniectomy for Severe Traumatic Brain Injury: A
Systematic Review.
Barthélemy EJ1, Melis M2, Gordon E1, Ullman JS3, Germano I4

CONCLUSIONS:
Our study underscores the importance of continued
international prospective data collection for assessing types
of surgical interventions in addition to DC and their timing in
patients who suffer from severe TBI. Additionally, in
geographical areas with limited access to advanced
medical treatment for severe TBI, DC is of benefit when
performed < 5hr after injury in younger patients with
GCS>5.

441
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DC in TBI
RESCUEicp
Randomised Evaluation of Surgery with
Craniectomy for Uncontrollable Elevation
of Intracranial Pressure
May 2014
43+ Centers
400/400 patients
Analysis is Pending

DC in TBI
RESCUEicp
Inclusion Criteria:
Age 10-65
Abnormal CT
ICP monitoring
ICP > 25 for <1-12 hours
Immediate OR allowed for mass lesion but no
DC

442
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DC in TBI
RESCUE-ASDH
New study: beginning recruitment of patients
and sites.
“Randomization” of pts to craniotomy vs
craniectomy at initial procedure for acute
SDH
All cranis need to be at least 11 cm
N=990
http://rescueasdh.org/

Severe TBI Management


Protocol
Intensive Care Unit
1. ICP monitor
Ventriculostomy
2. BTPO2
3. Normovolemia
4. CPP 50-70 mm Hg
5. Normocapnea
6. Induced normothermia
7. Hypertonic saline infusion Na+ 140-145

443
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Severe TBI Management


Protocol
Intracranial Hypertension (ICP > 20 x 10 min)
1. Improve Sedation (short-acting) (BIS)
2. CT scan
3. Maintain CPP 60-70
Second tier
4. Mannitol boluses, increase HTS
5. Mild hypocapnea (30-35 mm Hg)
6. Mild hypothermia (35-36 Celsius)

Severe TBI Management


Protocol
Intracranial Hypertension (cont.)
7. Consider decompressive
craniectomy/lobectomy
(depending upon CT, this can be moved up in
the chain)

Third Tier
8. Burst Suppression (Barbs, Propofol)
Other therapies:
Moderate Hypothermia

444
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Decompressive Craniectomy
Technical points:
Hemispheric:
Large: Good temporal,
12-15+, 1 cm from
midline
Bifrontal:
Midline bone island vs.
none
Cut falx vs. not

Decompressive Craniectomy
Technical points:
Open dura
Yoon, et al. “Ventricular pressure monitoring
during bilateral decompression with dural
expansion.” (JNS 91:953-9, 1999)
20 pts with brain swelling
50% decrease in ICP after craniectomy
Additional 34.5% decrease in ICP after durotomy
Hinge craniotomy as alternative

445
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Decompressive Craniectomy
Complications
*Subdural hygromas
High shearing forces, diffuse injury more prone
*Hydrocephalus
Mental status deterioration
Focal deficits
“Syndrome of the Trephined”
Headaches, seizures, irritability, psychiatric
symptoms

DC Trauma

446
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DC Trauma

DC Trauma

447
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DC Trauma

DC Trauma

448
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DC Trauma

Hinge Craniotomy
Schmidt, et al
Use of hinge craniotomy for cerebral decompression.
Technical note.
J Neurosurg. 2007 Sep;107(3):678-82.

Kenning et al.
A comparison of hinge craniotomy and decompressive
craniectomy for the treatment of malignant
intracranial hypertension : early clinical and
radiographic analysis
Neurosurg Focus 26 (6): E6 2009

449
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Hinge Craniotomy(plasty)

DC Trauma

450
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The Repair

The Repair

451
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The Repair

The Repair

452
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The Repair

The Repair

453
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The Repair

DC: The Future

454
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DC
Evidence vs Experience
Marrying RCT results and clinical experience
Negative/Equivocal RCT
1. Denial
2. Anger
3. Bargaining
4. Depression
5. Acceptance/Resignation

DC “Career-ending” trials
Cooper, et al, 1979 (2011): Comment

“Most Neurosurgeons can remember a case when decompression


for brain swelling probably prevented a disastrous clinical
outcome. And many neurosurgeons will continue to
decompress the brain by craniectomy when intracranial
pressure is out of control, despite the observations reported
here by Dr. Cooper and his colleagues… Whether reduced
cerebral perfusion in an intact skull is better than massive
cerebral edema in an open skull is the question. The answer is
not obvious yet.”
--- JT Hoff, MD

455
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Cervical Spine Trauma

John H. Chi, MD MPH


Brigham & Women’s Hospital
Harvard Medical School
Boston, MA

Disclosure
Reports no commercial interest

456
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Cervical Spine Trauma:


Introduction

-Evaluation and Assessment


-Classification and Types of Injury

-Management Options

Evaluation and
Assessment

History
Clinical Exam
Radiographic Tests

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Evaluation and
Assessment
Clinical factors
– Age
Younger- occult ligamentous injury?
Older- pre-existing stenosis?
– Co-morbidities
Rheumatoid arthritis
Ankylosing spondylitis increases risk of Chance fracture
– Mechanism of Injury
High speed vs. low speed
Flexion, rotation, axial loading?
Seatbelt?

C-Spine Clearance

Clinical Exam
– Awake, co-operative patient
No Pain, Normal Neurologic
– Cleared, no need for further work up
Pain to palpation or abnormal neurologic
– Imaging required
– Options include Xray and CT

458
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C-Spine Clearance

Clinical Exam
– Awake, non co-operative patient
Cannot rely on exam
Wait for reliable exam
Imaging

C-Spine Clearance

Clinical Exam
– Obtunded/comatose patient
Cannot rely on exam
Imaging required

459
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Evaluation and
Assessment
Radiographic Tests
– Xray
With flexion/extension (dynamic)
Good for awake patients with low index of suspicion for
injury
– CT
Test of Choice for bony evaluation
Completely negative CT can be used to clear C spine
– MRI
Test of Choice for spinal cord compression evaluation
Recommended if CT positive or if CT negative but
neurologic deficit present.

Evaluation and
Assessment
Radiographic Tests
– Xray
Must visualize from Foramen Magnum to C7-
T1 disc space
Flexion/Extension views to assess ligamentous
stability
1-2 mm of physiologic subluxation

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Evaluation and
Assessment
Posterior Spinal Line

Anterior Spinal Line Spinolaminar Line

Facet line

Evaluation and
Assessment
Radiographic Tests
– CT
Will identify majority of injuries
Highly sensitive for fractures
Debate regarding using CT to “clear” spine in
all trauma patients

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Evaluation and
Assessment
Radiographic Tests
– MRI
Increasing use to screen and clear spines,
especially in obtunded patients
High sensitivity to soft tissue/ligamentous
injury

Evaluation and
Assessment
Spinal Injury

Awake,
Awake, co-operative Obtunded/comatose
non co-operative

Clinical exam normal: C-collar:


Abnormal Exam Imaging with CT
C-spine Cleared Re-examine

Abnormal exam
Imaging with CT MRI if abnormal CT
High suspicion

Imaging with CT

Negative CT, with abnormal exam: obtain MRI and flexion/extension Xrays

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Classification and Types


Definition of instability
– Loss of ability of spine to maintain normal
relationship so as to prevent damage to neural
elements, incapacitating pain, or debilitating
deformity under physiologic loading
– In general >3.5 mm translation and >11 deg
angulation per level
– Injuries that cause substantial disruption to
anterior load-bearing ability, posterior tensile
strength, compromise of spinal canal or facet
joint integrity considered unstable.

Classification and Types


3 column model
– Anterior
Anterior half of vertebral body/disc
ALL

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Classification and Types


3 column model
– Middle
Posterior half of vertebral body/disc
PLL
Pedicle

Classification and Types


3 column model
– Posterior
Facet and facet capsule
Spinous process/lamina
Lateral mass
Interspinous ligaments and Ligamentum flavum

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Classification and Types

Upper Cervical (occiput-C2)


– Occipital fracture
– C1/Jeffersons fracture
– C2 pars/Hangmans fracture
– Odontoid/Dens fracture
– C1-2 subluxation

Classification and Types

Lower Cervical (C3-C7)


– Compression fracture
– Burst Fracture
– Facet fracture/dislocation
– Fracture dislocation

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Types of Injuries

Occipital Condyle fracture


– Type I
Non-displaced fracture
Stable- external orthosis
– Type II
– Type III

Types of Injuries
Occipital Condyle fracture
– Type I
– Type II
Same as type I with extension to
foramen magnum
Stable- external orthosis
– Type III

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Types of Injuries
Occipital Condyle fracture
– Type I
– Type II
– Type III
Wedge shaped alar avulsion fracture of condyle
Fragment can be displaced
May be unstable requiring surgery if severe

Types of Injuries
Occipital Cervical Dislocation
– Type I: anterior subluxation of condyle
– Type IIa: vertical distraction Occ-C1 > 2 mm
– Type IIb: vertical distraction C1-C2 > 2 mm
– Type III: posterior dislocation of condyle

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Types of Injuries
Occipital Cervical Dislocation
– All unstable requiring surgery
– I/III may be reduced with LIGHT traction
– Severe injury: may be fatal

Types of Injuries

Atlas Fracture (C1)/Jefferson’s


– Direct axial loading
– Usually no neurological deficit
– Anterior Arch
– Posterior Arch
– Lateral mass

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C1 Jefferson’s fracture

Rule of Spence
>7mm total lateral displacement of C1 lateral
mass on C2 – unstable due to ligament disruption

Occipital Cervical Fusion

For unstable C1 and occipital fractures


For O-C dislocation

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C2 Odontoid/Dens Fractures

Type I

Type II

Type III

Odontoid Fractures

• Type I
• Type II
• Type III

• Type II unstable

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– Odontoid Fracture
MRI imaging is recommended to rule out
disruption of the transverse ligament.
Injury to the transverse ligament is an
unstable injury
Disruption of the transverse ligament is a
contraindication for an anterior odontoid
screw

HALO/collar
Anterior Odontoid screw
– Contraindications
– Use bi-planar C-arm
C1-2 posterior fusion
Transarticular screw

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C1-C2 subluxation
Atlanto axial subluxation (C1-C2)
– Ligamentous injury of transverse ligament
– May avulse medial lateral mass of C1
– Lateral Xray or CT
– MRI evaluation by gradient echo for ligament
integrity

Atlanto axial subluxation (C1-C2)

– Atlanto dental interval


ADI 3-5 mm
– external orthosis vs surgery
ADI >5mm
– Unstable, surgery
Posterior displacement of lateral mass
– Unstable, reduce then surgery

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C1-2 posterior fusion


Transarticular screw

C2/Axis fracture
– Fracture through pars/pedicle of C2
– Rarely causes neurologic deficit
– CT test of choice, no need for flex/ex
– Vertebral artery injury?
CTA

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Traumatic spondylolithesis (Hangman’s)

– Type I
<3mm translation, no angulation
Hyperextension with compression
External orthosis 2-3 months (HALO)

Traumatic spondylolithesis (Hangman’s)

– Type II
>3mm translation, >11 degrees angulation
Hyperextension with axial load and flexion
Goal is to reduce gaps to allow union
HALO or surgery

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Traumatic spondylolithesis (Hangman’s)

– Type III
Consists of Type I fracture with facet
dislocation
Initial flexion-distraction, followed by extension
High rate of neurologic deficits
Surgery for fixation
– C1-C3 posterior fusion or O-C fusion

Types of Sub-axial Injuries


(compression/flexion)
Teardrop
– Anterior chip/corner fractures
– stable
Compression
– Anterior wedge fracture
– Generally stable
Burst
– Anterior/middle column fracture
– Surgery

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Types of Sub-axial Injuries


(distraction/extension)
Facet fractures/dislocations
– Perched/locked facets
Bilateral or unilateral
– Hyperflexion +/- distraction or compression
– Posterior ligament disruption
– Closed reduction with traction
– Surgical stabilization

Facet Injury

Double joint sign


Unilateral locked facet

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3 column fracture dislocation

Highly unstable
Chance –type fracture (DISH/AS)

Unstable C3-7 injuries

ACDF for traumatic disc herniation


ACCF (corpectomy) for burst fractures
Posterior cervical lami/fusion
– Cord compression
– Unstable facet fractures/injuries
– Fracture dislocation
– Burst fractures as adjunct to ACCF

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Landmarks for surgery

C1 lateral mass screws


– Junction of C1 pedicle with lateral mass
– Aim slightly medial and superior

Landmarks for surgery

C2 pedicle/pars screws
Visualize superior and medial borders
– Aim slightly medial and superior

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Landmarks for surgery

Lateral Mass screws


– Midpoint of lateral mass
– Aim up and out

Landmarks for surgery

T1-2 pedicle screws

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Spinal Cord Injury

American Spinal Injury Association


– ASIA A: complete injury
– ASIA B: Incomplete
Sensory function below level present
No motor function below level
– ASIA C: Incomplete
Motor function present below level but <3/5
– ASIA D: Incomplete
Motor function present >3/5 but abnormal
– ASIA E: Normal

Spinal Cord Injury

Steroids and spinal cord injury


– Incomplete Injury <3 hours
Bolus 30 mg/kg methyprednisolone for 15 min
After 45 min, 5.4 mg/kg/hr continuous for 23 h
– Incomplete Injury 3-8 hours
Bolus 30 mg/kg methyprednisolone for 15 min
After 45 min, 5.4 mg/kg/hr continuous for 47 h
– Complete Injury
No steroids

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Spinal Cord Injury

Steroids and spinal cord injury


– Still controversial
– Polytrauma with higher risk of poor
outcome with steroids (visceral injuries)
– Current AANS/CNS guidelines list steroid
administration for SCI as optional.

Thank you!

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Management of Thoracolumbar Spine


Trauma and Stabilization Techniques

Charles A. Sansur, MD, MHSc


Associate Professor of Neurosurgery
Director of Spine Surgery
University of Maryland School of Medicine

Disclosures
• Consultant for DepuySynthes, Medtronic, Stryker,
and Globus

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Maryland Shock Trauma

Thoracolumbar trauma as a public


health problem
• Incidence = ~5100 cases per year
• Prevalence = ~270,000
• Cost of first year = $347,484 – 518,904
• Yearly cost = 42,206 – 68,739
• Lifetime cost = ???

National SCI Database

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Overview Thoracolumbar Fractures


• The thoracolumbar junction is the most
commonly injured portion of the spinal column
• 20-25% of all traumatic fractures in young adults
• >15,000 major thoracolumbar injuries occur per
year in the US
• ~5,000 have neurological deficits

Overview Thoracic Fractures


• Fractures of true (T1 to T10) thoracic spine are
much less common (~9% of fractures)
– Why is this the case?
• 83% of patients with true thoracic fractures have
another major injury
– Head or chest trauma, pelvic or lower limb fractures
are common
• ~75% have neurological deficits

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Why is the T-L Spine Injured?


• T11 to L2 is a transition zone
• Thoracic spine is kyphotic,
immobile and stable
• The lumbar spine is lordotic and
mobile with large vertebrae
• T-L junction subject to rotational
and shear forces during many high
energy injuries

What is Spinal Stability?


• The ability to withstand stress without
progressive deformity or neurological
damage
• The anterior column provides most (80%) of
the axial load bearing while the posterior
column resists torsion and shear (80%)

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Mechanism of Injury
• Most T-L junction injuries are caused by indirect
trauma
• Combinations of flexion, axial load, lateral
compression, rotation, distraction, shear and
extension result in injury
• Loading rate is a critical determinant of type and
severity of injury
• The appearance on radiographic studies is not the
same as the moment of injury

L-1

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Classification of Fractures
• There is no universally agreed upon classification
• We will examine the evolution of a few different
classification schemes.

Classification of Fractures
• An ideal classification would be:
– Simple
– Include vast majority of injuries
– Reflect mechanism of injury
– Correspond to anatomic pathology
– Determine treatment options
– Determine prognosis

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The Column Theory


Anterior Column
3 Columns Posterior Column
– Anterior ½ Vertebral
Body & Annulus – Pedicles
– ALL – Laminae
– Facets
– Ligamentum Flavum
– Inter & Supra Spinous
Middle Column Ligaments
– Posterior ½ Vertebral
Body & Annulus
– PLL

McAfee ’83: 6 types


100 patients
Compression
CT - based
Stable Burst
Unstable Burst
Chance
Flexion - distraction

Fracture - dislocation

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Compression Fracture

Ligamenti
ntact

Canal intact

Stable Burst Fracture

Loss of height
Canal occlusion
Angulation
Comminution
No Posterior
Column Injury

Neuro intact

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Unstable Burst
Fracture
Loss of
Body Height
Posterior
Column
Injury

SCI

Flexion - Distraction
Injury and Chance
Fracture
Posterior
ligament
disruption

+ / - body
fracture

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Fracture Dislocation
Shear &
Translation
Dislocation
Injury to all 3
Columns
High incidence
Globally neuro deficit
unstable

AO Classification
• Introduced by Magerl et al. in 1994
• Based on a ten-year review of 1,445 consecutive
cases at five different institutions.
• Intended to serve as a comprehensive
classification system that could guide treatment

Magerl, Eur Spine J, 1994

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• Vertebral body study


Retrospective compression
of 1445
• A1 Impaction
TL injuries fractures
• A2 Split fractures
• A3 Burst fractures

Anterior & posterior


A element injury w/
rotation
• C1 Type A injuries
w/rotation
B • C2 Type B injuries
w/rotation
• C3 Rotational-shear
Anterior & posterior element injury
injuries
w/distraction
• B1 Posterior ligament
• B2 Posterior osseous
• B3 Anterior
C

AO Classification
• Initial report by Magerl included 53 separate injury
patterns
• Comprehensive, but complex

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Vaccaro, A.R. et al.,


J. Spinal Disorders & Techniques 2005

Thoracolumbar Injury
Classification and Injury Severity
Scale
Three Part Description
Injury Morphology

Integrity of PLC

Neurologic Status

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Point System
Injury Morphology
Select one
Translation /

Compression fx Rotation
Axial, Flexion 1 3
Burst - add 1

Distraction injury
4
•Only one morphologic subgroup is scored when multiple are present (highest one)

Posterior Soft Tissue Point System

Intact 0

PLC
Suspected/
(displaced in tension)
Indeterminant 2
Injured 3
Evaluated by MRI, CT,
Plain X-rays, Exam

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Neurology-Point System

Intact
0
Cauda equina Nerve root
3 2
Cord
And conus medullaris

Incomplete Complete
3
2

TLICS: Clinical Qualifiers


• Turn non-operative case to surgical case and
vice versa
• Local factors
– Open fractures
– Overlying burns
– Inability to brace
– Ankylosing spondylitis / DISH/Metabolic bone disease
– Sternal fracture
– Multiple rib fractures at same or adjacent levels as fracture
– Multiple trauma
– Coronal plane deformity
– Severe closed head injury
– Age
– General Health

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Treatment

• Injuries with 3 points or less = non


operative
• Injuries with 4 points=Nonop vs Op
• Injuries with 5 points or more = surgery

TLICS Algorithm
Identify fracture morphology Assess integrity of PLC
Assign points Assign points

Total TLICS points


Assess Neurological Status 3 or below-non op
Assign points 4 surgical vs. non op
5 or above surgical

Consider Clinical Qualifiers Provide Treatment

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Application of TLICS: Example Case


1- 35yo male fall from ladder, neuro
intact
• Burst Fracture- 2 points
• Neurologically intact- 0
points
• PLC intact- 0 points
Total score- 2 points
Non operative treatment

Application of TLICS: Example Case


2 – 38yo, mva, belted driver,
complete paraplegia
• Burst Fracture- 2 points
• Neuro: complete injury- 2
points
• PLC disrupted- 3 points
Total score – 7 points
Operative treatment

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Validation
• Reliability
– Harrop, J Neurosurgery Spine, 2006
– Forty-eight spine surgeons reviewed 58 clinical
thoracolumbar injury case histories at 3 month intervals
– More than 90% of the surgeons agreed with the
treatment recommendations of TLICS

Classification of injury: AOSpine


• 0-3 = non-
operative
• 4-5 =
surgeons
choice
• 6 or greater
= surgery

N0 = intact
N1 = resolved symptoms
N2 = radiculopathy
N3 = incomplete
N4 = complete
NX = cannot obtain exam Vacarro, 2015

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General Points Regarding


Classification Schemes
• Familiarize yourself with the classification
system used at your institution
• No classification is perfect
• Surgical approach may be based on other factors
such as
• Patient related issues
• Surgeon Preference

5 Treatment Goals

1. Prevent further neurological deterioration


– Promote neurological recovery
2. Stabilize the spine
3. Restore anatomical alignment
4. Facilitate early and active mobilization
5. Minimize pain and deformity

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T-L Injury Options


• Compression Fractures
– Brace or no brace for majority
– May benefit from vertebroplasty or kyphoplasty, but
controversial
• Stable Burst Fractures
– Brace majority
– Surgery (usually posterior) for multilevel or
concomitant injuries

T-L Injury Options


• Unstable Burst Fractures
– Surgery for majority
– Anterior +/- Posterior for neuro-intact or
incomplete
– Posterior for complete
• Chance Fractures
– Surgery for majority (Posterior)
– Percutaneous fixation ideal

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T-L Injury Options


• Flexion-Distraction
– Surgery (Posterior)
– 3600 for severe canal compromise
• Fracture-Dislocation
– Surgery
– Posterior complete injury (multisegmental)
– 3600 for incomplete

Non-operative Treatment
– Non-operative does not always =
conservative treatment
– Only a certain amount of immobilization
can be tolerated.

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Nonoperative Rx for Thoraco-


Lumbar Fx’s :
– Frequent clinic visits and close observation is
required for:
• Posterior ligament disruption
• Neurologic injury
• Morbidly obese
• Multisystem injuries

Surgical Results in Thoracolumbar Burst


Fractures
• Studies comparing anterior and posterior surgery
have equivalent neurological outcomes
• A tendency for less kyphosis and better pain &
function outcomes with anterior surgery
• Reduced degenerative changes resulting from
saving motion segments with anterior procedures
has not been proven

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Technique Pearls for Posterior


Instrumentation

• More instability or
deformity or poor bone
quality = more failure with
short segment posterior
instrumentation
– More points of fixation
– May require anterior column
support

Posterior Treatment of T-L Injuries


– Fractures in patients with the following conditions
have impaired bone quality
• Ankylosing spondylitis
• DISH
• RA
• Osteoporosis
• Malnourished

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Case 1, History
• 30 yr old male MVC
• Back pain
• Decreased motor and
sensory function at T12
– Iliopsoas 2/5
• Head, chest, abdomen,
and pelvis negative

Physical Examination
• Thoracolumbar pain
• May have palpable defect
posteriorly
• Motor strength 2/5 below
Illiopsoas
• Diminished sensation
below T12 level
• Intact perianal pin prick
sensation

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Radiographs
Plain Radiographs
• T12 fracture
• 40° kyphosis
• 50% loss of height
• Posterior element
splaying

Radiographs
CT
• T12 burst fracture
• 40% canal compromise
• Facet joint widening T12-
L1

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Radiographs
MRI
• T12 burst fracture
• T2: PLC signal changes
• No spinal cord edema
• 40% canal compromise

Diagnosis and Treatment


T12 Burst Fracture with Incomplete
Neurological Deficit

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Surgical Approaches
A. Bed rest/ TLSO
B. Anterior corpectomy/fusion/
instrumentation
C. Posterior
fusion/instrumentation
D. Posterior
Decompression/fusion/
instrumentation
E. Anterior
?
Decompression/Fusion/
Posterior Instrumentation

Postoperative Radiographs

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Case
• Patient is a 69 year old woman with a history of
osteoporosis presents to ER after ground level
fall. Chief complaint of mid thoracic back pain.
• Past Med Hx also includes COPD, and previous
T3-T7 fusion performed
• Patient is a smoker, and has a 60 pack year history
• Physical Exam: Neurological intact

• Focal kyphosis at T5 with


central canal stenosis from
bursted T5 vertebral body
along with cement.

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Surgical Options
• No surgery
• Extend fusion caudally with multiple Smith
Peterson osteotmies
• Anterior/Posterior Surgery
• Extend fusion caudally with single pedicle
subtraction osteotomy.

Before After

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Post-Op Course
• Patient developed post-op deep wound infection
requiring 2 washouts.

• 3 months later, patient is off dilaudid and requires


no pain meds.

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Pre-op vs. 12 month F/U

Slight lucency around T10 screws.

Instrumentation Techniques and


Technical Considerations in
Thoracolumbar Trauma

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Goals of Percutaneous Fixation for Thoracolumbar


Trauma

• Reduce soft tissue injury by limiting dissection stripping of muscle /


dead space, metabolic demand

INFECTION

Goals of Percutaneous Fixation for Thoracolumbar


Trauma
• Improve recovery time by allowing rapid mobilization and reducing
postop pain thus enhancing pulmonary fx, reducing ICP’s ……
• Reduce morbidities associated with delaying stabilization

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Disadvantages of Percutaneous Fixation

• Potentially Longer OR times

• Learning Curve: FOR EVERYONE

• Loss of tactile feel / visual of anatomy

• Can be difficult to compress or distract.


• Biological Fusion at Index procedure
• Removal of implants if no fusion

MIS Thoracolumbar Trauma Indications


• Thoracolumbar Burst Fx
• Flexion-Distraction Injuries
• Extension-Distraction Injuries
• Fracture-Dislocations

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Percutaneous Pedicle Screws

Pedicle Anatomy
• Familiar visual and tactile landmarks are not
available with percutaneous screws
• Therefore, knowledge of pedicular anatomy is
critical to successful screw placement

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Shape of the Pedicle


Lateral
• Shape of the pedicle is
cylindrical with a tapered
width in the middle

nerve

Medial

Lenke – 12-Step “Free Hand”


Technique of Thoracic Pedicle
Screw (TPS) Placement
1. Exposure
2. Starting point
3. Cortical burr
4. Pedicle gearshift – lateral
5. Pedicle gearshift – medial
6. Pedicle palpation
7. Pedicle length measurement
8. Pedicle tapping
9. Repeat pedicle palpation
10. Screw placement
11. Intraoperative x-rays
12. Screw EMG stimulation

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Set up ⇒ AP-image

Pedicles in
upper half of
vertebral
body. Endplates
parallel

Spinous
Process
Equidistant

Set up ⇒ Lateral

Endplates
Parallel

Pedicles
Superimposed

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Set up ⇒ En-face view

The En-face view


may aid in placement
of the JamShidi

Orient C-Arm 10-30°


oblique to true A-P

Set up ⇒ En-face view

Allows direct visualization down the pedicle

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Skewer thru Pedicle

20 mm

Mark Jamshidi !
20-25mm from the skin

Skin 25mm

Pedicle

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25mm

Lateral View

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Tap & Test

What About the Reduction?


• Patient positioning
• Coronal Plane
• Sagittal Plane

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Hybrid Approach

MIS Anterior Treatment of Burst Fxs

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MIS surgery advanced through image


guidance. O-Arm is an example

T-L fracture treatment in the elderly or


patients with poor bone quality.
• Increasingly common due to aging population.

Mayo Clin Proc. 2003 78(8):1026-40.

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POOR Bone Quality

Is there a way around poor bone


quality?
• Technique: Cortical Screw trajectory
• Santoni BG et al. Cortical bone trajectory for lumbar pedicle
screws. Spine J. 2009 May;9(5):366-73. doi:
10.1016/j.spinee. 2008.07.008. Epub 2008 Sep 14.
• New cortical trajectory screws demonstrated a
30% increase in uniaxial yield pullout load
relative to the traditional pedicle screws (p=0.080)

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Santoni BG et al. Cortical bone trajectory for lumbar pedicle screws.


Spine J. 2009 May;9(5):366-73.

Cortical Trajectory Red Cortical Trajectory Left


Regular Trajectory Purple Regular Trajectory Right

Biomechanics of Lumbar Cortical Screw–Rod Fixation Versus Pedicle Screw–Rod


Fixation With and Without Interbody Support

Perez-Orribo et al, SPINE Volume 38, Number 8, pp 635–641, April 2013

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Aknowledgement

• Dr Steven Ludwig for lending


slides on MIS TL spine trauma

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Cervical, Thoracic, and


Lumbar Disc Herniations
Charles A. Sansur, MD, MHSc
Associate Professor of Neurosurgery
Director of Spine Surgery
University of Maryland School of Medicine

Disclosures

Consultant for: Medtronic, Globus, Stryker,


DepuySynthes

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Disk Herniation
• Caused by a defect in the annulus
– excessive stress applied to the disk.
• Mostly occurs on the posterior or
posterolateral aspect of the disk.
– Due to morphology of the annular fiber bundles
– Directs the herniation toward the exiting and
traversing nerve roots

Disk Herniations
• About 20-30% of all herniations of the cervical
region occur at the C5-6 level; 60-75% occur at
the C6-7 level.
• About 90% of all lumbar disk herniations occur at
the L4-5 and L5-S1 levels, about equally.
– 93% occur inside the spinal canal
– 3% in intervertebral foramen
– 4% are extraforaminal or occur far laterally
• Thoracic herniations account for less than 1% of
all diskectomies
Carette S, Fehlings MG. N Engl J Med. Jul 28 2005;353(4):392-9.
Battie MC, Videman T. J Bone Joint Surg Am. Apr 2006;88 Suppl 2:3-9.

527
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Cervical Disc Herniations


• Conservative measures must be addressed first –
in the absence of myelopathy and weakness,
conservative measures can be instituted for as long
as tolerated by patient.
• Physical therapy, epidural injections, pain
management, and time may be enough to get
patient back to baseline without surgical
intervention

Surgery for Cervical Disc Herniation


• Anterior Cervical Discectomy and fusion,
pioneered by Cloward and Smith/Robertson

528
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Anterior Cervical Discectomy

• Cloward • Smith and Robinson

J Neurosurg 15:602-617, 1958 J Bone Joint Surg Am 40:607-624, 1958

Surgery for Cervical Disc Herniation

• ACDF is the gold standard, with excellent


results.
• What about Arthroplasty?
– 48 month follow-up may demonstrate superior
outcomes to ACDF. (Sasso et al., J Spinal
Disord Tech. 2010 Jan 16)
– Arthroplasty group had better VAS scores at 48 mo
– There were 6 surgeries performed in the ACDF group for
adjacent level disease versus 1 in the arthroplasty group.

529
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Sasso et al., J Spinal Disord Tech. 2010 Jan 16)

PRESTIGE® Cervical Disc


Clinical Trial Results

Journal of Neurosurgery:Spine 6:198-209,2007


Mummanenni, Burkus, Haid, Traynelis and
Zdeblick.

530
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Study Overview
• 541 Patients
– 276 PRESTIGE
– 265 Control
• Largest medical device study in the cervical spine
– Level I, Prospective, Randomized Controlled Clinical
Trial
• 32 Centers
• No Training Cases
• Gold Standard Control Group
– Single Level ACDF with Allograft and Plate

Results
• Neck Disability Index: Disc replacement
showed statistically significant difference at
6 weeks and 3 months

• Neck Pain: Disc replacement showed


statistically significant differences at
6 weeks, 3 months and 12 months

531
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Secondary Surgical Procedures


PRESTIGE® Disc Fusion
Revisions 0 5
Removals 5 9
Supplemental Fixation 0 9
Re-Operations 4 2

Statistically lower rate of revisions and supplemental fixations at the treated level

Arthoplasty vs. Fusion


Consider Arthroplasty Consider Fusion
• Single-level • Multi-level disease
• Primarily anterior or disc related • Combination of anterior posterior
pathology disease
• Motion at diseased level • No pre-op motion
• Preserved disc space height • Collapsed disc space
• No significant facet arthritis • Severe segmental ankylosis
• Sagittal balance • Spondylolisthesis
• Severe osteoporosis
• Significant kyphosis
• Instability
• Tumor
• Trauma
• Infection

532
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• 48 month f/u
• Patient outcome scores for satisfaction, NDI, SF-12
all significantly higher for arthroplasty group
• Re-operation rate was 4% versus 15% for
arthroplasty versus ACDF

J Neurosurg Spine. 2015 Jan;22(1):15-25. doi: 10.3171/2014.7.SPINE13953

• 5 year follow-up
• Significantly higher
satisfaction, NDI, and SF-
12 scores in arthroplasty
group
• Reoperation rate
significantly lower in
arthroplasty group (4%
versus 16%)

J Neurosurg Spine. 2016 Mar 25:1-12

533
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Other Options:
Anterior Microforaminotomy

Jho HD J Neurosurg 84(2):155-160, 1996

Anterior Microforaminotomy:
Not the way to go if not experienced
with this approach
Hacker et al. JNS 98, 2003 23 patients 1998-2000

30 % re-operation

4 patients recurrent HNP

3 mechanical neck pain

534
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Other Options:
Posterior Cervical Microforaminotomy/diskectomy

• Particularly helpful when the disc is soft


and lateral
• John Jane Sr, et al. reported his series of
patients undergoing this procedure in April
2009 Volume 10, Number 4
• Data available in 162 patients
• All for radicular pain and/or weakness

JNS Spine, April 2009 Volume 10,


Number 4 (cont’d)
• 93% improvement in NDI scores.
• Resolution of radiculopathy was 95%
• Postoperative instability on dynamic imaging was present in
8 patients (4.9%); 7 of these patients were clinically
asymptomatic and were treated conservatively, and 1
required cervical fusion.
• Postoperative loss of lordosis (defined as segmental Cobb
angle < 10°) was seen in 30 patients (20%), 9 of whom had
clinical symptoms and 4 of whom required further surgical
correction.
• Factors associated with worsening sagittal alignment (Cox proportional
hazards analysis, p < 0.05) included age > 60 at initial surgery, the
presence of preoperative cervical lordosis of < 10°, and the need for
posterior surgery after the initial foraminotomy

535
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Technique of Posterior Discectomy

Webb and Jane Sr et al.


Neurosurgical FOCUS Jan 2002, Vol.
12, No. 1, Pages 1-3: 1-3.

Jagannathan and Jane Sr. et al.


JNS Spine, April 2009 Volume 10, Number 4

Thoracic Disks

536
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History of Dorsal Approach


Reported in 1922 by Adson - laminectomy and
disc removal
In 1952, Logue reported the results of surgery in
a series of 11 patients: three paraplegias, two
deaths, and two cases of only mild improvement
Two extremes of posterior options:
Simple decompression without disc removal
Reach disc material via an intradural approach that
involved sectioning the dentate ligaments

Burke and Caputy, Neurosurg Focus. 2000 Oct 15;9(4):e9.

Posterolateral Approaches
In 1958 Hulme used costotransversectomy to treat
thoracic disc herniation.
rib resection and removal of the transverse
process - more ventral window

Hulme A: J Neurol Neurosurg Psychiatry 21:66, 1958

537
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Posterolateral Approaches
In 1978, Patterson and Arbit
described transpedicular
approach involving removal of
the entire pedicle and facet
direct line of exposure to the
ventrally located disc space.
Potential advantage to the
transpedicular approach over
costotransversectomy and
transthoracic is less damage to
radicular vessels.
(Adamkiewicz (arteria magna
radicularis) usually arises on
the left side at T8-L2.)

Ventral Approach
1958, Crafoord et al. reported thoracotomy and ventral
approach for a thoracic disc.
1969, Perot and Munro reported this technique for
thoracic disc herniation in two patients. Since then,
multiple series support this approach.
Excellent ventral exposure of the spinal cord
Permits multiple levels to be addressed via the same
approach if required.
The obvious disadvantage to the transpleural approach
is the risk of pulmonary morbidity.
Considerable amount of pain secondary to the
thoracotomy and chest tube.
Limited to treatment of the T-5 disc space or below.

538
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Recent Article on Thoracotomy


treatment of thoracic discs
Ayhan, Sciubba et al: J Spinal Disord Tech
Volume 23, Number 2, April 2010
27 patients, 28 transthoracic surgeries for
centrally located symptomatic calcified thoracic
disc herniations
American Spinal Injury Association scores
improved postoperatively in 12/27 patients,
remained unchanged in 13/27, and worsened in
2/27.
Major complications occurred in 6 cases (21.4%)
over an average follow-up of 12 months.

Thoracotomy for Thoracic Disc


Herniation

Sciubba et al: J Spinal Disord Tech Volume 23, Number 2, April 2010

539
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Thoracotomy for Thoracic Disc


Herniation

Sciubba et al: J Spinal Disord Tech Volume 23, Number 2, April 2010

Thoracoscopic Approach
Videoscopic-assisted thoracoscopic surgery (VATS)
Endoscope is established tool in thoracic surgery – good use for
spine surgery
Rosenthal and Dickman compared the rate of complications between
VATS, thoracotomy, and costotranversectomy.
no instances of postoperative neurological deterioration in
thoracoscopic or ventral group but in costotransversectomy
group, 7% experienced neurological deficits.
Intercostal neuralgia (16% rate in the VATS group versus
50% in thoracotomy group)
Rate of retained disc fragments
0% in thoracotomy group
4% in VATS
13% in costotransverstectomy group.

Rosenthal and Dickman, J Neurosurg 89:224–235, 1998

540
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Thoracoscopic Approach
Burke and Caputy, Neurosurg Focus. 2000 Oct 15;9(4):e9.

Lumbar Disc Herniations

541
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Lumbar Disc Herniation


First described in association with radiculopathy
by Mixter and Barr in 1934
In the absence of motor deficit and/or cauda
equina syndrome, first line of treatment is
conservative management
Bed rest
Physical Therapy with core muscle strengthening
NSAIDs with steroid trial, and other pain meds
Epidural steroid injection
Surgical Intervention after failure of conservative
measures

501 patients from 13 centers were randomized to either


open surgery or non-operative management
Only 50% of patients assigned to surgery received
surgery within 3 months of enrollment
30% of those assigned to non-operative treatment
received surgery
Intent-to-treat analyses demonstrated substantial
improvements for all primary and secondary outcomes
in both treatment groups.
Between-group differences in improvements were
consistently in favor of surgery for all periods but were
small and not statistically significant

542
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CONCLUSIONS: Patients in both the surgery and the


nonoperative treatment groups improved substantially
over a 2-year period.
Because of the large numbers of patients who crossed
over in both directions, conclusions about the superiority
or equivalence of the treatments are not warranted
based on the intent-to-treat analysis.

Further follow-up at 4 years was obtained. An as treated


analysis was performed.
Patients who underwent surgery for a lumbar disc
herniation achieved greater improvement in all outcome
variables except work status
Spine (Phila Pa 1976). 2008 Dec 1;33(25):2789-800.

Recurrent Disc Herniations


Broad spectrum of recurrence rates: approx 5-15%.

Early teaching: Radical discectomies with curettage of


endplates - potentially creating defect that could lead to
more herniation and instability.
This procedure was later modified to remove as much
NP as possible without interference of the endplate: also
termed subtotal discectomies
Limited discectomy: removal of only extruded fragment
and loose pieces in the disc space: only pituitaries are
used

543
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Recurrent Disc Herniations


Carragee et al. 2003 reported most
reherniations are in patients with large
anular defects (>6mm in 2 planes), or in
patients with sequestered fragments

60% of the 180 herniations described were


in patients with large anular defects as
described above.

A prospective controlled study of limited versus subtotal


posterior discectomy: short-term outcomes in patients with
herniated lumbar intervertebral discs and large posterior
anular defect.

30 patients prospectively underwent a


SUBTOTAL posterior lumbar discectomy for
lumbar disc herniation. Compared made with
historical cohort of 46 patients who
underwent LIMITED discectomy

Reherniation rates and clinical outcomes


were determined by independent evaluation
at 6, 12, and 24 months after surgery.
Carragee et al. Spine. 2006 Mar 15;31(6):653-7.

544
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A prospective controlled study of limited versus subtotal


posterior discectomy: Spine. 2006 Mar 15;31(6):653-7.

Reherniation rate in the limited discectomy group was 18%


versus 9% in the subtotal discectomy group at follow-up (P =
0.1).

Back pain (visual analog scale) (P = 0.02) and Oswestry scores


(P = 0.06) were worse in the subtotal discectomy group at 12-
month follow-up.

Time to return to work was longer, and pain medication usage


was higher in the subtotal discectomy group at 12-month follow-
up.

CONCLUSIONS: The more aggressive removal of remaining


intervertebral disc material may decrease the risk of
reherniation, but the overall outcome was less satisfactory,
especially during the first year after surgery.
Carragee et al. Spine. 2006 Mar 15;31(6):653-7.

A prospective controlled study of limited versus subtotal


posterior discectomy. Spine. 2006 Mar 15;31(6):653-7.

Carragee et al. Spine. 2006 Mar 15;31(6):653-7.

545
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Minimally Invasive Lumbar


Discectomy – what are the benefits
over open surgery?
Harrington et al: Minim Invasive
Neurosurg. 2008 Feb;51(1):30-5.
Retrospective review demonstrated that
the benefit was post-op pain requirements
and length of stay. All other parameters
were the same (Surgical times, blood loss,
complications, and outcome)

Minimally Invasive Lumbar


Discectomy – what are the benefits
over open surgery?
Tomasino et al: Spine (Phila Pa 1976). 2009
Aug 15;34(18):E664-72.
Retropsective review comparing obese to non-
obese patients and open vs MIS surgery
With MIS surgery, obese patients experienced
equally beneficial outcome compared to
nonobese patients
Incision lengths, blood loss, operative times, and
length of stay were less when compared to open
procedures

546
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Other benefits of MIS surgery


Fessler’s group: J Neurosurg Spine. 2009
Oct;11(4):471-6.
Retrospective review of over 1000
patients, 85% of which had lumbar MIS
procedure
Infection rate was 0.22%, a ten-fold
reduction when compared to open
infection rates from large series

Far Lateral Lumbar Disc Herniation


Far-lateral disc herniations represent 7–
12% of all lumbar disc herniations
Classically, posterior approaches put the
facet at risk
MIS techniques have been developed to
bypass the facet joint and gain direct
access to the disc space

547
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Far Lateral Lumbar Disc Herniation

Foley et al: Neurosurg Focus 7 (5):Article 5, 1999

Further Advances in MIS surgery


Madhok and Kanter: April 2010 Volume
12, Number 4: Transpsoas technique for
far lateral disc herniation
Extreme lateral interbody fusion had
traditionally been used to approach this
aspect of lumbar anatomy, and can be
effectively used for a far lateral disc.

548
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Extreme-lateral, minimally invasive, transpsoas approach


for the treatment of far-lateral lumbar disc herniation
Madhok and Kanter: April 2010 Volume 12, Number 4

Conclusions
Disc Herniation: a leading cause of of morbidity
in the US, with huge socio-economic
implications
As neurosurgeons, it our is our job to
understand what techniques are appropriate
under what circumstances to get patients to
return to maximal function
Despite the fact that technology is constantly
evolving, our gold standard treatments are well
established and very successful. Extensive
studies will be required to make changes in
standard of care

549
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Lateral Lumbar Interbody Fusion


Comprehensive NSGY Review
Adam S. Kanter, MD, FAANS

550
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Why consider lateral transpsoas approach?

• Muscle splitting
• Ligament sparing
• Large implants (e.g., 26 x 55 x 12mm)
• Maximizes stability; anterior support
• Indirect decompression
• Minimizes OR time, blood loss, …

Anatomy
A. Psoas Muscle
Muscle on lateral aspect of
lumbar vertebral bodies
Contributes to hip flexion
B. Lumbar Plexus
Lies in the posterior 1/3 of the
psoas muscle
C. Dorsal Lumbar Musculature
Erector Spinae/Quadratus
Lumborum
Enter retroperitoneal space
lateral to Erector Spinae
D. Retroperitoneal fat
Safe triangle of fat used for
access to psoas muscle
E. Peritoneum
Falls anterior when space is
created with finger in
retroperitoneal space

551
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Psoas tapering

Tension band preservation

552
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Anatomy of the Interspace

( apophyseal ring )

(Grant et al., Spine 2001;26(8):889-896)

• INDICATIONS
• DDD W/RADIC, STENOSIS (MODERATE), LG SPONDY
• DIRECT INTERVERTEBRAL DISTRACTION
• DISC HEIGHT RESTORATION (APOPHYSEAL RING)
• INDIRECT DECOMPRESSION
• LIGAMENTOTAXY (ALL & PLL)
• MECHANICAL IMMOBILIZATION
• ANTERIOR FUSION, SUPPLEMENTAL FIXATION

553
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• Patient selection
• stenosis, hypertrophic ligamentum fl,
spondy
• Lack of intervertebral distraction
• Endplate compromise / subsidence
(improper graft sizing, overdistraction)
• Lack of immobilization
• Inadequate discectomy
• Instability inadequately addressed (PSF)

Intervertebral height
restoration

554
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Indirect decompression /
ligamentotaxy

555
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Pre-op Post-op

Preop Post Op

556
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Clinical Indications:

Thoraco-lumbar cases above L5-S1 requiring access to


the disc space and/or vertebral bodies.

• DDD with Instability


• Recurrent Disc Herniation
• Stenosis / claudication
• Degenerative Spondylolisthesis (≤ grade 2)
• Degenerative Scoliosis
• Pseudarthrosis
• Discitis
• Trauma
• Arthroplasty Revision

LIMITATIONS
Anatomic
• scoliotic rotational deformities
• Iliac crest limits L5-S1 (~L4/5) access
• Nerves: lumbar plexus

Retroperitoneal scarring
• e.g. kidney surgery

Degenerative spondylolisthesis ≥ grade 3


• exiting nerve more anterior
• difficult to find lateral center

557
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Surgical Technique

Patient Positioning

A-
B-
C-

D-
Before
breaking
table!

558
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THEN BREAK

PRE-INCISION LOCALIZATION
Optimize AP & Lateral images
Adjust table (not C-arm)

Midline spinous processes


Symmetric pedicles

Linear endplates
Linear posterior cortex
Superimposed pedicles

* adjust each level as you go…

559
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TARGETING ENTRY

Once positioned, use K-wire to mark skin incision


Anterior border should stop approximately 1 cm behind the ALL
Target posterior 1/3 of the disc space

TARGETING ENTRY

In multi-level cases, incision can be performed between


disc spaces to minimize number of incisions
(may also be true when working within curve concavity)

560
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LATERAL INCISION

Split the muscle and fascia to the retroperitoneum and


advance the initial dilator to land atop the psoas.

EMG NEUROMONITORING

Advance dilator through psoas using


EMG to locate lumbar plexus

561
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562
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CONFIRM DISC SPACE POSITION WITH


FLUORO

When positioned properly, insert K-


wire ~3cm through dilator

AP IMAGE CONFIRMS DISC SPACE ENTRY

563
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SERIAL DILATORS & RETRACTOR INSERTION

NERVE LOCALIZATION WITH BLUNT TIP


PROBE

564
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Disc shim insertion

565
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567
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568
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569
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570
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571
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572
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573
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574
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575
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Is supplementary fixation necessary,


how much rigidity is required?

• Compare:
• 18 mm standard cage alone
• Cage with lateral plate
• Cage with spinous process fixation
• Cage with lateral plate + sp process fixation
• Cage with Ipsilateral pedicle screws
• Cage with Bilateral pedicle screws

576
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Supplemental fixation
Lateral plate

Supplemental fixation
Pedicle screws (unilateral or bilateral)

577
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Supplemental fixation
Spinous process fixation device

Supplemental fixation
Combinations…

578
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% ROM compared to intact spine

Flexion - Extension
40
A A
35

30

25 B

20 BC BC
C
15

10

0
Standalone lat Ipsilat Sp process Lat plate + Bilatped
plate Ped screws fixation Sp process screws

579
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% ROM compared to intact spine

Lateral bending
40 A
A
35

30

25 B

B
B
20
B
15

10

0
Standalone Sp process Ipsilateral Lateral Lat plate + Bilateral
fixation screws plate Sp process screws

% ROM compared to intact spine

Axial rotation
80 A A

70

B B
60
BC
50 C

40

30

20

10

0
Standalone Sp Lat plate Ipsilat Lat plate + Bilat PS
process screws Sp process

580
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Supplemental Fixation
• Standalone cages provide very good rigidity in flexion-
extension (31.6% of intact ROM)

• Addition of lateral plate (2 screws)


• Similar rigidity to standalone cage in flexion-extension
• Improved rigidity in lateral bending and rotation

• Addition of spinous process fixation


• Better flexion-extension rigidity than ipsilateral pedicle screws
• Similar to standalone cage in lateral bending and axial rotation

• Bilateral pedicle screws provides greatest rigidity in all planes

Transpsoas specific complications

581
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Youssef et al., Minimally Invasive Surgery: Lateral Approach Interbody Fusion. Spine 35: S302-311, 2010.

0%

30 %
Youssef et al., Minimally Invasive Surgery: Lateral Approach Interbody Fusion. Spine 35: S302-311, 2010.

582
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• N: 100
• Surgical time: 74 mins
• LOS: 1.5 days
2007 • VAS reduction: 68.7%
• F/U: 6 months

• Complications: 2%
• No infections
• No transfusions

• ** Thigh discomfort, numbness,


and weakness was noted but all
occurrences had resolved by six
weeks post-op.

• N: 58
• F/U: 15 months
• Overall complication rate: 22.4%
• (13.8% approach related)

• 10.3% ‘psoas spasm’


• 10.3% ipsilateral sensory dysfxn
• 3.4% motor deficit (residual 1yr)

583
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N: 313 (156 obese, 157 nonobese)


No infections
No transfusions

Compared to obese group that


underwent posterior lumbar fusions
(prone position):

4.2% infection rate


(13% historical cohort)
20.9% facial abrasions
4.6% ulnar neuropathies

Unlike traditional open lumbar fusion procedures, minimally invasive


transpsoas fusion surgery has no greater risk of complication in the
obese patient…

584
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Scoliosis
• N: 25
• EBL: 53cc/level
• Mean f/u: 11 mon
• Mean VAS improvement: 70.4%
• Mean ODI improvement: 44.2%
• Fusion (CT): 100%

No CSF leaks
No wound infections
No visceral injuries
No vascular injuries
No postoperative
weakness

No deep venous
thromboses, urinary
tract infections, or
ileus identified.

Complications: (1) Rhabdomyolysis


(1) Subsidence
(1) Hardware failure
(3) Transient thigh numbness (12%)

585
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Spinal Deformity
• N: 23
• Circumferential fusion:
transpsoas + perc screws
+/- TLIF @ L5/S1
• Levels: 3.7
• Mean f/u: 13.4 months
• EBL: 477cc
• Mean VAS (bk) delta: 3.96
• Fusion rate: 97.6%
• Cobb
Pre-op 31.4 deg
Post-op 11.5 deg

• Complications
• “Thigh Sx”: 30.4% (1 persistent)
2 returns to OR
(CSF lk, hardware failure)

• N: 107 (prospective)
• Mean: 4.4 levels/pt
• Supp PS fixation: 75.7%
• Lateral fixation: 5.6%
• Stand-alone: 18.7%
• Mean Op time: 178 mins
• Mean LOS: 3.8 days
• Transfusions: 4.7%
• ICU: 2.8%
• Inpatient Rehab: 0.9%

• Complications: 11.2%
MIS only: 7.7%
Open: 20.7%
(*wound infections = open only)

586
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587
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Post-op transfusion for anemia :


4.7% A-P fusion
26.5% instrumented PL fusion
63.4% revision fusion surgery
0.2% LLIF

Post-op infections :
3.6% TLIF
3.1% MIS TLIF
11% PLIF
3.2% Endoscopic ALIF
2.3% MIS decompression
0.0% LLIF

LLIF often considered a lateral MIS ALIF :


3% visceral injuries
2 - 3% vascular injuries
0.6 – 45% retrograde ejaculation
0.0% LLIF

588
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Durotomy :
5 - 20% posterior fusions
0.2% ALIF
5 - 19.6% TLIF
7.7% MIS decompression
0.0% LLIF

Permanent motor deficits :


0.8% - 3.6% PLF
1.0% - 6.1% PLIF
4.1% MIS TLIF
6.5% Endoscopic ALIF
1.5% Open ALIFs
0.5% MIS decompression
0.6% LLIF

LOS (days) :
4 ALIFs
3-6 PLIFs and instrumented
3-6 TLIFs
1.2 LLIF

Prospective study
N: 53

No vascular injuries
1 psoas hematoma

HF weakness (subj): 25%


Ant thigh pain: 23%

** 84% with complete


resolution by 6 months
(most by 8 weeks)

NO major injuries to lumbar


plexus encountered;
Leg Sx thought related to
psoas inflammation and
GF nerve stretch injury

589
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Subset analysis of single-level operations:

HF weakness:
L 1/2 0%
L 2/3 25%
L 3/4 33%
L 4/5 57%

Psoas tapering

590
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4 institutions, N: 568

10 identified with post-op


abdominal wall paresis

8 / 10 recovered without
intervention within 6 months

(remaining 2 lost to f/u at 1 and 4


months)

The abdominal wall muscles

rectus abdominis
internal oblique
external oblique
transverse abdominis

innervated by

subcostal nerve
iliohypogastric nerve
ilioinguinal nerve

While performing blunt finger


dissection into the retroperitoneum,
one must be careful not to confuse a
free-running nerve in the
retroperitoneal fat for an adhesion
and avulse or injure it…

591
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FINAL
TIPS
&
PEARLS

Positioning

592
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AVOID ‘OVER-BREAKING’ TABLE

PRE-INCISION LOCALIZATION
Optimize AP & Lateral images
Adjust table (not C-arm)

Midline spinous processes


Symmetric pedicles

Linear endplates
Linear posterior cortex
Superimposed pedicles

* adjust each level as you go…

593
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TWO INCISION TECHNIQUE

NEUROMONITORING

594
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ALL retractor

595
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596
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597
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Be cognizant of
graft over-sizing

598
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Be cognizant of
graft over-sizing =
over-distraction

Can lead to subsidence…

Post-op

Subsidence …
BEGINS in the OR

599
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1 month

6 months

600
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MINIMIZE SUBSIDENCE


• NOT

Conclusion
The lateral transpsoas approach is a safe and
effective less invasive option for the treatment
of a variety of lumbar pathology and should
exist in the tool belt of contemporary spine
surgeons.

Extensive experience is necessary to climb


the learning curve in a manner that limits
unnecessary morbidity and mortality.

601
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Lateral Lumbar Interbody Fusion


Comprehensive NSGY Review
Adam S. Kanter, MD, FAANS

602
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MIS Spine Surgery

Praveen V. Mummaneni, M.D.


Professor
Vice-Chairman
Dept. of Neurosurgery
University of California,
San Francisco

Disclosure
• Research Grants: AO spine

• Advisory Role:Depuy Spine

• Board Membership:SRS, CNS, AANS/CNS Spine Section

• Employment:UCSF

• Honoraria:AO spine

• Ownership Interests:Spinicity/ISD

603
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In 2025…
• According to World Health Organization:
– The world population will be 8 billion people
– People age 65+ will number 800 million
(currently 600 million)

• According to U.S. government:


– People age 65+ will number 70 million
(currently 40 million) and represent 20% of
total population

604
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Burgeoning Adult Population with


Spinal Diseases
• Need to Treat More Patients with
Stenosis/Degenerative Spinal Disease, Tumors,
and Adult Spinal Deformity
• Need to Avoid Morbidity
• Need to Deal with Osteoporosis
• Need to Avoid Reoperations
– Infection
– Pseudarthrosis
– PJK

“Potential” Advantages of Minimally


Invasive Spine Surgery

› Less postoperative pain


› Shorter hospital stays
› Less iatrogenic instability
› Less perioperative morbidity
› Better outcomes

605
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Common Causes of Neurological


Compression in the TL Spine
• Spinal Stenosis/Herniated Disc
– Cervical
– Thoracic
– Lumbar
• Associated with spondylolisthesis or scoliosis
• Tumor
– Extradural
– Intradural

Spine: Posterior Approaches

– Open Approach

– Mini-open approach
via expandable tube

– MIS/Tubular approach
via nonexpandable
tube

606
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Foley and Smith 1994

Introduced tubular retractor system directed at the pathology.


Previous percutaneous techniques could not address sequestered
disk fragments or far lateral disks

MIS Procedures

• Spinal Decompression/Discectomy
• Spinal Lami for Tumors
– Intradural
– Extradural
• Lumbar Fusion for Degenerative
Disease
• TL Deformity Correction

607
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Indications
• Cervical foraminal
stenosis
• Posterolateral or
foraminal disc
herniation
• Symptoms refractory
to conservative
treatment

Shaffrey and Jane, JNS 2009

Advantages
• Excellent access to
eccentrically located disc
fragments
• Avoids retraction on the
esophagus and laryngeal
nerve

608
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“Success” rates of
MIS Foraminotomy Range
from 54-97%
• Adamson - “Excellent or good” in 97%
– 100 pts
• Ruetten – 87.4% no longer had arm pain
– 175 pts
– 9.2% with residual pain
• Hilton – 85% with complete pain relief
– 222 pts
• Fessler – 92%
– 25 pts
– 54% with complete resolution of radiculopathy

– Standardized outcome measures are absent in these studies.


– Not as reliable as an anterior approach
• Pick and choose the correct surgical candidate

Contraindications
• Significant kyphosis
or mechanical
instability
• Signs or symptoms of
cervical myelopathy
• Spinal cord
compression on
imaging studies

609
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• Note that adjacent segment disease may still


occur following posterior cervical
foraminotomy
– Some adjacent segment disease is natural history
– Annual rate of 0.7% per year, cumulative

Disasters are possible with MIS


posterior cervical surgery…
• CSF leak
• Cord injury
– With k-wire
– With dilator tubes
– With reaching medially and retracting the cord
• Root injury
– If don’t drill pedicle
– Watch root traction on EMG

610
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Nuances
• Limited view
• Need to drill some of
the pedicle
• Blind sweeps under
the nerve root can
cause root
inflammation
• Can not reach
centrally located disc
pathology

MIS foramenotomy
• Less expensive than ACDF
• Not as reliable as ACDF???

611
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Potential Thoracic Disc Approaches

Posterior Incisions/Approaches
• What kind of incision?
– Linear
– C shape?
– J shape?
– Can we do this
minimally invasively?

612
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Min Inv. Trans-pedicular


Thoracic Discectomy
• Linear 3cm incision
over the pedicle with
muscle dilation gives
adequate access
– Decreases blood loss

– Chi, Mummaneni: Mini-Open


Transpedicular Thoracic
Discetomy. Neurosurg Focus
2008

Min Inv. Trans-pedicular Thoracic


Discectomy

613
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Minimally Invasive Transpedicular


Discectomy

614
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Nuances
• Patient selection is key
– Can consider for
paramedian soft
herniated thoracic discs
– Avoid calcified
“rocks”
• Unlikely to remove
with an MIS approach
as you can NOT retract
the cord
• Ventral approaches are
preferable for large
calcified herniated discs

MIS Lumbar Discectomy

615
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There is not much difference in outcomes


between “open” and MIS discectomy

What About MIS


Lumbar Discectomy Complications?
• Epstein N: Surg Neurol 2008
– 4 MIS lumbar discectomy cases reviewed
• 2 with “no scarring” near lateral disc bulge on
postop MRI
• 1 with postop discitis/osteomyelitis
• 1 with postop CSF fistula with cauda equina
syndrome

616
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Durotomy…
• Watch K-wires and
smallest dilator tube
with flouro
– Both can enter
interlaminar space

617
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Avoiding Durotomy
• Use a woodson to free
adhesions betw dura
and lig flav
• Use “sucker-retractor”
to push nerve roots
and dura away from
discectomy
instruments

Thoracolumbar Tumors

• Intradural
– Extramedullary
– Intramedullary

• Extradural

618
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Intraspinal Tumor Removal Options

– Open Approach
• Midline spinal incision
• Muscle Retraction
• Wide exposure of tumor

– Minimally Invasive (Tubular)


and Mini-open (Expandable tube)
• Smaller incision
– More limited tumor access?
• Muscles dilated
– Less tissue retraction
– Shorter hospitalization?
– Less blood loss?
– Decreased dead space for accumulation of
pseudomeningoceles?

Location of the
Minimally Invasive Incision
1 2 3

1- Disc
1- Midline intradural tumors
2 – Paramedian intradural or
2 – PLIF
extradural tumors 3 - TLIF
3 – Foraminal tumors

619
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1. Large Intradural Spinal Tumors

Traditional Open Approach to


Intradural Spinal Tumors
Traditional Approach:
● Midline incision (two
levels rostral and caudal
to pathology)
● Muscle Dissection,
Laminectomy
• If near cervicothoracic or
TL jxn – May add fusion
to prevent kyphosis

36

620
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Traditional Approach:
Intradural Spinal Tumor
+ Proven safety and
Efficacy
(McCormick Clin Neurosurg, 1994;
Tobias: Childs Nerv Syst 2008)

- Concern for: chronic


pain and post-
laminectomy
kyphosis (Iguchi ,Spine 2000)
- Need for fusion?

37

Intradural Spinal Tumor:


Min Inv Tech
• Limited tissue destruction
• Achieving same surgical
goal, possibly reducing
incidence of iatrogenic
instability
• Reduced blood loss
• Improved speed of recovery
Bresnahan Spine 2009;
Costa J Neurosurg Spine 2007;
Khoo Neurosurg 2002;
Rahman Minim Invasive Neurosurg 2008;
Thome J Neurosurg Spine 2005

38

621
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Intradural Spinal Tumor


Mini-Open trans-spinous
approach for intradural
tumors in the
thoracolumbar spine

Midline incision
● Utilizing expandable
retractors
● Preserve lateral lamina,
facets and muscle
attachments

39

A B C D

E F G H

Steps for MIS


Trans-Spinous
approach

40

622
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A B C D
Cadaveric Study:
Comparison of MIS vs Open Exposure of the T6-7 levels:
MIS affords 50-75% smaller incision
Lu, Dhall, Mummaneni: World Neurosurgery 2010

E F G H

41

Cadaver Findings: Incision length is


50% less in thin patients
and 75% less in obese pts (BMI >30)

Case No. BMI MIS Open Levels of


Incision Incision Thoracic
Length Length Lamina
(cm) (cm) Accessed
1 18 4.2 8.0 3.0
2 22 4.2 10.0 3.0
3 28 4.5 11.0 3.0
4 30 4.5 12.0 3.0
5 36 4.5 14.0 3.0
6 43 4.5 cm 15.0 cm 3.0

42

623
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2. Paramedian Intradural Tumors

43

Min Inv. Hemilaminectomy

• Paramedian Incision
• Dilate paraspinal
muscles
• Place retractor to
expose hemilamina

624
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Paramedian Intradural Spinal


Tumors
MIS Technique

• Hemilaminectomy
• Leave Spinous Process and Interspinous
Ligaments Intact

• Avoid Iatrogenic Instability

45

625
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Minimally Invasive TL Jxn


Hemi-Laminectomy: Avoids Fusion

Case Illustration: Hemilaminectomy for


Intradural, Extramedullary Tumor

• 20 yo woman with
back pain, bilateral leg
radicular pain
• Unable to sit for 1
minute
• Urinary urgency

626
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3. Mini-Open
Foraminal Tumor
Resection
Nerve Sheath Tumors account for one-
third of all primary spinal neoplasms
(Nittner, Acta Neurol Psych, 1968).

627
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Mini-Open Resection of
Nerve Sheath Tumor
(Lu, Dhall, Mummaneni, JNS Spine 2009)

• Traditional surgical approach is laminectomy, unilateral


facetectomy (if tumor extends beyond intervertebral foramen),
and fusion

– Jinnai Neurosurg 2005;


– Ozawa J Neurosurg Spine 2007

• Disadvantage of traditional approach is possible


destabilization, large incision, muscle dissection, pain.

Mini-Open Removal
of Foraminal Tumors

628
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Results

Case Illustration
• 48 y/o obese male
– h/o L3-S1
circumferential fixation
with one year of knee
pain and right knee
flexion weakness

• MRI - mass in left L3-


4 foramen

54

629
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Case Illustration

• Mini-open paramedian
approach
– Pseudarthrosis found at L3-4
level.
– Tumor resection performed.
– L3-4 instrumentation and
fusion performed.

• Follow-up at 1 year
demonstrated complete
recovery of motor strength.
Improving knee pain.

• MRI showed GTR and no


recurrence.

55

SECTION HEADING

Preop

Postop

56

630
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Thoracolumbar
Decompression and Fusion

Magerl-1982

First to describe percutaneous fixation using pedicle screws


attached to an external fixator.

631
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Foley 2001

Developed the first internal percutaneous fixation system.

Wiltse 1968
• Described a
sacrospinalis splitting
technique for doing
posterior spinal fusion
in patients with
spondylolithesis
• Allows access to
Kambin’s Triangle

632
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Indications for
Minimally Invasive Lumbar Fusion
– Spondylolisthesis
• Neural compression
• Failed conserv tx
• Mobile

– Spondylosis or DDD
• 1 level
• Nonsmoker
• No secondary gain
• Back pain
• Often radiculopathy

– Deformity?

• Lumbar Guidelines:
JNS Spine 2005

Spondylolisthesis
• Often associated with
stenosis
• Is it mobile on flexion
and extension x-rays?

• If Immobile – consider
MIS decompression
• If Mobile and painful,
may need fusion

633
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TLIF Options

– Open Approach

– Mini-open TLIF via


paramedian approach
• X-tube

– Minimally Invasive
(Tubular) TLIF via
nonexpandable tube

– Mummaneni, Haid,
Rodts: JNS Spine, July
2004

634
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Comparison of Mini-open
to Open TLIF

Comparison of
Open and Mini-open TLIF

635
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Learning Curve?

Pseudarthrosis example

636
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MIS TLIF RELIABILITY??


• UNILATERAL SCREWS?

Cheng and Mummaneni:


NS Focus 2013
• Compared 50 MIS TLIF with 25 open TLIF
• MIS TLIF with fewer complications and
lower EBL
• MIS TLIF had shorter LOS and saved $4k
compared to open TLIF
• Long term outcomes similar

637
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Degen Vs Deformity
• In Degenerative 1-2 level spinal disease, MIS
approaches decrease hospital stay and EBL
– The operations are interchangeable for Most cases

• Does this hold true for deformity?


– Are the indications for the MIS vs open deformity
surgery similar?

MIS Deformity
• Can decompression be achieved? Yes
• Can hardware be placed safely? Yes (even iliac
screws)
• Can sag balance be restored? Maybe
• Will you match LL-PI within 10 degrees? Maybe
• Will it take a long time to do? Initially - yes
• Can a succesful fusion be established?
– This is the Challenge…

638
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Why Would We Want To Do “Less”


Surgery for Adult Spinal Deformity?

• Complication rates
high
• Pseudarthrosis rates
problematic

Yadla and Harrop:


Neurosurg Focus March 2010
• Systematic review of 49 adult spinal deformity
articles
– Included articles form 1950-2010 with minimum 2
yrs follow up

• 40% incidence of periop adverse events


• 13% risk of pseudarthrosis

639
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Mummaneni et al: Neurosurgery 2008

Schwab et al:
Eur Spine J 2012
Risk Factors for
Major Peri-operative
Complications in
Adult Spinal
Deformity Surgery
A Multi-center Review
of 953 Consecutive
Patients

640
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Complication Group vs. Control Group


Summary of factors differentiating the 2 groups

No significant impact: Significant impact:


• Demographics • Number of stages (p=.011)
• Pre-op vitals • Surgical approach (p=.011)
• ASA, respiratory, cardiac,
alcohol, and smoking scores
• Common Co-morbidities

In this sample, MAJOR complications seem more


procedure than patient related

Conclusion
• Patient related risk factors
– Age, sex, BMI, number of co-morbidities, ASA, percentage of revision cases, number of redo
surgeries were not significantly different in patients with and without major complications
– May make a difference in minor complications?

• Procedure-related risk factors


– # of stages, surgical approach were significant variables Surgeon
affecting the rate of major complications controlled
parameters

641
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Anand, et al. NS Focus 2010


Complications

642
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Tormenti, et al.
NS Focus 2010
Complications

Dakwar and Uribe. NS Focus 2010

• Pitfall:
– The authors
concentrated on
coronal curve and not
on sagittal balance

643
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Dakwar and Uribe:


NS Focus March 2010

• 1/3 of the patients did NOT have sagittal


balance restored

• Remember: Coronal correction is NOT as


important as sagittal correction

Wang & Mummaneni


NS Focus March 2010

• 23 patients,
retrospective review
• High pseudo rate if no
interbody fusion is
done, can not rely on
MIS posterolateral
fusion

644
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When To Do MIS for Deformity?


• Need an algorithm…

NS FOCUS May 2014:


• Praveen Mummaneni
• Chris Shaffrey
• Lawrence Lenke
• Paul Park
• Michael Wang
• Frank LaMarca
• Justin Smith
• Greg Mundis
• David Okonkwo
• Bertrand Moal
• Richard Fessler
• Neel Anand
• Juan Uribe
• Adam Kanter
• Behrooz Akbarnia
• Kai Ming Fu
• MIS ISSG

When To Do MIS for Deformity?


• Need an algorithm…

NS FOCUS May 2014:


• Praveen Mummaneni
• Chris Shaffrey
• Lawrence Lenke
• Paul Park
• Michael Wang
• Frank LaMarca
• Justin Smith
• Greg Mundis
• David Okonkwo
• Bertrand Moal
• Richard Fessler
• Neel Anand
• Juan Uribe
• Adam Kanter
• Behrooz Akbarnia
• Kai Ming Fu
• MIS ISSG

645
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Class I Treatment
• MIS Decompression without fusion or with limited
one level fusion

52 year old woman with radicular right leg pain. Minimal back pain. MRI with
Right L3-4 lateral recess stenosis from disc bulge (axial shown below).

CA 15
PT 3
PI-LL -7
SVA<5

A B D

646
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Level I Treatment
• Decompression alone
– Neurogenic claudication secondary to central stenosis
• Requires limited decompression
• Minimal or no back pain
– Radiographic findings
• Decompression w/ limited instrumented PL Fusion
– Stenosis with minimal back pain
– Anterior supporting osteophytes
– No global imbalance, cobb <20,
– No LL-PI Mismatch

– Caution: Deformity progression and worsening of


symptoms

Class 2 “Medium” MIS Treatment


• Apex of lumbar curve is
included in instrumented fusion,
plus necessary decompression
– back pain associated with
deformity
• Radiographic
– LL-PI mismatch 10-30
degrees
– May have grade 1,2
spondylolisthesis or lateral
listhesis
– PT<25
– Coronal cobb over 20
degrees
Silva FE, Lenke LG: Adult degenerative scoliosis: evaluation and management. Neurosurg Focus 28
(3): E1, 2010

647
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Case Example
• 67 year old woman with low back pain and
bilateral sciatica and anterior thigh pain

– Failed multiple steroid injections


– On oral narcotics

36-Inch X-rays revealed

L2-3 lateral listhesis


SVA: 4.3cm
Lumbar lordosis: 27°

Dynamic X-rays

648
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MRI

L3/4 L4/5

What Levels to Treat?

649
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• 1st stage surgery:


– Lateral interbody fusion at L2-3, L3-4, L4-5

• 2nd stage surgery:


– Posterior MIS L2-S1 pedicle screw fixation and
right iliac screw fixation
– TLIF at L5-S1

650
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651
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A B

652
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HPI
• 59 yo female with mechanical low back
pain and left leg radiculopathy
– The pain radiates in the left L5 distribution
• She has failed conservative therapy
including multiple ESI and facet injections
• PMHx: negative

653
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MRI L-s Spine

Left: T2 Sagittal image


Right: T2 axial through L5-S1 disc space

Mobile spondylolisthesis of L5 on S1 on dynamic


imaging

654
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CT L-s Spine

655
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What to do??
• T3 – pelvis
• T9 – pelvis
• L5-S1 psf
• L5-S1 alif
• L5-S1 alif and psf
• MIS or open?

Stage I: L5-S1 ALIF

656
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Positioning

Flat spinal Jackson table in trendelenburg position in order to


improve visualization of L5-S1 disc space

657
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Mini-open ALIF
• Midline incision,
infraumbilical, 1-4 cm
above pubic
symphysis

Mini-Open ALIF:
Retroperitoneal of Transperitoneal

658
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Serial dilations

•Performed with running EMGs

659
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660
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661
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662
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663
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Stage II: L5-S1 mini-open PSF

Bilateral mini-open
foraminotomy

664
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Post-op: 15 Degree Improved Lordosis

Iliac Screws May Be Placed MIS

665
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MIS techniques in selected cases


may diminish complications

There is a limit (ceiling effect) to deformity


correction using current MIS techniques

666
Copyright © Oakstone Publishing, LLC, 2016. All Rights Reserved.

JNS: Spine (March 2016)

Conclusion:
MIS is NOT Ideal for Class 3
• Avoid 0
– Curves with Cobb >30
– Apical rotation > Grade II
– Lateral olisthesis >6mm
– Sag imbalance requiring PSO
– Thoracic kyphosis
• These characteristics predict
failure with limited MIS
decompression/fusion surgery
• Need to do OPEN surgery
• BUT IN FUTURE CAN WE
DO IT?

667
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Drivers of Perioperative Cost Differences: MIS vs.


Open Fusion
Average Per-patient Cost Differences (MIS – Open fusion)

Incremental
costs for MIS

Incremental
savings for
MIS

Reductions in length of stay (room and board) and blood-related utilization


were the most common cost offsets associated with MIS vs. Open fusion.

132 *Other perioperative events Included emergency room visits, hospital readmissions (excluding reoperations), postoperative rehabilitation,
and additional diagnostics.

668
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Biologics and Cost


• BMP’s?
• Teriparatide to combat osteoporosis?

Biomaterials
• Match Modulus of Elasticity of Bone
– PEEK?
– Stronger than PEEK?
– MRI compatible?
• Bio-absorbable instrumentation

669
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MIS fusion cost effective


relative to open fusion?

Cost savings may be attributed to:

• Reduced hospital length of stay,


The need for
improvement in these
• Reduced blood loss, outcomes is much
greater for patients with
adult spinal deformity
than for patients with 1-
• Reduced infection risk 2 level disease

• More rapid return to work.

Cost-effectiveness analysis in
minimally invasive spine
surgery. Al-Khouja et al:
Neurosurg Focus 2014

670
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Cost-effectiveness analysis in
minimally invasive spine
surgery. Al-Khouja et al:
Neurosurg Focus 2014

Cost-effectiveness analysis in minimally invasive spine


surgery. Al-Khouja et al: Neurosurg Focus 2014

• There is currently an insufficient amount of


studies published reporting the costs of MISS.

671
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Conclusions
• Prepare for the influx of “elderly” osteoporotic but active
patients who live for a century and have worsening
degenerative deformity…
• Must innovate to find cost effective solutions
– Cost per Qaly calculations…
• Appropriate Indications for surgery must be
followed

672
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Syringomyelia and Hydromyelia

Charles A. Sansur, MD, MHSc, FAANS


Associate Professor of Neurosurgery
Director of Spine Surgery

Disclosures
• Consultant for DepuySynthes, Globus,
Medtronic, and Stryker

673
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Syringomyelia and Hydromyelia


Introduction
• Both result in
cavitation of the
spinal cord, with
residual myelopathy
• syringomyelia is
lined by glial
cells
• hydromyelia is
lines by
ependymal cells

Syringomyelia Epidemiology

• Prevalence of 1 case per 10,000 in US


• Usually between 20 and 50 years of age
• 70% Chiari I or II
• 10% Basilar Invagination
• 12% Spinal Arachnoiditis or Deformity
• 4% Spinal Tumors
• 4% Other

• Symptoms: paralysis, sensory loss, chronic pain. Gradual


stepwise deterioration extending over many years

674
Copyright © Oakstone Publishing, LLC, 2016. All Rights Reserved.

Chiari Malformations
• In 1891, German pathologist Hans von Chiari
described the post mortem findings of hindbrain
malformations:
– Type I: cerebellar tonsils herniated into the cervical
spinal canal
– Type II: herniation of the medulla, vermis, and tonsils;
medullary kinking; 4rth ventricle is usually below the
foramen magnum; usually associated with
meningomyelocele
– Type III: rare (herniation of cerebellum and brain stem
into a high cervical meningocele

Chiari Malformation

675
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Old
Theories I

II

Gardner's
Hydrodynamic
Williams' Craniospinal Dissociation

Oldfield Theory 1994


• The Chiari I malformation partially
obstructs CSF pathways at the foramen
• The normally rapid efflux and influx of
CSF btw head and spine, which
compensates for brain expansion and
contraction during the cardiac cycle, is
blocked
• The cerebellar tonsils are displaced
during the cardiac cycle, creating a piston
effect on the partially enclosed
subarachnoid space
• Enlarged cervical subarachnoid pressure
waves are created which compress the
spinal cord from without, direct CSF into
the cord, and cause pulsatile syrinx flow
• This leads to syrinx progression

676
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Elucidating the Pathophysiology of Syringomyelia


Heiss et al: J Neurosurg. 1999 Oct;91(4):553-62.

• Pathophysiological mechanism
behind the progression of
syringomyelia associated with
the Chiari I malformation has
been poorly defined.
• Purpose of this prospective
study was to define the
pathophysiology of syrinx
development and its resolution
with surgery.

Material and Methods


• 20 pts mean age 34.6 (range 16-51) with
progressive syringomyelia and Chiari I
malformations were enrolled
• 18 normal adult volunteers mean age 33.2
(range 23-61) were enrolled to establish
normal CSF physiological parameters

677
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PreOp Evaluation
• Radiological Imaging of Anatomy
• Radiological Imaging of Physiology – cine
MRI
• Spinal Subarachnoid Pressure Recording
and Physiological Testing
• Cervical, lumbar SA pressure during rest, Valsalva
and jugular compression (Queckenstedt’s Test)
• Rate of rise and fall of pressure
• Compliance (ml of CSF/mmHg)

Testing During Surgery


• Physiological Testing
• Pressure recordings from intracranial, cervical, syrinx, lumbar areas
• Rates of rise in pressure were recorded in response to jug
compression and Valsalva
• Operative Procedure
• Subocciptal craniectomy, c1-c2 laminectomy, opening the dura
leaving the arachnoid intact, and duraplasty
• Intraoperative Imaging
• Simultaneous ultrasonography, electrocardiography, pressure
recordings
– AP diameter of syrinx according to time after R wave
– Amplitude of caudal movement of tonsils during systole

678
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PostOp Evaluation
• 6 days
• cine MR (while syrinx is still present)
• 6 months postop
• anatomical MR scan
• cine MR
• Pressure testing
• 12 months postop assessment of:
• Sx of headache, dysesthetic pain, extremity
weakness, sensory loss, and impaired ambulation
• Neurological signs: weakness, atrophy, and ataxia

Results

679
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Pressure Recordings: Pre, Intra, Post Op

Results (cont’d)

680
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Results of cine MR

Craniospinal Compliance

C= ∆Vol./∆Pressure

681
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Intraoperative Ultrasound

Results (Cont’d)

682
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Clinical Results

Conclusions
• Results support the proposed theory:
The Chiari I malformation produces a
block to the flow of CSF (shown by
MR, CINE MR, Jug Comp tests)
• Brain expansion during systole forces
the cerebellar tonsils into the partially
enclosed spinal subarachnoid space
(which has low compliance)
• Tonsillar decent has results in large
cervical subarachnoid pulse pressure
waves, which are transmitted through
the wall of the spinal cord.
• Pulsatile caudal flow of the syrinx
fluid during systole leads to syrinx
progression.

683
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Significance of Study
• Evidence that mechanism of syrinx origin and
resolution arises from outside the spinal cord (not
inside)
• Supports the craniocervical decompression +
duraplasty technique
• This technique will become adopted in a greater
number of academic and clinical centers, as it
arrests syrinx progression without invading the
CNS parenchyma or CSF pathway. Very limited
in its complication rate when compared to other
treatment modalities such as shunting.

Morphometric features of posterior cranial fossa are different between


Chiari I malformation with and without syringomyelia
Huang Yan

• 19 CMI patients without syrinx, 48 CMI with syrinx, and 40 age-


matched asymptomatic controls, all had MRI
• length of the clivus (AB), anteroposterior diameter of the foramen
magnum (BC), length of the supraocciput (CD), anteroposterior
diameter of the posterior fossa (DA), the posterior fossa height (BE)
and the clivus gradient.
• Small size of the posterior fossa was detected both in CMI cases with
and without syrinx. The clivus gradient served as the only morphologic
difference in the PCF between CMI-S and CMI-only patients and was
correlated with the severity of the syrinx,
• Supports theory that restricted circulation of CSF at the anterior
paramedial subarachnoid space contributes to the formation of a
syrinx.

Eur Spin J, pp 1-8 28 January 2016

684
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Improvement of syrinx resolution after tonsillar cautery in pediatric patients


with Chiari Type I malformation.
Stanko KM1, Lee YM1, Rios J1, Wu A1,2, Sobrinho GW1, Weingart JD1, Jackson EM1,
Ahn ES1, Chaichana KL1, Jallo GI1.

• 171 patients with Chiari Type I malformation with syrinx


were identified, and 43 underwent tonsillar cautery
• Patients who underwent tonsillar cautery had 6.11 times
greater odds of improvement in their syrinx (95% CI 2.57-
14.49, p < 0.001).
• Tonsillar cautery did not result in increased perioperative
complications, nor did it result in the need for repeat
decompressions.

J Neurosurg Pediatr. 2015 Oct 30:1-8

Pathophysiology of Persistent Syringomyelia after


Decompressive Craniocervical Surgery

Before 1st Surgery After 1st Surgery After 2nd Surgery

685
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Pathophysiology of Failed
Craniocervical Decompression

1. Partial Obstruction at the Foramen Magnum


2. Block of CSF Flow at the Foramen Magnum
3. Cerebellar Tonsil Motion on a Partially Enclosed Spinal
Subarachnoid Space Creates Elevated Cervical
Subarachnoid Pressure Waves and Syrinx Compression
4. Systolic Caudal Movement of the Syrinx Fluid
5. Re-Exploration Craniocervical Decompression and
Duroplasty Corrects Pathophysiologic Abnormalities and
Resolves Syringomyelia

Pathophysiology of Primary
Spinal Syringomyelia

686
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Primary Spinal Syringomyelia


Before Surgery After Surgery

Theory of Syringomyelia Development


and Progression

687
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Rate of
CSF Entry
into the
Syrinx

Rate of CSF Entry into the Syrinx


Before Surgery After Surgery
50 50

H.U. SAS H.U. SAS


40 H.U. SC 40 H.U. SC
H.U. Syrinx H.U. Syrinx
Hounsfield Units

30 30

20 20

10 10

0 0
0 10 20 30 40 50 60 0 10 20 30 40 50 60

time (hrs) time (hrs)

688
Copyright © Oakstone Publishing, LLC, 2016. All Rights Reserved.

Syringomyelia associated with


arachnoid cysts
J Neurosurg Spine. 2006 Aug;5(2):111-6.
Syringomyelia associated with intradural arachnoid cysts.
Holly LT, Batzdorf U.

• Series of 8 patients
• Removal of arachnoid cyst and restoration
of CSF flow results in syrinx resolution.

• Prospectively study of 36 adult patients with


spinal lesions obstructing the spinal SAS.
• Lumbar and cervical subarachnoid mean and pulse
pressures at rest, during Valsalva maneuver,
during jugular compression, and after removal of
CSF (CSF compliance measurement); All values
were obtained before, during, and after surgery
• Findings compared to 18 healthy volunteers.

689
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• In syringomyelia patients compared with healthy


volunteers, cervical subarachnoid pulse pressure
was increased (2.7 ± 1.2 vs 1.6 ± 0.6 mm Hg,
respectively; p = 0.004), pressure transmission to
the thecal sac below the block was reduced, and
spinal CSF compliance was decreased.
Intraoperative ultrasonography confirmed that
pulse pressure waves compressed the outer surface
of the spinal cord superior to regions of
obstruction of the subarachnoid space.

690
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Idiopathic Syringomyelia
• Must take very careful history
• Infection, Trauma, etc
• Must check for subarachnoid space
adhesions
• Must check for small posterior fossa

691
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Acknowledgements
• Drs. John Heiss and Edward Oldfield at
NIH and UVA, respectively

692
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Disclosure Statement
Reports no commercial interest

693
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694
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695
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696
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697
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698
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699
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700
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701
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702
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703
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704
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705
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706
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707
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708
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709
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710
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711
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712
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713
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714
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716
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722
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725
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726
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727
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728
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741
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742
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743
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What’s new with peripheral nerve


tumors and lesions?

Robert J. Spinner, M.D.*

* No disclosures

Peripheral nerve tumors:


The power of pattern recognition

744
Copyright © Oakstone Publishing, LLC, 2016. All Rights Reserved.

Patterns

Identifying Clinical and Radiologic


PATTERNS
Understanding their Implications

745
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1.5 T 7.0 T Brainstem Images

Courtesy of Professor Cho, Korea

746
Copyright © Oakstone Publishing, LLC, 2016. All Rights Reserved.

Normal Control Normal Control


1.5T 7.0 T

Imager/Interpreter

747
Copyright © Oakstone Publishing, LLC, 2016. All Rights Reserved.

Why is MR imaging important?

Tumors Lesions
• To identify tumors and • To distinguish tumors
distinguish between from other lesions
benign and malignant
forms • To define treatable from
untreatable disease
• To assess resectability • To localize site for
of large tumors
highest yield, safest
• To accurately biopsy
characterize them to • Can obviate need
help guide surgery for biopsy in some
cases

Tumors

Benign Malignant

Intraneural Extraneural

748
Copyright © Oakstone Publishing, LLC, 2016. All Rights Reserved.

Benign Nerve Sheath Tumor


Symptoms
No deficit
Mass (round/oval) within nerve

749
Copyright © Oakstone Publishing, LLC, 2016. All Rights Reserved.

Practical advantages of tumor


resection
• 1. often improves symptoms
• 2. treats tumor
• 3. decreases interval for f/u (may not
eliminate altogether)
• 4. surgery is safer, easier with smaller
tumor
• 5. tumors tend to grow over lifetime
• 6. definitive tissue diagnosis
• 7. neurofibromas can transform (small
risk)

Schwannoma

Save the nerve!

80-90% nerve function


preserving
NS Clinics 2008

750
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Schwannoma

NS Clinics 2008

751
Copyright © Oakstone Publishing, LLC, 2016. All Rights Reserved.

Benign Nerve Sheath Tumors


Symptoms
No deficit
Masses (round/oval) on different nerves =
SYNDROME

+/- deficit
On same nerve (different fascicles) =
? SYNDROME

752
Copyright © Oakstone Publishing, LLC, 2016. All Rights Reserved.

Schwannomatosis

NS Clinics 2008

753
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754
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755
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NF2: Plexiform Schwannomas

756
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NF2: Plexiform Schwannomas

JPRAS 2015

NF2: Plexiform Schwannomas

JNS 2010

757
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Plexiform schwannoma

JNS 2010

Tibial plexiform schwannoma

758
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Spectrum of Schwannomas

759
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Neurofibroma

• Often several
entering/exiting
fascicles
• 70-80% nerve
function preserving

Neurofibroma

760
Copyright © Oakstone Publishing, LLC, 2016. All Rights Reserved.

Neurofibromas + stigmata = NF-1

Neurofibromatosis I

• Benign
• Malignant
• Difficult to tell
what’s what

761
Copyright © Oakstone Publishing, LLC, 2016. All Rights Reserved.

Resectable

JNS 2006

Resectable

JNS 2006

762
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JNS 2006

Plexiform neurofibroma

763
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Unresectable

JNS 2006

Plexiform neurofibroma:
Subtotal (palliative) resection

764
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Benign Nerve Lesions


Symptoms
Deficit
Tubular Lesion (rather than a mass)

Benign Intraneural Lesions

• Ganglia
• Perineuriomas
• Lipofibromatous hamartomas
• Neuromuscular choristomas

Typically have pathognomonic MRI

765
Copyright © Oakstone Publishing, LLC, 2016. All Rights Reserved.

Intraneural Ganglia

An anatomical explanation:
New MRI technologies help visualize
connections

Neurosurgery 2006 J MRI 2007

766
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Peroneal Intraneural Ganglia


(typically predominant deep peroneal
palsy)

JNS 2003

Intraneural ganglia:
A clinical problem
• Suboptimal neurologic
outcomes
• High recurrence
rates (20%*)

• * underestimated

767
Copyright © Oakstone Publishing, LLC, 2016. All Rights Reserved.

Unifying articular (synovial) theory

Intraneural ganglia

JNS 2003

768
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An Anatomic, Surgical Solution

Intraneural Ganglia:
Occam’s Razor
• What works for the
peroneal nerve at
fibular neck should
work elsewhere

769
Copyright © Oakstone Publishing, LLC, 2016. All Rights Reserved.

Benign Intraneural Lesions


Symptoms
SLOWLY PROGRESSIVE Deficit
Lesion (rather than a mass)

Hypertrophic neuropathy
(perineurioma)
• Characteristic clinical
and MRI features
• Slowly progressive
predominant motor
deficit affecting young
(Brain 2009)

770
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Perineurioma

NS Clinics 2008

Perineurioma Tibial Division of Sciatic Nerve


Body Coil (1.5T) versus LegPA (3T)

peroneal

tibial

771
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Congenital Lesions

Hamartoma Choristoma

Fibrolipomatous hamartoma +
nerve territory bony and soft tissue
overgrowth

NS Clinics 2008

772
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Fibrolipomatous hamartoma (FLH)

• When it involves
median nerve at
wrist in adults,
perform carpal
tunnel release
• No need to biopsy;
characteristic MRI

NS Clinics 2008

Extreme form of overgrowth =


macrodystrophia lipomatosa

NS Clinics 2008

773
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Nerve-Territory Overgrowth =
Tumors

JPRAS 2014

Neuromuscular choristoma +
nerve-territory undergrowth

774
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MRI

Biopsy

775
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NF S100 EMA

776
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F/U

• 8 years later he presented with a


thigh mass and thigh pain

• FIBROMATOSIS (DESMOID)

777
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778
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779
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Benign Extraneural Tumors


Symptoms
+/- Deficit
Mass (round/oval) outside of nerve

780
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Benign Extraneural

• Lipoma
• Ganglia
• Others (any lesion in the
neighborhood)

Protect the nerve first!

Extraneural Lipoma

NS Clinics 2008

781
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Extraneural Lipoma

JNS 2012
NS Clinics 2008

Lipoma

NS Clinics 2008

782
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Extraneural Ganglion

Clin Anat 2006

783
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Brachial Plexus Tumors:


Other compressive masses in vicinity

Desmoid
• Infiltrative but benign
• Usually occur in difficult locations to
get wide resection

Principles and Practice of Neuro-oncology. A Multidisciplinary


Approach. Demos Publisher, New York. 2010.

784
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Desmoid
• Best treatment when gross total
resection (GTR) is not achievable? -
Nothing works very reliably

NS Clinics 2008

Malignant Peripheral Nerve Sheath


Tumors (MPNSTs)
Symptoms
Rapid Deficit
Mass (not perfectly round) within nerve
+/- SYNDROME (NF-1)

785
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NF-1 related MPNST

NS Clinics 2008

NS Clinics 2008

786
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Approach to MPNST

• Suspect
• Stage
• Biopsy (percutaneous or limited
open)
• Multidisciplinary approach for
surgery (wide resection or
amputation) in combination with
chemo, radiation preop and/or postop

Best treatment for MPNST ???? -


multimodality

787
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Targeted fascicular biopsy

An Image-Guided Surgical Strike


Progressive neurologic deficit
with MRI abnormalities

The Principle

Leksell Gamma
Knife

788
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Philosophy: Tissue is the issue

Companion to Peripheral Neuropathy: Illustrated Cases and New


Developments, Elsevier, Philadelphia, 2010

789
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Concept:
Robbing the bank without getting caught

SAFETY/EFFICACY

Methods

• 300 patients with progressive


proximal neuropathies and
plexopathies
• Patients with compressive lesions or
tumors were excluded

790
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Technique

• Average skin incision = 8 cm


• Typically, two non-functioning
fascicular groups
• Average fascicle length = 7 cm
• Disposable nerve stimulator

An MRI Target

791
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An MRI Target

NS Focus 2015

792
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The Operative Specimen

Perineurioma

793
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Results

• 85% yield (a variety of diagnoses)


• 5% complication rate with minor
neurologic deficit

Results

Most common:
• Inflammatory demyelination
• Inflammatory/vasculitis
• Perineurioma
• B-cell lymphoma
• “Metastatic” breast CA

794
Copyright © Oakstone Publishing, LLC, 2016. All Rights Reserved.

795
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Target-specific Therapy

• Stem Cell
Transplantation: a
potentially effective
therapy for neuro-
lymphomatosis

Ghobriel et al.
Cancer 2004

Radiation plexitis vs. recurrent


tumor?
• Difficult to • 30 cases of breast
distinguish CA with perineural
between these two spread to BP, even
entities > 30 years after
initial diagnosis

796
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Breast CA (not radiation plexitis)

797
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Breast Cancer to Brachial Plexus:


Mechanism (Perineural spread)

Results

Rare:
• Undiagnosed carcinomas
• Neuroleukemiosis
• Amyloidosis
• Etc.

798
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Rare Ones –
e.g., prostate CA to LS plexus/sciatic

Muscle Nerve 2006

799
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Perineural spread:
more common than thought

NS Focus 2015

Targeted fascicular biopsy

NS Clinics 2008

800
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Patterns

Treatment

It’s not the cards you are dealt,


but how you play your hand

801
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What’s new?

High resolution MRI

Pathogenesis Treatment

Improved understanding
Improved outcomes

802
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Disclosure Statement
Reports no commercial interest

803
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804
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805
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Disclosure Statement
Reports no commercial interest

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Reports no commercial interest

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Metastatic Brain
Tumors
Charles S. Cobbs, M.D.
Director, Ben and Catherine Ivy Center
for Advanced Brain Tumor Treatment
Swedish Neuroscience Institute
Seattle, WA

1093
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Conflicts of Interest
Acknowledgements
No conflicts of interest

Dr. Tony Asher, Steve Kalkanis, Mark


Linsky, Minesh Mehta, and other Brain
Metastasis Guidelines coauthors; J Neuro
Onc, Vol. 96, January 2010
Dr. David Larson, Washington Hospital,
Freemont, CA; UCSF

Overview
Overview Brain Mets Questions:
Overview biology Who gets surgery?
Who gets treated Who gets SRS?
Should WBRT be given
Survival too?
Symptom SRS with or without
management WBRT?
Types of therapy What to do for
Surgery recurrence?
SRS Guidelines
Chemo Case Examples

1094
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Introduction
10 times more common than primary CNS
tumors; about >200,000 / yr in USA
About 20-25% of metastatic CA goes to CNS
Mostly lung, breast, melanoma, renal cell
and colon
Presenting symptoms include HA, seizure,
encephalopathy, ataxia, and sensory and
motor deficits

Curr Oncol Rep (2010) 12:34–40

Brain Mets By Primary


Primary %

Lung ~50%
Breast 15-20%
Melanoma 10-15%
Unknown (1/3 lung) 10-15%
Colorectal 2-12%
Kidney 1-8%
Thyroid 1-10%
Lymphoma ?

1095
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Brain Mets are Increasing


Aging population (> 20% > 65yo by 2030)
accounts for >70% of cancers
Increased detection of asymptomatic and
symptomatic tumors with MRI
Improved therapy for primary CA increases
survival and risk of mets (e.g., as colon cancer
survival has increased with new therapies, brain
mets have increased from 2.3% to 6%)
Better therapies still lack good CNS penetration
thus patients live longer with primary but still
have increased risk of brain mets
Curr Oncol Rep (2010) 12:34–40

Biology of Brain Metastases

1096
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Biology of Brain Mets

Intravasation / Invasion
Intravasation:
(invasion into vasculature) poorly understood
Invasion:
Matrix Metalloproteinases: degradation of
basement membrane
Heparanase: breaks down heparan sulfate
proteoglycans (HSPG)

Puduvalli, Neuro Oncology 2001

1097
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Treatment of Brain Mets


GOALS:
Prolonging survival
Improvement of symptoms
Preservation of function
Enhancement of quality of life
TOOLS (largely based on prognosis):
Surgery
Radiation (WBRT, SRS)
Systemic Therapy

Curr Oncol Rep (2010) 12:34–40

1098
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Philosophical Context of Brain


Metastasis Treatment
Different than primary brain tumor
treatment where survival is key endpoint
In 50% of patients, systemic disease
predicts time of death
Thus, even best treatment of brain
metastases may not impact overall
survival
Symptom management key endpoint
Neurocognitive function key endpoint

Who Gets Treated?


Three categories of patients based on
RTOG Recursive Partitioning Analysis
(RPA)
RPA Class I (16-20%): KPS > 70, age < 65,
controlled primary tumor, no extracranial
mets, median survival 7.7 months
RPA Class III (10-15%): KPS < 70, median
survival 2 months
RPA Class II (60-65%): median survival 4.5
months

Curr Oncol Rep (2010) 12:34–40

1099
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Survival: Historical Context

Steroids alone 1-2 months

WBRT, 3-4 months

Combination of therapies, > 6 months

Symptom Management
Prevention and Treatment:
DVT, Infection, Pain, Neurologic, cognitive, emotional
dysfunction
Cerebral Edema
Dexamethasone (potent, CNS penetration, limited
mineralocorticoid effect)
Radiation Necrosis
Surgical Resection, steroids, hyperbaric oxygen,
anticoagulants
Seizures
AEDs, but no good evidence for prophylactic AEDs

Curr Oncol Rep (2010) 12:34–40

1100
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Steroids
Level III recommendation
4-8 mg/day provide temporary relief of
symptoms related to increased ICP,
peritumoral edema.
For severe symptoms of increased ICP,
higher doses such as 16 mg/day can be
considered
Dexamethasone is recommended

Treatment Algorithm: Obtaining


Diagnosis
No known primary cancer and
probable brain met/mets on MRI:
Systemic workup with CXR or chest CT
(80% have chest lesion), abdominal CT,
PET/ CT
Stereotactic or open biopsy/resection
recommended to establish diagnosis
If known primary but questionable
diagnosis of the brain lesion:
Stereotactic or open biopsy/resection
recommended

1101
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Treatment Algorithm: Treatment


Options Overview
Disseminated systemic disease, low KPS, <3 month
predicted survival (RPA class III)
WBRT
Newly diagnosed or stable systemic disease, or good
systemic disease prognosis (RPA class I or II):
Resectable? …resect followed by WBRT or SRS
(Category 1)
Or…SRS plus WBRT (Category 1 for 1 met)
Or…SRS alone (category 2A)
Unresectable….
WBRT +/- SRS
SRS alone

Whole Brain Radiation


Therapy
(WBRT)
RTOG studies in 1970s demonstrated that
WBRT alone could improve survival from 1-2 to
4-6 months
For single brain mets RCTs demonstrated
improved survival for Surgery plus WBRT vs.
surgery alone
Patchell et al. NEJM, 1990
Vecht et al. Ann Neurol 1993
Cerebral death was reduced 90-95% to around
50%

1102
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WBRT
Goal: Treatment of existing and future mets
Typically uses parallel-opposed external beams
to deliver 30 Gy (3 Gy/d x 10 days over 2 weeks)
Acute complications: encephalopathy, brain
edema, nausea, vomiting, alopecia, mucositis
Delayed complications: RN, dementia, optic and
otic toxicities, neurocognitive, endocrine deficits
Used as sole therapy for RPA class III patients,
and can improve survival from 1-2 to 4 months.
May be used in conjunction with local therapy
(surgery or SRS) in RPA class I/II patients

WBRT
Best for patients with:
Massive brain edema
>10 mets
Impending herniation
SCLC
Patients who cannot have local /
focal therapy

1103
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WBRT: Why 30 Gy in 10
fractions?
9 RCTs evaluated, class I evidence
obtained from a meta-analysis
Altered dose fractionation schedules do not
significantly result in change in median
survival, local control or neurocognitive
outcomes
< 30 Gy in 10 fractions suggests a trend
toward poorer survival
> 30 Gy in 10 fractions shows no benefit

WBRT Solo Therapy - RPA class III

1104
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WBRT Toxicity
Vascular injury
Endothelial cell death
Vascular sclerosis
Leukoencephalopathy
Accelerated brain atrophy
Neural stem cell death
Depressed hippocampal dependent
learning, memory, spatial processing

1105
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Surgery
Goals:
Establish diagnosis (in 80%)
Local control in non-eloquent locations
Rapid relief of symptoms of mass effect, hemorrhage,
hydrocephalus
Complications:
Infection, neuro deficits, hemorrhage, infarction, death
Most often used in RPA class I/II patients with
single met and minimal or controlled systemic
disease
Minimal impact on control of distant brain mets
or overall survival (without additional RT)

Surgery

1106
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Stereotactic Radiosurgery
(SRS)
Goal: Treatment of single or more mets in
outpatient setting, local control for eloquent
brain, relative cost-effectiveness compared with
surgery
Limitations: Indistinct lesions, Mets > 3cm
Complications: radiation necrosis, theoretical
risk of secondary malignancy
Control Rates (for most histologies): 60-75% at 2
yrs, distant brain met control rats of 46% at 2
yrs.
Overall Survival: 10 months
Similar to surgery with respect to min. impact on
distant brain mets and overall survival
Curr Oncol Rep (2010) 12:34–40

SRS: Two main types

Suh J, NEJM, 2010

1107
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Gamma Knife

Cyber Knife

1108
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SRS
Gamma Knife: Multiple intersecting Co-60 gamma
ray beams
Linear Accelerator (E.g., Cyberknife): High energy
X-ray beams
For both, dose is inversely proportional to diameter
of tumor
Typical dose 15-24 Gy to 50% isodose line
Biologically = 5-6 weeks of daily conventional
radiotherapy
No evidence that one system better than other
Typical treatment ½-3 hrs
Suh J, NEJM, 2010

Stereotactic Radiosurgery

With additional WBRT, SRS local control rates are as high as


97% compared to surgery, which is in range of 90%

1109
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Her2 + Breast Cancer


Aggressive disease with ? predilection for CNS
Trastuzumab produces good systemic response, but may
lead to increase in brain mets
Lapatinib
dual inhibitor of HER2 and EGFR
Minimal efficacy as single agent
Possible role combined with capecitabine
RTOG 1119 trial WBRT +/- high dose lapatinib

Lin, 2007

EGFR+ Lung Cancer


Mutations in the EGFR tyrosine kinase domain found in
up to 25% of NSCLC
Possible role for TKIs erlotinib & gefitinib ???
82 % response rate in small study of EGFR mutant
patients with brain mets
67% response rate in 9 patients treated with pulsatile
high dose erlotinib
Durable response 6-9 months common
WBRT + erlotinib mOS 19 months

Porta, 2011; Grommes, 2011, Welsh JCO 2013

1111
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Chemotherapy
Should patients with brain metastases
receive chemotherapy?

No survival benefit (Class I data)

But most data is based on NSCLC and Breast

Chemo + WBRT improves response rate in


some clinical trials

How do you choose?


Surgery vs. Stereotactic
Radiosurgery
Surgery:
Lesions > 4 cm
Rapid resolution of mass effect and edema
Removal of cancer
Histologic confirmation of cancer
Rapid tapering of steroids
Less intensive follow-up
Lower risk of radiation necrosis when
combined with WBRT
Suh J, NEJM, 2010

1112
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Surgery vs. Stereotactic


Radiosurgery
Stereotactic Radiosurgery
Treatment of small, deep lesions or eloquent areas
Minimally invasive or noninvasive
General anesthesia not required
Outpatient
Treatment of multiple lesions during same session
Short recovery time
Potential avoidance of WBRT
Rapid initiation of systemic therapies, (e.g.
coumadin)

Suh J, NEJM, 2010

Local Treatment: With or Without


WBRT???
Goals of WBRT with surgery or SRS:
Increased local control of existing mets and
prevention of future brain mets elsewhere in the
brain
Usually involves WBRT after surgery or SRS
Often used for RPA class I/II patients who
have 1-3 mets, with at least 1 treated locally,
and relatively radiosensitive histology

1113
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Combination Therapy (Surg or


SRS + WBRT)
Landmark Studies
Surgery + WBRT vs. WBRT alone:
Patchell et al, NEJM, 1990
Surgery + WBRT median survival 40 wks. vs.
15 weeks for WBRT alone
Surgery alone vs. Surgery + WBRT:
Patchell et al. JAMA, 1998
At 48 weeks, local control 54% vs 90%;
Distant control 56% vs. 86%
Likelihood of dying from CNS dz 44% vs. 14%

Patchell, JAMA, 1998


Surgery vs. Surgery + WBRT
- Neurologic death rate
is lowered
-Failure anywhere in
the brain is decreased
-Relapse at local site
lowered
- No significant change
in overall survival
- Neurocognitive
function was not
studied

1114
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Surgery + WBRT vs. WBRT alone


6 informative studies, 3 RCTs (class I)
Patchell et al. NEJM, 1990
Vecht et al., Ann Neurol, 1993
Mintz et al, Cancer 1996

Median survival increased from 4 to 10 months


KPS > 70 lasted 7-9 months compared to 2 months

Level 1 recommendation from Class I evidence


supports the use of surgical resection + WBRT
for patients with good functional performance
status and limited extracranial disease

SRS + WBRT vs. WBRT alone


5 informative studies, 2 RCT (Class I data)
Andrews et al., Lancet, 1999
Pts with single met with SRS + WBRT vs. WBRT alone had
increased survival (4.9 to 6.5 months)
Pts with 1-3 mets had 6 month PFS 43% (SRS + WBRT) vs.
27% (WBRT alone) but no increase in survival
Kondzoilka et al, Int J Oncol Biol Phys, 1999
Guidelines:
Level 1 recommendation:
Single dose SRS + WBRT leads to increased survival
compared to WBRT alone in patients with single brain mets
and KPS>70
Single dose SRS + WBRT is superior in terms of local tumor
control and maintaining functional status compared to WBRT
alone in pts. with 1-4 brain mets and KPS >70

1115
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Combination Therapy (Surg or


SRS + WBRT)
Landmark Studies
Mueller et al. 2009:
Large prospective randomized study
1-3 brain mets
Good KPS, stable systemic dz
Either Surgery or SRS + WBRT
In either case recurrent brain mets decreased from
40% to 15% at 6 months (p=0.0001)
Neuro death decreased from 43% to 25%
No difference in functional or overall survival (around
10 months in either case)

Benefits vs. Drawbacks of


Adding WBRT to Local Therapy
Benefits of combined therapy with WBRT:
Improved local and distant brain control
Reduction of neuro decline rate (assuming tumor
burden is cause of neurological decline)
Stability of performance status
Drawbacks:
Inconvenience of treatment
Absence in improvement in overall survival when
adding WBRT to SRS alone or surgery alone
Loss of reserving WBRT for recurrence
Diminished Neuro Cognitive Function

1116
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Why wouldn’t you give WBRT?


Encephalopathic effects of 3 Gy fractions
Latency of onset 6 months – 3 years (usually
1-2 years)
DeAngelis et al, Neurology, 1989
Another option in patients expected to
survive > 6 months is to give 40 Gy in 20
fractions over 4 weeks…potentially lower
neurocognitive risk

What about other local therapies


for brain metastases?
Gliasite
Gliadel Wafers
Must improve upon SRS and Surgery +WBRT with
local failure rates of <10%
Must have decreased complication / expense
These techniques are unlikely to challenge SRS or
surgery + WBRT in future RCT
Currently Phase 2, Multicenter, Exploratory Study,
Evaluating the Treatment Effect of Surgery Plus
GLIADEL® Wafer in Patients With Metastatic Brain
Cancer

1117
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SRS Alone
Guidelines? Evolution of
Thinking?

Category 2B evidence
For RPA class I patients
High KPS
Low systemic disease
1-3 mets

Table 1 Studies comparing SRS plus WBRT with SRS alone

Nicholas F. Marko and Robert J. Weil (2010) Neurocognitive considerations in the treatment of brain
metastases
Nat. Rev. Clin. Oncol. doi:10.1038/nrclinonc.2010.30

1118
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SRS +/- WBRT: What is impact


on neurocognitive function?
10 informative studies, 1 prospective non-randomized trial, 9
retrospective
Aoyama et al., Int J Radiat Oncol Biol Phys. 2007
SRS, 67 pts., LF 28%, BF 76%
SRS/WBRT, 65 pts, LF 11%, BF 47%
MMSE: avg. duration until MMSE 3 point drop was 16.5 months
in the WBRT+SRS group and 7.6 months in the SRS-alone
group (p = 0.05).
Chang et al., MDACC, Lancet Oncology, 2009
SRS, 30 pts., MS 15.2 mos, 1 yr free of brain recurrence 27%
SRS/WBRT, 30 pts., MS 5.7 mos, 1 yr free of brain recurrence
27%
Randomized, prospective trial powered to detect a 5-point
decline in the Hopkins Verbal Learning Test—Revised (HVLT-
R).
“Patients treated with SRS plus WBRT were at a greater risk of
a significant decline in learning and memory function by 4
months compared with the group that received SRS alone”

1119
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NCCTG N0574 (Alliance): A phase III randomized


trial of whole brain radiation therapy (WBRT) in
addition to radiosurgery (SRS) in patients with 1 to
3 brain metastases.
213 patients
median age was 60 and lung primary the most common (68%).
Cognitive worsening at 3 months was more frequent after WBRT + SRS vs. SRS
alone (88.0% vs. 61.9% respectively, p = 0.002).
There was more deterioration in the WBRT + SRS arm in immediate recall (31% vs.
8%, p = 0.007), delayed recall (51% vs. 20%, p = 0.002), and verbal fluency (19% vs.
2%, p = 0.02). Intracranial tumor control at 6 and 12 months were 66.1% and 50.5%
with SRS alone vs. 88.3% and 84.9% with SRS+WBRT (p < 0.001).
Median OS was 10.7 for SRS alone vs. 7.5 months for SRS+WBRT respectively (HR
= 1.02, p = 0.93).

Conclusions: Decline in cognitive function, specifically immediate recall, memory


and verbal fluency, was more frequent with the addition of WBRT to SRS. Adjuvant
WBRT did not improve OS despite better brain control. Initial treatment with SRS and
close monitoring is recommended to better preserve cognitive function in patients
J Clin Oncol 33, 2015
(suppl; abstr LBA4)

Chang et al.

“it seems that little is lost by deferring WBRT


when visible disease is treated with SRS.
What is gained is the application of WBRT
at the right time for appropriate patients,
leading to more individualized care based
on disease processes and avoiding over
treatment by categorically treating all brain
metastases with WBRT regardless of patient
disease and treatment characteristics”

1120
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43 yo High Functioning
Executive with Stable Systemic
Breast CA

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1122
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Recurrence / Salvage Treatment


WBRT
3 case series used WBRT for recurrent mets
Avg. dose 20-25 Gy over multiple fractions
Post re-WBRT mean survival 4-5 months
Surgery
4 case series of patients who had surgery after previously having
SRS+/-WBRT
10% major surgical complication rate
Median survival after surgery for recurrence 9-11 months
SRS
13 studies addressed role of SRS for recurrent/progressive brain mets
9 studies evaluates SRS in pts who had prior WBRT
4 case series evaluated SRS in pts who had prior SRS
In one study (43 pts) median survival after 2nd SRS was 8 mos and
6 month control rate was 91%
In another study with 45 pts, median survival after 2nd SRS
treatment was 7 months
Chemo

1123
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Summary (1-3 Mets)


1-3 metastatic lesions on MRI
Suspected tumor outside CNS > biopsy lesion
outside CNS
If no lesion found outside CNS > biopsy CNS
lesion
If CNS lesion is resectable
Consider resection +WBRT or SRS + WBRT
or SRS alone to the resection cavity
If CNS lesion is unresectable, SRS +/- WBRT

Summary (>3 mets)


If no known primary consider stereotactic or
open biopsy
Treat with WBRT (esp. with low KPS)
Treat with SRS +/- WBRT
For recurrence
In setting of systemic dz progression
Best supportive care or re-irradiation
Retreat with SRS
With stable systemic disease
Surgery or re-irradiation or chemotherapy

1124
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Recurrence
No prior WBRT > consider WBRT or best
supportive care
Prior WBRT > best supportive care or re-
irradiation (?SRS) if prior positive response
to RT

Resectable? > consider re-resection

Case 1
45 year old female with metastatic
breast adenocarcinoma (HER2+,
treated with Herceptin) presents
with 1 week history of headaches.
Systemic work up shows stable
small chest lesions. Brain MRI as
shown. KPS 80 on steroids. Your
treatment recommendations likely
include:
Surgical resection plus WBRT
Surgical resection plus SRS boost to
resection cavity
Surgery followed by observation
WBRT followed by SRS
SRS alone
Other (feel free to specify in chat box)

5/11/2016 CNS METS LECTURE 66

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Case 1 Management
Would recommend surgery followed by
SRS boost to tumor bed.
Resection confirms diagnosis
Would wait a couple of weeks prior to SRS for
tumor bed to shrink and edema to go away
Most patients with high KPS may wish to
follow with SRS alone, and hold off of
WBRT

Case 2
A 47 year old male (smoker) with
history of NSCLC (he had a 3 cm
LUL lesion treated 6 months prior
with surgery; there were clear
margins and clear nodes),
presents to your clinic with
headaches. His body imaging
shows no obvious systemic
disease. Brain MRI shows 4
enhancing lesions as shown. KPS
90. No neurological deficits. Your
treatment recommendations would
likely include which of the
following:
WBRT
WBRT followed by SRS boost
SRS Alone
Other (feel free to specify in
chat box)

1126
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Case 2 Management
Would recommend SRS to 4 lesions +/- WBRT
Improved survival (Andrews study) only found in
patients with 1 brain met, but suggestive in cases of 3
mets
Other considerations:
This patient has developed several brain mets within
months of primary tumor diagnosis
Suggests aggressive disease
Suggests other micrometastases are probably
already present

Case 3
46 yo man with cutaneous
melanoma resected 2 yrs
prior (Clark level IV)
presents with left focal
seizure. PET/CT is
negative. Stable on
steroids. 3 lesions are seen:
Recommend:
SRS
SRS + WBRT
WBRT
Resection plus SRS

1127
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Case 3 Management
Young person, relatively radioresistant primary
Melanoma has greatest risk of multiplicity, thus more
lesions may be present when re-scanning
SRS alone makes sense
SRS plus WBRT makes sense
WBRT alone doesn’t make sense due to radioresistance
Surgery (with mapping?) of one lesion plus radiotherapy
doesn’t make sense
Consider addition of Temozolomide?
Crosses BBB
anti-melanoma properties
synergizes with radiotherapy
? Give concomitantly or after radiotherapy

On The Horizon for Brain Mets


Increased emphasis of SRS

Decreased use of WBRT

Increased research on Mets

Potential of Serpin Inhibitor Drugs to


block brain metastases

Focused Ultrasound as novel targeted


therapy for brain mets

1128
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Malignant Glioma
Management and
Novel Therapies

Charles S. Cobbs, M.D.


Director, Ben and Catherine Ivy Center
for Advanced Brain Tumor Treatment
Swedish Neuroscience Institute
Seattle, WA

No conflict of interest

1129
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Overview
Definitions Chemotherapy
Biology Focal therapies
New concepts MGMT
Radiographic features 1P/19Q
Advanced imaging Stupp Protocol
Surgical Extent of Recurrence
Resection Options
Pathology Novel / New
Molecular Profiling Approaches
Radiation Therapy Clinical Trials
Focal Therapies Immunotherapy
Virotherapy

Malignant Gliomas: Background


About 24,000 cases / 13,000 deaths per year in USA
Incidence increasing 1.2% / yr
High mortality, GBM mean survival 12-15 mos.
Malignant glioma
GBM accounts for 60-70%
anaplastic astrocytomas 10-15%
anaplastic oligodendrogliomas and anaplastic oligoastrocytomas
10%
More common in men than women
Twice as common in whites as non-whites
Associated with profound immune suppression and cell
mediated immunological dysfunction

1130
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Malignant Glioma: Cause?

Only known risk factor is exposure to ionizing


radiation
Evidence from Cobbs and others indicates that
cytomegalovirus (CMV) infection is associated a
>90% malignant glioma

How Do GBMs Arise? 2001


Glioma”cell of origin”

p53 mutation,
FGF2, PDGF, EGFR
PDGFR-α amplification
overexpression (7p)
Low Grade
INK4A/ARF
Astrocytoma loss
CDK4 amplification (p16/p19
RB loss pathway)
Anaplastic
Astrocytoma PTEN loss
(10q)
PTEN loss
(10q)
GBM GBM
(secondary) (primary)
Modified after E.C. Holland, 2001

1131
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GBM = Undifferentiated glial cell + Loss of


p53 and Rb function + Sustained Ras/AKT

Dai C and Holland EC, Biochim Biophys Acta. 2001

GBM Expression Analysis

1132
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Proneural = Good
Mesynchmal/Proliferative
=Bad

TCGA GBM: Nature 2008

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1134
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Glioma Cancer Stem Cells

Dell’Albani, Neurochem Res 2008

Malignant Glioma Patients:


Immunocompromised?
MG patients are anergic, lymphopenic, have
impaired antibody production, reduced
lymphocyte protein synthesis, and impaired T-
cell function
MG tumors secrete immunosuppressive
molecules TGF- β, IL-10, and PGE-2
Immunosuppressive Tregs (CD4+/CD25+) are
present at high levels:
Potently inhibit cytotoxic T cell function and
impair anti-tumor effector T cells

1135
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Prognostic Markers and Molecular Classification of Gliomas

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1137
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Radiotherapy plus Concomitant and


Adjuvant Temozolomide for GBM

MGMT promoter hypermethylation


improves survival of GBM

1138
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1139
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TYPE 1 – IDH MUTANT OLIGODENDROGLIOMA - Lower grade glioma type 1 is characterized by


IDH1 (or IDH2) mutation and codeletion of one copy of chromosomes 1p and 19q.

TYPE 2 – IDH MUTANT ASTROCYTOMA. Lower grade glioma type 2 is characterized by IDH1
mutation, TP53 mutation, and ATRX mutation, and corresponds to IDH1-mutant astrocytoma.

TYPE 3 – IDH NON-MUTANT LOWER GRADE GLIOMAS. This type carries genetic alterations
that are characteristic of glioblastoma, and are not IDH mutated.

1140
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Malignant Glioma: Patient


Presentation
Patients present with a variety of
symptons:
Headache
Seizure
Focal neurological deficit

1141
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Malignant Glioma: Patient


Management
Extend Survival
Quality of Life
Overall Philosophy “primum non nocere”
Imaging
Surgery
Radiation
Chemotherapy
Local Therapies
Biological Targeted Therapies
Immunological Therapies

Malignant Glioma: Prognostic


Factors
Histological diagnosis New Prognistic Markers:
Age MGMT promoter
Performance Status methylation status
Type and duration of 1p/19q deletion status
symptoms RNA Expression
Extent of surgical pattern (e.g., proneural)
resection IDH1/2 mutation
1970’s: Survival at 1
year:
Surgery alone 3%
With BCNU 12%
With Postop radiation
24%

1142
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Malignant Glioma Best Practices


92% get MRI
75% attempted
resection
19% cortical mapping
99% received
corticosteroids
88% received AED
8% received
antidepressants
7% prophylactic heparin
87% radiotherapy
54% chemotherapy

Non Enzyme Inducing AEDs

1143
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Neuroradiology: Guidelines
Level I recommendation
Gadolinium enhanced MRI
Level II recommendation
CT with contrast
Level III recommendation
MR Spectroscopy
Functional MRI may help define speech and motor areas
Diffusion-weighted MRI, perfusion imaging to measure
relative cerebral blood volume, are helpful especially in
the era of bevacizumab (Avastin)

CT Scan

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1145
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Microneurosurgery, Yasargil, 1994

Pseudoresponse

1146
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Pseudoprogression

Increased rCBV in GBM

1147
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Restricted Diffusion (low


ADC) in proliferative GBM

Heterogeneous enhancing tumor involving the right frontal lobe, surrounded by


vasogenic edema. There is restricted diffusion in the nodular enhancing focus (yellow
arrow)with low ADC values

Combining Gad Enhancement, Diffusion (ADC), rCBV


and MR Spectroscopy to Dileniate Glioma Pathogenesis

1148
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fMRI in Preoperative Planning

Frameless Stereotaxis

1149
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Brain Shift with Neuronavigation

Diffusion Tensor Tractography

1150
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Intraop Stimulation Mapping


Complete anesthesia:
Phase reversal for localization of motor strip
Motor mapping
ECOG preferable
Bipolar stimulator 5mm apart, 2-16mAmp, 60hz
Current to trigger EEG or adjusted to event-related level
Subcortical mapping
Awake Speech mapping:
Consider preop neuro-psych and WADA testing
Essential area = complete speech arrest in absence of sz
“This is a …..”
1-2 cm border is considered safe
Awake Motor Mapping

Awake Speech And Motor


Mapping

1151
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70 yo Female with GBM in Motor Area


and left sided weakness

1152
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1153
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Malignant Glioma: Surgery vs.


Biopsy, ? Extent of Resection
Unequivocal Cases: Evolving body of
Mass effect, Shift, No evidence suggests EOR
diagnosis is correlated to survival
Less clear: Motor and/or awake
Smaller lesions not speech mapping assist in
causing mass effect preventing post-operative
neurological deficit
Diffuse lesions Must consider:
A prospective Age and KPS
randomized controlled
trial (RCT) in USA is Location (eloquent
unlikely to be performed brain)
More tissue is often Feasibility of
critical for diagnosis decreasing mass
effect
For recurrent dz, time
since last surgery

46 yo man with HA and grand mal seizure

1154
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Extent of Surgical Resection:


Guidelines
No PRC trial class I evidence to suggest
that extent of surgical resection statistically
correlates with survival
Level II recommendation: “maximal safe
resection” should be obtained
30 papers, 10 prospective and 20
retrospective, all but one showed improved
survival with extent of resection

Extent of Resection
Level II evidence:
Stummer et al, Lancet Oncology 2006:
RCT, 270 patients, extent of resection of MG with
use of fluorescence (5-aminolevulanic acid)
65% GTR (5-ala group) vs. 35% GTR (non 5-ala
group) based on post op MRI enhancement
6 month PFS 41% vs. 21% (p<.0001)
Non blinded
Pre-Temozolomide era

1155
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Prospective Trials and Clinical


Outcomes by Resection Status
Study Post-surg Median Survival by Extent of Hazard Ratio
Treatment Resection
Complete Subtotal Biopsy
(C) (S) (B)
Stummer* RT 16.7 mo 11.8 mo -- 0.54 (0.041-0.71)
(n = 243) (C vs S)
Gorlia† RT 14.2 mo 11.7 mo 7.9 mo 1.45 (1.22-1.73)
(n = 286) (S vs C)
Gorlia† RT + TMZ 18.8 mo 13.5 mo 9.4 mo 1.46 (1.22-1.74)
(n = 287) (S vs C)

*Utilized fluorescing agent 5-aminolevulinic acid (5-ALA) with surgery.


†EORTC / NCIC study of adjuvant TMZ.

Stummer W, et al. Neurosurg. 2008;62:564-576; Gorlia T, et al. Lancet Oncol. 2008;9:29-36.

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Age Bias in GBM Treatment?

1157
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Do High Volume Centers Have


Better Survival for GBM?

Neuropathology
Tissue diagnosis is critical
Biopsy size important to avoid sampling artifact
Biopsy of tumor edge may provide inaccurate tumor
grade diagnosis
Grade of tumor will determine treatment
Misdiagnosis of e.g., grade III astrocytoma vs.
malignant oligodendroglioma may impact
therapy
1p/19q codeletion
IDH1
ATRX, p53

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1159
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NCCN Guidelines Grade II

NCCN Guidelines Grade III /GBM

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Standard Therapy

External Beam Involved Field


Radiation Therapy
6,000 cGy given 200 cGy daily for 5 days / 6
weeks
Radiation Field obtained from T1 gad or T2
image, plus 2 cm. border surrounding tumor
XRT doubles overall survival compared to no
radiation (RCTs)
Focal Radiation for GBM:
Radiosurgery and Brachytherapy trials have not
demonstrated a survival advantage (RCT)

1161
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Involved Field External Beam RT

Chemotherapy
Nitrosourea (BCNU) were previously used
in combination with radiation therapy with
minimal effect
RCT of Temozolomide has clearly
established this agent as important
additive agent
Carmustine wafers have shown modest
effects in RCT

1162
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Radiotherapy plus Concomitant and


Adjuvant Temozolomide for GBM

Problems with TMZ

TMZ is unlikely to have


any benefit in MGMT
unmethylated GBM (up
to 70% of tumors!)
TMZ has some serious
side effects
TMZ promotes mutations
and specifically driver
mutations in the RB and
Akt-mTOR pathways

1163
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TMZ in Newly Diagnosed Elderly


Patients

RT + TMZ
Trial Age (yrs) N Median

RT60
RT45

RT34

TMZ
survival
(mo)

EORTC 60-69 170 X X 10.9/11.8


NOA-08 > 65 412 X X 9.8/8.2
Nordic 60-69 100 X X X 7.5/7/7.9
70 + 191 X X X 5.2/7.1/9
Turkish 60-69 215 X X 8/13
70 + 90 X X 7/12
NCIC > 69 560 X X ongoing

Wick W, et al. J Clin Oncol. 2010;28(15s). LBA2001; Malmstrom A, et al. J Clin Oncol. 2010;28(15s). Abstract
LBA2002; Dirier A, et al. J Clin Oncol. 2010;28(15s). Abstract 2048; Perry JR, et al. Neuro-oncology. 2010;12(suppl 3).
Abstract P.072.

Local Therapies
Brachytherapy (Implanted radioactive seeds)
Gliasite

Gliadel BCNU wafer


FDA approved for up front and recurrent GBM
Not for non-resectable tumors or tumors that contact
ventricles
Convection Enhanced Delivery (CED)

1164
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Gliadel
Phase III RCT BCNU wafer vs placebo
in newly diagnosed malignant glioma
International, multicenter, double-blind, placebo-controlled trial
of 240 patients with primary high grade gliomas
Randomized to resection and RT +/- Gliadel wafer vs. placebo
BCNU Placebo
Median survival (+2.3 mos) 13.9 months 11.6 months
(p=0.03)

Adverse events: CSF leak (5% bcnu vs 0.8% placebo)


Intracranial HTN (9.1% bcnu vs 1.7% placebo)

Westphal et al. Neuro-oncol 2003 (2): 79

Electrical Field Device


NovoTTF-100A System
Portable device with electrodes on surface of scalp delivering low-
intensity, changing electrical fields known as “tumor-treatment fields”
(TTF)
Thought to damage tumor cells based on their shape and electrical
characteristics
Approved by FDA on April 15, 2011 for relapsed or refractory GBM
Based on single randomized trial of 237 patients
OS similar in TTF and chemotherapy groups
TTF produced suggestion of improved quality of life, slight increased
risk of headache and convulsion compared with chemotherapy
Newly diagnosed GBM trial stopped due to positive
outcomes.

Available at: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm251669.htm. Accessed April 25, 2011.

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Recurrence

What is recurrence?
1990’s Macdonald criteria based on
enhanced tumor size
But what about Avastin, and radiation
necrosis (pseudo-progression)
In 2009 T2 and FLAIR sequences were
recommended to evaluate both enhancing
and non enhancing tumor progression

Response Assessment in Neuro Oncology


(RANO)
Complete Response, Partial Response, Stable
Disease, Progressive Disease

1167
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Recurrence
Nearly all glioblastomas will recur …
Three FDA-approved therapies
1. Gliadel…Carmustine wafer indication
For “recurrent glioblastoma multiforme patients as an
adjunct to surgery”
2. Bevacizumab indication
For “progressive disease in adult patients following prior
therapy as a single agent”
Based on “improvement in objective response rate”
3. Novo TTF-100A device
Wen PY and Kesari S. N Engl J Med. 2008;359(5):492-507; Stupp R, et al. J Clin Oncol. 2007;25:4127-4136;
Gliadel prescribing information. Available at: http://www.gliadel.com/Docs/Pdf/201241R1_Gliadel_PI.pdf and Avastin prescribing
information. Available at: http://www.gliadel.com/Docs/Pdf/201241R1_Gliadel_PI.pdf. Accessed April 11, 2011.

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Targeted Agents

-Often directed at more than one signaling


pathway
-Often non specific
-Often difficulty in obtaining appropriate tumor
cell concentrations

Select Targeted Therapies in


Development
EGFR pathway inhibitors VEGF inhibitors
Cetuximab • Cediranib, vandetanib,
PI3K pathway inhibitors XL184
XL765, XL147, BKM120 Stem cell targets
PDGFR inhibitors • γ-secretase inhibitors
Tandutinib, IMC-3G3 (MK-0752, RO4929097)
AKT pathway inhibitors • Sonic hedgehog
Temsirolimus and inhibitors (GDC0449)
everolimus (mTOR) HDAC inhibitors
Perifosine, MK-2206

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Targeted Agents

T1 Gad

FLAIR

Bevacizumab and
EGFR and mTOR
irinotecan
inhibitor

Bevacizumab (Avastin) +
Irinotecan
First trial in GBM, BEV+Irinotecan
Stark-Vance et al. 2005, 21 pts.
response rate of 43% and 52% stable dz in
21 pts with recurrent GBM
Vrendenberg et al., JCO, 2007, 35 pts.
6 month PFS 46%

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Does Avastin Extend Survival?


RTOG 0825 AvaGlio

NEJM Feb 2014

RTOG 0825 AvaGlio

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Bevacizumab/Avastin:
Take Home Message
Does not prolong survival in newly
diagnosed GBM
Helpful/indicated for:
Symptomatic/bulky tumors
Patients maxed on steroids
Herniation with edema
Progressive GBM

Side Effects of Bevacizumab


Monotherapy (JCO, 2009)
Fatigue (45%)
HA (37%)
HTN (30%)
Nose bleeds (19%)
Proteinuria (5%)
Arterial and Venous thromboembolism (9%)
Impaired craniotomy wound healing >?? (2%)
Intracranial Hemorrhage (2%)(don’t give BEV if
hemorrhage on MRI)
Need to look at Pre-contrast MRI images for
hemorrhage

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Prior to Bev After 6 weeks After 12 months

T1 Gad

FLAIR

Immunotherapy for GBM

CMV antigens

Front. Surg., 02 March 2016

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Immunotherapy for GBM

Immunotherapy Trials 2014


DC Vax – Northwest Biotherapeutics, Phase III
RCT – Newly diagnosed GBM
Derived from Linda Liau tumor lysate vaccine
Available in Germany
Celldex (EGFRvIII) – Phase III RCT in newly
diagnosed and recurrent – No Benefit
ICT 107 – ImmunoCellular Therapeutics –
Phase IIb newly diagnosed GBM post RT/TMZ
DCs pulsed with 6 GBM tumor associated antigens
ICT 121 – ImmunoCelllular /Cedars Sinai
Phase I DC vaccine vs. CD133 in recurrent GBM

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Immunotherapy for GBM 2016


A randomized, placebo-controlled phase III trial testing DCVax-L, a dendritic cell vaccine derived from a
patient’s own tumor, for newly diagnosed glioma (including glioblastoma/glioblastoma multiforme and
astrocytoma) (NCT00045968).
A randomized, placebo-controlled phase IIb trial studying ICT-107, a dendritic cell vaccine that targets six
different antigens associated with glioblastoma multiforme, in patients with newly diagnosed glioblastoma
following resection and chemoradiation (NCT01280552; this study is ongoing, but not recruiting
participants).
A phase II trial testing the HSPPC-96 vaccine in patients with recurrent glioma that can be removed with
surgery (NCT01814813).
A phase II trial testing ERC1671, a cancer vaccine composed of a combination of glioblastoma tumor cells,
in patients with recurrent or progressive, bevacizumab-naïve glioblastoma multiforme or gliosarcoma
(NCT01903330).
A phase I/II trial testing SL-701, a vaccine comprised of multiple synthetic peptides, in adult patients with
glioblastoma multiforme in first recurrence (NCT02078648).
A phase I trial testing ICT-121, a dendritic cell vaccine pulsed with CD133, which is expressed on
glioblastoma and glial stem cells, in patients with recurrent glioblastoma multiforme (NCT02049489).
A phase I trial testing two adenoviral vectors, with one testing HSV1-TK, which is expected to kill brain
cells and expose the tumor antigens, and one testing Flt3L, a cytokine known to cause proliferation of
dendritic cells, in patients with newly diagnosed high grade glioma (NCT01811992).
A phase I trial testing a dendritic cell vaccine administered with imiquimod, a Toll-like receptor 7/8 agonist,
in adult and pediatric patients with glioma (NCT01808820) and pediatric patients with brain cancer
(NCT01902771).
A phase I trial testing a tumor vaccine given with the adjuvant Montanide (ISA 51) in adult patients with
newly diagnosed glioblastoma (NCT01702792).
A phase I trial testing a tumor vaccine that targets the brain tumor initiating cell (BTIC) line, GBM-6, given
along with imiquimod, a Toll-like receptor 7/8 agonist, in pediatric patients with diffuse intrinsic pontine
glioma (NCT01400672).
A phase I trial testing a personalized cancer vaccine, NeoVax, in adult patients with MGMT-unmethylated,
newly diagnosed glioblastoma (NCT02287428).
A phase I trial testing ADU-623, a vaccine targeting the EGFRvIII and NY-ESO-1 antigens, in patients with
treated and recurrent grade III/IV astrocytomas (NCT01967758).
A phase I trial testing a dendritic cell vaccine for patients with newly diagnosed or recurrent glioblastoma
(NCT02010606).
A phase I trial testing a cytomegalovirus vaccine given along with basiliximab (Simulect®), an antibody
that targets an immune-suppressing molecule in tumors, in patients with newly diagnosed glioblastoma
multiforme (NCT00626483).
A pilot study to test glioma antigen peptides given along with Poly-ICLC (Hiltonol®), a Toll-like receptor 3
agonist, in pediatric patients with glioma (NCT01130077).
A pilot study testing glioma antigen peptides given along with imiquimod, a Toll-like receptor 7/8 agonist,
in children with recurrent ependymomas (NCT01795313).
A pilot study testing a tumor vaccine that targets the brain tumor initiating cell (BTIC) line given along
with imiquimod, a Toll-like receptor 7/8 agonist, in adult patients with grade II gliomas (NCT01678352).
A pilot study testing a dendritic cell vaccine in patients with newly diagnosed glioblastoma (NCT01957956).

Checkpoint Inhibitors
A phase III trial testing Opdivo® (nivolumab) and Yervoy® (ipilimumab)—anti-PD-1 and anti-
CTLA-4 antibodies, respectively—in patients with recurrent glioblastoma (NCT02017717).
A phase II trial testing MEDI4736 (durvalumab), an anti-PD-L1 antibody, in patients with
glioblastoma (NCT02336165).
A phase II trial testing Keytruda® (pembrolizumab), an anti-PD-1 antibody, with or without
Avastin® (bevacizumab), in patients with recurrent glioblastoma multiforme
(NCT02337491).

Oncolytic Virus Therapies


A phase I trial testing DNX-2401 in patients with recurrent glioblastoma or gliosarcoma
(NCT02197169).
A phase I trial testing a measles virus that produces carcinoembryonic antigen (CEA) in
patients with recurrent glioblastoma multiforme (NCT00390299).
A phase I trial testing Toca 511 (vocimagene amiretrorepvec), a retroviral replicating vector
that expresses the cytosine deaminase gene, in adult patients undergoing surgery for grade III or
IV gliomas (NCT01985256).
A phase I trial testing the herpes simplex virus HSV-1716 in pediatric patients with refractory or
recurrent high grade gliomas that can be removed with surgery (NCT02031965).
A phase I trial testing a genetically engineered poliovirus for adult patients with recurrent
glioblastoma multiforme (NCT01491893).

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Adoptive Cell Therapy


A phase I/II trial testing anti-EGFRvIII chimeric antigen receptor (CAR) T cells in
patients with malignant glioma (NCT01454596).

A phase I trial testing anti-EGFRvIII chimeric antigen receptor (CAR) T cells in


patients with glioblastoma (NCT02209376).

Adjuvant Immunotherapies

A phase II trial testing Poly-ICLC (Hiltonol®), a Toll-like receptor 3 agonist, in patients


with recurrent pediatric grade I or II astrocytoma (NCT01188096).

A phase I/II trial testing indoximod, an IDO inhibitor, in patients with recurrent glioma
(NCT02052648).

Monoclonal Antibodies
A phase I/II trial testing TRC105, an anti-endoglin antibody, in patients with recurrent
glioblastoma multiforme (NCT01648348).

A phase I trial testing ABT-414, an antibody-drug conjugate (ADC) that targets


EGFR/EGFRvIII, in patients with newly diagnosed glioblastoma (NCT01800695).

Malignant Glioma
Conclusion

“the times they are


a’changin”

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Meningiomas

Ossama Al-Mefty, M.D.,FACS


Brigham & Women hospital
Harvard Medical School

Disclosure Statement
• Reports no commercial interest

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meningioma

H. Cushing. Cavendish lecture, 1922

“MENINGIOMA”

all-embracing name for


unknown cell origin

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Arachnoid cap
cell

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Distribution of primary brain


tumors (1935 - 1977)
♦Including postmortem data:
Meningioma - 40%
♦Excluding postmortem data:
Meningioma - 21%

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“Some die from


meningiomas,

OTHERS (DIE) WITH THEM”


Rengachary, 1991

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Only 1/3 grow


2 mm per year
Mean follow up 67 Mons

7/98

2/00
8/99

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Abolfotoh and Al-Mefty. Observation of small meningiomas.


in controversies in Neurosurgery , 2nd ed. Thieme.

6/93 11/04

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•They need no
“control”
when they Are
self controlled

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Fibroblastic

Meningeothelial

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Transitional

Psammomas Body

Psammomatous

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WHO 2000 MENINGIOMAS


Grade I - Low risk of recurrence &
aggressive growth:

•Meningothelial
•Fibrous (fibroblastic)
•Transitional (mixed)
•Psammomatous
•Angiomatous
•Microcystic
9o%
•Secretory
•Lymphoplasmacyte- rich
•Metaplastic

Atypical

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Atypical meningioma
Increased mitotic activity (> 4mitoses /10 HPF)
or three or more of following features:

•increased cellularity
•small cells with high nucleus
•cytoplasm ratio
•prominent nucleoli
•sheet-like growth
•foci of necrosis

WHO 2000 MENINGIOMAS


Grade II – greater likelihood of
recurrence and/or aggressive growth:

•Atypical
•Clear cell
•Chordoid

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WHO 2000 MENINGIOMAS


Grade III – greater likelihood of
recurrence and/or aggressive growth:

•Rhabdoid

•Papillary

•Anaplastic (malignant)

Almefty treated Meningioma patients


N=85
Last 2 years
Grade I Grade II Grade III
N=53 (62%) N=21(25%) N=11 (13%)
Grade
Primary
I
Aggressive
Grade
Primary
II
Post XRT
Grade
Primary
III
Post XRT
62% features
N=41 25% N=0
N=11 13%
N=3 N=1
N=9
Radio-
Post XRT induced
N=1 N=1

Recurrence Post XRT Recurrence Primary grade I Recurrence Primary


N=12 N=1 N=10 N=8 N=8 lower grade
Radio- N=8
Post XRT
induced N=5
N=1 Post XRT
N=6
Primary grade II
N=2 Radio-
Al-Mefty/Boskovitz Post XRT induced
SNS 2013 N=2 N=1

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Atypical and malignant meningioma


1 do novo
2 radiation induced
3 transformed

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7ys f-up

8/95 3/02

Preop. Postop.
3ys 1y

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Presence of progesterone
receptors in meningioma is a RU 486
favorable prognostic factor

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GRANT from ASTA


“Use of Octreoscan
as a Sensitive
Diagnostic Tool for
Brain Tumors”

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239 patients with meningioma

68%
ER+
6q25.1

PR+
11q22
7%
25% -non

Aggressive pathology
35%
**
*
30%

25%

20%
*, **
15%

10%

5%

0%
PR NON ER

Aggressive pathology

10% 31% 33%

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16 Ki67 [%] PCNA[%]

14
*
12
**
10
*,**
8

6
*
4

2
*
0
PR NON ER

Chromosome abnormalities in de
novo meningiomas

70%

60%
**
50%
*
40%
**
30%

20% *,**
*,** * *
10%
*
0%
PR NON ER

Ch.22 Ch14 Ch19

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Recurrence from residual Recurrence without residual

80
70
60
50
40
30
20 *
10
*, ** **
0
PR NON ER

DEATH FROM PROGRESSION


25%

*
20%

15%

10%

5%
*
0%
PR NON ER

3% 8% 22%

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ETIOLOGY
Trauma
Viruses Papovavirus antigen
BK viral DNA
SV40 viral DNA
Radiation Low dose
High dose

1. Occur in the irradiated field


2. Appropriate latency period after radiation.
3. Different from preexisting pathology

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12/96 Postop.
1/00 recurrence

Before G-Knife (3/00)


8/98- recurrence 11/98-Postop.

11/99 recurrence
12/23/99 -Postop. F-up GK 5/02

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Radiation induced meningioma


16 cases
F-up – from 2 to 11 ys for 13 pt
Latency period –from 6 to 58 ys
Recurrence -100%
Second recurrence -58%
Third recurrence -17%
Total N of recurrences 24
Total surgeries -27
Radiation -8 (GK, XK, CK)

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High Dose

Low Dose

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TRAUMA

Berlinghieri (1772-1825)
Meningioma might develop
1. as many as 10 to 12 y after
head injury
2. H. Cushing
1897 –U.S. Army General Leonard Wood - head
injury from a low-hanging chandelier
1905 – meningioma, first surgery
1910- two stage surgery for parasagittal
meningioma. Pt was discharged in good health
and in 1920 he was the republican favorite to
succeed Woodrow Wilson as president.

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Follow up 21+0.1 mos


( 4- 60 mos )
N Recurrence Mortality

31 5 0
Normal karyotype 29% 16 % 0%

75 31 6
73% 41% 8%

Clonal autosomal aberrations

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Monosomy 22 in Telomere fusions


involving to loss of 1p
benign associated with the
progression to
atypical and malignant

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Sequencing: a complete analysis of genetic changes in tumors

Can reveal genetic mutations, gains/losses of chromosomal regions, and


translocations by comparing tumor with normal reference DNA

Normal

Tumor

Meyerson, 2010

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Back to the future


Individual treatment plan
NOT ONLY BY
INDIVISUAL PATIENT
INDIVISUAL TUMOR
INDIVISUAL HISTOLOGy
BUT BY
SPESIFIC GENITIC ABBERATION

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Bernasconi-Cassinari
artery (1956)

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CURE

Classification of the extent of tumor removal

Grade I: Complete removal with


resection of dura & abnormal bone
Grade II: Complete tumor removal with
coagulation of dural attachment
Grade III: Complete tumor removal without
resection or coagulation of its dural attachment
(evaded sinus )
Grade IV: Subtotal removal
Grade V: Simple decompression.

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Recurrence Risk
Simpson’ s Recurrence
Grade Rate (%)
I 9
II 19
III 29
IV 39
V 89

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Meningiomas are neoplasm.


They grow, and regrow

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3/88

GRADE 1

6/02- recurrence

8/02- postop.

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9/18/03preop. 4

Pathology- Grade II

9/24/03 postop. 4 plus RT

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6/04

9/04

9/04 preop.

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Grade III

POSTOP.

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He died 3 ms late
from progression

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ANTERIOR THIRD
MIDDLE THIRD
POSTERIOR THIRD

OPEN
PARTIALLY CLOSED
OCCLUDED

ONE WALL
TWO WALLS
THREE WALLS

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Origin

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Alike

But,
quite different

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Adcok,
Burden

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M.Yasargil, 1984

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“Tumor Control”
>90%

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Neurosurgery 1996; 36:2-9

Average f/up 18 years


At 10 years
Survival advantage to patients with radiotherapy
At 20 years
No difference in survival
Most patients treated with SRS
recurred - delayed
Term effect

Conventional fractionated radiotherapy


45 pt with meningiomas.

Subtotal resection plus radiation


Recurrence 75%
Complications 56%

F-up > 5 ys

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99 pt (86% - skull base meningioma)


Clinical control 93%
(No resection required)
Increase in size 5%
To surgery 7%
Complications 14%
F-up 5-10 ys

Basal meningioma
γ- Knife
99 pt (89 - skull base meningioma)
Clinical control 93%
(No resection required)
Increase in size 5%
To surgery 7%
Complications 14%
F-up 5-10 ys

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179 patients
140 tumor-for f-up 37.3 mos
Complications-25%

MRI changing- edema- 33 (23.6% )


Symptomatic edema-9%
Seizures - 4

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4/91 12/94
Add GK post GK

9/99

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MENINGIOMAS
Delayed aggressive growth after
initial control by radiosurgery
12 cases
Average of latency- 37.85 mo (6-108)
Rapid growth 10
Change of pathology (B-A) 4 (from 9)
Cytogenetic abnormality 3 (from 5)

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53% 67%

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VA
20/400

VA
20/20

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Visual improvement
Curative removal

OPTIC CANAL INVOLVEMENT – 73 %

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OPTIC CANAL INVOLVEMENT – 73 %

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The D,D,D,D of
Meningioma Surgery

• D: Disrobe
• D: Devascularize
• D: Debulk
• D: Dissect

ENDOSCOPE IS great tool


learn it
master it
and use it

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Ultra short

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Post op

Post op

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SURGICAL STRATEGY
Exposure with minimal
brain retraction.
Vascular preservation.
Cranial nerve preservation

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ER PR Ki67

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VEINS RULE

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Defeated
by
BIOLOGY
Preop. Postop.
(R5)

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There is today nothing in the


whole realm of surgery more
gratifying than the
successful removal of a
meningioma with
subsequent perfect function
recovery...
Harvey Cushing, 1922

Malignant

High -
proliferative ER+

index

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GRANT from ASTA


“Use of Octreoscan
as a Sensitive
Diagnostic Tool for
Brain Tumors”

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Estrogen is bad

Progesterone is
good

4/04
10/03
1989

3/04

9/03

4/04
12/03
3/01

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Planes

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Devascularization
Al-Turky

State Street, 1905

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58 pt with benign brain tumors


Complications - 21 pt (36%)
rad necrosis – 17 pt (29%)

Average f-up- 8.1 years

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Personal experience
1000 and 1
meningiomas

MEET
ANDI –
The ancestor of the
future perfect human

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“Do not harm”

First pathology

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Recurrence

Second recurrence

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First surgery Third surgery

Second surgery

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Dr. John Kepes’ drawing

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Adhesion

Wittaker

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Neurosurgery 1996; 36:2-9


Average f/up 18 years
At 10 years
Survival advantage to patients with radiotherapy
At 20 years
No difference in survival
Most patients treated with SRS
recurred - delayed
Term effect

SRS FSRT
35 pt 18 pt
Dose 1400 cGy 5400 cGy
Volume 6.8 ml 8.8 ml
3y TC 92.7% 93.3 %
WHO Gr I 92.9% 92.3 %
Compl. 2 pt 1pt
F-up 4-97 mo 6-63 mo

1300 124
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ICE

1301 125
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-25º F with windchill

1302 126
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A meningioma is, in many ways, the


soul of neurosurgery. The progress in
meningioma treatment mirrors
advances in neurosurgery, while
advancements in neurosurgery are
put to maximum use to improve the
treatment of meningiomas.

1303 127
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Meningiomas’ Future =
Neurosurgery’s Future

Personal experience
1000 and 1
meningiomas

1304 128
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Francesco Durante
(1844-1934)

Chair of Clinical Surgery


at Rome’s Mazzoni Clinic

1885-total resection of olfactory groove


meningioma.
Pt had recurrence 11 ys late in 1896
and required a second operation.

1305 129
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1306 130
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7/98 8/99 2/00

1307 131
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1308 132
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1309 133
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1310 134
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1311 135
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1312 136
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Basal meningioma (1982-2003)

810

Witaker

1313 137
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1314 138
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Monfort

1315 139
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1316 140
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1317 141
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Cavernous sinus meningioma


163 cases
Mortality
Perioperative mortality 1 (0.61%)
from pulmonary embolism (Home)
Mortality within 1 year postop.,
related to surgery 2 (1.2%)
Ischemic deficit 7 (4.2%)

1318 142
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Preop
F-up 3 mo

Postop.

1319 143
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1320 144
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GK and I

Actuarial
Prediction
Guess
Wrong Guess?

1321 145
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γ- Knife
159 patients
Average follow-up 35 mo
◊Clinical control 93%
◊Radiological control 94%

1322 146
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Recurrence-free survival after


gamma knife treatment of residual
meningioma

Recurrence in patients with residual


All Locations
recurrence
100100

8080
ANY Growth
Survival probability (%)

6060
group
mix

4040

2020

00 50
50
100
100
150
150
200
200

Time (Months)
Time

1323 147
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11/99

5/00

11/04

Small Skull Base Meningioma


N - Knife - 39
♦Control 100%
♦Increased in size slightly - 4 (10%)
♦Complications -0
Average f-up 47.33 + 9.5 mo
(1 - 84 mo)

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Small Skull Base Meningioma

Operated - 28

Mortality / Morbidity - 0

CURE
♦Surgical removal

Forever

1325 149
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Surgery is the red flower


that blooms among the
leaves and thorns that are
the rest of medicine.
- RICHARD SELZER

1326 150
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1328 152
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1329 153
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1330 154
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Skull Base Highways

1331 155
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Petroclival meningioma
194 cases (1983-2003)
OUTCOME
•Surgical mortality 0%
•Partial resection 10%
•Non cranial nerve morbidity 4 (3%)
Temporal lobe venous infarct 1 pt
Mid brain infarct 2 pt
Repeated intraventricular hemorrhage 1 pt

The Bermuda Venous


Trangle

1332 156
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Parasellar Meningioma
317 cases

♦ Mortality within 30 days 2 (0.6%)


♦ Stroke 7 (2.2%)
♦ Total tumor resection 282 (90%)
♦ Recurrence 21 (7%)
(subtotal resection)

1333 157
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Principles in
the Operative
Management
of Low-Grade
Gliomas
Nader Sanai, MD, FAANS, FACS
Associate Professor of Neurological Surgery
Director, Division of Neurosurgical Oncology
Director, Barrow Brain Tumor Research Center
Barrow Neurological Institute

Disclosures

Reports no commercial interest

1334
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Current Glioma Overall Survival Data

Median
2-Year 5-Year 10-Year
Age at
Survival Survival Survival
Diagnosis

Grade I 17 91% 88% 84%

Grade II 40 55% 45% 35%

Grade III 42 40% 25% 20%

Grade IV 55 12% 5% 3%

Source: SEER Cancer Incidence Research Database

Heterogeneity in LGG Overall Survival


Median
2-Year 5-Year 10-Year
Age at
Survival Survival Survival
Diagnosis
Grade I
17 97% 94% 91%
JPA
Grade II
40 61% 47% 35%
Astrocytoma
Grade II
32 90% 79% 64%
Oligodendroglioma
Grade II
35 75% 57% 46%
Mixed Glioma

Source: SEER Cancer Incidence Research Database

1335
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Distribution of Adult Gliomas

7% Grade I: Least aggressive

14% Grade II: Less aggressive

“Malignant”
9% Grade III: More aggressive

70% Grade IV: Most aggressive

All Grade II gliomas eventually become high-grade

Pitfalls of Conventional Radiology for LGGs


All non-enhancing gliomas are not low-grade gliomas (LGG)
MD Anderson* 60 % WHO grade II
40 non-enhancing gliomas
40 % WHO grade III
40-50 % false-positive rate
UPMC* 50 % WHO grade II
20 non-enhancing gliomas
45 % WHO grade III

Astrocytoma Oligodendroglioma
WHO Grade III WHO Grade II

* Ginsberg et al.Surg Neurol 1998; 49: 436-40


* Kondziolka et al.J Neurosurg 1993; 79: 533-536

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Predicting Grade: The Inaccuracy of a Biopsy


Low-Grade Glioma on Stereotactic Biopsy:
How Often is the Diagnosis Accurate?
Muragaki et al.
Minim Invas Neurosurg 2008; 57: 275-279

36 % Concordance in tumor
histology, grade,
and MIB-1 labeling

72 % Concordance in tumor
grade

Early Resection vs. Watchful Waiting

Jakola et al, JAMA 2012; 308(18):1881-1888

1337
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Low-Grade Gliomas: Extent of Resection

LGG Surgery in the Modern Literature


30
Favor More Extensive Resection
25 No Significant Benefit for Extent of Resection
Cumulative Publications

20

15

10

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Volumetric Analysis of LGG Survival Benefit


Role of Extent of Resection in the Long-Term Outcome
of Low-Grade Hemispheric Gliomas
Smith et al.
J Clin Oncol. 2008; 26(8):1338-45
Hazard Ratio

P Point Estimate † 95% CI


n = 216
Log pre-op tumor vol (cm3) 0.004 4.442 1.601–12.320

Post-op tumor vol (cm3) 0.03 1.010 1.001-1.019

Extent of resection (%) <0.001 0.972 0.960-0.983

* Adjusted for the effects of patient age, KPS, tumor location and tumor subtype.
† Per unit of measure (e.g. log cm3, cm 3, %)

EOR Influence on LGG Overall Survival

Number of Extent of 5-Year Multivariate


Patients Resection Survival p-value

100% 98%
Claus (2005) 156 <0.05
<100% 92%
>90% 97%
Smith (2008) 216 <0.001
<90% 76%
100% 100%
Capelle (2013) 1091 0.0199
<100% 77%

Claus et al., Cancer 2005; 103(6): 1227-33


Smith et al. J Clin Oncol. 2008; 26(8):1338-45
Capelle et al. J Neurosurg. 2013; 118(6): 1157-68

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‘Malignant’ Transformation
Risk of Transformation
Literature is varied: incidence ranges from 11-100%
median time to transformation ranges from 2.1-6.4 years
50-75% of Grade II gliomas become Grade III or IV within 7-8 years*
*Jaeckle et al., J Neurooncol 2011; Aug; 104(1): 253-9

Persistent Growth
Even without transformation, Grade II gliomas continuously grow 4.1mm / year*

1-2mm every 6 months =


no observable growth on q6 month MRIs

Need to compare serial MRI scans over longer intervals

*Mandonnet et al., Ann Neurol 2003; 53: 524-528

‘Malignant’ Transformation
Risk of Transformation
Tumor
Literaturegrowth
is varied:
rate can be incidence
instructive
ranges from 11-100%
median time to transformation ranges from 2.1-6.4 years
Changes
12.0 in growth rate identify LGGs that
50-75% of Grade
have become II gliomas
or will becomebecome Grade
anaplastic in III or IV within 7-8 years*
Jaeckle
*the al., J Neurooncol 2011; Aug; 104(1): 253-9
nearetfuture*
11.8
Tumor Volume (ml)

11.6
Persistent Growth
11.4

11.2

11.0

10.8

10.6
Transformers
10.4
0 6 12 18 24
Non-Transformers
Time (months)

* Rees et al. Eur J Radiol 2009;72(1):54-64

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EOR and its Impact on LGG Transformation

5-year Malignant
Progression-Free
Survival:
88% with EOR ≥ 90%
71% with EOR < 90%
Sanai et al, J. Neurosurg. 2010; 112(1):1-9

EOR and its Impact on LGG Transformation

n=190 patients P<0.001

Ius et al, J. Neurosurg. 2012; 117:1039-1052

1341
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Low-Grade Glioma Heterogeneity

World Health Organization (WHO) Grade I WHO Grade II


Juvenile Pilocytic Astrocytoma (JPA) Diffuse Astrocytoma
Subependymal Giant Cell Astocytoma (SEGA) Oligodendroglioma
Myxopapillary Ependymoma Oligoastrocytoma
Subependymoma Pleiomorphic Xanthroastrocytoma
Dysembryoplastic Neuroepithelial (DNET) Pilomyxoid Astrocytoma
Ganglioglioma Ependymoma
Choroid Plexus Papilloma Central Neurocytoma

Low-Grade Glioma Heterogeneity

Astrocytomas Oligodendrogliomas Mixed Gliomas


World Health Organization (WHO) Grade I WHO Grade II
Juvenile
JPA Pilocytic Astrocytoma (JPA) Diffuse Astrocytoma
Subependymal
SEGA Giant Cell Astocytoma (SEGA) Oligodendroglioma
Myxopapillary Ependymoma Oligoastrocytoma
Subependymoma Pleiomorphic
PXA Xanthroastrocytoma
Dysembryoplastic
DNET Neuroepithelial (DNET) Pilomyxoid Astrocytoma
Ganglioglioma Ependymoma
Choroid Plexus Papilloma Central Neurocytoma
Glioma with Ependymal Differentiation Others

1342
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LGG Heterogeneity: Oligodendrogliomas


Extent of resection impacts the rate for transformation
• Hemispheric LGGs: EOR > 90%: 5-year MPFS of 93% (p=0.05)*
• Insular LGGs: EOR > 90%: 5-year MPFS of 88% (p=0.04)*
100

Is the biological impact of EOR driven by histology?


Progression-Free Survival
Cumulative Malignant

80 EOR > 90
Laura Snyder, MD
Assistant Professor of Neurosurgery
60 EOR < 90
Barrow Neurological Institute

40
p=NS

20

0
0 20 40 60 80 100 120
Time (months)
*Smith et al. J Clin Oncol. 2008; 26(8):1338-45
*Sanai et al., J. Neurosurg. 2010; 112(1): 1-9

Low-Grade Glioma Extent of Resection

Early resection is preferred to biopsy and


watchful waiting

Complete and near-complete resections


confer an overall survival benefit

Complete and near-complete resections can


suppress the rate of transformation

1343
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Glioma Rates of Gross-Total Resection:


Results in the Modern Literature
2005-2015
Low-Grade Glioma
Reported Rates of Gross-Total Resection
11% - 46%
Disaggregated Dataset
460 of 1912 Tumors = 24.1% GTR

High-Grade Glioma
Reported Rates of Gross-Total Resection
30% - 84%
Disaggregated Dataset
1714 of 2616 Tumors = 65.5% GTR

Improving Glioma Extent of Resection


Intraoperative Techniques
Employ natural subarachnoidal planes whenever possible
Design your approach around the planned point-of-entry
Position patients to enhance gravity-retraction
Traverse functionally-silent corridors to reach your target

Intraoperative Technology
Fluorescence-guided surgery for low- and high-grade gliomas
Intraoperative MRI for identification of residual tumor
Intraoperative ultrasound to visualize local microvasculature
Intraoperative CT to compensate for brain shift

1344
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Improving EOR: Arachnoidal Dissection

Improving EOR: Entry-Point Selection

1345
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Improving EOR: Gravity-Retraction

Balancing EOR with Functional Outcomes


Less tumor = longer survival Less morbidity = longer survival
% Survival

Months Months
Sanai et al., J. Neurosurg., 2011 McGirt et al., Neurosurgery, 2009

1346
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Improving LGG EOR: Intraoperative Mapping

Alexia
LanguageTraditional Targets for Intraoperative Awake Mapping Motor
Broca’s mouth
Motor
Naming
Reading
Sensory
Writing
Visual
Anomia
Speech
Subcortical arrest
Broca’s Area Wernicke’s Area

Improving LGG EOR: Intraoperative Mapping

• Meta-analysis of 6095 cases


• Similar rates of gross-total resection
• Eloquent locations more frequent with stimulation mapping
• Two-fold reduction in late severe deficits with stimulation
mapping (8.3% vs. 3.4%)
DeWitt et al., J Clin Oncol. 2012 Jul 10;30(20):2559-65

1347
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Improving EOR: Non-Functional Corridors

En Bloc Approach
Windowing Approach

Improving LGG EOR: 5-Aminolevulinic Acid

5-aminolevulinic acid is a pro-drug metabolized by


all gliomas to fluorescent protoporphyrin IX

Orally administered; essentially nontoxic; t1/2 = 45 min

Macroscopically-visible in WHO Grade III / IV gliomas

Microscopically-visible in WHO Grade II gliomas

Isihara et al., Neurol Med Chir (Tokyo) 2007


White Light 5-ALA HGG Fluorescence

1348
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Improving EOR: Fluorescence-Guided Surgery


Image intensity of wide-field microscopy is subjective,
particularly at the diffuse margins of a glioma

Poor sensitivity when detecting sparse tumor cell populations

Liu JT et al., Neurosurgery 2014 Jul;75(1): 61-71

Improving EOR: Fluorescence-Guided Surgery


PpIX fluorescence observed in 46% of nonenhancing gliomas
85% of PpIX(+) nonenhancing gliomas had grade III histology
Proliferation index, cell density, and nuclear pleomorphism
were significantly higher in areas of focal PpIX fluorescence
Grade II
Grade III

Widhalm et al., PLOS One 2013; Oct 18

1349
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Improving EOR: Fluorescence-Guided Surgery


High-Grade Gliomas Low-Grade Gliomas

Improving EOR: Fluorescence-Guided Surgery


Negative
Positive

Sanai et al., J. Neurosurg., 2011

1350
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Improving EOR: Fluorescence-Guided Surgery


Microscopic Fluorescence
Tumor Tumor Macroscopic Initial Mid-point Cavity Volumetric
Age Sex
Location Grade Fluorescence Encounter Resection Margin EOR
19 M Frontal Grade I No Yes Yes Yes 100%

37 F Frontal Grade II/III No Yes Yes Yes 100%

21 M Frontal Grade II No Yes Yes No 98%

64 M Temporal Grade II No Yes Yes No 87%

39 F Parietal Grade II No Yes Yes Yes 99%

32 F Frontal Grade II No Yes Yes No 94%

38 F Temporal Grade II No Yes Yes Yes 92%

49 M Insular Grade II No Yes Yes Yes 93%

24 M Temporal Grade II No Yes Yes No 97%

30 M Insular Grade II No Yes Yes Yes 90%

Sanai et al., J. Neurosurg. 2011; 115(4): 740-8

Improving EOR: Intraoperative Ultrasound

Lenticulostriate arteries visualized intraoperatively with 3D ultrasound


3D ultrasound images fused to neuronavigation in real-time

Stenoet al, J. Neurosurg. 2016 Feb 5: 1-8 [Epub ahead of print]

1351
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Improving EOR: Intraoperative Ultrasound

Lenticulostriate arteries visualized intraoperatively with 3D ultrasound


3D ultrasound images fused to neuronavigation in real-time

Stenoet al, J. Neurosurg. 2016 Feb 5: 1-8 [Epub ahead of print]

Improving EOR: Intraoperative Ultrasound

Lenticulostriate arteries visualized intraoperatively with 3D ultrasound


3D ultrasound images fused to neuronavigation in real-time

Stenoet al, J. Neurosurg. 2016 Feb 5: 1-8 [Epub ahead of print]

1352
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Improving EOR: Intraoperative CT

Portable CT scanner, 1.25mm cuts transferred to navigation system


Residual detected via tumor calcifications
Can correct brain shift by leaving radio-opaque cottonoids in the field
Barbagallo GM al, Neurosurg. 2015 Nov 9 [Epub ahead of print]

Principles in the Operative


Management of Low-Grade Gliomas
Early and aggressive intervention improves overall
survival, but must be balanced by risk of morbidity

Low-grade glioma extent of resection can be


associated with improved transformation rates

Intraoperative technique should emphasize greater


exposure, as well as identification of functional sites

Surgical strategies should evolve alongside new


intraoperative tumor visualization technologies

1353
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Conclusions: Low-Grade Gliomas


Low-grade glioma extent of resection improves outcome
• Improved overall survival
• Modification of malignant transformation rates

Low-grade glioma heterogeneity influences treatment effects


• Regional subtypes (e.g.: insular): impact of microenvironment?
• Histological subtypes (e.g.: oligodendroglioma): impact of EOR?

Extent of resection impacts tumor biology and can be improved


• Operative corridor selection
• Intraoperative mapping
• Fluorescence-guided surgery

Handheld devices enhance visualization of cellular infiltration


• 5-ALA reliably identifies non-enhancing low-grade glioma cells
• Real-time quantification of residual tumor burden has arrived

Thank you for your attention

Email: Nader.Sanai@bnaneuro.net

1354
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Surgical Management of
Pineal Region Tumors

Jeffrey N. Bruce, MD
Columbia University

Disclosure Statement
• Reports no commercial interest

1355
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Histological Considerations

Tumor Types Diversity/Heterogeneity


• Pineal cell • Malignant vs benign
• Germ cell – Intermediate grade
• Glial cell • Mixed cell types
• Miscellaneous • Non-neoplastic pathology
– Vascular
– Inflammatory/infectious
– Benign cysts

Historical Perspective

• early surgical results = high morbidity


• shunt and “blind radiation”
• current emphasis on tissue dx

1356
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Potential RT complications
• Hypothalamic/endocrine
dysfunction
• cerebral necrosis
• RT-induced tumors
• cognitive impairment

Radiographic variations are not


reliable for predicting histology

ependymoma

pineocytoma

germinoma

1357
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Pineal cysts

Diagnostic considerations
• tissue diagnosis mandatory

• germ cell markers (ß-HCG/AFP)


– trt with RT and chemo
– 2nd look surgery for residual

1358
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Stereotactic
Biopsy
vs
Open Resection

Advantages of Open
Resection for Pineal Tumors
• definitive diagnosis
• resection curative for benign tumors
• resection curative for some non-benign tumors
• malignant tumors can benefit from debulking
• operative risks are acceptable
• control of hydrocephalus

1359
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Stereotactic biopsy considerations

• sampling errors
– 25% of GCT are mixed
• small sample difficult to interpret
• hemorrhage
• ignores benefits of removal or debulking

Stereotactic biopsy for pineal tumors

• bleeding risks
– deep venous
system
– vascular tumors
– vascular
anomalies

1360
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Indications for
stereotactic biopsy
• tumor
dissemination
• medical
contraindications
to craniotomy
• invasive tumors

Endoscopic considerations

• Useful for selected cases (cysts)


• Sampling error
• Bleeding risks
• Can be combined with ETV
– Separate burr hole usually required

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Stereotactic biopsy approach

Choice of surgical approaches

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Supracerebellar Infratentorial Approach

ADVANTAGES
• direct midline approach
• avoid deep veins
• gravity assists exposure

DISADVANTAGES
• sitting position
- air embolus

Supracerebellar Infratentorial Approach

1364
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Supracerebellar Infratentorial Approach

Surgery of the third ventricle, Apuzzo ed. 1996

Supracerebellar Infratentorial Approach

Surgery of the third ventricle, Apuzzo ed. 1996

1365
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Supracerebellar Infratentorial Approach

Surgery of the third ventricle, Apuzzo ed. 1996

Supracerebellar Infratentorial Approach

Surgery of the third ventricle, Apuzzo ed. 1996

1366
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Supracerebellar Infratentorial Approach

Surgery of the third ventricle, Apuzzo ed. 1996

Supracerebellar Infratentorial Approach

Surgery of the third ventricle, Apuzzo ed. 1996

1367
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1369
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1370
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Occipital Transtentorial Approach


ADVANTAGES
• broad exposure
• good view of quadrigeminal
plate
• prone or lateral position

DISADVANTAGES
• venous system over tumor
• occipital retraction
• +/- sacrifice bridging veins
• visual field deficits
• difficult to resect tumors
projecting anteriorly

Occipital transtentorial approach

Surgery of the third ventricle, Apuzzo ed. 1996

1371
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Occipital transtentorial approach

Surgery of the third ventricle, Apuzzo ed. 1996

1372
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Occipital transtentorial approach

Occipital transtentorial approach

Surgery of the third ventricle, Apuzzo ed. 1996

1373
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Midbrain Gliomas

1374
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Intramedullary ependymoma

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Pernkopf: Atlas of Human Anatomy/Head and Neck 2nd ed.

Occipital Transtentorial Approach

Pernkopf: Atlas of Human Anatomy/Head and Neck 2nd ed.

1377
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Occipital Transtentorial Approach

30 yo woman with Parinaud’s

preop postop

1378
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Transcallosal Interhemispheric Approach

ADVANTAGES
• broad exposure

DISADVANTAGES
• venous system over tumor
• parietal retraction
• sacrifice bridging veins

Surgery of the third ventricle, Apuzzo ed. 1996

Transcallosal Interhemispheric Approach

Surgery of the third ventricle, Apuzzo ed. 1996

1379
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Transcallosal Interhemispheric Approach

Surgery of the third ventricle, Apuzzo ed. 1996

Operative approaches
n = 181

Infratentorial-supracerebellar - 83%

Occipital-transtentorial - 6%

Interhemispheric-transcallosal - 5%

Stereotactic biopsy - 5%

1380
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Summary of Patients Undergoing


Surgery at NYNI
PATHOLOGY

Germ cell (23%)

Pineal cell (32%)

Glial cell (23%)

Miscellaneous (22%)

TOTAL = 181

Surgical Results
(n=181)
Radical
histology Bx STR STR/GTR

BENIGN 2 5 70
MALIGNANT 12 29 63

Total 14 34 133

GTR/radical STR in 91% of benign and 61% of malignant


OVERALL = 73%

1381
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Results of Pineal Tumor Surgery

Total - 181

Operative-Related Deaths -2%

Permanent Major Morbidity - 2%

Transient Major Morbidity - 5%

Common Postoperative
Complications
• EOM dysfunction

• Ataxia

• altered mental status

• shunt malfunction

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Venous complications

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Factors associated with


increased risk

• prior radiation therapy


• malignant or invasive tumor
• advanced preop sx
• subtotal resection

Benign tumors
teratoma, dermoid, epidermoid,
pilocytic astro, meningiomas

• 100% 10 yr tumor-free survival


following complete resection

• 43% of all pineal tumors

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OUTCOME

MALIGNANT TUMORS

• 5 year survival = 75%


• 10 year survival = 62%
• Radiographic resection in 60%

Benefits of surgical resection for


pineal region tumors
• Significant benefit:
– All benign tumors
– Pineocytoma
– Ependymoma
• Moderate benefit:
– Pineoblastoma
– glioma
– metastases
– MNGCT
• Questionable benefit:
– germinoma

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Postoperative Staging of
Malignant Pineal Tumors

• complete spinal MRI +/- gado


• CSF cytology???
• measurement of tumor markers
• head MRI 24-48 hrs postop

Radiation Therapy

• for malignant tumors


• 4000 cGy whole brain with 1500 to pineal
• less than 5000 cGy assoc with recurrence
• field size controversial

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RT field size considerations


• risk for ventricular seeding
– pineoblastoma - high
– germinoma - medium
– pineocytoma,ependymoma - low
– glioma - low
• many long term survivors

Spinal RT

• Not indicated for routine prophylaxis


• Reserved for documented seeding
• Pineoblastomas=highest seeding
propensity
• Dose: 3500 cGy

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Germinomas

• 75-80% 5 yr survival with RT alone


– recent reports of 90%
• consider chemo for pediatric ptnts
• elevated ß-HCG - worse prognosis
– consider adjuvant chemo

Malignant NGCT
Before chemotherapy After chemotherapy

• poor prognosis
• recent results promising
• cisplatinum/VP-16 and RT

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Radiosurgery
preop postop recurrence

• useful for recurrent tumors


• limited by 3 cm diameter
• may be useful to provide boost
• associated with transient EOM dysfunction
• long term results unknown

Surgical Management of Pineal Region Tumors


• Histological diagnosis mandatory
• Aggressive surgical approach results in long term
survival (71% 10 yr survival)
• Surgical morbidity is acceptable
– Important principles of tumor surgery – internal debulking
following by careful dissection of tumor-brain interface
• Multiple surgical approach options based on
location
• Venous infarct is an unpredictable and devastating
complication in 1% of patients
– Can be avoided with occipital transtentorial approach
although more difficult for tumors extending into third
ventricle

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Posterior Fossa Tumors of


Childhood

Tord D. Alden, MD
Assistant Professor,
Division of Neurosurgery
Ann & Robert H. Lurie Children’s Hospital of Chicago
Feinberg School of Medicine, Northwestern University
talden@luriechildrens.org

Disclosures
• There are no off-label usage described
below
• There is no industry support or affiliation

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History
• 1926 Harvey Cushing presented at
pediatric meeting children with brain
and spinal cord tumors
• 1929 Franc Ingraham started
neurosurgical service at Boston
Children’s Hospital
• 1931 Harvey Cushing lectures on series
of cerebellar astrocytomas

History
• 1939 Drs. Bailey, Buchanan, and Bucy
publish “Intracranial Tumors of Infancy
and Childhood”
– Considered first textbook on Pediatric
Neurosurgery
– Pediatric brain tumors are different than
adult disease
– Sparse and inconsistent data published on
this subject

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Pediatric Brain Tumors --


Epidemiology
• NIH 1973 – 1990
– most common solid malignancy
– incidence of malignant brain tumors 2.8 per
100,000 individuals (age 0-14)
– second to acute lymphoblastic leukemia as
the most common pediatric malignancy
– brain tumors account for approximately
25% of all cancer deaths
– significant morbidity associated with tumor
and therapy

Pediatric Brain Tumors --


Epidemiology
• NCI
– incidence of primary malignant brain
tumors among children increased by 35%
between the years 1973 and 1994
• Why?
– better imaging
– increased reporting
– environmental/genetic cause?

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CNS Tumors are Common


• CNS Tumors are the second most common
malignancy among children ages 0-19
• They represent the most common solid tumor
in in children and adolescents
• By the numbers:
– 4000 new pediatric CNS tumors diagnosed in the
United States annually
– 150-160 new patients seen annually at our
Pediatric Brain Tumor Program
• Despite recent advances in therapies, CNS
tumors are the leading cause of cancer related
mortality in children

Pediatric Brain Tumors –


Histology
• Different from adult pathology
(metastases, glial tumors, meningomas)
– Varied sub-classification within each
pathologic entity
– Metatstatic brain tumors are rare
• Most common
– Astrocytoma (40%)
– Medulloblastoma (20%)
– Ependymoma (10%)
– Malignant Glioma [WHO III and IV] (10%)

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Pediatric Brain Tumors –


Histology
• Astrocytoma • Other tumor types
– Most common benign and – Atypical teratoid rhabdoid
most common overall tumors
tumor – Supratentorial PNET
– WHO I and II – Ganglioglioma
• Medulloblastomas – Hemangioblastoma
– Most common malignant – SEGA
brain tumor in pediatrics – Germ cell tumors
– Second most common – Craniopharyngiomas
pediatric brain tumor – Choroid plexus tumors
overall
– Meningiomas
• Ependymomas
– Third most common
pediatric brain tumor

Posterior Fossa – Tumor types


• Benign • Malignant
– Cerebellar Pilocytic – Medulloblastoma
astrocytoma – Ependymoma
– Low grade glioma in – Diffuse Intrinsic Pontine
brainstem glioma
– Choroid plexus papilloma – Atypical teratoid rhabdoid
– Hemangioblastoma tumor
– Gangioglioma – Choroid plexus carcinoma
– Epidermoid cyst – Glioblastoma multiforme
– Anaplastic astrocytoma

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Posterior Fossa Tumor –


Presentation
• Depends on location and type of tumor
• Nearly all locations can result in
Hydrocephalus
• Brainstem – Cranial nerve palsy
• Cerebellar hemisphere – dysmetria of
arm/leg
• Cerebellar vermis – truncal ataxia
• CP Angle – Cranial nerve palsy,
dysmetria arm/leg

Posterior Fossa Tumors


• Patient Presentation
– Syndrome of raised ICP
– Vomiting per se
(Ependymoma)
– Nuchal rigidity
– Cranial nerve deficits
– Cerebellar signs

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Posterior Fossa Tumors –


Tumor Specific Symptoms
• Cerebellar pilocytic astrocytoma: indolence,
long history; arm/leg ataxia
• Brainstem glioma: ipsilateral cranial nerve
signs and crossed motor signs
• Ependymoma: vomiting (projectile) precedes
other S+S
• Medulloblastoma: truncal ataxia, raised ICP,
acute obstructive hydrocephalus in 90% of
cases

Posterior Fossa Tumors –


Clinical Presentation
• In infants and young children:
– Progressive macrocephaly
– Arrest or regression of development
– Emesis and irritability
– Failure to thrive
• In older children:
– Morning headaches
– Vomiting secondary to increased ICP or direct pressure on the area
postrema
• Later signs include:
– Truncal titubation and unsteady gait
– Head tilt
– Lethargy
– Diplopia or blurred vision
• Infrequent findings:
– Nystagmus, hemiparesis, and seizure

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Neuroimaging Features
• Pilocytic Astrocytoma: cystic tumor,
solid nodule; hypodense on CT
• Medulloblastoma: hyperdense on CT,
midline arising from vermis, enhances
• Ependymoma: expands 4th ventricle,
creeps out lateral recesses, enhances,
calcium

Treatment Modalities
• Surgery
• Chemotherapy
• Radiation therapy
• Autologous Bone marrow transplant
after chemotherapy
• Many factors determine treatment
– Histology type and sub-type
– Age
– Disease burden (extent, location)

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Posterior Fossa Tumors –


Surgical Goals
• Histological confirmation
• Maximal cytoreduction
• Restoration of CSF pathways
• Minimizing neurologic morbidity

Posterior Fossa Tumors –


Surgical Considerations
• Often present with hydrocephalus
– Treat with EVD, ETV, some will Shunt
– Good to control CSF post-op
• Know the patient’s blood volume and stay
ahead
• NeuroNavigation
• Neuromonitoring (CN, BAER, SSEP, MEP,
EMG)
• Intraoperative MRI or US
• CUSA

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Surgical Management –
Hydrocephalus
• Endoscopic third ventriculostomy
• External ventricular drain
• Ventriculoperitoneal shunt

Surgical Management –
Hydrocephalus
• Pre-resection CSF shunt
– improves pre-op patient physiology
– provides slack surgical field
– risk of upward herniation of posterior fossa
structures
– potential for shunt-related tumor
dissemination
• Only 10 -30% of patients will need
shunts post operatively

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Posterior Fossa Tumors –


Surgical Considerations
• Find floor of the 4th ventricle
• Identify the tumor’s blood supply early
– Medulloblastoma – at interface of vermis
– Ependymoma – often from PICA and
Vertebral Artery
• Identify Cranial Nerves early

Fourth Ventricle
• The floor must be
identified along with the
peduncles
• Tumor may be transected
to the plane of the floor
• Tumor resection from the
brainstem is not advised

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Fourth Ventricle
• Complications:
– facial palsy
– abducens palsy
– vocal cord paralysis
– cerebellar ataxia
– injury to peri-aqueductal
structures
• INO
• horizontal gaze palsy

Posterior Fossa Tumors –


Surgical Management
• General:
– Admit with frequent neuro examination
– Consider high dose corticosteroid hormone
– Earliest, scheduled tumor resection
– Post-operative external ventricular drainage
• Infrequently, emergent CSF diversion is
indicated
• Rarely, need CSF diversion and brainstem
decompression
• Place EVD at time of surgical resection
• Posterior fossa craniotomy

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Sub-Occipital Craniotomy

Approach
• Transvermian
– midline tumors
• Transcortical
– hemispheric tumors
• Cerebello-medullary fissure
– less retraction
• Cerebello-pontine angle

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Posterior Fossa Tumors – Post-


Operative Care
• Contrast enhanced imaging should be
obtained within 24 to 36 hours
• Post-operative external ventricular
drainage to control ICP and drain bloody
CSF
• Steroid taper

Complications
• Surgical mortality is near zero
• Postoperative worsening needs evaluation
– hematoma
– pneumocephalus
– cerebellar edema
• Neurological morbidity is high
– Cerebellar ataxia
– Nystagmus
– Hydrocephalus
– Cerebellar mutism

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Complications
• Aseptic meningitis
– Headaches
– Photophobia
– Fever
– Meningismus
• Low dose corticosteroids may be helpful

Complication – Posterior fossa


syndrome
• AKA
– Cerebellar mutism
– Cerebellar akinetic syndrome
• Presents as
– Cessation of speech 24-48 hours postoperatively
– Increased emotional lability
– Cerebellar ataxia, occasionally hemiparesis with
hypotonia
• Anatomic site of disruption is controversial
– Dentate nucleus, peduncle, brainstem
• Takes over 2-6 months to recover

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Complication – Posterior Fossa


syndrome
• Estimated to occur in 25 to 40% of patients
• Initially thought that most resolve, recent
studies find up to half have permanent deficit
• Symptoms
– Mutism
– Ataxia
– Irritabilty
– Hypotonia

Complication – Hydrocephalus
• N=343 1989 to 2003
• age <2 yrs 3
• presence of papilledema 1
• moderate/severe hydrocephalus 2
• cerebral metastases 3
• preop estimated tumor diagnosis
– Medulloblastoma 1
– Ependymoma 1
– Dorsal exophytic brainstem glioma 1
• total possible 10

Riva-Cambrin, Drake, et al. Predicting postresection hydrocephalus in pediatric patients


with posterior fossa tumors. JNS pediatrics May 2009.

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Probability of Hydrocephalus at
6 months after Resection
• 0 0.071
• 1 0.118
• 2 0.191
• 3 0.293
• 4 0.422
• 5 0.562
• 6 0.693
• 7 0.799
• 8 0.875
• 9 0.925
• 10 0.950

Treatment Late Effects


• Injury
– Tumor type and location
– Therapy
• Surgery
• Chemotherapy
• Radiation therapy
• Most common
– Neurologic deficit
– Neurocognitive injury
– Endocrinopathy
– Ototoxicity
– Secondary malignancy

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Specific Tumors

Posterior Fossa Tumors


• Pilocytic astrocytoma
• Medulloblastoma
• Ependymoma

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Cerebellar Pilocytic
Astrocytoma

JPA – Epidemiology
• 10% of all pediatric brain tumors
• 25% of posterior fossa tumors
• 90% pilocytic: do not reoccur when
totally resected
• Mean age at presentation 6 to 8 years
• M:F ratio equal
• 96% 10-year survival

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Cerebellar Pilocytic
Astrocytoma
• A circumscribed, morphologically and
biologically distinct astrocytoma subtype
• A unique intraaxial tumor
– surgically curable
• Represent 35 - 40% of all posterior fossa
tumors
• Sometimes termed juvenile or cystic
cerebellar astrocytomas
• Usually present between 5 - 10 years of age
– infrequent in neonates and infants
• A second peak occurs in young adults

JPA – Clinical features


• Indolent history
• Headache and vomiting for several
weeks to months
• 25 to 60%: Cerebellar findings, limb
ataxia secondary to hemispheric origin
• 40 to 80%: Papilledema, optic atrophy,
blindness
• VIth nerve palsy
• Bone remodeling

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JPA – Imaging studies


• Can be in any location
Hemispheric, Midline, CP
angle
• CT: hypodensity
• MRI:
– cystic, solid or mixed signal
– T1 hypo to iso
– T2 hyper
– Enhancement

JPA – Classification

Cystic: 30% Solid: 20 to 30% Mixed: 40 to 50%

Nearly all are Low Grade


Astrocytomas

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Cerebellar Pilocytic
Astrocytoma
• Two histologic patterns:
– densely compact regions with hair like
processes
– loose spongiform foci
• Rosenthal fibers
• Low mitotic activity
• Cysts
• Usually no necrosis

JPA – Surgery
• If the cyst wall enhances or is thickened,
attempt to remove it
• If the cyst wall does not enhance, no need to
remove it

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JPA – Outcome
• 95% 25 year survival after GTR
• If residual
– Re-explore
– Evidence for tumor involution
• 5 to 10% recurrence after GTR

Outcome
• Routine surveillance scanning should be performed on
a regular basis
• Regression or involution of residual disease has been
documented
• Reoperation is the treatment of choice for recurrent
disease
– Adjuvant therapy rarely required

• Patients with gross total resection have survival rates


approaching 100%
– 5 year survival: 86 - 100%
– 10 year survival: 83%
– 20 year survival: 70%

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Outcome
• The most important predictive parameter in
determining outcome is the extent of tumor
removal
– Midline = hemispheric
– Cystic = solid
• Brainstem infiltration is a poor prognostic sign
• Most recurrences occur within three years of
diagnosis
– Late recurrences have been reported
– Residual tumor may not always recur
• Recurrence occurs locally
• CSF dissemination is exceptionally rare

Low Grade Astrocytoma


Biology
• In the last 3-5 years, there has been considerable insight
into pathway alterations in low grade astrocytoma driven
initially by investigation of NF-1 related astrocytomas

• The Mitogen-Activated Protein Kinase (MAPK) pathway and


mTOR pathways are critical to astrocytoma development
and progression

• BRAF is a critical member of the MAPK pathway and BRAF


rearrangements and mutations have been well
described in pediatric low grade astrocytomas

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BRAF Alterations drive the MAPK pathway

• BRAF rearrangements are common in


pediatric low grade gliomas – and present in
up to 70% of juvenile pilocytic astrocytomas
(Grade I)
• Adult low grade gliomas have a much lower
frequency of these rearrangements – which
may explain their unique clinical behavior
• Presence of the rearrangement may be
favorable prognostic marker in pediatric
low grade astrocytomas (Grade I and Grade
II tumors)

Medulloblastoma

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Medulloblastoma
• One of the most common tumors of the
posterior fossa
• Comprise between 15-25% of all childhood
brain tumors
• Occur at any age but predominate in
childhood
• Mean age at presentation is 5-6 years
• Most frequently present in the fourth ventricle
• Tend to invade cerebellar tissue and the
cerebellar peduncles
• The brainstem is usually compressed and
often invaded

Medulloblastoma
• Typically protrude through foramen of
Magendie
• Early CSF dissemination is common
• The aqueduct of Sylvius is frequently
enlarged
• Less frequently located laterally within
the cerebellar hemispheres

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Medulloblastoma
• Hyperintense on NECT
• Enhance strongly
• Hemorrhage rare
• Calcification rare
• Displace IV anteriorly
• Hydro is common

Medulloblastoma
• Fills fourth ventricle
• Heterogeneously
hypointense to gray
matter on T1WI
• Enhancement varies
• Variable on T2WI
• Cysts are common
• CSF dissemination ?

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Medulloblastoma
• Disseminated disease occurs in 50% of
cases
• 66% Leptomeningeal
• 15 to 33% extracranial
– bone
• 10-50% of initial images

Medulloblastoma
• Highly cellular
• Round to oval cells
• Hyprchromatic nuclei
• Scant cytoplasm
• Ill defined borders
• Homer Wright rosettes

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Medulloblastoma – surgical
findings
• Blood supply arises at interface with
vermis
• Identify the floor of the 4th ventricle
early
• Residual tumor
– Superior most vermis
– Lateral recess
– Foramen of Luscka

Staging
• Based on surgical impression and post
op imaging
• Whole brain and spinal MRI is required
• Patients with disseminated disease at
diagnosis are at highest risk
• Unfavorable factors:
– Younger age
– Brain stem involvement
– Subtotal resection (1.5 cm3 residual)
– Non-posterior fossa tumor

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Staging
• Average risk
– Age > 3 years with posterior fossa tumor
– Total or “near total” resection (<1.5cc residual)
– No dissemination
• High risk
– Age < 3 years
– Metastatic disease
– Subtotal resection (>1.5cc residual disease0
– Non posterior fossa tumor
– Anaplasia on pathology

• Treatment: Radiation / chemotherapy

Molecular Markers

Medulloblastoma Comprises Four Distinct Molecular Variants. Paul A. Northcott, Andrey Korshunov, Hendrik Witt, Thomas Hielscher,
Charles G. Eberhart, Stephen Mack,Eric Bouffet, Steven C. Clifford, Cynthia E. Hawkins, Pim French, James T. Rutka, Stefan Pfister, and
Michael D. Taylor. J Clin Oncol 29:1408-1414. 2010

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Molecular Markers

Molecular markers
• Shh (Sonic Hedgehog) pathway
alterations (favorable)
• Wnt pathway alterations (favorable)
• c-myc amplification (unfavorable)

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Outcome
• Overall survival after surgery and radiation
therapy:
– 50-60% @ 5 years
– 33-53% @ 10 years
• Recurrence:
– Most occur within two years of diagnosis
– Common sites: posterior fossa, CSF pathways,
cribiform plate, temporal tips
– Systemic metastases: bone, lymph nodes
– Almost all occur within the period of risk defined
by Collins’ rule
– Treatment options very limited

Successes and Challenges: Medulloblastoma


Success: Childhood
Medulloblastoma

Challenge: Infant
and Adolescent
Medulloblastoma

Smith M A et al. JCO 2010;28:2625-2634

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Histopathological Features
Medulloblastoma
Classic Anaplastic
Medulloblastoma Medulloblastoma

Desmoplastic Nodular Medulloblastoma


Medulloblastoma extensive nodularity Large Cell
Medulloblastoma

Medulloblastoma in Inherited Syndromes

• Nearly all cases of medulloblastoma occur


sporadically, however there are three inherited
syndromes associated with medulloblastoma
– Gorlin syndrome – mutations in the PTCH1, PTCH2
or SUFU genes resulting in the dysregulation of the
Sonic Hedgehog (Shh) Pathway
– Turcot Syndrome – mutation in the APC gene and
resulting deregulation of the WNT/β-Catenin
pathway
– Li-Fraumeni Syndrome – germline p53 mutation
• If the same tumor can occur as a result of three
distinct genetic mutations, are there mutations
that characterize sporadic tumors?

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From histology to molecular


subtypes
• Sporadic medulloblastomas were found to have
mutations in the PTCH1 gene which activates
the Sonic hedgehog (Shh) pathway
• Mutations have also been identified in CTNNB1
and APC genes resulting in Wnt Pathway
dysregulation
• Retrospective characterization of
medulloblastoma patients treated uniformly
suggested that patients with evidence of Wnt
pathway activation (regardless of histology)
had a superior outcome to others

Molecular Characterization

J Clin Oncol. 2011 April 10; 29(11): 1424–1430.

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Molecular subgrouping predicts outcome

Acta Neuropathologica Volume 123, Number 4 (2012), 473-484

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Ependymoma

Ependymoma
• Ependymal cells are related
to other glial cells
• Ependymomas are slow
growing neoplasms that are
often partially cystic
• Arise most commonly in the
fourth ventricle (60%)
• Have a tendency to “ooze”
through foramina (“plastic
ependymoma”)

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Ependymoma
• Peak age range is 1 to 5 years
• 4 to 6 times more common in children
• 15% of all childhood brain tumors
• Usually have a long clinical history
• Cranial nerve dysfunction is more common
compared to other posterior fossa tumors
– compression or invasion of the floor (VI, VII)
– CPA spread (V, VII, VIII)
– lateral foramen magnum (IX, X, XI)

Ependymoma
• Findings are variable

• Non enhanced CT
– Mixed density mass
– 50% calcified
– inhomogeneous enhancement
– hemorrhage uncommon
– hydrocephalus

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Ependymoma
• Lobulated mass casted or molded into
fourth ventricle
• Extrudes out foramina
• T1WI - iso or hypo
• T2WI - hyper
• Inhomogeneous enhancement

Ependymoma
• Appearance and
architecture is variable
• “Leopard skin”
• Dense palisades of nuclei
around vessels
• “Pseudorosettes” and
“ependymal rosettes”
• Low mitotic index
• Moderately cellular

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Ependymoma
• Grow through foramina of IV vent.
• Frequently in CPA where they displace
the brainstem and cerebellum
• Well demarcated
• Limited infiltration

Surgery
• Resection is frequently limited by
adjacent neural structures
– invades floor
– surrounds cranial nerves
• Most morbidity consists of various
cranial nerve palsies

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Ependymoma
• Careful and full inspection of Foramen
of Luschka
• Blood supply from brainstem
• Can wrap around vessels and CN out
laterally

Results
• Improved progression-free survival with multi-agent
regimens in concert with radiation therapy
• Spinal seeding is uncommon, but can see
intraventricular spread
• Chemotherapy can be used to delay radiation in
patients under 3-yrs of age
• Survival at 5-years:
– Complete Resection with XRT 60-80%
– Incomplete Resection 0-30%
– Complete resection with posterior fossa 3D radiation with high
survival
• Consider “second look” surgery after chemotherapy for
those with incomplete resection

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Brainstem Gliomas
Midbrain
Focal
Tectal
Pontine
Diffuse Intrinsic
Dorsally Exophytic
Focal
Cervicomedullary

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Diffuse Intrinsic Pontine


Gliomas
• Tumors confined to
the pons
• Patients present with
cranial nerve palsies
and long tract signs
• Hydrocephalus later
in course
• Nearly all are
anaplastic tumors

Diffuse Intrinsic Pontine


Gliomas
• MRI is imaging study
of choice
• Most lesions are low
signal intensity on T1
• May or may not
enhance
• Frequently surround
the basilar artery

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Diffuse Intrinsic Pontine


Glioma
• Diagnosis is often made
radiographically
• In past, have rarely been
biopsied
• Studies underway to exam
pathology and outcome
• Currently, median survival 12
– 18 months
• 10 % overall survival
• XRT and chemotherapy trials

Brainstem Gliomas
• Excluding the DIPG, other brainstem
tumors can have better prognosis
• Tumors that are exophytic and
surgically accessible are often lower
grade
• Surgical resection may be sufficient

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Brainstem Glioma
• Recent and renewed interest in
obtaining a tissue diagnosis
• Complication rates of biopsy as high at
10 to 25%
• New techniques to stratify
– Proteomic analysis of CSF
– Gene and protein specific markers for
customization of therapy

Other Tumors

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Neonatal tumors
• Blood volume 70cc per kg
• The younger the child, the smaller the
reserve
• Plan operatively
• Pathology is often more aggressive due
to primitive nature

Skull tumors
• Can be found throughout the skull
• Pathology
– Langerhans cell histiocytosis
– Dermoid
– Epidermoid
• Treatment
– Excisional biopsy

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Atypical teratoid rhabdoid


tumor – ATRT
• Comprises 1% to 2% of all pediatric brain tumors
• Present in children younger than 3 years
• Supratentorial to infratentorial location is 1.3:1
• Dissemination by CSF is common
• Similar gross appearance to medulloblastoma and
supratentorial primitive neuroectodermal tumor
• Microscopically are heterogeneous lesions
• Cytological features
– Rhabdoid cells
• eccentric nuclei
• abundant cytoplasm
• eosinophilic inclusions

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ATRT
• Most often found at CP angle in
posterior fossa
• Often involving multiple cranial nerves
• Consider monitoring with EMG
stimulation of appropriate CN
• Prognosis is poor with median survival
<12 months

Atypical Teratoid/Rhabdoid
Tumor
• First recognized by Lucy Rorke in 1987
– Senior pathologist at U of Penn
• 1993 the WHO classified ATRT as Grade IV
Embryonal neoplasm
• Incidence
– Unknown given its late recognition
– Children’s Cancer Group (9921) 10-15% of
infants
– Ped Onc Group & Ped BT Consortium – 15% of
malignant tumors < 36m old
• Usually in younger Children (<2y)

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ATRT Pathophysiology
• Prior to its recognition was often
diagnosed as a medulloblastoma or
PNET
– Components of ATRT resememble other
primitive tumor types
• Pathologically resembles malignant
rhabdoid tumors of the kidney
• Immunohistochemically can vary widely
so molecular analysis can but used to
help diagnose

Imaging

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Work Up & Treatment


• All patient should get neuro-axis
imaging
– ~ 25% will have disseminated disease

• Diagnosis made via pathology

• Tx: Resection & Chemo +/- XRT

Surgical Resection
• Goal = gross total resection

• Surgical impact is now known


– Retrospective analysis of the ATRT registry has
shown longer survival in GTR

• Invasive <1/3 can be GTR

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Pathology
• Malignant rhabdoid cells on a
background of primitive neuroectoderm
cells, mesenchymal cells, or epithelial
cells.
– Rhabdoid cell: medium
sized, eccentric nucleus,
pink cytoplasmic
inclusion body

Pathology

H&E
Vimentin

EMA
MIB

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Pathology
• Histological identification can be difficult
• Staining:
– + vimentin, GFAP, EMA, cytokeratin,
synaptophysin, chromagranin, Smooth muscle
actin
– MIB > 50%

Molecular Analysis
• Histological Phenotype can differ
• Molecular Analysis
– Majority of ATRT have mutations of
hSNF5/INI1 gene on chromosome 22
• Encodes for chromatin remodeling complex

– COG protocols for ATRT pt require analysis


of genome

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Choroid Plexus tumors


• Account for 2% of pediatric brain tumors
• Predominantly in supratentorial locations
• May be found in the 4th ventricle as well as
Foramen of Luschka
• Three classifications
– Papilloma
– Papilloma with anaplasia
– Carcinoma

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Choroid Plexus Papilloma


• “En Bloc”
– Continous and circumferential coagulation
– Find blood supply
– Remove “en bloc”
• “Piecemeal”
– Coagulate major branches and resect to debulk
– Find blood supply
– Remove remainder
• Do not internally debulk like meningioma

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Choroid Plexus Carcinoma


• Recognition that tumor is invasive
• Vascular
• Often responds to chemotherapy and
radiation
• Biopsy – chemotherapy and radiation –
re-resection

Conclusion
• Pediatric brain tumors have been a
challenge since the beginnings of
pediatric neurosurgery
• Surgery still plays a major role in
defining the disease
• Multi-modality treatment paradigms
targeting genes and their protein
products are on the horizon

1448
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Thank You

1449
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Kalmon D. Post, M.D.


Mount Sinai Medical Center
New York, New York

Vestibular Schwannomas and


Meningiomas of the Cerebello-Pontine
Angle

Disclosures
Reports no commercial interest.

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• Are AN more common now or is diagnosis


earlier because of imaging?
• Do cell phones lead to AN?

1451
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1452
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Cancer Epidemiol. 2011 Oct;35(5):453-64

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Vestibular Schwannoma Removal

4.5 Cm Vestibular Schwannoma

1455
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Post-op 4cm Acoustic Neuroma

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Options
• Conservative follow-up
• Surgical removal
• Radiation treatment
– Stereotactic radiosurgery
– Stereotactic radiotherapy
• Combined surgery and radiation

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50% surgery
25% radiation
25% observation

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Conservative Management
• What percent of tumors show growth?
• What is at risk over the period of
observation?

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Neurosurgery Volume 70 / Number 5 / May 2012


Breivik et al.

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Neurosurgery Volume 70 / Number 5 / May 2012


Breivik et al.

Neurosurgery Volume 70 / Number 5 / May 2012


Breivik et al.

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VDT:
volume
doubling
time

Surgery

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Intracanalicular Vestibular Schwanomma

Hearing Preservation
with Surgery
• Is it worthwhile?
• Is preserved nonuseful hearing more aggravating?
• Is a total resection possible with hearing
preservation?
• Will hearing preservation be long-lasting?
• Is tinnitus altered by tumor removal?
• Are post-op headaches so severe to preclude
surgery?
• Are CSF leaks still a problem?
• Is quality of life acceptable after surgery?

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Approaches

• Suboccipital transmeatal
• Translabyrinthine
• Middle fossa

Supine Position

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Intracanalicular Vestibular Schwanomma

High jugular bulb

Technical Pearls-1
• Supine position
• Facial nerve monitoring

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Facial Nerve
Monitoring

Technical Pearls-1
• Supine position
• Facial nerve monitoring
• BAER monitoring (or direct VIII)

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Hearing Monitoring
• BAER: scalp electrodes
• measures N1 and N5
• direct recording of VIII - cochlear n.

BAERs
• Intra-operative use of BAERs to guide vestibular
schwannoma resection
– Wave I-II and I-III interpeak intervals
– Wave I-V interpeak interval latency
• Hearing may be diminished or lost completely
even with anatomic preservation of CN VIII

III IV V

I II

Hall JW. Handbook of Auditory Evoked Responses,1992.

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Results
• A total of 133/205 patients met inclusion
criteria
– 79 female/54 male
– Mean age = 46.9 (SD 10.69)
• 68/133 (51.1%) BAER latencies < 2ms
– 37/68 (54.4%) non-functional hearing
– 31/68 (45.6%) functional hearing
• 65/133 (48.9%) BAER latencies ≥ 2ms
– 60/65 (92.3%) non-functional hearing
– 5/65 (7.7%) functional hearing

Results
• Patients with
100
pre-operative 90
BAER latencies 80

≥ 2ms had 70
Percent (post-op)

Functional
60
Hearing
significantly 50
decreased 40 Non-
30 Functional
functional 20 Hearing
hearing post- 10
0
operatively
< 2ms ≥ 2ms
– p < 0.001 Latency

1471
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Results
• Multivariate analysis:
– Hearing preservation was less likely in patients
harboring larger tumors (p = 0.038)
– Hearing preservation was less likely in patients with
pre-operative BAER latencies ≥ 2ms independent of
tumor size (p < 0.001)

BAER Summary
• A ≥ 2ms latency is statistically significant in
predicting post-operative functional hearing
loss
• We suggest that the utilization of pre-operative
BAERs as a prognosticator of post-operative
hearing is a reliable tool that can guide
decision making in hearing preservation
patients

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Intracanalicular Vestibular Schwanomma

Decision can be directed by BAER results

Technical Pearls-1
• Supine position
• Facial nerve monitoring
• BAER monitoring (or direct VIII)
• Adequate bone opening (4cm)
• Open dura inferiorly and release CSF
• Keep dura moist
• Expose angle – usually one retractor

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Technical Pearls - 2
• Drill canal before opening arachnoid
• Wash out all bone dust
• Open arachnoid
• Stimulate entire surface for VII
• ? Place electrode on VIII
• CUSA the core of the tumor

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Post-operative Problems
• Headaches
• Tinnitus
• CSF Leak

Post-op Headaches

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AICA

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AICA Dissection

AICA Dissection

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AICA Free

AICA retracted medially

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Technical Pearls -3
• Identify VIII, isolate vestibular and cut
• Identify VII
• Decompress tumor in canal
• Identify intracanalicular VII and VIII
• Gentle teasing with countertraction or sharp
dissection
• Papaverine irrigation
• Nothing on VIII

Follow crotch of VIII

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Mainly intracanalicular tumor 11 mm

Drill canal, gut the tumor

1485
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Follow the planes, either or both ways

Papaverine irrigation

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15mm Schwannoma

Canal drilled

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Debulk tumor and find planes

Often view entire tumor

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Follow planes

Final view

1489
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Very thin facial nerve in 35mm Tumor

VII takes a course over superior


aspect of tumor

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Technical Pearls - 4
• Inspect lateral end of canal
• Bone wax/cement and muscle/fat
• Dural closure
• Cranioplasty
• Steroids for 1-2 weeks
• Serial LPs

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Facial Function Post-op 145 Patients


House-Brackmann
Immediately 3 months 6 months *
1 118 (81%) 124 (86%) 128 (89%)

2 13 (9%) # 5 (3%) 8 (6%)


3 3 (2%) 11 (8%) 6 (4%)

4 1 (1%) - 1 (1%)
5 2 (1%) 3 (2%) -

6 8 (6%) 2 (1%) 1 (1%)


#1 pt presented at Gr 2 *1 pt not at 6mo f/u 2003

Facial Function Post-op 145 Patients


House-Brackmann
Immediately 3 months 6 months *
1 = 40 (91%) 1 = 41 (93%) 1 = 41 (93%)
2 = 2 (5%) (# pre op) 2 = 1 (2%) 2 = 1 (4mos. p.o.)
3 = 2 (5%) 3 = 2 (5%) 3 = 2 (5%)
0 – 1.4 cm 4 4 4
44 pts 5 5 5
6 6 6
1 = 27 (96%) 1 = 25 (89%) 1 = 26 (93%)
2 = 1 (4%) 2 = 1 (4%) 2 = 2 (7%)
3 3 = 2 (7%) 3
1.5 – 1.9 cm 4 4 4
28 pts 5 5 5
6 6 6
1 = 51 (70%) 1 = 58 (79%) 1 = 61 (84%)
2 = 10 (14%) 2 = 3 (4%) 2= 6 (8%)
3= 1 (1%) 3 = 7 (10%) 3= 4 (5%)
2.0 – 4.5 cm 4= 1 (1%) 4 4= 1 (1%)
73 pts 5= 2 (3%) 5 = 3 (4%) 5
6= 8 (11%) 6= 2 (3%) 6= 1 (1%)
2003

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99.9% is:

• 2 unsafe landings per day at O'Hare Airport


• 16,000 pieces of lost mail per hour
• 20,000 wrong prescriptions per year
• 500 incorrect surgical operations per week
• 50 newborns dropped by physicians per day

source: Rowen, Roger: "Financial implications of TQI"


Health Systems Review, Mar/Apr 1992

Tinnitus in Hearing Preservation


Cases
• 26 patients with hearing preserved

+ tinnitus - tinnitus

Pre-op 10 16

Post-op 4/10 0/16 22/26(85%)

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Tinnitus in Hearing Preservation


Cases
• 51 consecutive cases with pre-op hearing

+ tinnitus - tinnitus

Pre-op 23 28

Post-op 12/23(52%) 35/51(69%)


4/28(14%)

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Post-op Hearing vs. Pre-op Hearing & Size


Pre-op Size/Hearing Post-op Hearing
# patients good measurable none
Tumor <1.5cm
pre-op good 20 14(70%) 3(15%) 3(15%)
pre-op measurable 2 0 1 1
Tumor 1.5-2.0cm
pre-op good 12 5(42%) 0 7(58%)
pre-op measurable 2 0 0 2
Tumor >2cm
pre-op good 17 3 1 13(76%)
pre-op measurable 3 0 1 2

1995

Post-op Hearing vs. Pre-op Hearing & Size


Pre-op Size/Hearing Post-op Hearing
# patients good measurable none
Tumor <1.5cm
pre-op good 45 22 (49%) 2 (4%) 21(47%)

Tumor 1.5-2.0cm
pre-op good 27 11 (41%) 6 (22%) 10 (37%)

Tumor >2cm
pre-op good 73 7 (10%) 5 (7%) 61(84%)

2003

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Audiogram Results

• Pre-Operative
– PTA average 23.02dB
– Range 5-57 dB

• Immediate Post-Operative
– PTA average 34.95dB
– Range 8-69 dB

Audiogram Results
• Pre-Operative
– Discrimination average 89.91%
– Range 60-100%

• Immediate Post-Operative
– Discrimination average 82.35%
– Range 8-100%

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Long Term Audiogram Results


• Average follow-up time 2 year 9 months
• PTA average 36.92 dB
• Discrimination average 79.65%

•Immediate Post-Operative
–PTA average 35.09dB
–Range 8-69 dB
–Discrimination average 82.48%
–Range 8-100%

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WORLD NEUROSURGERY 82 [6]: 1271-1275, DECEMBER 2014

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Post Operative Complications

• CSF Leak
• Headache
• Facial Weakness
• Wound Infection
• Meningitis
• Ataxia
• Diplopia
• Keratitis

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Self-Assessed Quality of Life


after Acoustic Neuroma Surgery

• Single surgeon
• 135 consecutive patients, 101 responded
• minimum of 6 months post op

Quality of Life after Acoustic


Neuroma Surgery

1516
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Radiosurgery vs. Microsurgery


for Acoustic Schwannomas

Debate

Radiosurgery Microsurgery

Size
Age

1517
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Treated with a single fraction on 12/8/2005

Delboruck et al (Brussels) Preservation of hearing in vestibular


schwannomas treated by radiosurgery using Leksell Gamma Knife:
preliminary report of a prospective Belgian clinical study. Acta
Otorhinolaryngol Belg. 2003; 57:197-204.

• 95 patients 2000-2002
• 48 patients followed > one year
• 67% preserved serviceable hearing (50/50 level)
• 82% preserved hearing if Class I to begin
• No new trigeminal dysfunction
• One patient with previous VII weakness worsened
at one year fu

1518
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Rowe et al (Sheffield) Gamma knife stereotactic radiosurgery for


unilateral acoustic neuromas. J Neurol Neurosurg Psychiatry.
2003; 74: 1536-42.

• 234 consecutive patients 1996-1999


• Mean fu 35 months
• Tumor control rate 92%
• 3% required surgery afterward
• Larger tumors: 35-45mm control rate 75%
• Facial nerve affected in 4.5%, 1% persistent
• Trigeminal dysfunction developed in 5%, 1.5% persistent
• Hearing maintained in 75%
• Treatment of choice for small and medium

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Kondziolka, D., et al. Neurosurg Focus 33:1-9, 2012

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Kondziolka, D., et al. Neurosurg Focus 33:1-9, 2012

Summary

1526
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Issue #1 Tumor Response to


Radiosurgery
• 90-95% tumors are smaller or stay the same
size at 10 years. Most tumors treated are
< 3cm.
• Transient increases can occur
• Microsurgery: Most can achieve complete
resections especially in smaller tumors

1527
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What is the natural history?


Is Gamma knife any better than
conservative therapy?

Still some debate.

Issue #2 Facial Nerve Function


• More recent series < 2% with reduced doses.
Some losses are transient and permanent losses are
typically partial function loss.

• Microsurgery: varies from 10-20% but may be


better for smaller tumors typically treated by
radiosurgery. But can everyone reproduce these
rates?

1528
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Issue #3 Trigeminal Neuralgia


• Gamma Knife: Dose reduction to less than
14 Gy: 4% transient and 1-2% permanent

• Microsurgery: Trigeminal neuralgia is very


rare.

Issue #4 Hearing Preservation


• Radiosurgery: may be as high as 75% at
five years, but may decrease over time.

• Microsurgery: 50% in tumors less than


2cm, 70-80% in tumors less than 1 cm.

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1530
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Yang et al., J Neurosurg. 112:851-859,2010

1531
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Yang et al., J Neurosurg. 112:851-859,2010

Yang et al., J Neurosurg. 112:851-859,2010

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Issue #5 Mortality

• Radiosurgery: 0
• Microsurgery: 1-2%

Issue #6 CSF leak

• Radiosurgery: 0
• Microsurgery: 5-10%

1533
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Issue #7 Cost
• Advantage Radiosurgery

Issue #8 - Oncogenesis
• The concerns that stereotactic radiosurgery
may lead to the development of delayed
radiation-induced neoplasms remain
unsubstantiated; an increased incidence of
new neoplasm development has not been
reported despite more than 26 years of
experience and the treatment of more than
20,000 patients worldwide.
• Kondziolka D. NEJM, 82:1426-1432, 1998.

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Kondziolka, D., et al. Neurosurg Focus 33:1-9, 2012

Issue #9 Microsurgery after


Radiosurgery?

• Reports conflicting
• Samii – Nerves are paler and more tenuous.
• Malis – No change

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1536
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Group A: Radiosurgery followed by microsurgery


Group B: Microsurgery followed by radiosurgery followed by microsurgery.
Group C: controls

Issue #10 Quality of Life

1537
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Problems not yet totally resolved


• Will the lower doses given today result in long-
term control?
• Will the incidence of facial weakness and hearing
loss increase with time following GK
• What is the role of fractionated radiosurgery?
• What are outcomes in 20 or 30 years?

1538
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Debate

Radiosurgery Microsurgery

Size
Age

Elderly Patients: Conservative


Approach
• Elderly patients with small acoustic
neuromas may not need surgery
• They may be followed by CT or MRI

1539
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Elderly Patients: Indications for


Surgery
• Large tumors with brainstem
compression
• Documented growth
• Hydrocephalus

Post-op 3cm Acoustic Neuroma

1540
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Posterior Fossa Meningiomas

Right cerebellum was removed: 7-12 cranial nerves, AICA, PICA

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1542
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Type I: Tumor Posterior to IAC

Z.B. Wu, et al
J. Neurosurgery (2005)

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Type I

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Type II: Tumor Anterior to IAC

Z.B. Wu, et al
J. Neurosurgery (2005)

Type II: Tumor Anterior to IAC

Z.B. Wu, et al
J. Neurosurgery (2005)

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Type II

Type II

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Type II

Type III: More Extensive Attachment of Tumor


to Posterior Petrous Bone

Z.B. Wu, et al
J. Neurosurgery (2005)

1547
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Type III

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Type III

Type III

1549
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Z.B. Wu, et al
J. Neurosurgery (2005)

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Z.B. Wu, et al
J. Neurosurgery (2005)

M. Samii & M. Ammirati


Cerebellopontine Angle Meningiomas (2001)

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1552
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Leonetti et al
Otolaryngology-Head and Neck Surgery (2006)

Leonetti et al
Otolaryngology-Head and Neck Surgery (2006)

1553
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Leonetti et al
Otolaryngology-Head and Neck Surgery (2006)

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Petroclival meningiomas
• A different entity
• Aggressive, but incomplete surgery
• Combination therapy

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CPA Meningiomas
Is total resection reasonable if nerves need to be
sacrificed?
The selection of operative approach and the goal of
surgery should be part of the whole treatment strategy
The attempt to achieve complete resection can be
justified only if the associated long-term morbidity is
minimal.
The retro sigmoid suboccipital approach is the most
effective and safe approach – i.e. The gold standard
for lesions in the CPA.

“The expertise of the surgeon is not


reflected in his or her ability to perform the
most complex approaches, but in the ability
to select the approach that affords both
removal of the tumor and preservation of
patient’s neurological function and quality
of life”. Magid Samii, MD, PhD 2008

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Proposed Algorithm
Age Tumor Presentation First therapeutic Following
Size option evaluation
Young small no signs conservative growing tumor: GKS
signs GKS
Large or microsurgery residual tumor
brainstem (optimal radical small: GKS
compression resection or planned large: another surgery or
two-step strategy) radiotherapy (also if
malignant)
Elderly small conservative growing tumor: GKS
large no signs conservative growing tumor: total sub-
optimal removal
signs microsurgery (total Residual tumor:
suboptimal removal) small: GKS
stereotactic radiotherapy if
too large

1572
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Radiosurgery for Brain Metastasis,


Arteriovenous Malformations, and
Trigeminal Neuralgia

Jason Sheehan, MD, PhD


Departments of Neurological Surgery
and Radiation Oncology
University of Virginia

Disclosure Statement

• Reports no commercial interest

1573
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Critical Advances in
Neurosurgical Treatment
Technique Decade Need

1. Microsurgery 1970’s Magnification;


Illumination

2. Stereotactic 1980’s Precision; Surgery


Safety

3. Radiosurgery 1990’s Reduced Risk;


New Option;
Minimally
invasive

What is “stereotactic
radiosurgery”?
• The delivery of a very high dose of
irradiation to a small and critically
located intracranial volume
through the intact skull
• Alternative and adjunct to surgery
and radiation therapy
• Tumor, vascular malformations,
functional disorders
• Use of:
– Stereotactic principles/guidance
– 1-5 fractions
– High conformality
– Steep fall off

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Lars Leksell, MD, PhD

GK Icon

Modern Stereotactic
Systems
• Incorporate all
advanced
neuroimaging (e.g.
SPECT, PET,
functional MRI)
• MR compatible
• Accurate and precise
• User friendly
• Concept of “minimally
invasive surgery”

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Unparalleled clinical flexibility

Vascular disorders Multiple tumors All brain targets

Stereotactic radiosurgery

Saves cost and enhances


quality of life
Time
Open Days A week of Several weeks
surgery in ICU hospitalization convalescence

Symptom Diagnosis

Radio
surgery

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Basic Units
Measurement Common Units Official (SI) Unit
Joules (J), Mega Joules (J)
Energy
electron-volts (MeV)
Activity –
disintegrations per Curie (Ci) Becquerel (Bq)
unit time
Exposure – Coulombs/kg
Roentgen (R)
ionization (C/kg)
Absorbed Dose – Gray (Gy)
energy deposited in Rad
tissue 1 Gy = 1 J/kg

Dose equivalent –
Rem Sievert (Sv)
biological effect

Just remember this...its easier!

http://deepseanews.com/2013/11/true-facts-about-ocean-radiation-and-the-fukushima-disaster/

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Radiosurgery chain of uncertainty

Dosimetric calibration

Dose calculation Mechanics

Patient positioning
Target definition

3D Imaging
Biological model

Target localization

What you see is not (exactly)


what you get!

Computer
displays
this…..

You
deliver
this!
Image courtesy of Stan Benedict, UC Davis

1578
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Step 1: Frame Placement

Step 2: Neuro-Imaging

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Step 3: GK Planning

Physicians and Physicists Patient

Dose Planning
• Isocenter based dose planning.
• 4^8 (i.e. 65,536) unique
combinations per isocenter
• Multiple isocenters per target.
• All make for highly conformal
plans and shielding around
eloquent structures.

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Step 4: Treatment

Step 5: Follow-up

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Fine Balance Between


Tumor Control and
Major Complications

Multidisciplinary Approach to
Stereotactic Radiosurgery

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Types of Stereotactic
Radiosurgery
• Gamma Knife
• Modified LINAC’s
• Proton Beam
• Cyberknife
• X-Knife
• Versa HD
• Tomotherapy
• Novalis
• Edge

LINAC Based Stereotactic


Radiosurgery Devices

TrueBeam X-Knife NovalisTX


(Varian) (Radionics) (BrainLab)

Synergy S Tomotherapy Cyberknife


(Elekta AB) (Accuray Inc.)
---State of the art linear accelerators
---Amorphous silicon flat panel detectors or MV CT scanner
---Allow for real time imaging during radiosurgery

1583
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Major Intracranial Indications for


Radiosurgery
• Meningiomas
• Pituitary adenomas
• Arteriovenous
malformations
• Vestibular Schwannomas
• Brain metastases
• Ocular Melanoma
• Temporal lobe epilepsy
• Functional disorders (e.g.
Parkinson’s disease)
• Trigeminal neuralgia

Arteriovenous Malformations

1584
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Natural History of AVM’s


• 2-4% annual risk of
bleeding dependent
in part on
– AVM size
– Presentation
– Prior bleeding
• 3% combined
annual
morbidity/mortality

The Aruba Trial

• Intent
– 400 patients
– Followed for 5 to 10 years
– Randomized to medical tx vs. intervention

• Halted on April 15, 2013


– Mean f/u of 33 months
– 224 participants
– Enrolled from 39 sites

• Data and safety monitoring


Issues with equipoise
Board note 3x higher “event
Short f/u
rate” than medical management
Clinical proficiency of centers
group
• Accrued pt’s will be followed

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Aruba Results

• Risk lower in
Death or Stroke

medical tx group
• However mean f/u
33.3 months (SD
19.7 months)
• What about long-
term risk?

Risk of Hemorrhage

1586
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Stereotactic radiosurgery for


Arteriovenous Malformations

At the University of Virginia,


more than 1400 patients have
been treated for AVM’s.

The obliteration rate is 80%.

We have also observed a decrease


in seizure frequency and severity
even with partial
obliteration of the AVM.

AVM Illustration

1587
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Predictors of an
unfavorable outcome
N=2236 patients

Prior Hemorrhage
Prior Embolization
Larger Volume
Eloquent location
Lower dose
More isocenters (likely related to volume but possibly
dose heterogeneity)

Dose-Volume-Location
Interrelationship 100
% obliteration

80

• Dose impacts 60

40
– Obliteration
20
– Complications through V12
0

• Limitations of dose 0 4 10 16 20
dose (Gy)
24

minim um dose to AVM nidus


29 34 38

related primarily to
– Volume
– Location
• Deep vs. superficial
• Eloquent vs. noneloquent
– Prior radiation
– Neurological function

1588
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UVA SRS AVM Grading


System
• Nidus volume >
• Prior hemorrhage
• Eloquent location

Unfavorable

Favorable
N=2236 patients

All scales were good but


UVA AVM Scale
was the best predictor

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Unruptured AVM’s—Does it
Matter in terms of obliteraton?
• Should we treat
AVM’s with GKRS
That have not
ruptured?
• Analyzed 2236
patients from 7 busy
SRS centers
• Isolated 509 ARUBA
eligible pts

GKRS Obliteration of
Unruptured, ARUBA eligible
AVM’s

Most complications occur in the first 3 years


Appreciable benefits will take >10 years to realize
with GKRS in unruptured AVM’s
Obliteration comparable to ruptured AVM’s

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Large (>3 cm) AVM’s


• May be treated with a
volumetric, staged SRS.
• Pre-SRS embolization
can be useful to reduce
the size of the nidus.
• The rate of obliteration
varies but is less than
50%.
• Partial obliteration may
at times be advantageous
to patients with focal
neurological deficits.

Volume Staged AVM


Example
GK 3 years post GK
SM V AVM
• Seizure
cessation at 15
months post
SRS
• Obliteration at
3 years post
SRS

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Volume vs. Dose Staged


SRS

1592
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Trigeminal Neuralgia

The Problem

• Trigeminal neuralgia
(TGN) is a
– Paroxysmal lancinating pain
– Confined to a distribution
encompassing one or more
of the branches of the
trigeminal nerve
– Usually on one side of the
face
• Other kinds of facial pain
associated with post-
herpetic neuralgia,
multiple sclerosis,
diabetes, or trauma.
• Incidence 4/100,000/year
• Rare familial incidence

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Trigeminal Neuralgia History

• Nicholas Andre (1677)


coined the term "tic
douloureux" to describe
this disease, one that had
been called "spasme
cynique" or cynical
spasm- the expression of
a dog about to bite.
• It is a terrible pain.
• Patients have been known
to be driven to suicide in
frustration.

Patient Demographics

• Typical patient > 50 years


old
• Female:Male ratio 1.5:1
• Location
– 1/3 V2 and V3
– 1/6 V2 alone
– 1/6 V3 alone
– 1/3 various
combinations including V1
– Only 4% with V1 alone
• 4% bilateral

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BNI Pain Score for TGN

Radiosurgical History
of Facial Pain
• In his book Brain Fragments, Dr.
Leskell wrote,
“One can accept death, but one cannot
accept the deep, devastating pain.
Sharp, intractable pain is like hell
‘without escape, without hope and
without Heliotrope when Venom burns.’
Standing at the bedside without ever
having experienced pain, it is
impossible to imagine the patient’s
agony, and it is impossible to
understand that a short time without
pain can be extreme happiness.”

• The Gamma Knife was designed by


Leksell to perform deep seated
surgeries for pain and psychiatric
disorders.

• Minimally invasive neurosurgical


approach with safety and accuracy in
mind

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Techniques Critical to SRS

• Stereotactic frame or
mask for maximum
accuracy and precision
• High resolution MRI (1.5
or 3T, 1mm slices) or CT
cisternography
• T1 and T2 sequences for
MR
• Dose planning
• Dose delivery via small
beamlets (3 to 5mm)

The DREZ at the level of


The Vth nerve according to Jannetta
Can be of variable length
Spreading more distally in
some patients

Ridder NS 2002

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Dose Planning

• Affected by length of
cisternal segment of
trigeminal nerve
• Must consider
– Integral nerve
A B dose
– Brain stem dose
– Prior nerve
dysfunction
– Prior treatments

C D

Patients with Pacemakers

• Can image the


trigeminal nerve
well with CT
cisterography

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SRS Mechanism

• Disruption of
myelin
• Possibly some
intimal
hyperproliferation
of adjacent vessels

Hodaie et al., PloS One, 2012

Effect of Vessel Adjacent to


CN V
• Retrospective review
• 106 patients with typical
trigeminal neuralgia
• No previous surgery for TGN
before GKRS
• Stereotactic MRI’s assessed
– Presence or absence of vessel
compression
– Extent of Compression
– Dose to the point of vessel contact
• Clinical F/U at 6 month intervals

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Results
• Median follow-up of 31 months
• BNI pain score of 1 was achieved in
59.4% of patients
• Vessel impingement was seen in 63
patients (59%)
• No difference was seen in the pain
relief between those with and without
vascular impingement following GKRS

Vascular Compression versus


Nonvascular Comprehension
Cohorts

Vascular compression Vascular P


(+) compression (-)
Gender (male/female) 20/43 23/20 0.017
Mean Age (years) 64.3 59.5 0.092
Mean Maximum 78.7 78.1 0.515
dose (Gy)
Mean Peripheral 39.3 39.0 0.515
dose (Gy)
Pain free (i.e. BNI 1) 37/26 26/17 1.000
after GKRS
(Yes/No)

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Vascular Impingement

• For those with vascular


compression, improved
BNI scores were seen with
– Increased dose (p=0.019)
– closer proximity of the isocenter
to the site of vessel impingement
(p=0.012)

Pain Relief in the Vascular


Impingement Group
Factors P

Proximal nerve diameter (mm) 0.79


Diameter of nerve at impingement (mm) 0.84
Distal nerve diameter (mm) 0.29
Fraction of Impingement 0.86
Radiation dose at impingement (Gy) 0.019
Distance of isocenter to impingement (mm) 0.012

1600
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UVA Results with SRS

• Evaluated 151 cases of


trigeminal neuralgia with
SRS.
• The types of trigeminal
neuralgia were as follows:
– 122 patients with typical TGN
– 3 with atypical TGN
– 4 with multiple sclerosis associated
TGN
– 7 patients with TGN and a history of
a cavernous sinus tumor
• Median age = 68 yo
• Median time from
diagnosis to SRS = 72
months

Results

• mean time to relief of Delay of pain cessation

pain = 24 (range 1-180) since GK surgery


1,0
days
• Improvement in pain at ,8
Cumulative survival

– 1 year= 90% ,6

– 2 years=77% ,4

– 3 years=70% ,2

0,0 censored
0 30 60 90 120 150 180 210

Days since GK surgery

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Maintenance of Pain Relief:


Proximal vs. Distal Targeting

Proximal
Proximal

Distal
Distal

Complications:
“No Free Lunch” (Burchiel)
• Pain relief maintained longer in
those with some numbness
• 9% of patients had new onset of
facial numbness
– Pollock et al. (2002) showed New numbness
this correlated with a dose of
90+Gy
• 19% had new or worsened facial
numbness
• No cases of new onset corneal
reflex loss or anesthesia dolorosa No numbness
• New onset of facial numbness
following SRS correlates with
– more than one SRS
– pain relief

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SRS and Quality of Life

• Evaluate patients
with TGN
undergoing SRS
– VAS
– BNI pain scale
– SF-36

• SRS produced significant improvement


in SF-36 indices that correlated with
pain relief.

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Major SRS Series

Trigeminal Neuralgia Case


Illustration

• 63 yo male with right V2 and V3


distribution trigeminal neuralgia
for 12 years.
• The patient found it difficult to
shave and was unable to smile
without excruciating pain.
• Pain became refractory to
tegretol. The pt. had only short-
term relief with a glycerol
injection.
• He underwent Gamma surgery
and received 80Gy to CN V.

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Post SRS for TGN

Three weeks post-op, he noted improvement in his TGN.

By six months post-op, he was pain free without medications.

Brain Metastasis

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Epidemiology of Brain Metastases

Primary Tumor Relative Prevalence of Brain Metastases*

Colon: 5% Annual U.S. incidence:


170,000 to 300,000
Melanoma: 9% Ratio Mets/Primary: 10:1
All Cancer Patients: 15 - 30%
Unknown primary: 10%
Autopsy incidence: 10 - 30%
Other : 13% Mean age: 60 years
Median survival: ~ 6 months
Breast: 15%

Lung: 48%

*Incidence increasing with better systemic Rx


and improved survival
Wen PY, et al. In: DeVita VT Jr, et al (eds). Cancer: Principles & Practice of Oncology. 2001:2656-2670.

Brain Metastases

Hematogenous Origin Leptomeningeal Origin

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Approaching
Brain Metastasis
Patients
• Symptom management
• Staging of extracranial
disease
• Chemotherapy
• Intracranial disease staging
– 1 Lesion
• With evidence of systemic
disease (single)
• Without evidence of
systemic disease (solitary)
– Multiple Lesions
• 2-3
• All others
• KPS, RPA, GPA, and
Disease specific GPA status

Historical Treatments
• Surgical resection of solitary, symptomatic
metastases in patients fit for a craniotomy
• Corticosteroids
• Whole brain radiation therapy (WBRT)
• Chemotherapy

• Median survival of approximately 6 months


with patients typically dying of intracranial
disease progression.

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RTOG-9508:
Randomized SRS Trial
• Enrollment
Arm 1: WBRT (37.5 Gy) +
SRS: n=164
Arm 2: WBRT (37.5 Gy)
alone: n=167

• Stratification
1. Number of brain
metastases (1 vs 2 - 3)
2. Extracranial mets
(none vs present)
Andrews DW, et al. Lancet 2004;363:1665-1672.

RTOG-9508 Results
Survival Analyses WBRT + SRS WBRT P-value
(months) (months)
Overall 6.5 5.7 0.13

1 brain met 6.5 4.9 0.04


Post-Hoc Subsets

1-3 mets & age <50 9.9 8.3 0.04

1-3 mets & NSCLC 5.0 3.9 0.05

1-3 mets & RPA Class 1 11.6 9.6 0.05

Selected subsets benefit from radiosurgery.


Andrews DW, et al. Lancet 2004;363:1665-1673.

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November Vol 10:1037-44, 2009

Prior and Posterior Distributions


5

SRS prior: mean = 25%


SRS: mean = 23%
SRS+WBRT: mean = 49%
4

SRS+WBRT
Based on level I evidence presented,
SRS alone coupled with close clinical
3

Prior monitoring could be considered the


Density

preferred treatment for pts newly


diagnosed with 1 - 3 brain metastases
2

SRS alone preferred treatment for 1-3


1

melanoma and renal cell CA brain


mets. Practice starting to change for
0

other histologies.
0.0 0.2 0.4 0.6 0.8 1.0

Event Probability

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Myth #1:
Number of Metastases
• There is no holy 1…3…
grail for cut-off 4… 5?
number of brain
mets
• SRS devices allow
almost limitless
number of lesions
to be treated

Does volume of metastases matter?

5 x 0.1cc Tiny Mets 1 met x 5 cc


0.5 cc total volume 5 cc total volume
Asymptomatic Asymptomatic
All treatable with SRS Treatable with SRS

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Total intracranial met volume is a greater


Prognostic factor than number of metastases

Myth #2:
Micrometastases are everywhere
• Modern volume acquisition,
3T post contrast MRI can
detect even small mets
• Surveillance scanning
detects
– Early local or distant progression
– Leptomeningeal spread

• Intervene when it is
prudent

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Myth #3:
All Mets Need Treatment
• Some mets are asymptomatic
• A number of studies have shown that a
disconnect between intracranial disease
control and overall survival
• We are not curing these patients. Our
intervention is palliative.

Myth #4:
All patients with WBRT suffer
neurocognitive decline

• Most studies show only half have


appreciable decline after WBRT
• Neurocognitive decline is worse
with widespread intracranial
progression than WBRT
• Thus use WBRT when it makes
sense
• Consider newer techniques (e.g.
hippocampal sparing)

1612
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Myth #5:
All Brain Mets are Created Equal

• Outcomes vary
tremendously by
– Type of cancer
– Histological subtype
– Genetic subtype

• Implications for risk


stratifying brain mets
patients who will truly
benefit from SRS

Myth #6:
Brain Mets are Genetically Identical to Regional
and Extracranial Mets

• Recent work shows that Brain Mets are


Genetically Distinct
• Disparate genetic mutations
may impact targeted therapy
responses Brastianos et al., Cancer Discovery, 2015

• Genetic analysis of brain met tissue


may be of value

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Carcinoma type and Impact

• Tumor histology impacts survival


– In 2002 we reported that NSC lung CA outcomes
varied by subtype with adenoCA most favorable
KPS,
• In 2011, weRPA,
showedGPA do not include
breast CA tumor biology
receptor status impactaresurvival
All histologies after
not created equal.
SRS
• More recently, we found that
melanoma receptor status also
impacts survival

However sometimes WBRT


is needed

12-19% risk of leptomeningeal dz


New lesions in >48%

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Radioresistant
Metastasis
Pt with metastatic melanoma;
KPS=100;
At SRS (above left) and 7 months
post Gamma surgery (below right)

Little role for WBRT in melanoma


And renal cell CA.

Avoid 2-5 fraction SRS for


Radioresistant Brain Mets
Single Session SRS 2-5 fraction SRS

>35 month median local control 14.4 month median local control
For radioresistant mets For radioresistant mets

Oermann, et al., JNS, 2013

1615
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Radiosurgery to a Tumor
Resection Cavity
• Following a gross total
resection of a brain
metastasis, recurrence
occurs 47% of time.
• WBRT reduces the
chance of recurrence.
• Radiosurgery with a 2
mm margin around
– Also reduces recurrence
– May avoid sequelae of
WBRT
– Hold WBRT until really
needed

SRS for Multiple Metastases

• How many are too


many?
• WBRT?
• Patient
Expectations?
• Q of L >
life expectancy>>
Intracranial Disease
Control

1616
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JLGK0901 Study
Up to 10 BM is reasonable for SRS
• Comparable
survival for
those with
5-10 versus
2-4 BM’s

Yamamoto et al., Lancet Oncology

1617
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Hospital Cost Comparison


Craniotomy vs. Gamma Knife Surgery

UVA data from 2011 to 2014 Caruso, J Clin Neurosci, 2015

Cost of SRS versus WBRT

Lee et al., J. Clinical Neuroscience 16:630-634, 2009.

1618
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Era of “Big Data” for AVM’s

• AANS and ASTRO SRS


Registry
• Close collaboration with
corporate partners and
Quintiles
• Many data elements
populated in automated
fashion
• Prospective data from 30
high volume SRS sites

Conclusions
• Radiosurgery is a safe
and effective strategy
for many intracranial
pathologies.
– Low morbidity
• Minimally invasive
• Low risk of delayed
neurological deficits
• Rare incidence of
radiation injury

– Essentially zero mortality

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Conclusions
• Stereotactic radiosurgery
frequently affords:
– Tumor volume stabilization
– Preservation or improvement of
neurological function
– Enhanced quality of life
– Extended life expectancy in
patients with malignant tumors
– Pain relief
• Dose escalation or repeat
radiosurgery may be
needed to treat certain
malignant lesions.

1620
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Modern Management of Spinal


Column Metastasis

Neurosurgery – A Comprehensive
Review

Michael W. Groff, MD
Director of Spinal Neurosurgery

Brigham and Woman’s Hospital


Harvard Medical School

Disclosures

Research Grants: Neurosurgical


Research and Education Fund

Advisory Role: Biomet Spine, Depuy


Spine

Independent Contractor:
BestDoctors, Inc

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Goals: NOMS
Neurologic
• Decompression
Oncologic
• Resection
Mechanical Stability
• Instrumented Fusion
Systemic Disease
• Death or Prolonged Hospital Stay

Mark Bilsky

Oncologic: Tumor Pathology

Metastatic Primary
• Palliation • Cure
• Intra-lesion • En bloc
• Adjuvant therapy • Limited adjuvant

1622
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Incidence of Spinal Metastases

40-60% of cancer patients harbor spinal


metastasis
• 10% are symptomatic
18,000 new cases annually in NA
Most common malignant spine tumor
Most common site of bone metastasis

Primary Tumor

Breast 22%
Lung 15%
Prostate 10%
Myeloma 9%
Lymphoma 7%
Renal 6%
Thyroid 3%

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Metastatic Cord Compression


Histology is unknown at presentation in 10%
of cases with metastatic spinal cord
compression
50% of those cases will turn out to have lung
cancer

Spinal Level

Thoracic 70%
Lumbar 20%
Cervical 10%
Probability of met =
f (number of bodies,
size of bodies)

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Location Within Body

Vertebral body 85%


• Early involvement of pedicle
Paravertebral 15%
Epidural space 5%
Intradural rare

Manifestations of Spine Metastases

Back Pain
Cord Compression
Pathologic fracture - 8% incidence

1625
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“Metastatic” Back Pain


Most common presentation Pain onset to neuro signs
Constant dull ache avg 7 mos
Progresses to frank pain [Hatrick et al, Radiother Onc 2000]
Awakens from sleep
Aggravated by valsalva
Etiology
• Tumor spread/tissue
destruction
• Periosteal innervation
• Cord compression
• Spinal instability
• Nerve root irritation

Pathologic Fracture

50% destruction required


[Edelstyn et al, Clin Radiol 1967]

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Pathologic Fracture

Results of Treatment for Spinal Cord Compression:


Radiotherapy Alone

Authors Year Patients (n) % Improved % Worse


Mones et al. 1966 41 34 -
Khan et al. 1967 82 42 -
Cobb et al. 1977 18 50 22
Gilbert et al. 1977 29 41 21
Marshall & Langfitt 1977 130 49 -
Greenberg et al. 1980 83 57 7
Stark et al. 1982 31 35 -
Constans et al. 1983 108 39 26
Obbens et al. 1984 83 28 23
Harrison et al. 1985 33 27 36
Bach et al. 1990 149 35 18
Maranzano 1995 209 76 0
Mean - 44 17
Total 996

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Results of Treatment for Spinal Cord Compression:


Laminectomy with or without Radiotherapy
Authors Year Patients (n) % Improved % Worse % Mortality
Hall & McKay 1973 129 30 - -
Brady et al. 1975 90 61 - -
Merrin et al. 1976 22 22 0 0
Cobb et al. 1977 26 46 23 -
Gilbert et al. 1977 65 45 - -
Marshall & Langfitt 1977 17 29 - -
Gianotta & Kindt 1978 33 30 18 12
Kleinman et al. 1978 20 15 5 15
Livingston & Perrin 1978 100 58 - 0
Baldini et al. 1979 140 30 19 0
Gorter 1979 31 39 - 13
Dunn et al. 1980 104 33 23 10
Levy et al. 1982 39 82 15 8
Stark et al. 1982 84 37 - -
Constans et al. 1983 465 46 13 -
Klein et al. 1984 194 54 16 -
Kollmann et al. 1984 103 56 - -
Garcia-Picazo et al. 1990 53 41 - -
Back et al. 1990 91 59 11 -
Landmann et al. 1992 127 58 2
Mean 44 13 7
Total 1933

Results of Treatment for Spinal Cord Compression:


Laminectomy (Posterior Decompression) and Stabilization
% Motor % Pain
Authors Year Patients (n) Improved Improved % Mortality
Brunon et al. 1975 20 - 100 -
Hansebout et al.1980 82 84 100 -
Miles et al. 1984 23 65 100 -
DeWald et al. 1985 17 45 65 6
Overby et al. 1985 12 75 - -
Solini et al. 1985 33 48 - 3
Heller et al. 1986 33 70 79 -
Perrin et al. 1987 200 82 80 8
Olerud 1996 51 38 100 0
Bauer 1997 67 76 0 -
Bilsky 1999 25 90 - 12
Mean 67 89 8
Total 563

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Results of Treatment for Spinal Cord Compression:


Vertebral Body Resection and Stabilization
Improved Improved %
Authors Year Patients (n) Motor % Pain % Mortality
Slatkin and Posner 1982 29 56 60 7
Harrington 1984 52 65 80 6
Siegal and Siegal 1985 61 80 91 6
Sundaresan et al. 1985 101 70 85 8
Onimus et al. 1986 36 72 97 6
Perrin & McBroom 1987 21 95 90 5
Moore & Uttley 1989 26 62 71 30
Sundaresan et al. 1991 54 100 90 6
Hall & Webb 1991 15 86 - 20
Fidler 1994 18 93 94 20
Hosono et al. 1995 90 81 94 0
Gokaslan et al. 1998 72 78 92 3
Mean 76 85 10
Total 575

Work-up
History
• Ambulation, B/B, Pain worse at night or positional
Physical exam
• LE weakness, long tract signs, sensory level, point
tenderness
MRI of the spine - compression
CT of the spine - stability
Restage primary
• CT chest, abdomen, and pelvis
• FDG PET
• 10 - 30% with synchronous lesions
Labs with LFT’s

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Stability Assessment
Anatomic
• 2 column
• 3 column
Physiologic
• History positional pain
Trauma is not Oncology

Harms

Case EW

66 year old man


C2 metastasis of non-
small cell lung CA
Severe neck pain
Neurologically intact
Metastasis to liver

1630
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What to do?

Do No Harm!

1631
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Case CM

48 year old woman


LE weakness, back pain
Metastatic osteosarcoma
from hip
What to do?

CM intraop

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Post op - 1 year

MRI

Study of choice
Unsuspected lesions
in 30%
Whole body fast-imaging
techniques:
• STIR 30-45 min
• Echo-planar 6 min
False positives

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Radionuclide Imaging

50-80% more sensitive


than plain films
Detection up to 18 mos
earlier
[Pagani & Libshitz, Radiol Clin North
Am 1982]

2% cold

55 yo prostate CA & LBP

1634
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MRI vs Bone Scan


Bone scan assesses cortical bone
Early lesions small and intramedullary
MRI more
sensitive
Bone scans
more cost
effective

Taoka et al, AJR 2001

SPECT or PET/CT

SPECT more sensitive,


better localization
Benign: ↑ uptake in
endplate, lateral body
border, facet, spinous
process
Malignant: ↑ uptake in
pedicle, central body, entire
vertebra, cold lesions with ↑
uptake at margins
[Sedonja et al, Clin Nucl Med 1999]

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Myelography

Risk of LP below hi-


grade block
Use high cervical
cisternal puncture
Be prepared for
emergent OR

Importance of Biopsy

Benign tumors
Myeloma/plasmacytoma
Primary bone sarcomas
Paget’s disease
DDX - CT guided biopsy
• Core bx preferable to FNA

1636
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Breast CA
50 year old woman
Back and leg pain
Worse s/p XRT
Known Breast CA
Only known met

Intraop - LECA

1637
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IntraOp

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Postop

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Study Design
All patients
• Underwent MRI
• Treated with Decadron
• Diagnosis confirmed with biopsy
Stratification based on
• Tumor type
• Ambulatory status
• Spine stability
Randomized to
• surgery with XRT or XRT alone (30Gy)

Treatment
Radiation started within 24 hours
Surgery within 24 hours
Goals
• Remove as much tumor as possible
• Immediate decompression
• Stabilization when needed
XRT started less than 14 days post-op

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Entry Criteria
Known cancer
Symptomatic lesion
Resectable based on MRI
Not paraplegic > 48 hours
No prior XRT
Exclusion: lymphoma, leukemia, multiple
myeloma, germ cell tumor, primary spinal tumor

Endpoints

Primary
• Ambulation
Secondary
• Continent
• ASIA and Frankel grade
• Narcotic and steroid use
• Survival

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Results
Ambulation
• Surgery + XRT 126 days
• XRT alone 35 days
• For non-ambulatory patients 56% vs 19%
Continent
• Surgery + XRT 142 days
• XRT alone 12 days
Survival
• Surgery + XRT 129 days
• XRT alone 100 days

Results

Steroid use 1.6mgs vs 4.2 mgs


Narcotic use 0.4 mgs Morphene vs 4.8 mgs
Complications Post-op 12%
• Hardware/ fusion - half
• Wound breakdown – half

1642
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Day Patient Enrolled

25
Number of Patients

20

15

10

0
Sun Mon Tues Wed Thu Fri Sat
Day of Week

Conclusion

Surgery + XRT is superior to XRT alone for


symptomatic Spinal Column Metastasis.

1643
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Evolution of Surgical Technique for


Spinal Cord Compression

Laminectomy + XRT

Posterolateral with instrumentation

Anterior column reconstruction

Is a thorocotomy necessary?
Pros
• Direct visualization of decompression
• Reconstruction of anterior column
Cons
• Transpedicular/costotransversectomy is
better tolerated
Katonis Spine ‘99, Vornanen Spine ‘95

1644
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Thoracic Approaches
Laminectomy
Transpedicular
Transfacet-pedical sparing
Costotransversectomy
Lateral Extracavitary
Retroplural
Transthoracic
Trans-sternal
Thoroscopic/Endoscopic

Lateral Extracavitary Approach


Advantages Disadvantages
Logical: decompression, Big operation and EBL
instrumentation, fusion Multilevel access limited
Surgical exposure of the Difficult to instrument
Spine: An Extensile anteriorly
Approach Benzel ‘95 Technically demanding
Second surgeon not Second surgeon not
required for exposure available for exposure

1645
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History of LECA

Etude pratique sur le mal de Pott


Menard 1900 Paris: Masson et Cie
The evolution of lateral rhachotomy
Capener JBJS ‘54
Lateral extracavitary approach to traumatic
lesions of the thoracic and lumbar spine
Larson JNS ‘76

Exposure 1

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Exposure 2

Exposure 3

1647
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Exposure 4

Exposure 5

1648
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Exposure 6

Ligate nerve root


Proximal rib resection
Expandable cage

Definition of LECA?

1649
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LECA Take Home Message

Soft tissue prevents


visualization
Removal of proximal rib
head
Anterior column
reconstruction

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Incision Design

Ligate nerve root


Resect rib head
Ventral decompression

1651
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Importance of rib head resection

Cage insertion

1652
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Approach corridor created by the tumor

1653
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Summary
Decompression
Optimize ventral exposure
Bilateral exposure
Anterior column reconstruction
Remove proximal rib head
Anterior/Posterior versus LECA
Not Anterior versus LECA

1654
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Vertebroplasty for Tumor

Originally applied to osteoporotic


burst fractures
Addresses the structural deficiencies
of the anterior column
An adjunct to either
• XRT
• Surgery

VP/KP

1655
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Complications

Anterior Column Augmentation

T4

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Intraop

Predicting Spinal Collapse


Collapse = f(tumor size & location, loading,
BMD)
• Tumor size exponential increase
• Finite element analysis
• Whyne et al Spine 2003
• Roth et al Clin Orthop 2004
Costovertebral joint or pedicle involvement
increases risk of collapse
Loading is related to spinal level (C,T,L)

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Spinal Radiosurgery

Evolution of intracranial radiosurgery


Minimally invasive
Steep radiation fall off curve
• Avoids radiation toxicity to spinal cord
• Allows higher tumorcidal doses to tumor

Radiosensitive Metastasis

Tumor Control Shrinkage


Breast Good Good
Lung (small cell) Poor Good
Renal Worst Worst
Melanoma Worst Worst
Prostate Poor Good
Follicular Thyroid Good Poor

1658
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CyberKnife Overview
Frameless image-guided stereotactic
radiosurgery
A lightweight linear accelerator mounted on a
robotic arm that has 6 axes of rotation
Two ceiling mounted cameras perform near
real-time image tracking
Mathematical transformation from image space
to target space
Target is radiated by robot controlled linear
accelerator

CyberKnife

0.3 mm accuracy
< 1 mm clinical accuracy
Arbitrary beams
Over 100 nodes
Over 1200 beams
Approximately $3 x 106

1659
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Management Goals

NOMS
SRS
VP

Separation Surgery

Summary

Treatment must be individualized


Patient’s quality of life must be
emphasized
Anterior column reconstruction
Surgery for symptomatic lesions is on
stronger footing then it has been
Other modalities are evolving as well

1660
Copyright © Oakstone Publishing, LLC, 2016. All Rights Reserved.

Michael Groff mgroff@partners.org


cell 617-849-2938

1661
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Paul C. McCormick MD, MPH


Columbia University College of
Physicians and Surgeons

Reports no commercial interest

1662
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Glial tumors (80-85%)


Ependymoma
Astrocytoma
Subependymoma, gangliocytoma
Hemangioblastoma (5-10%)
Inclusion tumors and cysts (1-5%)
Dermoid, epidermoid, lipoma
Metastatic (<1%)
Pediatric
Astrocytoma>ependymoma, pilocytic subtypes,
inclusion tumors

Majority are benign


Surgery is treatment of choice or
only proven treatment option in
most cases
Adjuvant therapy is of unpredictable
value

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Assume majority of tumors are benign and


resectable
Treatment goals:
1. preservation of function
2. long-term control or cure
Avoid MRI histological prediction
Gross determination of tumor/cord interface is
most important principle governing removal
Biopsy for confirmation

Diagnosis/Management
Sensitivity of, access to diagnostic
imaging
Earlier diagnosis
Incidental/asymptomatic
Sensitivity>Specificity
Differentiation from non-neoplastic,
non-surgical conditions

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Diagnosis,
localization,
characterization
Earlier diagnosis
Smaller size
Less edema
Higher level of
function

Incidental tumors
Biologically
indolent
Can’t make
normal patient
better
Post-op posterior
column deficits
are expected

1665
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Patients don’t get better after


surgery
Pre-op deficits remain in addition to
new proprioceptive deficits
Post-op function most correlated
with pre-op function (Better in-
Better out)

Medical myelopathy
Multiple Sclerosis
Transverse Myelitis
Sarcoidosis

1666
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Medical myelopathy
Multiple Sclerosis
Transverse Myelitis
Sarcoidosis
Extrinsic
myelopathy

Medical myelopathy
Multiple Sclerosis
Transverse Myelitis
Sarcoidosis
Extrinsic
myelopathy

Pre-op 6 mos. Post-op

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1668
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MR: Sensitivity > specificity


Medical vs. surgical differentiated on
clinical basis
Open myelotomy
Non specific inflammation
No specific diagnosis
Does not direct treatment

Current Techniques
Positioning, exposure
Spinal cord/tumor access
Myelotomy, retraction
3 hands better than 2
Tumor/cord interface
Internal decompression
Monitoring

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1670
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Unencapsulated
Histologically benign

Non-infiltrative at tumor/cord margin

Slow growth

Some biologic variability

1671
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Adequate bone/dural exposure


Midline myelotomy over entire
rostrocaudal extent of solid tumor, and
few millimeters beyond
Identify dorsal tumor surface, lateral
margins
Identify rostral/caudal tumor
poles/cysts

Pial traction sutures


Biopsy
Develop plane (traction/countertraction)
Cauterize, divide fibrous attachments,
feeding/draining vessels
Internal decompression as necessary
(Cusa, laser)

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Most histogically benign (80%)

Rare progressive anaplasia

Relative circumscription in most cases

Most show infiltration at margin

Uncertain benefit of marginal resection

1677
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Neurologic Morbidity

20 40 60 80 100
Extent of Resection
Disease Free Survival (Yrs)

20 40 60 80 100
Extent of Resection (%)

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1679
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1681
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•Pial origin/attachment; Variable intramedullary extension


•Circumferential detachment at tumor/normal pial margin

1682
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• Polar myelotomy for large intramedullary component

1683
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Facility with ventral,


lateral approaches
Instruments
Dural repair
Reconstruction
Implants
grafts

1684
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1685
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1686
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1687
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1688
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Morbidity in the Exposure

1689
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1690
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Long term tumor control with


preservation of function is treatment goal
Patients rarely improve following
surgery
Most patients sustain posterior column
deficit following midline myelotomy
Surgery is treatment of choice or only
effective treatment for most
intramedullary tumors

1691
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Paul C. McCormick
Columbia University
College of Physicians and Surgeons

1692
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Solitary schwannomas
Origin
Preganglion (intradural)
Postganglion
(extradural)
Dumbbell extension
Nerve of origin
Access/exposure
Stability

Pre-ganglionic (intradural) Post-ganglionic (extradural)

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Lack of well
defined connective
tissue supportive
matrix (epineurium,
perineurium,
endoneurium)
Nerve root of origin
Non-functional
Not salvageable

Well defined
connective tissue
supportive matrix
(epineurium,
perineurium,
endoneurium)
Spinal nerve of
origin
Sacrifice single
fascicle
Functional fascicles-
salvageable

1694
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Type
Nerve of origin II
Pre vs. post ganglionic
Pre-ganglionic I, II
Post-ganglionic III, IV
Dumbbell (spinal Type IV
canal)
II (intradural),
IV(extradural)
Functional nerve of
origin- III, IV

Origin: Intradural
No extension through root
sleeve
Sacrifice non-functional root of
origin
Spare functional corresponding
sensory or motor
Access: laminectomy
Stabilization: No

1695
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Root of origin: non-functional,


sacrifice
Corresponding root: functional,
preserve

Corresponding
functional root may be
attached to tumor
within common
arachnoid sheath
Applied to tumor
surface but separable/
salvageable up to DRG

1696
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1697
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Origin: Intradural
Extradural extension through
root sleeve
Sacrifice entire nonfunctional
motor/sensory nerve root
Access:
laminectomy/facetectomy
Stabilization

Intradural component with


extension beyond DRG via root
sheath= root sacrifice

1698
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Origin: Postganglionic
Peripheral nerve tumors
Functional nerve
displaced onto tumor
capsule
Sacrifice only fascicle of
origin

1699
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Origin:
Postganglionic
Variable paraspinal
extension
Spare functional
nerve root
Access:
Posterolateral/
anterolateral
No stabilization

1700
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Origin: Postganglionic
Significant intraspinal
extension (extradural)
Spare functional nerve
root of origin
Access: Posterolateral
May need stabilization

1701
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Type IV

1702
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1703
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1704
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Ventral to dentate
Tumor type
Tumor
consistency/
vascularity
Level
Cord rotation
Extension beyond
midline

1705
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Pure Ventral
No cord rotation
Meningioma
Nerve sheath tumor
Pial based
hemangioblastoma
AV fistula

1706
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Standard anterior
cervical exposure
Corpectomy
Midline durotomy
Tumor resection
Corpectomy
reconstruction and
stabilization

1707
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Primary dural
closure
Duragen
Wide strut allograft
Gelfoam lateral
gutters
Bedrest 3 days
Spinal drain 3-5
days

Fibular allograft
Translational plate
Hard Collar 8
weeks

1708
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1709
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1710
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1711
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Minimally invasive approaches to ventral pathology

1712
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1713
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1714
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Meningiomas of the Skull Base and


Other Skull Base Tumors

Ian F. Dunn, MD
Associate Professor of Neurosurgery
Skull base and pituitary surgery
Brigham and Women’s Hospital

Disclosure Statement

Reports no commercial interest

1715
Copyright © Oakstone Publishing, LLC, 2016. All Rights Reserved.

Overview
• Meningiomas

• Schwannomas

• Chordomas/chondrosarcomas

• Paragangliomas

Skull base meningioma distribution


Cavernous sinus 174
Sphenoid wing 114
Petroclival 102
Tuberculum sella 65
Sphenopetroclival 54
Anterior clinoid 45
Tentorial 44
Anterior petrosal 40
Falcine 39
Foramen magnum 37
Olfactory groove 33
Cranio-orbital 15
Jugular foramen 13
Cerebellar convexity 13
Optic sheath 12
Diaphragma sella 10

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Mortality and morbidity: overall


• 30 day mortality: 0.6%
• 1 year surgical mortality: 1%
• Ischemic deficit,
hemiplegia, aphasia 1.8%

Skull base approaches


4 main approaches:

Cranio-orbitozygomatic
Extended middle fossa approach
Transcondylar
Petrosal approaches

1717
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Foramen magnum meningiomas


31 cases:
Surgical mortality 0 (0%)
Total removal 24 (92%)
Death since treatment 2 (6%)
Post-operative lower cranial 13 (41%)
nerve deficit (50%)

1718
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Surgical anatomy

1719
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Surgical approach: transcondylar

• Head in line with


torso for vertebral
artery position
• Neuro-monitoring

1720
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Vertebral artery mobilization

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1722
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Bony anatomy removed

Jugular fossa meningiomas

1723
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Parasellar meningiomas
• Cavernous sinus 160
• Tuberculum sella 65
• Clinoidal 44
• Sphenoid wing 62
• Sphenopetroclival 48

Outcomes
• Mortality within 30 days 0.6%
• Stroke 2.2%
• Complete resection 90%
• Recurrence 7%

1724
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Clinoidal meningioma: Grade I


Tumor arises proximal to
the carotid cistern.
Tumor adheres directly to
the arterial adventitia

1725
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Clinoidal meningioma: Grade II

Tumor engulfs the CA and


its branches.
Intervening arachnoidal plane

1726
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Clinoidal meningioma: Grade III


Origin-optic foramen
Small with extension into the
optic canal
An arachnoid plane is present
between the CA and tumor

Optic canal decompression

• Falciform ligament/dura
• Drill bony canal--
constant irrigation

1727
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Opening optic sheath

• Falciform ligament/dura
• Drill bony canal--
constant irrigation
• Open optic sheath
• Careful tumor resection

1728
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Select series, cavernous sinus


meningiomas

Lateral view, cavernous sinus

1729
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Cranio-orbitozygomatic

1730
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Critical: carotid artery control


clinoidectomy

Petrous carotid exposed

1731
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Cavernous sinus access corridors


Lateral access

Superior access

1732
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Intracavernous Cavernous sinus


involvement
1
1

Cavernous sinus meningioma

163 cases:

• Recurrence rate: 26%


– From residual tumor: 88% of recurrent cases
– After initial total resection: 12% of recurrent
cases

1733
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Petroclival meningiomas

Originate medial to the Vth nerve, upper 2/3 of clivus

Symptom
Diplopia
Facial numbness/pain
Hearing loss
Headache

1734
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Approach through the temporal bone

AP

PP

Approach Number of cases


Anterior petrosal 25
Posterior petrosal 8
Combined petrosal 16
Total petrosectomy 3
Transcondylar 2

Petrosal bone flap with mastoid cortex

1735
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Sectioning the tentorium

Posterior petrosal approach

1736
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Outcomes
GTR: 35/55 patients with “true” petroclival meningioma

Cranial neuropathies: 49% had new deficits, the majority of which


improved

Other complications:
CSF leak
PE
respiratory failure
DVT
brainstem stroke
venous infarction
seizure
IVH

Approach selection in petroclival


meningioma
MRI, MRV, CT, hearing test

Small tumor Large tumor Large, extending Large, involving


Superior to IAM Below IAM across midline of anterior CS
clivus

Anterior petrosal

Combined petrosal
Hearing + Hearing -

Posterior petrosal Total petrosectomy

1737
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Recurrence of skull base meningiomas

Average f/up 18 years


At 10 years
Survival advantage to patients with radiotherapy
At 20 years
No difference in survival
Most patients treated with SRS recurred - delayed
Term effect

Recurrence of skull base meningiomas

1738
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Trigeminal schwannomas
28 cases (3yr mean follow-up):
• Relief of pain 73%
• Improv. of V sensory 40 %
• Improv. of V motor function 80%
• Improv. of VI function 63%
• Perm. worsening of V sensory n 8%

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Meckel’s cave
• Sleeve of arachnoid covering trigeminal
nerve

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Middle fossa approach

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Chordoma
Sacrococcygeal region -49-50%

Spheno-occipital region
(at the clivus) -30-35%

Vertebral chordomas
(lumbar, cervical, thoracic) -15% of
total chordomas

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Remnant of Embryonal rests


Notocord of the cranial
cartilage
Epithelial Origin
Mesenchymal
Origin

Cytokeratin + Cytokeratin -
EMA + EMA -

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Metastases

12%

10%

8%

6%

4%

2%

0%
Chordoma Chondrosarcoma

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% of children under 17 yo

40%
35%
30%
25%
C
20%
CS
15%
10%
5%
0%
C CS

Recurrence
100
90
Chondrosarcoma
Survival probability (%)

80
70
60
50
40
30 Chordoma
20
10
0
0 20 40 60 80 100 120 140 160 180 200
Time

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Treatment of Chordoma
Surgery (as many surgical approaches) Proton Beam radiotherapy

PFS and Survival

Recurrence-free survival curve Survival curve


100 100
Chondrosarcoma
80 80

Chondroid
60 60
Chordoma
40 40

20 20
Chordoma
0 0
0 50 100 150 200 0 50 100 150 200
Time (months) Time (months)

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PFS and Survival


Results:
• Follow-up of 48 + 37.5 months (range =1-191).
• No reliable clinical or radiological distinguishing
feature.
• Chondrosarcoma had a significantly better
outcome than chordoma in survival and
recurrence-free periods (p= .028 and <.001,
respectively)
• Chondroid chordoma and chordoma have similar
poor outcomes in survival and recurrence-free
periods (p= .337 and .906, respectively).

Overall recurrence rates

• Chordoma 35%
• Chondroid chordoma 29%
• Low-grade chondrosarcoma 0%

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Clival involvement
Upper clivus 32 cases (86%)

Middle clivus 31 cases (84%)

Lower clivus 16 cases (43%)

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Complications
• Meningitis 5%
• Cranial nerve palsy 25%
• Hemiparesis 4%
• Hydrocephalus 3%
• CSF leak 7%
• Radiation necrosis 6%

Skull base chordoma outcomes


89 patients (168 surgeries):
• Perioperative mortality 2%
• Death from disease 17%
• Alive without progression 68%
• Alive with progression 11%
• Metastasis 9%

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Upper cervical involvement in


chordoma
139 cases
– 21 % upper cervical involvement
– 9% required fusion

Craniocervical junction chordoma

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Recurrent chordoma: a challenge


28 cases:
Mean follow-up 43 months

death 16
progression 11
stable disease 1

Time to recurrence by tissue type


Chondrosarcoma

Chordoma

Chondroid chordoma

Rec. chordoma

Rec. chondroid chordoma

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Genetic prognostic factors


• NORMAL karyotype: 3% recurrence
• ABNORMAL karyotype: 45% recurrence
Recurrence Recurrence
100 100

Survival probability (%)


Survival probability (%)

80 80

60 60

Group Group
40 A 40 DA
N DN
20 RA
20
RN

0 0
0 20 40 60 80 100 120 0 20 40 60 80 100 120
Time Time

Chromosome 3/13 alterations

Recurrence Recurrence
100 100
Survival probability (%)

Survival probability (%)

80 80

60 group 60 Group
3 13
40 N 40 N

20 20

0 0
0 20 40 60 80 100 0 20 40 60 80 100
Time Time

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The case for complete resection


Chordoma outcome was significantly improved in de novo cases compared to
recurrent cases. (p<.001, p<.001)

Chordoma outcome was significantly improved when no residual tumor was


observed in post-operative MRI (p= .044).
In de novo cases, when no residual tumor was observed, 10-year
recurrence free survival was 74%
Recurrence-free survival Recurrence-free survival
100 100

80 80 No residual

60 60
D
40 40
Residual
20 20
R
0 0
0 30 60 90 120 150 180 0 30 60 90 120 150 180
Time (months) Time (months)

Paragangliomas

Carotid body Glomus Glomus


vagale jugulare

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Paraganglioma signs/symptoms
• Hoarseness
• Hearing deficit
• Dizziness
• Swallowing difficulty
• Tinnitus
• Hypertension
• Headache
• Neck pain
• Ear pain/mass

Secreting tumors
• Can secrete catecholamine, Dopamine,
Serotonin, etc.
• Incidence of catecholamine secretion is 4%
• Potentially serious complications
of intraoperative or perioperative
hypertension crisis
• All patients need to be evaluated
for catecholamine secretion
• Anesthetic management considerations

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Multiple tumors
Occur in more than 10% of cases

Paraganglioma in one location must be


fully evaluated for other lesions

Most multicentric tumors are bilateral


carotid body tumors

Morbidity of bilateral cranial nerve dysfunction

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Outcomes

• Of 43 cases:

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Approaches
Cranio-orbito-zygomatic (“COZ”) Supra-orbital
Transsphenoidal

Middle fossa
zygomatic

Transpetrosal

Transcondylar
Transtemporal

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Disclosure Statement
Reports no commercial interest

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Endocrine Evaluation
of Pituitary
Anterior the Neurosurgical
Hormone Regulation
Patient
Adriana Ioachimescu, MD, PhD
Neurosurgery Grand Rounds
October 30, 2008

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Pituitary Adenomas Classification


Functioning Nonfunctioning
GH-PRL-TSH family
- Lactotroph: ↑PRL - Silent lactotroph
- Somatotroph: acromegaly - Silent somatotroph
- Somatomamotroph

- Thyrotroph: hyperthyroidism - Silent thyrotroph


ACTH family
- Corticotroph: Cushing’s disease - Silent corticotroph
FSH and LH family
- Gonadotroph: hypergonadism - Silent gonadotroph
Unclassified
- Plurihormonal - Null-cell

Pituitary Adenomas: “1 in 5”
Epidemiology
20% general population at autopsy
10-20% incidentally by brain imaging
Prevalence ↑ w/ age
Except prolactin- and ACTH-secreting tumors (peak 20-40 y.o.)
Gender: PRL- and ACTH-secreting adenomas more frequent in
women
Familial predisposition is rare
Syndromal associations: MEN-1 (11q13), Carney complex
(PRKAR1), McCune Albright (X-linked)
In patients with sporadic pituitary adenomas younger than 30,
AIP (germline aryl hydrocarbon receptor interacting protein)
mutations were detected in 8.6% cases and MEN-1 mutations
in 3.4%

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Pathogenesis of Pituitary Adenomas


Combination of genetic events (epigenetic silencing of tumor
suppressors, putative oncogenic factors), hormone and growth
factors effects

Usually monoclonal neoplasms


However, rare cases of pituitary adenoma progressing to malignancy may
involve a different clone profile in the metastasis and primary tumor

Folate receptor alpha expression

Germline aryl hydrocarbon receptor interacting protein (AIP)


mutations or AIP decreased expression

MicroRNAs downregulation
Asa SL, Ezzat S. Annu Rev Pathol. 2009;4:97-126.
Evans CO, et al. Cancer Res. 2003 Jul 15;63(14):4218-24.
D'Angelo D, et al. J Clin Endocrinol Metab. 2012 Jul;97(7):E1128-38.

Clinical Manifestations
Pituitary hormone oversecretion
PRL
GH: acromegaly
ACTH: Cushing’s disease
TSH: central hyperthyroidism
FSH or LH: hypergonadism
Mass effect
Headaches
Vision loss: bitemporal hemianopia
Diplopia: cranial nv. III, IV, VI (apoplexy)
Compression of the stalk or normal pituitary gland
(hypopituitarism, galactorrhea)

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Cushing’s disease

Cushing’s Disease

1. Feelders RA et al. Presented at ENEA, Napoli, Italy, 4–6 December 2009;Poster 18. 2. Data from CDC statistics and NHANES III (2005–
2006) 2011. Available at: http://www.cdc.gov/nchs/nhanes.htm

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Establishing dx of Cushing’s syndrome

Screening tests should have high sensitivity

AND
Differentiate between CS and reactive hypercortisolemia
Severe obesity
Psychiatric disorders: depression, anxiety disorder,
anorexia nervosa, OCD
Chronic alcoholism
Poorly controlled DM
Obstructive sleep apnea

Cushing’s Disease: Therapeutic Options


Surgery – TSA – microsurgery, endoscope
Medical
Neuromodulators
(Bromocriptine, Cyproheptadine, valproic acid, Octreotide)
Steroid biosynthesis inhibitors (Ketoconazole, Metyrapone, Mitotane,
Aminoglutethimide)
Cortisol Blockade
Pasireotide
Radiotherapy
SRS
Fractionated SRT
Adrenalectomy

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Treatment of Cushing’s Disease


Pituitary surgery: excellent outcomes in expert hands
But… long-term recurrence rate
Radiation therapy effective within 2 years
Short-term tx w/ steroidogenesis inhibitors followed by
bilateral adrenalectomy for non-responsive cases
FDA approval of 2 new Cushing meds in 2012:
Pasireotide (somatostatin analog)
Mifepristone (glucocorticoid receptor blocker)

Surgical Strategy
Wide opening of the sella

Careful, systematic and complete exploration of


the gland

Selective adenomectomy

Early/repeat postoperative assessment

Hypophysectomy or hemi-hypophysectomy

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Reported Remission Rates after TSA

At 2-3 months postoperatively: 59-95%


Uniform criteria to define remission is lacking
Early postoperative serum cortisol
Early postoperative UFC
Suppression to low-dose dexamethasone
Cortisol response to CRH
Glucocorticosteroid replacement
Sustained remission rates 64-100%
Esposito F. J Clin Endocrinol Metab. 2006 Avgerinos PC. J Clin Endocrinol Metab. 1987
Bochicchio D. J Clin Endocrinol Metab. 1995 Lindsay JR. J Clin Endocrinol Metab. 2011
Valassi E. J Clin Endocrinol Metab. 2010 Alwani RA. Neuroendocrinology. 2010

5.6% non-controlled patients


(based on early postop UFC)
became normo- or
hypocortisolemic after 38±50
days

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Predictors of Short-Term Postoperative


Remission
Tumor size –microadenoma have a better chance for
remission c/w “no tumor seen” or macroadenomas

Cavernous sinus invasion

Lower preop ACTH

Early postoperative serum cortisol ≤5 mcg/dL

Early UFC ≤10 mcg/day


Shah R et al. Oral Presentation at Endo 2011

Predictors of Sustained Remission


Low early postoperative AM Serum Cortisol predicts favorable
outcome
≤ 1.8 mcg/dL (Trainer, 1993)
≤ 5 mcg/dL (Esposito, 2006 and Lindsay, 2011)
≤ 10 mcg/dL (Simmons, 2001)
Low early postoperative AM Serum Cortisol does not necessarily
predict favorable outcome (Invitti, 1999; Atkinson, 2005)
Preop visualization of the pituitary adenoma (Bochicchio, 1995)
Histopathological confirmation of ACTH+ adenoma (Bochicchio,
1995)
Combination of histological confirmation and radiological
identification (Chee, 2001)

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Cushing’s Disease: Role of Medical Rx

Adjuvant to surgery/radiotherapy
Side effects common and limiting
Unsatisfactory in most cases
Response rates poor ∴
⇒ Poor surgical candidates
⇒ Preoperative preparation
⇒ Awaiting results from XRT

Pituitary gland ←---- pasireotide


- Cortisol levels ↓

Adrenal glands ←----steroidogenesis


inhibitors
- Cortisol levels ↓

Glucocorticoid receptor ←mifepristone


- Cortisol levels ↑

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Pasireotide

Multi-receptor ligand SSRA with high binding affinity


of 4 out of 5 receptor subtypes (1,2,3 and 5)

Affinity for SSTR5 is x 50 c/w octreotide

First therapeutic compound with activity targeted at the


pituitary adenoma in clinical trials for Cushing’s disease

162 patients with persistent/recurrent or de novo


Cushing’s disease
Most patients (n = 135) had persistent or recurrent
Cushing’s disease after prior treatment; 27 patients had
new-onset Cushing’s but were not eligible for surgery
Pasireotide dose - 600 mcg or 900 mcg bid
Primary endpoint: normalized UFC at 6 months

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Reduced UFC levels in the majority of patients


Resulted in normalization in 26% patients in the 900
µg group and 14.6% of the 600 µg group
Most patients maintained lower UFC levels after 1
year of treatment
Provided significant clinical benefit regardless of
achieving normal UFC
Body mass index, blood pressure, and low-density
lipoprotein cholesterol levels

Pasireotide - Safety profile


Safety of pasireotide was generally similar to other
somatostatin analogues, except for hyperglycemia
Most frequently reported AEs were gastrointestinal (diarrhea, nausea, abd
pain)
12% of patients had ≥1 SAE suspected to be drug related
No deaths during treatment

70% of patients had at least one hyperglycemia-related


AE

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Glucocorticoid receptor antagonist


(Mifepristone)

Mechanism: blocks GR-II and progesterone receptors

Advantage for Cushing patients: rapid decreased of clinical


signs of hypercortisolemia within a month

Major drawbacks:
Biochemical parameters are not useful to establish cortisol status at
end organ level
Both ACTH and cortisol ↑during tx, although patient may have
clinical signs of adrenal insufficiency
Hypokalemia

http://www.corcept.com/news_events/pr_1307237503

SRS for Cushing’s Disease


LINAC/GK

More rapid induction of remission c/w XRT

Definable intrasellar target (+/-)

Remission 35-90% , latency 3-38 mths, hypopit 16-55%

Control of tumor growth ~ 80%.

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Acromegaly

Acromegaly/ Gigantism
10-15% of pituitary adenomas; mostly macroadenomas
Changes in appearance, headaches, sweating, joint pain
hypogonadism
HTN, DM, OSA, cardiomyopathy, colon polyps, thyroid
nodules

A single GH level is inadequate due to pulsatile secretion


Screening test: plasma IGF-1
Confirmation test: GH during OGTT (nl: <0.4 ng/ml)

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ACROMEGALY: Therapeutic Options


Surgery – TSA

Medical
SST analogues (short, pump, long)
Dopamine receptor agonists (Parlodel, Dostinex)
GH Receptor antagonist (Pegvisomant)

Radiotherapy
SRS
Fractionated SRT

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Multimodality Treatment Required in 50% of


Patients

Emory Surgical Experience


Acromegaly
Long-term remission predicted by:
Smaller tumor size
Lack of cavernous sinus invasion
Lower preoperative GH (<40 ng/mL)
Early postpoperative GH <1.53 ng/mL

Multivariate analysis: cavernous sinus invasion

Jeremy Anthony et al. Abstract submitted to AACE 2014

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Medical Treatment for Acromegaly

Medical Therapy - Acromegaly


Bromocriptine
~20mg/qd in 3-4 doses
GH <5 µg/L in 20% of patients, ↑ prolactin favorable
IGF-I normalized in 10% of patients
Tumor shrinkage ~30% of patients
Nausea, GI, postural ↓BP

Cabergoline
~0.5-1.0mg twice weekly
Normalizes IGF-1 in 35% of patients, ↑prolactin favorable
Tumor shrinkage ~50% of patients
Nausea, GI, postural ↓BP

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Medical Therapy- Acromegaly


Octreotide & Octreotide(LAR):
sc tid or pump, 300-1500 µg/day
once-monthly, IM, 20-30 mg
GH <5 µg/L 86-100%, GH <2.5µg/L 39-75%, GH <1 µg/L 24-40%
IGF-1 normalized in 65% of patients
Tumor shrinkage 20-70% in 29-72% of patients, not cytotoxic, tumor re-
expands if discontinued
Improves medical comorbidity & symptoms
Improves metabolic and hemodynamic indices in high risk patients
preoperatively
s/e: gallstones, nausea, GI cramps
Clayton et al. Endocr Rev, 2003
Bevan et al. JCEM, 2002

Effect of Octreotide on Tumor Size

a) Left – T1-weighted MRI of pituitary macroadenoma in 48-year-old woman.


b) Right – After 3 years octreotide, showing tumor shrinkage.

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Medical Therapy GH receptor antagonist


Action of Pegvisomant (▼IGF-1)

Pegvisomant in the Medical Therapy of Acromegaly

10-20 mg sc qd
Normalizes IGF-1 in 80-90% patients after ≥ 12 mths
Improves symptoms
Long-term impact on tumor growth?
Indication: failed surgery and other medical therapy
GH levels increase up to 6 mths after Rx
MRI monitoring of tumor size, monitor LFTs
Well-tolerated

Van der Lely et al. Lancet, 2001

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Radiosurgery for GH adenomas


GH: ↓ 65% ≥6 mths and 77% after 12 mths
67% GH (< 5 ng/ml) after 32 mths
20-30% : normal mean GH and IGF-1 -latency 10-38 mths
Control of tumor growth
~ 100% up to 4yrs , 50% tumor reduction.
N= 82 with active acromegaly, 63 had previous transsphenoidal surgery
GKRS
17% percent of patients in remission w/out add’l treatment
Withdrawal of somatostatin agonists at time of radiosurgery no effect on
outcome

Castinetti F. Taieb D. Kuhn JM. Chanson P. Tamura M. Jaquet P. Conte-Devolx B. Regis J.


Dufour H. Brue T. Outcome of gamma knife radiosurgery in 82 patients with acromegaly:
correlation with initial hypersecretion. Journal of Clinical Endocrinology & Metabolism.
90(8):4483-8, 2005

Prolactinoma

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Prolactinomas

Prolactinomas account for approximately 60% of


pituitary tumors, 50-60% of functional tumors

Effective medical and surgical therapy

Non-tumoral causes of
hyperprolactinemia

“Major drug offenders”:


-Metochlopramide
-Risperidone
-Phenothiazines
-Butyrophenones

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Prolactin Assay: Hook Effect

Very high prolactin levels may result in a normal or


slightly elevated prolactin level in some assays
therefore
In all patients who have large tumors found on a scan,
prolactin levels should be measured undiluted and at
1:100 dilution

Prolactinoma
Women
Microadenomas (≤1 cm)
Amenorrhea/galactorrhea
Infertility, osteoporosis

Men
Macroadenomas
Headaches /visual loss
Sexual dysfunction
Gynecomastia, infertility
Osteoporosis

Williams Textbook of Endocrinology, 11th ed.

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Guidelines of the Pituitary Society

Goals of therapy:
1. Suppress clinical
consequences of increased
PRL level
2. Control tumor mass
- Significant decrease in size is
not a goal for
microprolactinomas if
symptoms are controlled

Clinical Endocrinology, 2006

Medical Rx in prolactinomas

Dopamine agonists (cabergoline, bromocriptine)


Improve PRL and shrink/stabilize the tumor in 75%
patients
Bromocriptine tb taken 1-3 times/day

Cabergoline tb taken twice a week


May be effective in bromocriptine-resistant cases
Well-tolerated, but valvular heart disease may occur at
high doses taken x many years

Both considered safe w/ pregnancy

Long-term tx:
Until menopause in women, lifelong in most
macroadenomas

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PRL levels ↓ ± normalize in ~90% of macro and microPRLomas


Serum testosterone levels normalize in hypogonadic men
Tumor shrinkage/reversal of visual loss:
( > 25%) in 60 to 79% of patients within 3- 12 mths
Resumption of menses, libido, fertility, galactorrhea
10-15% of patients resistant
Insufficient data to support withdrawal

The risk of valvular heart disease in


patients with prolactinomas treated with
cabergoline

Colao A, JCE&M, 2008

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FDA-recommended max. dose Cabergoline : 2 mg/wk

CT/MRI – Skull Base lesion, PRL 60


PRL with dilutions – 38,000
Dostinex PRL - 621 + CSF leak
TS repair of CSF leak – tumor debulking –
Dostinex

Male or postmenopausal Fem


PRL >>>> 1000ng/ml
Operation only necessary for CSF leak,
poor or no response XRT not very
effective

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Failure of medical Rx

Lack of tumor shrinkage despite reduction in PRL

PRL falls but does not normalize

Cystic macroprolactinoma

Intolerance or resistance to dopamine agonists

Macroadenomas in women who wish to become


pregnant

CSF leak during drug therapy

TSA for prolactinomas

Predictors of surgical success:


PRL< 200 ng/mL
Microprolactinoma

Rate of remission
67% in intolerant vs. 36% in dopamine agonists-
resistant patients
75% for microprolactinomas vs. 30% for
macroprolactinomas
Rate of recurrence
18% for microprolactinomas vs. 23% for
macroprolactinomas
Recurrence defined by reappearance of
hyperprolactinemia *Hamilton DK, Pituitary, 2005

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Emory Surgical Experience


Prolactinoma (1995-2010)
15 M, 14 F
Age 33±1.8 years

Indications for surgery:


- Inadequate response to dopamine agonists (45%),
- Patient’s preference (34.4%; including poor compliance with DA)
- Intolerance to DA (10.3%)
- Apoplexy/vision loss (10.3%)

Predictors of postoperative remission:


Preoperative prolactin level
Tumor diameter ≤ 1 cm
Postoperative day 1 Prolactin <10 ng/mL

Endo Society abstract 736, Ioachimescu et al, 2012

Radiosurgery for Prolactinomas


Primary Rx: Biochemical cure 52%,
improvement in 28%

Longer latency, less effective, better medical


alternatives

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Nonfunctioning
Pituitary Tumors
and Pituitary
Incidentalomas

Clinically
Nonfunctioning
Pituitary Adenomas
Asymptomatic* Symptomatic

*Incidentalomas

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Pituitary Incidentalomas
Questions to be asked
Is it Functioning or Nonfunctioning
Is it causing mass effects?
Headache
Visual field defects
Hypopituitarism
Who needs surgery?
If surgery is done, what postoperative
surveillance is needed?
What therapy is indicated if there is
postoperative residual tumor?

Frequency of Pituitary Adenomas


Found at Autopsy

18,631 unselected pituitaries examined at


autopsy in 30 series
1,969 (10.6%) had pituitary adenomas
(range 1.5 – 27.0mm)
All but 7 were < 10 mm
304/765 (40%) stained positively for prolactin

Molitch. Endocrinol Metab Clin N Amer 2008;37:151

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Frequency of Pituitary Incidentalomas on


MRI in Normal Individuals
Chong et al: found 2-5 mm lesions in 20/52 normal
subjects with nonenhanced images using 1.5 T
scanner and 3 mm thick sections
Hall et al: found > 3mm lesions in 100 normal
volunteers with gadolinium enhancement
If 1 radiologist - 34 lesions
If 2 radiologists had to agree - 10 lesions
If 3 radiologists had to agree - 2 lesions

Chong et al. Am J Neuroradiol 1994;15:675


Hall et al. Ann Intern Med 1994;120:817

Types of Lesions Removed as Nonfunctioning


Intrasellar Masses (n=176)
Nonfunctioning Adenomas Other
Gonadotroph 133 Craniopharyngioma 3
Corticotroph 13 Germinoma 1
Somatotroph 3 Plasmacytoma 1
Thyrotroph 2 Meningioma 1
Lactotroph 1 Chordoma 1
Plurihormonal 5 Rathke’s cleft cyst 2
Nonsecreting 3 Metastatic cancer 2

Asa et al., JCEM 1992;74:1128

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Evaluation of the Patient with a


Pituitary Incidentaloma
Symptoms
Headaches
Visual disturbance
Hypopituitarism
Hormone Oversecretion
Visual Fields if tumor abutting chiasm
Evaluation for Hypopituitrarism
Evauation for Hormone Oversecretion

42 Patients with Pituitary Incidentalomas

Size
Macroadenomas – 29 (63%)
Microadenomas – 13 (37%)
Hypopituitarism – 19 (41%)
Prolactinomas – 7 (15%)
Hyperprolactinemia – 10 (22%)
Visual Field Defects – 10 (33 % of macros)
Surgery in 17 (37%) – 1 cranio, 16 adenomas
Gonadotropinomas – 23%
Plurihormonal – 31%
Somatotropinomas – 15%
No staining – 31%
Fainstein Day et al., Pituitary 2004;7:145

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Natural History of Untreated


Pituitary Incidentalomas
Microadenomas Macroadenomas
Total 160 353
Enlarged 17 (11%) 85* (24%)
Decreased 10 (6%) 45 (13%)
No Change 133 (83%) 223 (63%)
Yrs followed 0.6 - 15.0 0.6 – 12
*Some had tumor enlargement secondary to hemorrhage into the tumor

Reinecke et al., JAMA 1990;263:2772 Donovan & Corenblum, Arch Int Med 1995;155:181
Nishizawa et al., Neurosurgery 1998;43:1344 Feldkamp et al., Clin Endocrinol 1999;51:109
Igarashi et al., Neuro Med Chir 1999;39:592 Sanno et al., Eur J Endocrinol 2003;149:123
Fainstein Day et al, Pituitary 2004;7:149 Arita et al., J Neurosurg 2006;104:884
Karavitaki et al., Clin Endocrinol 2007;67:938 Dekkers et al., Eur J Endocrinol 2007;156:217

Pituitary Incidentalomas
Indications for Surgery
Secreting tumors other than prolactinomas

Visual Field Defects


Hypopituitarism
Headaches
Increasing size
Ophthalmoplegias
Apoplexy (+)

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Restoration of Pituitary Function by


Transsphenoidal Surgery in Patients with
Clinically Nonfunctioning Macroadenomas

Axis Mean Range

LH/FSH 22% 11-34%

ACTH 42% 10-73%

TSH 40% 13-67%

↑PRL 76% 58-95%

Molitch. Endocrinol Metab Clin N Amer 2008;37:151

Visual Field Recovery Following Transsphenoidal


Resection of 184 Clinically Nonfunctioning
Macroadenomas

Normalized 45%

Improved 28%

No Change 27%

Worsened 0%

Cohen et al., Neurosurgery 1985;17:446

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Preop MRI –contrast

Nonfunctional Adenomas
Giant Adenomas
TS (± staged)
Craniotomy
Extended TS
Extracapsular

Surgical enhancements:
LD/Image Guidance/
Intraoperative MRI/
Endoscope

Limitations:
Fibrous (5-8%)
Dumbbell tumors
Eccentric parasellar extension

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SURGICAL OPTIONS

69

The “Endoscopic view”

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3D Endoscopy

Wide View Optic Design


Provides more lateral viewing than VS
Standard View Cameras
Optic design provides significantly more
light

Available in 0° and 30°


HD - Better resolution

Nonfunctional adenoma – pre + postop MRI

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Combined simultaneous TS-Craniotomy

Clinically Nonfunctioning Adenomas


Therapy of Patients with Residual Tumor
Postoperatively

Observation
Second Surgery
Medical Therapy
Dopamine agonists
Bromocriptine
Cabergoline
Octreotide
Radiotherapy
Conventional
Gamma Knife

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Radiosurgery for Nonfunctional Tumors


Secondary line of treatment
Residual tumor
Endpoint : cessation of tumor growth
Tumor-control rate (88% at 5yrs -GKRS)
Losa et al J Neurosurgery, 100:438-444, 2004
Hypogonadism (12-20%)
Hypothyroidism (8-23%)
Hypoadrenalism (2-8%),
Hyposomatotropism (13%)
Feigl et al J Neurosurgery 97, 2002
Anatomic contraints: chiasm & optic nerves (8-1) anterior b-
stem
Margin 3-5mm
Prescription dose: tumor control
15-16Gy

Percentage of Transsphenoidal Operations in 3


Experience Groups Resulting in Each
Complication: Results of National Survey

COMPLICATION <200 ops. 200-500 ops. >500 ops


Death 1.2% 0.6% 0.2%
Meningitis 1.9% 0.8% 0.5%
CSF Leak 4.2% 2.8% 1.5%
Carotid injury 1.4% 0.6% 0.4%
Loss of Vision 2.4% 0.8% 0.5%
Hypopituitarism 20.6% 14.9% 7.2%
Diabetes Insipidus 19% - 7.6%

Ciric et al., Neurosurgery 1997;40:225

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Pituitary Tumors
Conclusions

Treatable and Curable


Judgment
Evolving Surgical and Medical Options

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Diagnosis and Management of


Pituitary Adenomas

Edward R. Laws
Brigham & Women’s Hospital
Harvard Medical School

Pituitary Adenomas
Third Most Common Primary Brain Tumor
20% of Routine Autopsies
19% of Primary Brain Tumors are
Operated Upon Transsphenoidally at US
Training Centers

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The Pituitary
The “Master Gland”
Controls
Growth Metabolism
Sexual maturation Stress response
Reproduction Fluid balance

Pituitary Tumors
Common Complaints
Depression Weight gain
Apathy Fluid retention
Sleep disorders Sexual dysfunction
Memory Loss Infertility
Anger, Agitation Fatigue, weakness
Irritability Visual loss
Moodiness Emotional lability
Anxiety Headache

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Gerard Guiot Jules Hardy

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The Microadenoma

Selective Microsurgical
Removal

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Transsphenoidal Surgery for


Pituitary Disorders – 1972-2008
Pituitary Adenoma 4328
Craniopharyngioma; RCC 323

Arachnoid and other Cysts 143

CSF Rhinorrhea 93
Hypophysitis 29
Hypophysectomy 23
Miscellaneous Sellar 160
Lesions
Total 5099 04/09

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Goals of Treatment of Pituitary


Adenomas

Relief of Mass Effect


Normalization of Hormonal
Hypersecretion
Preservation/Restoration of Normal
Pituitary Function
Prevention of Recurrence
Obtaining Tissue for Pathological and
Scientific Study

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Indications and Results

Specific Pituitary Lesions

Non – Functioning Adenoma

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Indications for Surgery

Mass Effect – Visual


Loss
Headache
Hypopituitarism
Apoplexy

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Non- Functioning Adenomas


Outcomes

Visual Improvement – 87 %
Relief of Headache - 95 %
Preservation of Normal Function – 95 %
Restoration of Normal Function – 30 %
Recurrence – 16 % (6 % symptomatic)
Living & Well at 10 Years- 83 %

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Indications for Surgery


Acromegaly

Active Acromegaly
Mass Effect – Visual
Loss
Hypopituitarism
Apoplexy

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Criteria for Diagnosis and


Remission
Abnormal IGF-1 Normal IGF-1
Active Acromegaly Improvement in
acromegalic
features
Improvement in
Co-Morbidities

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GH Adenomas
Outcomes
Relief of Mass Effect – 95%
Improvement in Acromegalic Symptoms
and Signs – 95 %
Normalization of GH Secretion – 50-72 %
Preservation of Normal Pituitary Function
– 95 %
Recurrence – 1.3 – 8 %
Living & Well at 10 Years – 70 %

Prolactin Microadenoma

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Criteria for Diagnosis and


Remission
Elevated PRL Normal PRL
Symptoms and Cessation of
Signs of Galatorrhea
Hyperprolactinemia Resumption of
Menses/Fertility
Improved
Testosterone/sexu
al dysfunction

Prolactin Adenomas
Outcomes

Relief of Mass Effect – 95 %


Normalization of Prolactin – 50-87 %
Preservation of Normal Function – 95 %
Recurrence of Adenoma – 13 %
Postop Fertility – 87%
Living and Well at 10 Years – 90 %

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Indications for Surgery – Cushing’s


Disease

ACTH dependent Cushing’s disease


Mass effect (macroadenomas)

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Cushing’s Disease
Association with Cerebral Atrophy

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Decreased Brain Connectivity in Cushings

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Criteria for Remission

Normalization of Cortisol/ACTH
Improvement in Symptoms, Signs and Co-
Morbidities

Cushing’s Disease
Outcomes
Relief of Mass Effect – 97 %
Normalization of ACTH – 55- 91 %
Preservation of Normal Function – 95 %
Recurrence – 12 % (10 yrs)
Living and Well 10 Years after Surgery
– 75 %

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Current Aspects of Pituitary Tumor


Therapy
Endoscopy and Minimally Invasive
Surgery
The Extended Trans-Sphenoidal Skull
Base Approach
Extracapsular Tumor Removal
Radiosurgery
Novel and Combined Medical Therapies

Extended Transsphenoidal
Approaches

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Craniopharyngioma

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Advantages and Disadvantages


of Transsphenoidal Endoscopy

It is Here to Stay

Endoscopic Anatomy

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Extracapsular Tumor Removal

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Arachnoid cyst

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chordoma

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New Methods of Medical Therapy


Effective Hormone Replacement Therapy
Long Acting Somatostatin Analogs
Hormone Receptor Blocking Agents and
Antagonists
Chimeric and Combination Agents
Inhibitors of Hormone Synthesis
Radioactive Ligands
Inhibitors of Tumor Cell Invasion
DNA Replication Inhibitors - TMZ

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Peter Bent Brigham Hospital

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Craniopharyngioma
A Treatment Algorithm
R. Michael Scott, M.D.
Department of Neurosurgery
The Boston Children’s Hospital and Harvard Medical
School, Boston, Massachusetts

May 2016

NO DISCLOSURES

May 2016

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The Radiology of Craniopharyngioma


• MRI demonstrates cystic areas containing fluid
that is bright on T1 and has differing intensities
on T2
• Gadolinium enhancement may be present
around cyst margins or within solid portions of
tumor
• Tumor may surround and adhere to vessels in
the circle of Willis, and may elevate or invade
third ventricle
• Calcifications in children are virtually universal,
but often not well seen on MRI
– We obtain CTs in each patient
• calcium often demarcates areas of greatest tumor attachment
• bone erosion to aid in diagnosis and operative planning
• post-op CT scan verifies total excision

May 2016

T1 enhanced MRI Unenhanced CT -- bone window

May 2016

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Radiological studies may not be


diagnostic in certain patients
• Masqueraders:
– germ cell tumors, hypothalamic-optic system
astrocytomas, pituitary adenomas
• Check endocrinologic data; pay special attention
to prolactin, germ cell markers
• “stalk effect” due to interference with dopamine-
mediated control of prolactin secretion
• An acceptable explanation for prolactin levels of up to
150 ng/ml
• most prolactin-secreting tumors have much
higher levels
• Frozen section at surgery should be done in any
questionable cases

May 2016

May 2016

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Clinical presentations in the


pediatric patient
• I. Endocrine dysfunction: delayed growth, and
hypopituitarism in all manifestations.
• II. Visual disturbance: can be very severe, with
blindness occurring without notice by patient or
family
• III. Increased intracranial pressure when tumor
obstructs third ventricle and causes
hydrocephalus.

May 2016

Elective preoperative evaluation in


craniopharyngioma
• MRI and CT scan
• Ophthalmology consult:
– For ophthalmologic baseline
– to alert surgeon to areas of greatest optic system
compromise and, occasionally, to plan approach
• Endocrinologic consult: particularly for diabetes
insipidus and hypothyroidism, which might affect
fluid and anesthetic management during surgery
– (formulate a DI management protocol collaboratively
with endocrinologists, intensivists, anesthesiologists!)

May 2016

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May 2016

May 2016

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May 2016

Treatment of Craniopharyngioma

• The traditional preferred method is total excision


-- subfrontal transorbital approach for large
tumors extending up into third ventricle,
-- fronto-temporal (pterional) for smaller ones
• Our group has used transsphenoidal approach
for certain tumors with aerated sphenoid sinuses
with or without expanded sella (15 cases, with
GTR in 12; surgical candidates tend to be older
patients)
– One significant post-op complication in a
multiply reoperated 8 year old male (bleeding
at surgery pseudoaneurysm)
May 2016

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Incidental finding during work-up for “sinus headaches”

May 2016

Post-op CT revealed two small calcifications

May 2016

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T1 MRI Gad+ 14 years post-op

May 2016

1995 – age 5 2014 – age 19

May 2016

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May 2016

May 2016

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May 2016

May 2016

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May 2016

May 2016

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May 2016

May 2016

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Other treatment options


• Subtotal resection for decompression of mass
followed by radiation therapy (SRT--stereotactic
radiotherapy using LINAC or proton beam Rx)
– Most of these cases at our institution receive protons
• Side effects:
– late endocrine dysfunction, radiation vasculopathy
(moyamoya), radiation-induced tumors, learning
disabilities
– appear age-related and worse in youngest patients
• 10 year survival rates in literature approach 90%
-- but recurrences > 10 years post treatment
can occur

May 2016

This tumor had been irradiated in 1983 (patient age 10)


and tumor growth stopped

May 2016

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In 1995, patient age 22, moyamoya was diagnosed following left MCA stroke;
In 1997, a malignant meningioma was diagnosed and removed
In 2000, she died at age 27 from tumor invasion of brain stem,
17 years after initial diagnosis and radiotherapy

May 2016

Cyst aspiration and instillation

• P32, Yttrium, Bleomycin, interferon


• In all cases, dose regimens are idiosyncratic,
individualized, and not without complication
– One patient suffered a third nerve palsy and
severe ischemic vasculopathy after cyst instillation
of bleomycin,
– another patient developed a third nerve palsy after
P32 instillation

May 2016

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May 2016

All of these adjuvant treatments


have potential side effects
• 11 year-old boy presented with personality changes,
weight loss and right homonymous hemianopsia
• Studies disclosed large cystic tumor
• Treated with cyst catheter placement and intracystic
bleomycin
• Tumor cyst shrunk dramatically, but patient
developed 3rd nerve palsy and reduced vision in left
eye
• Craniotomy revealed tumor adherent to ACA, ICA
and chiasm
May 2016

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Treated with 30 sessions of conformal radiation


therapy (total dose of 5220 cGy) in 1997
• 3 years after initial surgery, presented with
TIAs and studies revealed moyamoya
• Bilateral pial synangioses in 2000-1
• Asymptomatic recurrence in 2005, and repeat
craniotomy for subtotal resection
• Proton beam therapy to focal residual 2006
• Stable until 11/2015 when large meningioma
noted on routine scan
May 2016

Initial scans 1997

May 2016

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MRA in 2000, three years post op

May 2016

Cystic and solid recurrence before 2nd surgery


in 2005

May 2016

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Meningioma detected in 2015, 18 ½ years


after first diagnosis
May 2016

R ECA injection arteriogram pre-meningioma resection


Tumor pathology = atypical meningioma

May 2016

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Personal Operative Series


January 1, 1988 – December 31, 2013

• 67 patients under age 21 (36M; 31F)


• Ages 2 to 19 (average = 8.7 years)
• Follow-up of 3 to 28 years (median of
17 years)
• Total resection in 39 (58%)

May 2016

Clinical Presentation (at primary


operation)
• 14– Increased ICP
• 11 -- Visual disturbance
• 7 -- Headache
• 6 -- Endocrinologic symptoms
• 2 -- Incidental finding
• 4 -- other
A number of patients had multiple symptoms at presentation

May 2016

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Recurrences in Total Resections


6 recurrences (15%) in 39 cases
– Melissa Sh., 3 months postop* [no recurrence after 2nd
reoperation (16 yrs f/u)]
– Nicholas deF., 9 months postop* [no recurrence after 2nd
reoperation (13 yrs f/u)]
– George Dask., 1 yr postop* [no recurrence after 2nd operation (5
yrs f/u)]
– Felipe R., 18 months postop* [no recurrence after 2nd
reoperation (18 yrs f/u)]
– Patrick Sk., 8 years postop (second reop elsewhere)
– Breanna R.. 6 months postop* (repeat recurrence 5 months
later)

• *First operation at another institution

May 2016

Recurrences in Subtotal Resections (plus


Radiotherapy)

• 4 recurrences (18%) in 22 patients with STR


followed by radiotherapy (all “salvage” cases)
– E.deB -- intracyst Yttrium previously, surgery here 1993; Rad rx,
posterior fossa recurrence (excised); five years later, posterior
fossa recurrence (excised); one year later, optic nerve region
recurrence (excised); post fossa recurrence 2 yrs later; alive,
huge recurrence, nearly blind 2006; death ’09 (nearly 20 yr
course)
– J.O’D -- TransSph cyst aspirations, radRx, subtotal resect 5 yrs
later by RMS, RadSx for residual (blind)
– B.J.M -- multiple surgeries elsewhere, RadRx ‘94, skull & brain
surface drop metastasis removed ‘95; subtotal resect RMS
1999; subsequent SRS
– P.Ch. --initial TR ‘84; RadRx ‘91; cyst catheter ‘98; intracystic
P32 ‘03; well 2010

May 2016

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Deaths
• No operative deaths
• 2 deaths in the first year after surgery in children
who had made excellent recoveries from surgery
• Their deaths were due to overwhelming sepsis
unrelated to and remote from craniotomy:
– J.Ch--from strep. Pneumoniae, 6 months post-op
– K. M-J-- from upper respiratory infection, 3 months
post-op
• These cases emphasize importance of post-op
endocrine supervision and stress steroids (no
similar deaths in past 20 years)
May 2016

Other complications:
• Endocrine--most total resections have DI
• New or worsened visual deficits (4)
• Behavior and/or appetite changes (3)
• Intraoperative bleeding from vessels on basilar-
posterior cerebral artery (1)
• Subdural hygroma (1)
• Stroke -- Huebner artery territory (asymptomatic) (1);
MCA stroke 2 months post-op of unknown cause (1)
• 1 year postop chickenpox encephalitis -->devastating
encephalopathy
• Arteriopathies – ectasia, aneurysms (2)

May 2016

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Arterial ectasia noted on late post-op MRI and CTA

2004 – 5 years post-op 2011 – 12 years post-op

May 2016

28 month old female (O.S.)


• Complained of headache
• Normal exam otherwise
• Surgery via subfrontal route for large tumor

May 2016

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Recurrence three years later


• Reexploration
• Dense scarring and very little tumor removed
• Proton beam treatment age 5
• Surveillance scan age 7 revealed new
abnormality in right subfrontal area

May 2016

Mass was excised – “metastatic” craniopharyngioma

May 2016

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Incidental aneurysm clipped age 9. She is doing well at


age 13, after having undergone 4 craniotomies, now 11
years after her first operation
May 2016

MRI 2015, ten years after initial surgery


No evidence of tumor recurrence

May 2016

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• 1st operation OSH, “total resection,” age 10. Gained 90 lbs.


• 2nd operation at BCH for “total resection,” age 11
• 3rd operation at BCH, 4 months later, age 12 (2001)
• No further recurrences; but morbid obesity (325 lbs) age 24

May 2016

Age 27.
One year after
gastric bypass,
16 years post-op.

Weight loss of
130 lbs, holding
steady

(picture used by
permission)

May 2016

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Surgical Lessons
• Plan operative exposure based on tumor location
and size, but leave intraoperative options open --
wide exposure or provide opportunity to extend
initial opening
• Clearly identify all normal anatomy before
working on tumor; split sylvian fissure
• Clear tumor from vessels and nerves before
decompressing it when possible
• Identify and protect vascular supply to optic
apparatus
• Reoperation is feasible in the event of recurrence
and can be curable in certain patients
• Surgically implanted metastases can occur
• Vascular injury is not uncommon, leading to
stroke or ectasia

May 2016

CONCLUSIONS

• Craniopharyngioma has classic presentations,


radiological and histopathologic appearance
• This “benign” tumor can cause devastating symptoms
with or without treatment
• The growth rate can be extremely variable; smaller
tumors are easier to treat
• Each treatment option has its own set of side-effects
and complications
• Treatment plans must be individualized -- flexibility in
operative planning and during the procedure is
extremely important
• True natural history requires observation over
decades

May 2016

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May 2016

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Hydrocephalus and
Arachnoid Cysts

Tord D. Alden, MD
Assistant Professor, Neurological Surgery
Northwestern University, Feinberg School of Medicine
Ann and Robert H. Lurie Children’s Hospital of Chicago
talden@luriechildrens.org

Disclosures

• There are no off-label usage described


below
• There is no industry support or affiliation

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Cerebrospinal Fluid
• Mechanical buffer
– Systole
• Blood moves caudally from the brain
• CSF moves to the lumbar cistern
– Diastole
• Blood moves from the brain to the heart
• CSF moves cranially from the lumbar cistern
• Removes waste
• Provides a stable environment for the CNS

Cerebrospinal Fluid
• Produced • Absorbed
– Choroid Plexus – Arachnoid granulations
– Ependymal surface – Ependymal surface
– Subarachnoid space – Meninges
– Pia – Pia
– Brain Parenchyma – Perineural space
– 300 to 500 ml/day
• Pathologic states
– Over production
– Under absorption

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CSF flow

Timeline of CSF absorption

Childs Nerv Syst. 2006, 22(7):662-9. Proposal of "evolution theory in cerebrospinal fluid
dynamics" and minor pathway hydrocephalus in developing immature brain. Oi S, Di Rocco C.

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CSF dynamics
• Oi (Childs Nervous System, 2006)
• Describes major and minor pathways of CSF
circulation
• Minor pathways during gestation and first
year of life
• Major pathways start during end of gestation
but do not dominate absorption until 1 year of
age

What is Hydrocephalus?
• Production of CSF in excess of ability to
reabsorb
– Too much production
– Too little absorption
• Classified
– Communicating vs Non-communicating (Dandy
1914)
– Obstructive vs Non-obstructive (Russel 1949)
– Congenital vs Acquired

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Classification
• Terminology can be confusing
• Important for surgical treatment
– Ventriculoperitoneal shunt
– Endoscopic third ventriculostomy
– Surgical removal of cause
• Choroid plexus tumor
• Tumor in CSF pathway

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Causes of Hydrocephalus
• increased production • decreased absorption
– Choroid plexus tumor – Abnormal brain
• decreased absorption development
– Mechanical blockage • Myelomeningocele
• Foraminal atresia • Encephalocele
• Colloid cyst • Holoprosencephaly
• Aqueductal stenosis • X-linked hydrocephalus
• Arachnoid cyst • Dandy-Walker
• Tumor malformation
– Poor absorption
• IVH
• Infectious (meningitis /
ventriculitis)
11

Causes
• Congenital
– Genetic
– Infection
– Malformations
• Tumors
– Increased CSF production
– Obstruction of pathway
• Increased venous sinus pressure
• Iatrogenesis
• Idiopathic
• Acquired
– Infection
– Intraventricular hemorrhage

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Hydrocephalus
• Pediatric
– Congenital
– Prematurity / Intraventricular hemorrhage (IVH)
– Open neural tube defect
– Meningitis
• Adult
– Idiopathic
– Subarachnoid hemorrhage
– Meningitis
– Normal pressure hydrocephalus

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Epidemiology
• Congenital 3/1000 live births
• Acquired hydrocephalus depends on cause
– 10% of patients with SAH
• Bimodal age distribution
– Children 0 to 10
– Adults 40 to 70

Symptoms/Signs – Age dependent


• Neonate/Infants • Adult
– Vomiting – Headaches
– Irritability – Vomiting
– Developmental delay – Eye movement/Vision
– Increasing head disturbance
circumference – Cognitive decline
– Eye movement disturbance – Gait abnormality
• Children – Urinary incontinence
– Headaches
– Vomiting
– Eye movement/Vision
disturbance
– Gait abnormality
– Cognitive decline

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Work-up
• History
• Clinical exam
• Imaging
– Ultrasound (open fontanel)
– CT
– MRI
• Thin section through the aqueduct
• Examine space in front of brain stem

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Consequences of Hydrocephalus
• Altered neuronal cell proliferation and migration
• Axonal degeneration
– focal neuronal loss
– decrease in synapses
– Gliosis
• Thinning of the cerebral cortex
• White matter suffers from chronic hypoperfusion
• Delay/Prevention of normal myelination

19

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Surgical treatment
• Treat Cause
– Choroid plexus tumor
• Over production and Under absorption
– Lesions in pathway
• Foramen of Monro
• Third ventricle
• 4th ventricle
• Arachnoid cysts
• CSF diversion
– Endoscopic third ventriculostomy (ETV)
– Ventriculoperitoneal (ventriculo-extracranial site) shunt
– Ventriculo-ventricular shunt

Shunts
• Many devices in use
• Pressure versus Flow control valves
• Siphon versus Anti-siphon devices
• Adjustable versus Fixed valves
• Many possible locations

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Terminus of shunt
• Peritoneum (abdominal pseudocyst)
• Right atrium of heart (cor pulmonale)
• Pleural space (symptomatic effusion)
• Gall bladder
• Urinary bladder (infection)
• Ureter (loss of kidney)

Shunt Infection
• 5-15% incidence
• Most in first 6 months
• Skin flora
– Staphylococcus aureus
– Staphylococcus epidermidis
– Proprionobacter acnes
– Enterococcus faecalis
• Symptoms:
– Fever
– Redness along shunt tract
– Abdominal pain/Shunt peritonitis
– CSF collection
• Abdominal pseudocyst
• Pleural effusion

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Shunt Infection

Shunt Infection
• The use of protocol to
standardize insertion
• Overall infection rate of
6.0 percent

Kestle et al. J Neurosurg Pediatr 17:391–396, 2016

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Shunt Malfunction
• 40% in first 2 years
• 80% in the first 10 years
• Proximal shunt failure
most common (95% of
time)
• Failure anywhere along
the system

Shunt Malfunction
• Drainage
– Over-drainage
• Low pressure headaches
• Subdural hygroma/hematoma
– Under-drainage
• Increased ICP
• Increased ventricular size
• Improper placement
– Intracranial
– Intra-abdominal
• Obstruction of component
– Ventricular catheter
– Valve
– Distal catheter
• Disconnection
• Failure of absorption of CSF

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Shunt Malfunction Work-up


• History
– Description of headache
– Often stereotypical headache
– Look for other causes (migraine)
• Physical exam
– Eye movement disturbance
– Motor exam
– Often without change
• Imaging
– Ventricular (Fast brain MRI, Head CT, Head US)
– Shunt (Shunt series)
– CSF drainage site (Abdominal ultrasound)

Shunt Malfunction treatment


• Over drainage • Under drainage
– Change valve – Explore shunt
• Increase pressure – Fix what is broken
• Anti-siphon device
– Most commonly
– Change distal catheter ventricular catheter
• Add distal slit valve
– Change valve
• Increase length
• Decrease pressure
– Subdural fluid may need • Remove Anti-siphon
treatment – Change distal catheter
• Move to other CSF
absorbing space

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Shunt Malfunction

Shunt Malfunction risk factors


• Age younger than 6 months at first shunt
placement (HR 1.6 [95% CI 1.1–2.1])
• Cardiac comorbidity (HR 1.4 [95% CI 1.0–2.1])
• Endoscopic placement (HR 1.9 [95% CI 1.2–
2.9])

Riva-Cambrin et al. J Neurosurg Pediatr 17:382–390, 2016.

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Alternatives to ventricular shunting


• Endoscopic third ventriculostomy
• Aqueductoplasty
• Choroid plexotomy/coagulation
• Combination of above

34

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35

Anatomy

• Foramen of Monro

36

1881
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Lateral Ventricle

• Foramen of Monro
• Anterior Septal Vein
• Thalamostriate Vein
• Anterior Caudate Vein

37

Anatomy

• Third Ventricle
– Mamillary bodies
– Infundibular recess
– Tuber cinereum
– Basilar artery

38

1882
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Anatomy

• Third Ventricle

39

Ventricular anatomy

1883
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Anatomy

• Posterior Third Ventricle

41

Third Ventriculostomy

• Approach

42

1884
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Third Ventriculostomy
• Obstructive hydrocephalus
– Third ventricle
• Pineal region lesions
– Aqueduct
• Aqueductal stenosis
• Tectal plate tumors
– Fourth ventricle
• Posterior fossa tumors
• Chiari malformation
• Posterior fossa arachnoid cyst

ETV: Surgical Steps


• Enter lateral ventricle
• Confirm side
• Medial structures: choroid plexus, anterior
septal vein
• Lateral structures: thalamostriate vein
• Foramen of Monro: follow the choroid plexus
to the foramen formed by the fornix

1885
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ETV: Surgical Steps


• Inspect the third ventricle floor
• Identify: Mamillary bodies, median
eminence/tuber cinereum, infundibular
recess, chiasm, optic recess, basilar artery
• Make the hole
• Anterior to the mamillary bodies and basilar
artery but posterior to the median eminence
• Key: Identify the pituitary recess and then
make hole just posteriorly

ETV

1886
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ETV: Outcome

Potential Complications
• Infections
• Intraventricular hemorrhage
• Fornices: memory
• Hypothalamus: diabetes insipidus
• Optic tracts
• Basilar artery

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ETV

ETV – Outcome
• Most series report success rate of 50 to 95%
• Poor predictors
– Age less than 12 months
– Etiology
• Myelomeningocele
• Meningitis
• IVH
• Highest success
– Tectal plate glioma
– Aqueductal stenosis

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ETV: Not a cure


• Late failures do occur
• Most failures occur in 2 to 6 weeks
• Age correlates with incidence of failure after
initial success
– < 6mos 50% fail
– greater than 2 years of age only 16% fail
• Repeat ETV can be successful in over half of
patients

Arachnoid Cyst
• Account for 1% of intracranial mass type lesions
• Estimates are highly variable
– Prevalence of 0.2 to 2.6% reported
• Incidental finding
• Male to Female ratio of 2:1
• Left side more common than right
• Most common locations
– Posterior fossa
– Temporal
– Suprasellar
– Frontal

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Middle Fossa Classification (Galassi)


• Type I: Communicate Freely with adjacent
Cisterns. Lentiform shape; no treatment
usually needed
• Type II: May or may not communicate with
adjacent cisterns. Quadrangle shape; usually
treatment required
• Type III: No communication. Cause Mass
effect and require surgical treatment

Etiologies
• Temporal hypoplasia
– Unlikely to see re-expansion after treatment
• Secretory elements
– Na/K pump activity
– Enlargement over period of time.
• CSF trapping
– Ball-Valve mechanism demonstrated on cine MRI and
endoscopy
• Cysts may develop as diverticulum
• CSF absorption abnormality.

1890
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Arachnoid Cyst: Symptoms/Signs


• IF symptomatic ….
• Headaches
• Increased ICP
• Seizures
• Cognitive decline
• Visual disturbance

Natural History: Pediatrics


• Prevalence of 2.8%
• Enlargement of 10% (less than age 4)
• No change in those > age 4
• Variable indication for surgical intervention

Prevalence and natural history of arachnoid cysts in children. Wajd N. Al-Holou, M.D., Andrew Y. Yew, M.D.,
Zackary E. Boomsaad, M.D., Hugh J. L. Garton, M.D., M.H.Sc., Karin M. Muraszko, M.D., and Cormac O. Maher,
M.D. JNS Pediatrics 2010

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Arachnoid Cyst: Treatment


• Indications are highly variable
– Mere presence
– Symptoms of increased ICP
– Significant Headache
– Increase in size over time
– Direct measure of ICP
– Papilledema/Visual disturbance
– Midline shift
– Seizures
– Neurologic change
– Cyst rupture
– Behaviorial concerns
– Neuroendocrine disturbance

Arachnoid Cyst: Treatment


• Severe, quality of life changing headaches
• Change in size over time
• Significant mass effect
• Evidence of increased ICP

1892
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Arachnoid Cyst: Treatment


• Endoscopic fenestration
• Craniotomy for fenestration
• Shunt placement, Cysto-peritoneal shunt

Arachnoid Cyst: Case


• 11 year old boy
• Short stature
• Headaches
• Worsening school performance

1893
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Arachnoid Cyst: Case

Arachnoid Cyst Fenestration

1894
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Arachnoid Cyst: Activity Restrictions


• There are no data on restriction of activity
• ASPN meeting
– Informal poll
– 50% restrict
– 50% do not restrict
• At our institution, middle fossa arachnoid
cysts is rare cause of subdural hemorrhage

Suprasellar Cyst

• MRI

64

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Suprasellar Arachnoid Cyst


• Fenestration
– Top
– Bottom
• Partial resection
• Hole is larger than ETV

65

Arachnoid Cyst Fenestration

1896
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Conclusions
• Understanding the CSF dynamics will guide
treatment
• Hydrocephalus is the common pathway of
multiple disease processes
• Arachnoid cysts warrant treatment if
symptomatic – defining what is symptomatic
is debated by many

1897
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Stereotactic and Functional Neurosurgery:


In My Experience

G. Rees Cosgrove MD, FRCS(C)


Director, Epilepsy and Functional Neurosurgery
Brigham and Women’s Hospital
Harvard Medical School

Disclosure Statement
• Reports no commercial interest

1898
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Stereotactic and Functional Neurosurgery:


In My Experience

definition: - that subspecialty of


neurosurgery that attempts to improve or
restore neurological function by altering or
modifying the nervous system

• Surgery for Epilepsy, Movement Disorders,


Pain, Spasticity and Psychiatric Illness

Stereotactic and Functional Neurosurgery:


WSSFN 2015

definition: - that branch of neurosurgery that


uses dedicated structural and functional
imaging to identify and target areas in the
brain and CNS in order to perform specific
interventions (resection, ablation, stimulation,
neuromodulation, transplantation, etc.) using
specialized instruments and tools in order to
relieve neurologic symptoms and improve
function.

1899
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Stereotactic and Functional Neurosurgery:

• Imaging and localizing techniques


– MRI, PET/SPECT, EEG, MEG
• Surgical tools and techniques
– Frames, RF electrodes, DBS, iMRI, GK, fUS, SCS,
intrathecal pumps
• Physiologic techniques
– Awake surgery, mapping, MERs, Evoked potentials,
diagnostic blocks/injections

Stereotactic and Functional Neurosurgery:


In My Experience

• Is disease and patient focused


• Requires expert multidisciplinary teams
…….. with neurosurgical leadership
• Requires detailed outcomes assessment
• Is a form of applied neuroscience

1900
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Stereotactic and Functional Neurosurgery:


In My Experience

• Epilepsy
– Resection, ablation, intracranial electrodes, VNS, DBS
• Movement Disorders
– Pallidotomy, Thalamotomy, DBS, fUS
• Pain
– Rhizotomy, MVD, Spinal cord stimulation, cingulotomy, cordotomy,
intrathecal morphine
• Spasticity
– Myelotomy, selective rhizotomy, intrathecal baclofen
• Psychiatric Illness
– Cingulotomy, anterior capsulotomy, limbic leucotomy, DBS

Goals of Epilepsy Surgery

• To abolish or control the patient’s seizures

• To accurately localize the epileptogenic region and


remove it without causing significant neurological
deficits

1901
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Presurgical Evaluation – Phase I

• Clinical examination and seizure semiology


• Neuroimaging
– MRI, PET, SPECT
• Electroencephalography
– Routine
– 24 hour video EEG monitoring – interictal, ictal
• Neuropsychology testing
– FSIQ, VIQ, PIQ, memory

Localizing Value

**** Neuroimaging
*** EEG
** Clinical semiology
* Neuropsychology

1902
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Cortical Mapping – Awake craniotomy

Functional MRI
24 y.o. M with new onset seizures and secondary generalization

Verb Generation Tongue Tumor

1903
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Epilepsy surgery - Lesionectomy

Tumor Language Tongue

Epilepsy Surgery – Resection


26 y.o. F with neonatal febrile sz’s
CP Sz 2-3X/week, rare GTC, refractory to medication
Video/EEG monitoring: R temporal lobe spikes, R FT onset
Neuropsychology: impairment in spatial memory and P IQ

1904
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Epilepsy Surgery – Temporal Resection

Anteromedial TL Selective AH

Epilepsy Surgery - Anterior Temporal Lobectomy


20 y.o. M with 12 year Hx of CPS’s characterized by early speech arrest

EcoG

1905
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Epilepsy Surgery – Sensorimotor Seizures

• 42 yo RH female
engineer
• Focal sensory
seizures involving R
side of tongue with
speech arrest
• Frequency: 2 - 4 / day

Epilepsy Surgery – Sensorimotor Seizures

1906
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Epilepsy Surgery – Frontal Resection

Epilepsy Surgery – Central Resection

1907
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Epilepsy Surgery -
Resection

Epilepsy Surgery – Frontal Resection


• 6 y.o. girl with 15 - 20 focal seizures/day beginning age 3
characterized by head/eye deviation to the right, right arm
extension followed by right sided clonic activity

1908
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Epilepsy Surgery – Frontal Resection

Epilepsy Surgery – Frontal Resection

1909
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Epilepsy Surgery – Frontal Resection

Essential Tremor – L Thalamotomy

• 64 y.o. RH man with Essential Tremor for


35 years
• Disabling intentional and postural tremor
• Unable to write, difficulty feeding himself
• Unresponsive to inderal, mysoline

1910
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L Thalamotomy – Stereotactic Targeting

L Thalamotomy – focused Ultrasound

1911
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L Thalamotomy – focused Ultrasound

L Thalamotomy – focused Ultrasound

1912
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Deep Brain Stimulation (DBS)

Indications:
Tremor
Parkinson’s Disease
Dystonia
Other……..

All represent human neural circuit disorders

Deep Brain Stimulation (DBS)

1913
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Parkinson’s Disease – Bilateral Pallidal DBS

• 56 y.o. woman with PD dx’d age 47


• Initially responsive to Sinemet
• 4 years of severe ON/OFF fluctuations and
bilateral drug induced dyskinesias L>R
• Marked freezing and painful dystonias
when OFF

Deep Brain Stimulation (DBS)

1914
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Deep Brain Stimulation (DBS)

Parkinson’s Disease – Bilateral Pallidal DBS

1915
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Surgery for Psychiatric Disorders -


Current Indications
• Severe, incapacitating psychiatric illness
– Major Depression (BDI > 30, GAF < 50)
– Obsessive Compulsive Disorder (YBOCS >
25-30)
– other
• Refractory to all conventional treatment
– pharmacotherapy
– behavioral therapy
– ECT

Outcome Measurements -

• Responder
– > 50% improvement in BDI or Ham-D
– > 35% improvement in YBOCS
• Partial Responder
– > 25 - 50% improvement in BDI or Ham-D
– > 25 - 34% improvement in YBOCS
• Non-Responder

1916
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Surgical Technique
• local anaesthesia with sedation
– valium 10 mg po; droperidol 5 mg im
• stereotactic MR
• target anterior cingulate
• lesion parameters - 85oC for 90 secs, 10 mm exposed tip

MGH Cingulotomy 1960 - 1995

chronic acute and chronic

1917
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MGH Cingulotomy 1995 - 2004


Axial

Sagittal

MGH Limbic Leucotomy 1994 - 2010


Axial

Sagittal

1918
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MGH Cingulotomy Experience for MDD


Shields et al, Biol Psychiatry 64:449, 2008

• N = 33 pts, F/U @ 42 mos


– Responders ……………………33%
– Partial responders ……………. 42%
75%

24
32

25

MGH Cingulotomy for OCD (1989 - 2009)


Sheth, Dougherty, Eskandar, Cosgrove et al, J Neurosurg 2012

• N = 64 pts, 42 M; 22 F
• Mean age 34.7 ( range 16 - 69 yrs)
• Mean duration of illness @ 10 years
• Mean pre-op YBOCS 31.1
• Failed:
– 3 SSRI trials with augmentation ( 12 week
minimum)
– behavioural therapy ( 20 week minimum)

1919
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MGH Cingulotomy for OCD (1989 - 2009)


Sheth, Dougherty, Eskandar, Cosgrove et al, J Neurosurg 2012

• N = 64 pts, at first F/U @ 11 mos


– Responders ……………………34%
– Partial responders ……………. 7%
41%

24
32 Mean YBOCS Improvement
25 26%

MGH Cingulotomy for OCD (1989 - 2009)


Sheth, Dougherty, Eskandar, Cosgrove et al, J Neurosurg 2012

• N = 64 pts, at last F/U @ 62 mos


– Responders ……………………49%
– Partial responders ……………. 22%
69%

24

32 Mean YBOCS Improvement


25 36%

1920
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MGH Limbic Leucotomy 1993 - 2000


Montoya et al Neurosurgery 50:1043,2002

• N = 21 pts, F/U @ 47 mos


• MDD:
– Responders ……………………36%
54%
– Partial responders ……………..18%
• OCD:
– Responders ……………………10%
40%
– Partial responders ……………..30%

Limbic Leucotomy for Self-Mutilation


Price et al J Clin Psychiatry 62:12,2001

– N = 5, ages 29 - 46 yrs
– Disease duration 14 - 30 yrs, mean 22
– F/U: 16 - 47 mos, mean 31.5
– 4/5 improved
– Mean GAF increase of @32.5
– 1/5 remain institutionalized

1921
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MGH Limbic Leucotomy Experience


for Self-Mutilation
• N = 5 pts, mean F/U @ 31.5 mos
100
90
80
70
GAF 60
pre-op
50 post-op
40 post-op
30
20
10
0
Pt A Pt B Pt C Pt D Pt E

Limbic Leucotomy for Self-Mutilation


Long term F/U

– Pt A – pre-op 2:1 care


• 16 year F/U
• Working/living independently
• IQ improved form 77 to 92
• Obtained GED
– Pt B – pre-op 1:1 care
• 15 year F/U
• Working/living independently
• IQ unchanged
• Obtaining Masters degree

1922
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Stereotactic and Functional Neurosurgery:


In My Experience

• Surgery for epilepsy, pain, movement


disorders, spasticity, psychiatric illness
• Utilizes advanced technology both
diagnostically and therapeutically
• Provides opportunities to understand human
brain function

1923
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Neurofibromatosis & VHL


Ashok R. Asthagiri, M.D.
May 2, 2016

Disclosures
• None

1924
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Learning objectives
At the conclusion of this program, participants will be
able to:
• List the clinical manifestations of the
neurofibromatoses and von Hippel Lindau
disease
• Describe the genetics and molecular biology
underlying these disorders
• Understand treatment options and surveillance
paradigms available to patients with central and
peripheral nervous system lesions associated
with NF1, NF2, Schwannomatosis & VHL

Neurocutaneous disorders
• NF1, NF2, Schwannomatosis
• VHL
• Sturge-Weber
• Ataxia-Telangectasia
• Tuberous sclerosis

1925
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Neurocutaneous disorders
• Common theme - rare diseases
- US definition - less than 200K affected
in US (1 in 1500)
- Autosomal dominant transmission vs.
sporadic mutation

Neurocutaneous disorders
• Tumor suppressor gene syndromes
• Multiple neoplasia syndrome

1926
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Neurocutaneous disorders
• Common findings (descending order of
neurosurgical impact)
- Benign tumors of the central and peripheral
nervous system
- Seizures
- MSK - Skeletal dysplasia, weakness, ataxia,
deformity, spasticity
- Pain
- Ophthalmologic manifestations
- Learning disability, developmental delay
- Visceral manifestations
- Cancer (Renal cell CA, MPNST)

1956
Crowe et al. series
1992 & 1994
reports 5% of patients
Evans et al.
1822 with multiple
Parry et al.
Wishart - first probable neurofibromas have
Clinical characteristics
case report of NF2 acoustic neuromas
of NF2

2007
1916 1971 Germline mutation of
Harvey Cushing brackets central NF & von INI1/SMARCB1 in familial
the disorders as von Recklinghausen’s Schwannomatosis
Recklinghausen’s disease are distinct identified
disease clinical entities

1 1 1 1 2
8 9 9 9 0
0 0 5 9 0
0 0 0 0 0

1930
Gardner & Frazier
suggest BAN represent a
central form of von
Recklinghausen’s
disease
2003
1882 1993 Schwannomatosis and
von Recklnghausen’s NF2 gene cloned & NF2 are clinically and
report product identified as molecularly distinct
Merlin / Schwannomin
1987
NIH Consensus Statement
on Neurofibromatosis

Mapping of NF1 to ch 17 &


NF2 to ch 22

1927
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Neurofibromatoses
• NF1
• von Recklinghausen’s disease
• peripheral nf
• “cafe-au-lait” spots, (plexiform) neurofibromas,
intertriginous freckling, Lisch nodules, skeletal
abnormalities, optic nerve gliomas
• NF2
• central nf
• bilateral acoustic nf (BANF)
• Schwannomatosis
• Multiple schwannomas w/o Vestibular
schwannomas

NF2
• multiple neoplasia syndrome

• NF2 tumor suppressor gene located on 22q12

• autosomal dominant inheritance

• wide phenotypic variability

• 100% penetrance by age 60

• 50% of cases due to new/sporadic mutations

• Incidence - 1 in 25,000 births

• Prevalence - 1 in 100-200,000 persons

1928
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Genotype-phenotype correlations
Increasing disease severity

Constitutional nonsense & frameshift


mutations
Wishart phenotype

Splice-site mutations, exons 1-5

Somatic mosaicism

constitutional missense & in-frame


Gardner Phenotype mutations

Splice-site mutations, exons 11-15

1929
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Somatic mosaicism

• 33% of classical sporadic NF2 cases are from


Somatic Mosaic Mutations

• 1 in 8 transmission

• 60% of UVS sporadic NF2 cases are from


somatic mosaic mutations

• 1 in 12 transmission

1930
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Schwannomas

Schwannomas

1931
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Meningiomas

Meningiomas

1932
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Ependymomas

Ophthalmologic manifestations

1933
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Cutaneous manifestations

NF2 diagnosis

1934
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Clinical presentation

Mean age Mean age @


Symptom %
@ onset diagnosis
Deafness 44.4 25.7 34.3

Other CNS tumors 22.2 20.6 25.7


Painful or growing skin
12.7 14.1 23.3
tumors
Visual loss / diplopia 12.7 5.6 19.4

Kaplan-Meier survival curve: Age at diagnosis Baser et al. 2002

Age at diagnosis
1-19
20-39
40+

1935
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Vestibular schwannomas
• hearing loss & tinnitus, usually unilateral
• 60% adults, 30% children

• retrospective auditory analysis - likely to have stable


hearing for 2 years
• rapid hearing loss may develop unrelated to tumor size or growth rate

• rate of hearing loss often differs between ears

• highly variable growth rates that decrease with


increasing age

1936
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VS treatment

modality VII preservation measurable hearing


59% at 10 years
early surgical
75-92% 30-65%
management
50% at 8 years
radiosurgery
54 mo. f/u 92-100% 33-57%
74-100% local control rate

Buchman CA, Chen DA, Flannagan P, Wilberger JE, Maroon JC. The learning curve for acoustic tumor surgery. Laryngoscope. 1996;106(11):1406-11.
Charabi S, Tos M, Thomsen J, Borgesen SE. Suboccipital acoustic neuroma surgery: Results of decentralized neurosurgical tumor removal in Denmark. Acta Oto-Laryngologica.
1992;112(5):810-5.
Fayad, J.N., Bassim, M.K., Brackmann, D.E. Hearing preservation and rehabilitation in vestibular schwannoma surgery (2010) Neurosurgery Quarterly, 20 (2), pp. 53-59.
Brackmann, D.E., Fayad, J.N., Slattery III, W.H., Friedman, R.A., Day, J.D., Hitselberger, W.E., Owens, R.M. Early proactive management of vestibular schwannomas in neurofibromatosis
Type 2 (2001) Neurosurgery, 49 (2), pp. 274-283

Kida Y, Kobayashi T, Tanaka T, Mori Y. Radiosurgery for bilateral neurinomas associated with neurofibromatosis type 2. Surgical Neurology. 2000;53(4):383-90.
Mathieu D, Kondziolka D, Flickinger JC, Niranjan A, Williamson R, Martin JJ, et al. Stereotactic radiosurgery for vestibular schwannomas in patients with neurofibromatosis Type 2: An analysis
of tumor control, complications, and hearing preservation rates. Neurosurgery. 2007;60(3):460-8.
Roche PH, Regis J, Pellet W, Thomassin JM, Gregoire R, Dufour H, et al. Neurofibromatosis type 2. Preliminary results of gamma knife radiosurgery of vestibular schwannomas.
Neurofibromatose de type 2 Resultats preliminaires de la radiochirurgie gamma knife des schwannomes vestibulaires. 2000;46(4):339-54.
Rowe JG, Radatz MWR, Walton L, Soanes T, Rodgers J, Kemeny AA. Clinical experience with gamma knife stereotactic radiosurgery in the management of vestibular schwannomas

VS treatment

1937
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VS treatment

• Clinical trials
• Bevacizumab (VEGF inhibitor -
angiogenesis)
• Rapamycin (mTOR inhibitor)
• Lapatinib (tyrosine kinase inhibitor)

Meningiomas

1938
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Meningiomas

17

44
Convexity

23
Parasagittal

9
10

20
Falcine

New tumors during follow-up


66 tumors (47.5%)
16
Posterior Fossa

16
11
Tentorial

Sphenoid Wing

8
Intraventricular

5
Olfactory groove

2
4
Cavernous Sinus

1
2
Optic Sheath

1
1

1939
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Meningiomas
Exponential (7.8%)
Quiescent periods / tumor 10 tumors
• Mean - 1.36 ± 0.7
• Range - 1 to 4
• Frequency - every 4.5 years
Duration
• Mean – 2.4 ± 2.3 years Stuttering (60.9%)
• Range – 0.4 to 11.7 years 78 tumors

Linear (31.2%)
40 tumors

Meningioma management
• Symptom driven
• Skull base tumors
• Surgical debulking + radiotherapy

1940
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Nonvestibular schwannomas
• Nonvestibular nerve cranial nerve
schwannomas
• up to 50% of patients
• III, V, VII most frequent
• Lower cranial nerves most frequently
symptomatic

NF2
• Nonvestibular nerve cranial nerve
schwannomas
• up to 50% of patients
• III, V, VII most frequent
• Lower cranial nerves most frequently
symptomatic

1941
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Ependymomas
• 18-53% of patients
• Typically confined to spinal cord
• less than ⅓ need operation

NF2 surveillance
• Annually:
• Brain/spine MRI annually (when feasible)
• Audiology (starting at 10)
• Ophthalomology - at diagnosis

1942
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NF1 genetics
• Multiple neoplasia syndrome
• Autosomal dominant inheritance
• NF1 tumor suppressor gene located on
17q
• Penetrance of 100% by age 20
• Significant variability in expressivity
• Half of cases due to new mutations

NF1 epidemiology
• Most common form of Neurofibromatoses
• 1 in 3,000 live births
• No gender, race or ethnic specificity

1943
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Somatic mosaicism in NF1


• Generalized vs. “segmental”

NF1 genetics/molecular biology


• NF1 gene - 350kb genomic DNA that
encodes for a 220 to 250 kDa protein
product, termed Neurofibromin
• Neurofibromin inhibits Ras, a key
regulator of signal transduction,
proliferation and malignant transformation
• NF1 haploinsuffiency may cause some
non-neoplastic neurologic manifestations

1944
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NF1 diagnosis
Must have 2 or more of the following:
• 6 or more cafe´ au lait macules (.5 cm in children or
.1.5 cm in adults)
• 2 or more cutaneous/subcutaneous neurofibromas or
one plexiform neurofibroma
• Axillary or groin freckling
• Optic pathway glioma
• 2 or more Lisch nodules (iris hamartomas seen on slit
lamp examination)
• Bony dysplasia (sphenoid wing dysplasia, bowing of
long bone pseudarthrosis)
• First degree relative with NF1

Neurocutaneous manifestations

1945
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Clinical course
• Features usually present by age 8
• Generally progressive
• Disfigurement (dermal / plexiform
neurofibromas)
• 2.7x relative risk - development of cancer
• Reduced life expectancy of 54/59 years (vs
70/74)
• Cumulative risk for development of CNS
tumor is 7.9% (vs .46%)

Optic pathway gliomas


• Prevalance in NF1 (15-21%)
• Pilocytic astrocytomas (WHO I)
• Peak incidence @ 4-6 years of age

1946
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Optic pathway gliomas


• More indolent than sporadic cases
• Surgery is reserved for mass effect,
hydrocephalus
• Radiotherapy - secondary malignancy,
endocrinopathy & cerebral vaculopathy
• Documented progression
• Combination chemotherapy
(vincristine + carboplatin)

Brainstem gliomas
• Prevalence in NF1 (4-18%)
• Distinguish from UBO (unidentified bright
objects) - do not progress
• Incidental discovery (most common)
• WHO Grade I through IV
• Favorable imaging findings
• Medullary / midbrain
• Focal tumor
• Up to 89% may remain stable

1947
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Brainstem gliomas
• Treatment is generally reserved for cases
with radiographic and clinical progression
• Focal tumors - surgical resection attempt
• Diffuse tumors - radiotherapy
• CED
• chemotherapeutics

Plexiform neurofibromas
• 10% lifetime risk of developing an MPNST
• Complete resection will likely cause
neurological deficit

1948
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MPNST
• 5-10% of all soft tissue sarcomas
• Risk Factors
• NF1 (10% lifetime risk)
• (internal) plexiform neurofibroma (not dermal)
• radiation

MPNST
• Diagnosis = low index of
suspicion
✓rapid increase in size
✓new/progressive
neurologic deficit
✓subacute/acute onset of
pain
✓hard and immobile on
palpation

1949
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MPNST
• Diagnosis
✓ MRI/CT (hemorrhage,
necrosis, cystic areas,
heterogenous
enhancement are not
dependable markers)
✓ 18FDG PET
✓ Percutaneous biopsy

MPNST
• Treatment
• Wide local
excision (including
amputation if
needed)
• Radiation therapy
(60-70 Gy with 5
cm margin)
• Sarcoma based
therapeutics forequarter amputation, 2009
(ineffective)

1950
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MPNST

Characteristics Sporadic NF1

Incidence (%) 0.001 8-13

Age at diagnosis
40-62 26-36
(yrs)

Development De novo in PN

Clinical findings pain, rapid growth, neurologic compromise

Chemotherapy
55 18
response (%)

Molecular biology not distinct

5-year survival (%) 42-57 16-38

NF1 surveillance
• Under 16
• Annually:
• Pediatric evaluation (scoliosis, painful
cutaneous lesions/rapid growth,
neurologic examination)
• Ophthalmology
• Endocrine, cardiology, neurosurgical
evaluation as needed

1951
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NF1 surveillance
• Over 16
• Annually:
• Scoliosis less important
• Ophthalmology less important
• Primary care evaluation
• MPNST evaluation

1956
Crowe et al. series
1992 & 1994
reports 5% of patients
Evans et al.
1822 with multiple
Parry et al.
Wishart - first probable neurofibromas have
Clinical characteristics
case report of NF2 acoustic neuromas
of NF2

2007
1916 1971 Germline mutation of
Harvey Cushing brackets central NF & von INI1/SMARCB1 in familial
the disorders as von Recklinghausen’s Schwannomatosis
Recklinghausen’s disease are distinct identified
disease clinical entities

1 1 1 1 2
8 9 9 9 0
0 0 5 9 0
0 0 0 0 0

1930
Gardner & Frazier
suggest BAN represent a
central form of von
Recklinghausen’s
disease
2003
1882 1993 Schwannomatosis and
von Recklnghausen’s NF2 gene cloned & NF2 are clinically and
report product identified as molecularly distinct
Merlin / Schwannomin
1987
NIH Consensus Statement
on Neurofibromatosis

Mapping of NF1 to ch 17 &


NF2 to ch 22

1952
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Schwannomatosis
genetics
•Multiple neoplasia syndrome
•Tumor suppressor gene
•Similar annual incidence to NF2
➡1 in 30,000 live births
•No gender, race or ethnic specificity
•Majority of cases are sporadic
➡INI1/SMARCB1 (50% familial cases, 10% sporadic cases) -
22q11.23
➡ LZTR1 (80% of SMARCB1 negative familial cases)
๏ MUST EXCLUDE NF2 (vestibular nerve, ophthalmic findings)

Schwannomatosis
• Most common presentation - intractable pain
from peripheral nerve tumor
• Non-vestibular nerve cranial nerve
schwannomas (including facial nerve tumors)
• Management analagous to sporadic tumors

1953
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VHL

von Hippel-Lindau disease

• Autosomal dominant
• VHL gene - ch. 3
• 1 in 39,000 live births
*25-33% of patients
presenting with a
hemangioblastoma will
have VHL

1954
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Hemangioblastoma

Brainstem (10%)

Cerebellum (37%)

Spinal Cord (50%)

1955
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Hemangioblastoma

• Signs and symptoms


• Mean age 33+10 years
• Symptoms referable to anatomic location

Hemangioblastoma
• Signs and symptoms
• Related to mass effect
•Tumor growth
•Peritumoral cysts
• Presence of a peritumoral cyst and symptoms
• 72% of symptomatic cerebellar tumors
• 75% of symptomatic brainstem tumors
• 95% of symptomatic spinal cord tumors
• Cyst enlarged faster than tumor
• 7 times faster in cerebellum
• 15 times faster in brainstem
• Cyst was larger than tumor
• 34 times larger in cerebellum
• 19 times larger in brainstem

1956
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Hemangioblastoma

Edema to cyst formation 36+23 months (range, 8 to 72 months)

Hemangioblastoma

T1-weighted FLAIR precontrastFLAIR postcontrast

1957
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Hemangioblastoma

• Growth
• 1278 (51% of tumors evaluated) stable and 1227
(49%) grew

saltatory (886 tumors [72%])
• linear (76 [6%])

exponential (264 [22%])

Hemangioblastoma
• Symptom formation
• 58 (41%) tumors became symptomatic requiring
intervention
•26/58 (45%) of the tumors that eventually produced
symptoms were not apparent on initial imaging
• 49/58 (85%) of symptom producing tumors had an
associated cyst/syrinx
• If surgery for growth only (not symptom formation)
each patient would have had 4 additional
surgeries over 10 years

1958
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1959
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• 20 VHL patients
• 44 CNS hemangioblastomas
• Average age - 37
• Average follow up – 8.5 years
• Treated volume - .5 cm3
• Mean prescribed dose – 18.9 Gy

1960
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SRS for VHL hemangioblastomas

Results

1961
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Audiovestibular
symptoms
• Endolymphatic sac
tumors

• 11% of VHL patients

• 15% are bilateral

• Mean age at symptom


onset - 22 years (12-50
years) • hydrops

• First symptom • direct invasion (size)


(audiovestibular) in 63%
• hemorrhage (sudden)
of patients

ELSTs

• Clinical findings (T.J. Manski et al., JAMA, 1997; D.I. Choo et al., J Neurosurg, 2004)

• Hearing loss - 95%


•Sudden hearing loss - 86%
•Gradual - 14%
• Tinnitus - 85%
• Vertigo - 66%
• Aural fullness - 40%
• Facial nerve paresis - 8%

1962
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ELSTs

• Patients with imaging evidence of ELST


• Many without otic capsule invasion but hearing loss
• Patients without imaging evidence of
ELST
• 65% have some degree of hearing loss
JAMA, 1997)
(T.J. Manski et al.,

• Significant increase in audiovestibular dysfunction


Choo et al., J Neurosurg, 2004)
(D.I.

1963
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ELSTs

Retinal hemangioblastomas ( 60%)

Pancreatic
RCC Pheochromocytomas neuroendocrine tumors
(10-20%) (8-17%)
(24-45%)

1964
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VHL surveillance
• AGE > 16
• Annually:
• Eye/retinal examination
• General/neurological examination
• Quality abdominal ultrasound
• Fractionated metanephrines
(normetanephrine blood test or 24-
hour urine test) - MRI or MIBG scan if
abnormal

VHL surveillance
• >16
• during pregancy
• Regular retinal & OB checkup to
anticipate potentially more rapid
progression of lesions.
• Endocrine evaluation each trimester
• 4th month - MRI without contrast

1965
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Key points
• Neurofibromatosis type 1 is associated with the development of brain tumors,
including optic pathway gliomas and brainstem gliomas. These tumors, when
compared to their sporadic counterparts, have a more favorable natural
history and do not require treatment unless clinical and/or radiographic
progression is clearly identified. The lifetime risk of development of a
malignant peripheral nerve sheath tumor in NF1 is 10%.

• In addition to bilateral vestibular schwannomas, patients with


neurofibromatosis type 2 may develop other brain tumors including:
intracranial meningiomas, non-vestibular nerve cranial nerve schwannomas,
and brainstem ependymomas. Treatment of intracranial tumors associated
with NF2 typically remains symptom driven.

• Patients with schwannomatosis may develop non-vestibular nerve cranial


nerve schwannomas in addition to schwannomas of other peripheral nerves.
A diagnosis of schwannomatosis requires exclusion of a diagnosis of NF2.

• VHL is a multiple neoplasia syndrome that results in the formation of CNS and
retinal hemangioblastomas, endolymphatic sac tumors and visceral
manifestations including renal cell cancer and pheochromocytomas.

• Tailored surveillance paradigms need to be made for patients with these rare
disorders.

1966
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Coma and Brain Death

Oakstone 2016

Dr. Allan Ropper, M.D.


Brigham and Women’s Hospital
Department of Neurology

Disclosure

Reports no commercial interest

1967
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Traditional Approaches
(Anatomical)
• Direct damage to RAS in upper midbrain-lower
midline thalamic nuclei
– Top of basilar stroke, tumor, hemorrhage, inflammation
• Diffuse or large bilateral hemispheral lesions
– Trauma (DAI, subdural hematoma, contusion), global
anoxia-ischemia, hydrocephalus, tumor
• The “herniation” syndromes and secondary
compression of upper brainstem

Herniation Syndromes
• Central • “Uncal”
– Early drowsiness – Early ipsilateral pupillary
– Small reactive pupils enlargement (10%
– Cyclic breathing contralateral)
– Preserved eye movements – Later reduction in alertness
early – Followed by loss of eye
– Later pupils mid-sized and movements and corneals
fixed – Pupils mid-sized and fixed
– Ostensibly from downward – Followed by agonal
displacement and buckling of respiratory patterns
upper brainstem – Ostensibly from lateral
compression of midbrain

1968
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Traditional Approaches
(Physiological)
• Toxins, anesthetics, and drugs
– (probably affect both RAS and cortical neurons)
• Seizures
– (similarly uncertain anatomical locus of action)
• Hypoxia and trauma (sometimes seizures) as
special cases that have initial physiologic and
later destructive effects

Main Pitfalls for the Clinician


• Metabolic coma with focal signs
• Oddball diagnoses including catatonia
• Non-convulsive status epilepticus
• Unusual Intoxications
• Locked eyes with overdose
• Peculiar eye signs

1969
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Focal Signs in Metabolic Coma


• Common: hyperosmolar hyperglycemia
• Focal seizures and transient hemiparesis with
hypoglycemia
– (<3% according to Malouf and Brust Ann Neurol 1985, but
hypoglycemia is common)
• Reported with hepatic encephalopathy
– (8/34 in series of Cadranel, Am J Gastroenterol 2001)
• Common in TTP, especially focal seizures
• Uncommon in uremia unless from SLE (focal visual sxs
usually from RPLE)
• Problem of re-emerging stroke hemiparesis in context
of drug or metabolic change

Catatonia

• Catalepsy with extreme behavioral withdrawal,


mutism or stereotyped behavior
• Applied to schizophrenic and affective illness but
similar syndrome in variety of cerebral disease
• Increasing occurrence in elderly
• “Malignant catatonia” refers to loss of ability for self-
care and subsequent physical deterioration

1970
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Non-convulsive Status Epilepticus


• Fixed stare; repetitive blinking, chewing, or
swallowing; small myoclonic twitches of face or
extremities
• Circumstances
– Prolonged pos-ictal state
– Acute and fluctuating confusion ro stupor
– Stupor with myoclonus
– Episodic partial complex signs
– Acute catatonia

Unusual Intoxications
• Not cocaine unless NCSE
• Can occur with sympatholytics (e.g., clonidine)
• Anticholinergics (coma especially in children; tricyclics,;
phenothiazines, anti-parkinson, OTC)
• Cholinergics (organophosphates also with atropinic effects)
• Serotonin syndrome (especially with concurrent MAOIs)
• Anion gap acidosis poisonings (ethylene glycol. salicylates,
methanol, toluene, paraldehyde-and uremia, DKA)
– And lactate—i.e., cyanide CO, INH

1971
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Other Deceptive Causes of Coma


• TTP
• Hashimoto encephalopathy
• Wernicke disease
• ADEM and intravascular lymphoma
• Episodic “endozapine” comas
• Migraine coma

TTP and Coma


• Systemic features always present: low grade fever,
anemia, and, of course, petechiae with
thrombocytopenia.
– Platelets may initially be just under 100K
• MRI shows variable changes and CSF normal (slight
increase protein)
• Seizures, coma and NCSE
• Remitting and fluctuating hemiparesis
• Premium on diagnosis because of successful
treatment with plasma exchange

1972
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Hashimoto Encephalopathy
• Confusion, stupor, multifocal myoclonus progressing
to coma over days
• Normal MRI and CSF
– Some with rapidly evolving, even unilateral, white matter
lesions that simulate ADEM
• Normal thyroid function in most but characteristic
anti-thyroid peroxidase and anti-thyroglobulin
antibodies
• Differential diagnosis—CJD, lithium intoxications
(commonality of myoclonus)
• Cases appearing in children and young adults

Unrevealed Wernicke Disease


• Still occurs in hospitalized patients
– Especially in ICUs, with glucose infusions or
dialysis, and in malnourished AIDS patients
• Eye movement changes may be incorrectly
attributed to drugs
• MRI changes highlighted in literature but are
subtle
• Everyone should get thiamine

1973
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Prognostication in Coma

Prognostication in Metabolic (Mainly


Anoxic) Coma
• SSEPs—strong specificity when absent
• Levy, Bates Caronna algorithms
– Eyes, vocalization and best motor at 24 hrs
• BUT these apply to only a minority of patients and do
not give absolute values AND, no group of signs
strongly predicts good outcome

1974
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Booth’s meta-analysis (JAMA 2004)


• LR = likelihood ratio = presence of sign with bad outcome
compared to good outcome
– LR of poor outcome @ 24h:
• Absent corneal: 12.9
• Absent pupillary response: 10.2
• Absent motor response: 4.9
• Absent withdrawal: 4.7
– LR of poor outcome @ 72h:
• Absent motor: 9.2
• Absent pupil: 3.4
• Seizure of myoclonus: 1.4

Minimally Conscious State


• MCS as a new syndrome—formerly “severely
demented”
• Tracking and regarding
• Some motor response
• Usually mute but may mutter or say few
words
• Sleep-wake cycles

1975
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MCS and PVS patients may have cognitive


function
• PVS patient had fMRI evidence of some
internal cognition 6 months after head injury
(imagining tennis, house tour); (Owen et al:
Science 2006; Monti et al NEJM 2010)
• Other big lesson-PVS not easy to diagnose

Mental-Imagery Tasks

Monti MM et al. N Engl J Med 2010;362:579-589

1976
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DBS in MCS
• Medial thalamic DBS improved one MCS patient’s
performance on some scales 6 years after head
injury (Schiff et al, Nature 2007)
– Large areas of preserved cortex and connections
– Longer periods of eye opening, functional use of objects
and intelligible speaking with optimized DBS
– No improvement on motor and communication scales
(?ceiling effect or measurement scales)
– Implication that MCS is an arousal defect

Brain Death
• Sociologic, legal and medical dividing line from
severe and irrevocable brain damage
• Clinical diagnosis:
– Irreversibility (cause must be defined)
– Lack of function of
• Cerebrum-deep, unresponsive coma
• Midbrain-fixed, mid-sized pupils
• Pons-absent caloric-induced eye movements
• Apnea by formal testing

1977
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Brain Death Issues That Vary


• One vs two exams and interval between them
• Need for ancillary tests: EEG, blood flow,
transcranial Doppler (also, atropine test)
• Toxicology screen
• Admissibility of spinal reflexes
• Lazarus sign

1978
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1979
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Anticoagulation, Reversal, and


Hemostasis in Neurosurgery

Christopher M. Loftus MD, Dr.h.c., FAANS


Professor and Chairman
Department of Neurosurgery
Loyola University Stritch School of Medicine
Chicago, IL, USA
Treasurer – WFNS
Chair, International Programs – AANS

Disclosure Statement

Advisory Role: 3M, Portola


Honoraria: Scanlan

1980
Copyright © Oakstone Publishing, LLC, 2016. All Rights Reserved.

Add HAS BLED

1981
Copyright © Oakstone Publishing, LLC, 2016. All Rights Reserved.



Part 1: General Principles 14. Heparin-Induced Thrombocytopenia (HIT) by Jeanine M. Walenga and M.
Margaret Prechel
1. Physiology of Hemostasis by Jawed Fareed and Omer Iqbal
15. Anticoagulation in Cardiovascular Diseases by Shermeen B. Memon, Lara
2. Laboratory Assessment of Physiologic and Pathologic Hemostasis by Jeanine Bakhos, and Mushabbar A. Syed 28. Is it Safe to Shunt Anti-coagulated NPH Patients? By Eric W. Sankey, Rory
Goodwin, Ignacio Jusue-Torres, and Daniele Rigamonti
M. Walenga
16. Workup and Treatment of Pulmonary Embolus by Agnieszka A. Ardelt

3. Current anticoagulation drugs and mechanisms of action by Tarik F. Ibrahim, 29. Surgical Hemostasis in the Era of Anticoagulation: Guidelines and
Recommendations Summary by Drew A. Spencer, Paul D. Ackerman, Omer
Sean Maxwell and Omer Iqbal Part 3: Coagulation Issues Specific to Neurosurgery

Iqbal, and Christopher M. Loftus

4. Reversal of Target-Specific Oral Anticoagulants by Walter Jeske 17. Classes of Drugs and Blood Products for Acute Reversal of Anticoagulant
Effect by Christopher D. Witiw, Laureen D. Hachem, and Michael G. Fehlings

5. Overview, Treatment, Measurement, and Modification of Platelet Function by 18. Rescue Strategies to Facilitate Emergency Neurosurgery in Patients on
Daphne Li, Wael Hassaneen-Mostafa, and Asterios Tsimpas Antiplatelet or Anticoagulant Agents by Erinç Aktüre, Andrew Goodwin, and
Bruce Tranmer
6. Role of Antiplatelet Therapy in Neurosurgery: Efficacy and Safety Profiles by
19. Considerations for Coagulation in the Multi-Trauma Patient by Craig Rabb
Nicholas Bowen and Shaker A. Mousa
and Allison Strickland

Part 2: Coagulation Issues Across all Patient Spectrums 20. Cerebral Venous Sinus Thrombosis by William W. Ashley Jr.

7. Congenital Coagulation Disorders by Danielle Sterrenberg and Sucha Nand 21. Coagulation studies in preoperative neurosurgery patients byHugh J.L.
Garton
8. Acquired Coagulation Disorders by Kimberly Kruczek, Kathrine Cooper, Hanh
Mai, and Sucha Nand 22. Safe strategies for gradual suspension and re-institution of anticoagulation to
permit elective surgery by Chirstopher Roark


9. Regulation and Dysregulation of Fibrinolysis by Omer Iqbal, Paul O’Malley, 23. Spontaneous Intracerebral Hemorrhage due to Coagulation Disorders by W.
and Nil Guler Caleb Rutledge, S. Andrew Josephson, and Michael T. Lawton

10. Risks Associated with Administration of Allogeneic Blood Components by
Phillip J. DeChristopher 24. Prophylactic Screening for Venous Thromboembolism in Neurosurgical
Patients by Michael Schneck


11. Common Coagulation Disorders that may arise Intraoperatively by Srikanth 25. Venous Thromboembolism Prophylaxis in Neurosurgery by Vikram C.
Nagalla and Geno Merli Prabhu

12. Evaluation and Management of Untoward Intraoperative Bleeding by Michael 26. Can Patients with known intracranial and intraspinal vascular lesions be
P. Wemhoff and W. Scott Jellish anticoagulated? By Christopher P. Robinson, Michael Star, and José Biller


27. Intrathecal Access and Devices in Patients on Antiplatelet or Anticoagulant
13. Treatment of Disseminated Intravascular Coagulation (DIC) by Marcel Levi Therapy by Kevin N. Swong, Drew A. Spencer, and Christopher M. Loftus

1982
Copyright © Oakstone Publishing, LLC, 2016. All Rights Reserved.

Poignant Cases in Neurosurgical


Hemsotasis

1983
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CML 12/11

CML 12/11

1984
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CML 12/11

CML 12/11

1985
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CML 12/11

SH 1247052
77 yo RH F PMH of DVTs and possible PEs on Xarelto (rivaroxaban) admitted to trauma after fall down
stairs with CT head demonstrating a left cerebral intraparenchymal hemorrhage with left posterior subdural and
6mm MLS. GCS 13 on arrival. Kcentra administered on admission.
• PMH/PSH: Baseline Dementia, DM, Bone Cancer, Thrombocytopenia, PE, Hypothyroidism
• Home Meds: alendronate, ASA81, donepezil, fexofenadine, insulin, hydroxyurea, lantus, synthroid,
xarelto, simvastatin, vesicare
• Allergies: Amoxicillin
• SH: Denies tobacco use, Denies alcohol use, Denies illicits. Lives at home with daughter who is at bedside.
Retired legal secretary.
• FH: noncontributory
• ROS: Negative except for as specified above.
Recs:
- ICU with Q1 hour neuro checks. Contact Neurosurgery for changes in neurologic exam.
- Please avoid hypo-osmolar and dextrose containing fluids as these can exacerbate cerebral edema and
ischemia.
- Repeat CT head 6 hours after initial scan. Repeat CT head sooner if there is deterioration in neurologic exam
- Avoid hypotension
- Keppra for seizure ppx x 7 days
- Discussed prognosis and potential intervention with daughter at bedside. Daughter states that the patient would
not want a undergo surgical intervention given the poor prognosis.
- Maintain normal body temperature
- Total fluids 83ml / hr

1986
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Cranial Imaging

Initial 6 hours

The Fundamental Questions

• Does the patient need A/C?


• Should we reverse A/C or wait?
– Is a single reversal dose sufficient?
• Will surgery be needed?

1987
Copyright © Oakstone Publishing, LLC, 2016. All Rights Reserved.

Cranial Imaging

18 hours 42 hours

1988
Copyright © Oakstone Publishing, LLC, 2016. All Rights Reserved.

Anticoagulation, Reversal, and


Hemostasis in Neurosurgery

Christopher M. Loftus MD, Dr.h.c., FAANS


Professor and Chairman
Department of Neurosurgery
Loyola University Stritch School of Medicine
Chicago, IL, USA
Treasurer – WFNS
Chair, International Programs – AANS
Oakstone Publications Video Lecture
April 2016

1989
Copyright © Oakstone Publishing, LLC, 2016. All Rights Reserved.

MR 2865992
22 M with no PMH hit by car (30MPH) while
crossing the street. Patient was intubated on
arrival to the ED. Injuries include pulmonary
contusions, facial fractures, bilateral
frontotemporal contusions and midline frontal
bone fracture extending to a diastatic fracture
of the sagittal suture.
Initial Exam: intubated, eyes open to voice, full
strength x4

1990
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Initial CTH

Traumatic hemorrhagic contusions

Diastatic Sagittal fracture

1991
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CTV at admission

What would you do?

• Heparin for SSS thrombosis?


• No heparin in trauma patient with
contusions?
• Decompressive surgery?
• EVD/monitor?
• Endovascular thrombectomy?

1992
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We’re not done yet……

• The patient’s Exam deteriorated and a right frontal


EVD was placed (OP 15). MRI/MRV showed new
acute infarcts and persistent SSS thrombosis.
• The patient was initiated on heparin drip on post
trauma day 2. Patient required sedation for
elevated ICPs and subsequently required
Pentobarbital coma/hypothermia for refractory
ICPs on post trauma day 3 with good response.

MRI post 24 hours

1993
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19 days from the STARTING ANTICOAGULATION

1994
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PM 2862516 – January 2016


56yo F PMH of widely metastatic ovarian cancer to colon and colectomy on chemotherapy with
thrombocytopenia (27 at OSH) and DVT on coumadin who presents to LUMC as a trauma transfer from St.
Catherine’s in Indiana where she presented after being found unresponsive by her husband after she had gone
home from work earlier today with a headache. She was intubated and was started on pressors. A head CT
was obtained at 2pm demonstrating 1cm left holohemispheric SDH with 14mm MLS and 4th ventricular
hemorrhage and duret hemorrhages. The patient was given 1 U FFP, Vit K, 77g mannitol before presentation to
LUMC. Per the patient’s husband, her coumadin had been held after the thrombocytopenia was diagnosed a
week ago.

Neuro Exam:
GCS: 3T
Intubated
Right Pupil 5mm irregular nonreactive
Left Pupil 6mm nonreactive
Negative corneal reflex bilaterally
Negative Gag
Cold calorics performed with no eye movement

Selected OSH Labs:


Na 143; K 2.5; Cr 0.8
74>8.4<27,000 platelets
INR 1.4
PTT 92 - ??

1995
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PM 2862516

The Fundamental Questions

• Does the patient need A/C?


• Should we reverse A/C or wait?
– Do we replete platelets?
• Will surgery be needed?

1996
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This Presentation

• A discussion of specific anticoagulation


and reversal cases/problems that we
encounter
• Multiple specific case examples
• Discussion and questions

• Bleeding is our enemy


• Coagulation is our friend

1997
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We don’t want to operate on any patient


with compromised coagulation
- with one exception………
So we need to understand and deal with:
- Congenital coagulation disorders
- Antiplatelet drugs
- Heparin
- VKA’s
- TSOAC’s

Classes and mechanisms of A/C drugs


How do we shut off for emergencies:
ASA
Clopidrigel
Vitamin K antagonists
NOAC’s
How do we shut off for elective surgery:
ASA
Clopidrigel
Vitamin K antagonists
NOAC’s
Who needs a bridging strategy?
When is it safe to restart A/C postop?
How do we restart A/C:
Bridge
Bolus dose
Maintenance dose rampup
How do we screen and prophylax for DVT and PE?
Who needs an IVC filter? What type?

1998
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1999
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Surgical Hemostasis in the Era of


Novel Anticoagulation

Why is anti-coagulation problematic?


• Growth of the aging and elderly populations
– Highest age-specific incidence of TBI[1]
– 25% of all trauma-related deaths
• Pre-injury antiplatelet
– Mortality 23% vs 9% in controls[2]
– Some advocate for platelet transfusion in all cases[3]
• Expanding indications for
antiplatelet/anticoagulant therapy
• Newer agents approved and used, while
inhibitors and reversal agents still in development
phase

2000
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Patients We Encounter
• Atrial fibrillation
• Prosthetic heart valves
• DVT/PE
• Endovascular devices (coronary/cerebral)
• Hypercoagulable states
• Unknown therapy

Classes and mechanisms of A/C drugs


How do we shut off for emergencies:
ASA
Clopidrigel
Vitamin K antagonists
NOAC’s
How do we shut off for elective surgery:
ASA
Clopidrigel
Vitamin K antagonists
NOAC’s
Who needs a bridging strategy?
When is it safe to restart A/C postop?
How do we restart A/C:
Bridge
Bolus dose
Maintenance dose rampup
How do we screen and prophylax for DVT and PE?
Who needs an IVC filter? What type?

2001
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Antiplatelet Agents

• 1Aspirin

– COX-1 Arachidonic 2
• 2Clopidogrel, prasugrel, ticlopidine, Acid

3 Aggregation
ticagrelor 1
– ADP binding
• 3Abciximab, eptifibatide, tirofiban Prostaglandin
G2/H2

– GpIIbIIIa inhibition

Thrombo Activation,
xanes
Aggregation,
Degranulation

Anticoagulants

Parenteral Oral

Heparins Anti-Thrombin VKA Non-VKA oral


anticoagulants
Ximelagatran
UFH Argatroban Warfarin Dabigatran
LMWHs Desirudin Phenprocoumon Rivaroxaban
U-LMWHs Bivalirudin Acenocoumarol Apixaban
Oligosaccharides Edoxaban

2002
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Anticoagulant Agents

• Vitamin K antagonists XII XIIa


– Warfarin
• ↓ II, VII, IX, X, proteins S and C XI XIa
• NOACs
– Direct Thrombin Inhibitors IX IXa VIIa VII
• Pradaxa (dabigatran)
– Factor Xa inhibitors
X Xa X
• Xarelto (rivaroxaban)
• Eliquis (apixaban)
• Lixiana (edoxaban) Prothrombin (II) Thrombin
• Arixtra (fondaparinux)
• *Thrombin also a platelet linker via the Fibrinogen (I) Fibrin
GpIIbIIIa receptor

Currently Available Anticoagulant Drugs


and their Mechanism of Action
Mechanism of
Legend Class Example Action

Vitamin K
Inhibit synthesis of
# antagonists Warfarin
II, VII, IX, X
(VKA)

UFH Indirectly inhibit Xa,


# Heparins IIa, TFPI release
LMWH via ATIII

Fondaparinux
Indirectly inhibit Xa
Pentasaccharide
activity via ATIII
Idraparinux

Argatroban

Bivalirudin
Direct thrombin
II
inhibitor (DTI)
Dabigatran

Lepirudin

Apixaban

Direct Xa inhibitors Edoxaban Xa

Rivaroxaban

2003
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Clinical scenarios
• Elective surgery patients on AP/AC
– A) bridge
– B) stop
• Emergencies (non bleed) presenting on AP/AC (tumor, acute disc,
hydrocephalus…)
• Bleeds occurring on AP/AC (cerebral or spinal)
• Surgery patients who develop AP/AC needs postop
– DVT
– PE
– CVST
• Patients who need ICU/office procedures on AP/AC
– LP or LD (CVST, diagnostic)
– EVD (pre/post GDC)

2004
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56 yr old RH M w PMH HTN w 3 wks h/o progressive


R hemiparesis

Neuro exam:
AOX3
R B4/D4/T4/DF 0 otherwise intact

Preoperative

Left parietal craniectomy and resection (one vein taken)

Exam deteriorated in POD#0 overnight with evolving R hemiparesis and aphasia

2005
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Postoperative

Venous infarct: thrombus extended to SSS

Fresh postop with brain bleed - Anticoagulation?

Heparin drip started

Patient developed Heparin induced thrombocytopenia

Argatroban infusion started for one wk till CTV showed patent SSS

Patient kept on ASA and transferred to rehab

Exam stable. No progression of hemorrhage

2006
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How do we reverse?
• Antiplatelet drugs
• Heparin
• Lovenox
• Warfarin
• TSOAC’s
– DTI type
– Factor Xa type

How We Reverse A/C Now


• Aspirin, Plavix – DDAVP, platelet transfusion
• Heparin – Protamine or just turn off
• Enoxaparin (Lovenox) - 1mg protamine per 1mg
enoxaparin
• Warfarin and VKA – VK, FFP, PCC
– alternate is rfVIIa
• TSOAC – PCC, rfVIIa, FEIBA (nonspecific)
– DTI – PCC + FFP = replacement of inactivated factor
(thrombin or II) and activated VII – now Praxbind
– Xa inhibitors – Same as above. FFP alternative but
large volume and doesn’t include activated factors

2007
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Reversal for Emergency Surgery


• All antiplatelet agents
– Pack of platelets
• High risk situations
– ICH
• 2 packs platelets, 0.3 µg/kg DDAVP
• Continue platelet transfusions q12h for 48h

75 y/o RH F w/ h/o MI on ASA + Plavix s/p stent + Defibrillator also w/ chronic hyponatremia
related to polydipsia associated w/ B parotid gland resection in the 1980’s complicated
infrequently by seizures though not on daily AED due to polydipsia who presented to the
LUMC ED as a Trauma II after husband found her at the base of their staircase
minimally responsive. CT head demonstrated scattered, largely cortical tSAH. CT
cervical was negative.
On arrival, patient awake, but would not regard. Roving eye mvts w/ nystagmus. Symmetric,
purposeful movements x 4, but would not follow commands. Incomprehensible sounds.
GCS 11 (E: 4|V: 2|M: 5)
Na 112.
Trauma concerned patient not protect airway if still actively seizing Intubation (11:53 am)
NS examined patient prior to intubation and recommended the following:
1. Platelet transfusion for ASA + Plavix
2. Neurology consultation for AED + Na management
3. EEG
4. Repeat CT head in 6’ or w/ exam change

2008
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Platelets ordered at 1:14 PM.


SICU RN initiate “blood issue request” at 2:19 PM.
MD notified by SICU RN at 3 PM of pupillary irregularity w/ minimal reactivity. NS
resident immediately to bedside and confirmed RN exam.
Patient to STAT CT.

Chief resident to bedside at 3:25 PM.


Exam: 3T. Intubated. No sedation. P: irregular, midposition, non-reative. No corneals. Weak
gag. No extremity mvt to stim.
Inquired regarding platelet transfusion. Trauma said “ordered.” RN: “Hanging now.”

Reversal for Emergency Surgery details


• Vit K antagonists
– IV Vit K
– FFP
• Variable factor concentration
• Large volume required
– Factor VIIa
• $$$
• Fast onset
• Must give with vit K, FFP, PCC
– PCC, K-Centra
• II, IX, X, some VIIa
• 4.6X faster than FFP[1]
– FEIBA (Factor Eight Inhibitor Bypass Activity)
• II, IX, X, VIIa
• NOACs
– DTI
• Praxbind
• VIIa, PCC, FEIBA in case reports
– Factor Xa inhibitors
• None FDA approved (Portola andaxanet alfa mid-2016?)
• FFP alone not effective
• VIIa, PCC (rivaroxaban), FEIBA case reports
– Current recommendation start with Praxbind for dabigatran, PCC for others

2009
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• JH – VKA patient needs emergency craniotomy and EVD


• 55 y/o RH M with ESRD on hemodialysis, mechanical heart
valves x2 with supratherapeutic INR on VKA who awoke
with HA, N/V, LUE incoordination.

• PMH/PSH: as above + R radical nephrectomy 2 ½ yrs prior to


presentation for RCC, PE, CAD s/p stent, C. Diff colitis s/p
colectomy and ileostomy, G tube placement

• Exam:
– AO X3
– EOMI w horizontal nystagmus
– R PF 4/ EHL 3
– L IP 4/ PF 4/ EHL 3
• INR 4.3, APTT 58.1, Platelet 275

2010
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CT Head wo contrast on admission

5.4 cm x 3.8 cm

CT angio H&N was negative

2011
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The Fundamental Questions


• Does the patient need A/C?
• Should we reverse A/C or wait?
– Is a single reversal dose sufficient?
• Will surgery be needed?
• What will we do postop?

• Sequence of events:
– Patient given prothrombin complex concentrate,
Vit K (FFP volume is an issue of course)
– OR for R frontal EVD and SOC and evacuation of
L cerebellar IPH.

2012
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Immediate Postop. CT head wo contrast

• Post op Exam:
– AOX3
– EOMI, horizontal nystagmus
– L dysmetria
– Motor: 5/5 X4

• A/C held postop


• EVD weaned over 7 days
• Pathology: Metastatic RCC
• CT C/A/P: 2 cm L upper lobe nodule

2013
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1 wk postop

• Anticoagulation started on POD#9


(Coumadin/Lovenox bridging strategy)
• Adjuvant therapy: RT/Chemotherapy

2014
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• CD – Lumbar SEA with neuro deficit in VKA


patient
• 62 y/o RH M (who recovered from recent urosepsis, septic
shock). He presented to the ED with fever, LBP and BLE
weakness.
• Exam:
– Bilateral DF/EHL 2/5
– Rectal tone intact
• On Coumadin for DVTs. INR 3.1
• CRP 15.1
• PVR 330

2015
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2016
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• Plan:
– Prothrombin Complex Concentrate
– L4-S1 laminectomy and evacuation of epidural chronic
abscess/phlegmon 3/12/15

• Cultures: negative
• ID: Abx for 6 wks

• Coumadin restarted POD#18 no bridging strategy

What has been our experience with NOAC’s?

Remember – not taking NOAC’s for prosthetic valves…

2017
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NOAC Therapies Compared to Warfarin:


Stroke or Systemic Embolism
Study Drug Better Warfarin Better

Dabigatran 150 mg BID1 HR 0.65 (95% CI, 0.52 to 0.81)

Dabigatran 110 mg BID1 HR 0.90 (95% CI, 0.74 to 1.10)

Rivaroxaban 20 mg QD2 HR 0.88 (95% CI, 0.74 to 1.03)

Apixaban 5 mg BID3 HR 0.79 (95% CI, 0.66 to 0.95)

Edoxaban 60 mg QD4 HR 0.87 (95% CI, 0.73 to 1.04)

HR 1.13 (95% CI, 0.96 to 1.34)


Edoxaban 30 mg QD4

0.5 1 1.5
Hazard Ratio
This chart may not be reproduced for other internal training or for external use.

1. Connolly SJ et al. N Engl J Med. 2010;363:1875-1876.


2. Patel MR et al. N Engl J Med. 2011;365:883-891.
3. Granger CB et al. N Engl J Med. 2011;365:981-992.
4. 84
Giugliano RP et al, for the ENGAGE-AF TIMI 48 Investigators; NEJM; 2013, doi: 10.1056/NEJMoa1310907

2018
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NOAC Therapies Compared to Warfarin:


Major Bleeding
Study Drug Better Warfarin Better

Dabigatran 150 mg BID1 HR 0.93 (95% CI, 0.81 to 1.07)

Dabigatran 110 mg BID1 HR 0.80 (95% CI, 0.70 to 0.93)

Rivaroxaban 20 mg QD2 HR 1.04 (95% CI, 0.90 to 1.20)

Apixaban 5 mg BID3 HR 0.69 (95% CI, 0.60 to 0.80)

Edoxaban 60 mg QD4 HR 0.80 (95% CI, 0.71 to 0.91)

Edoxaban 30 mg QD4 HR 0.47 (95% CI, 0.41 to 0.55)

0.5 1 1.5
Hazard Ratio
This chart may not be reproduced for other internal training or for external use.

1. Connolly SJ et al. N Engl J Med. 2010;363:1875-1876.


2. Patel MR et al. N Engl J Med. 2011;365:883-891.
3. Granger CB et al. N Engl J Med. 2011;365:981-992.
4.85
Giugliano RP et al, for the ENGAGE-AF TIMI 48 Investigators; NEJM; 2013, doi: 10.1056/NEJMoa1310907

NOAC Therapies Compared to Warfarin:


Intracranial Hemorrhage
Study Drug Better Warfarin Better

Dabigatran 150 mg BID1 HR 0.41 (95% CI, 0.28 to 0.60)

Dabigatran 110 mg BID1 HR 0.30 (95% CI, 0.19 to 0.45)

Rivaroxaban 20 mg QD2 HR 0.67(95% CI, 0.47 to 0.93)

Apixaban 5 mg BID3 HR 0.42 (95% CI, 0.30 to 0.58)

Edoxaban 60 mg QD4 HR 0.47 (95% CI, 0.34 to 0.63)

Edoxaban 30 mg QD4 HR 0.30 (95% CI, 0.21 to 0.43)

0 0.5 1.0 1.5 2.0


Hazard Ratio
This chart may not be reproduced for other internal training or for external use.

1. Connolly SJ et al. N Engl J Med. 2010;363:1875-1876.


2. Patel MR et al. N Engl J Med. 2011;365:883-891.
3. Granger CB et al. N Engl J Med. 2011;365:981-992.
4. 86
Giugliano RP et al, for the ENGAGE-AF TIMI 48 Investigators; NEJM; 2013, doi: 10.1056/NEJMoa1310907

2019
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When do we need emergency NOAC


antidotes -1 ?
• Bleeding problems
– ICH on NOAC’s
– SDH or epidural on NOAC’s
– Spinal hemorrhage on NOAC’s
– Stroke requiring EVD on NOAC’s
• Vascular Procedures that can’t wait on NOAC’s
(SAH, EVD)
• NB – shorter half-life means elective or semi-
elective procedures can just wait it out…

What Pharma will want you to do…..

• Give a shot of Praxbind or andaxanet alfa


when you see an ICH on TSOAC’s

• To prevent this……

2020
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When do we need emergency NOAC


antidotes – 2 ?

• Non-bleeding problems
– Trauma EVD on NOAC’s
– Procedures that can’t wait on NOAC’s
• (SAH)
• Critical intracranial lesions (see example next)
• Spinal diseases
• Shunts

2021
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• 59 y/o RH F w PMH pulmonary sarcoidosis on


prednisone, asthma, bronchopulmonary
aspergillosis, candida esophagitis, Afib,
DVT/PE on Xarelto presented with AMS
• Exam:
– AOX3
– L DF 4+ otherwise intact

On admission

2022
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• Internal Medicine recommended postponing


surgery for 24 hours.
• Drift down strategy – no reversal used
• Open surgery done7/9/15 – culture Nocardia
• Cleared to anticoagulate POD#10 – unclear if
actually done

Postop

T1WI T1WI + C

2023
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Reversal of the TSOAC’s


• Best method is just stop if you can
• Currently 4-factor PCC (for Xa)
• rfVIIa, FEIBA
• Hemodialysis – dabigatran
• Activated charcoal – partial for all
• Novel specific antidotes:
– Boehringer Idarucizumab – dabigatran - approved
– Portola andaxanet alfa – Xa
– Perosphere PER 977 – many claims as below
– “Breakthrough” drugs – idarucizumab, andaxanet alfa
– “Fast track” – PER 977
• LMWH, UFH, NOAC’s
• In theory, when approved, this will be easier than warfarin reversal
– Because the antidote is target-specific, unlike VKA
– NB: infusion and/or re-dosing

Target Specific Reversal Agents for


NOACs
• To prevent NOACs from expressing
anticoagulant activity
– BI655075; idarucizumab (Boerhinger Ingelheim)*

– PRT064445; andexanet alfa (Portola Pharmaceuticals)

– Per977; aripazine (Perosphere)

* FDA approved for use October 2015 !!

2024
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Idarucizumab (Praxbind®)

• Humanized monoclonal antibody fragment as antidote


for dabigatran
• Specific for dabigatran reversal
• Renders dabigatran unavailable for binding to thrombin
• Short half-life

2025
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New Reversal Agents for NOACs


in Development

PRT064445 vs Per977
Andexanet (Portola Agonist) Aripazine (Perosphere Agonist)
• Recombinant protein • Synthetic lysine-mimetic
• Large molecule (35,000 D) • Small molecule (1,000 D)
• Specific for FXa • Non-specific effect
• Some enzymatic activity (does it • No enzymatic activity
have procoagulant and other • Able to access clot bound FXa
biological effects?)* • Should not generate antibody
• Able to access clot bound FXa? • Cost of goods may be lower
• May generate antibody
• Cost of goods may be high

*D-dimer increased with use; unclear why.

2026
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How do we best manage anticoagulants in patients who need


elective surgery?

Elective Surgery
• Antiplatelet
– Wait 5-7 days[4]
• Vit K antagonists
– Hold for 5 days
– ~90% of patients will have INR < 1.4 at 5 days (goal
INR 2.0-3.0)[4,5]
• NOACs
– Dabigatran, rivaroxaban (renal clearance)
• 1-2 days if CrCl >50
• 3-5 days if CrCl < 50
• But we can’t measure them….

2027
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Peri-Procedural Management of NOACs

Gregory Connolly • Alex C. Spyropoulos J Thromb Thrombolysis (2013) 36:212–222

NOAC Dosing and Neuraxial Anesthesia


North Shore UHS May 2014
Drug Trade Half-life Duration of Minimum interval Minimum Minimum Restart
name effect between Last dose interval time to
and catheter between restart med
placement or Catheter after
spinal injection placement Catheter
and when removal or
next dose spinal
can be given injection

Apixaban Eliquis 12 hrs 12-24 hrs 48 hrs Avoid while Avoid redose > 5 hrs
catheter in wait > 24h
place after last dose

Dabigatran Pradaxa 12-17 hrs 4 days CrCl > 50 ml/min 3- Avoid while Avoid while 2 hrs
4 days catheter in catheter in
CrCl < 50 ml/min 5-6 lace place
days
Rivaroxaban Xarelto 7-11 hrs 48 hrs 48 hrs Avoid while Avoid while 6-8 hrs
catheter in catheter in 24 hrs if
place place if trauma
redosed 18 or bloody
hrs minimum tap

J. Caprini, MD, NorthShore System

2028
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Antiplatelets with stent/coil/shunt for SAH


84 yr old F on ASA 81 mg with a PMH HTN, CHF, breast cancer s/p left
mastectomy, cataracts. transferred from OSH with spontaneous SAH

Neuro Exam:
Intubated, sedation held
Eyes open to voice
Sticks tongue out to command
Face symmetric
Left pupil 3-2. Right pupil irregular and non-reactive
Follows commands symmetrically x4

R Frontal EVD was placed Cerebral angiogram

Unable to coil without stent due to morphology

2029
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The conundrum: How can we shunt after stent/ASA/Plavix?

2 days later: L frontal VP shunt was placed prophylactically

2 days later: the patient was loaded on ASA 325 and Plavix 300 in a plan for
Stent-assisted coiling

Antiplatelet therapy in the setting of SAH?

Complete occlusion of the aneurysm after Y-stent-assisted coil embolization

Conditions requiring peri-op bridge


• Afib + CHADS2 ≥ 3
• Recent VTE (6 months)
• VTE with severe thrombophilia
• Mechanical heart valve
– Mitral highest risk
– Aortic low risk
• Lupus
– Antiphospholipid Ab+
– Previously on AC
• Anti-thrombin III deficiency

2030
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CHA2DS2VASc Score and Adjusted


Stroke Rate
Adjusted stroke rate according to CHA2DS2-VASc score
CHA2DS2-VASc score Adjusted stroke rate (%/year)
0 0%
1 1.3%
2 2.2%
3 3.2%
4 4.0%
5 6.7%
6 9.8%
7 9.6%
8 6.7%
9 15.2%
Eur Heart J, 2010;31:2369-2429

How to Bridge Therapy


Pre-op Post-op
• No consensus • No consensus
• Low to moderate bleeding risk
– Stop warfarin 5 days prior
• Low to moderate bleeding
– Start UFH/LMWH bridge 36 risk
hours after last dose – Warfarin in first 24 hours
– Last UFH/LMWH dose 6/24 post-op
hours prior to surgery
• ½ dose if LMWH – UFH, LMWH bridge
• High pre-op bleeding risk • High bleeding risk (this is us)
– Wait (closer to op) 48-72 hours
after last warfarin to start – Wait 48-72 hours
bridge (less overlap time) – Can delay by 1-4 weeks
– Same pre-op stop parameters
– ↑ risk of thromboembolism

2031
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Resuming Therapy without Bridge


• Antiplatelet
– Lack of clear data
– Case by case consideration and decision-making required
• Heparin Bolus
– Therapeutic PTT reached faster
– No clear data on hemorrhagic complications
• Progressive or increased maintenance dose
– Response can be altered by nutrition, CYP enzyme-altering meds
• Warfarin
– Loading (2X maintenance) vs maintenance dose after invasive procedures [6]
– Day 5 INR >2.0: 50% vs 13%
– No adverse events
• DTI, Xa inhibitors
– Return to pre-op dose 24-72 hours

DVT Screening
• Symptoms
– Non-specific
– DVT
• swelling/pain most common
– PE
• Dyspnea, tachycardia, tachypnea, pleuritic pain
• Wells score
• D-dimer (reference <250µg/L)
– High NPV (~90%)
• Combined score and D-dimer effective to rule out[7]
• Confirmation
– Compression US
– CT PE or V/Q scan
• Still requires much clinical judgement

2032
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Clinical Screening Tools – Wells criteria

DVT PE
• Active cancer (1) • Signs/symptoms of DVT (3.0)
• Lower extremity immobilization • Alternate diagnosis less likely
(paralysis, paresis, injury) (1) than PE (3.0)
• Bedridden ≥ 3 days in last 12 weeks • HR > 100 (1.5)
(1)
• Immobilization, surgery in last 4
• Local tenderness (1) weeks (1.5)
• Calf swelling (1) • Prior DVT/PE (1.5)
– 3 cm > contralateral
• Hemoptysis (1.0)
• Unilateral pitting edema (1)
• Collateral superficial veins (1) • Cancer (1.0)
• Prior DVT (1) • Probability
– Low < 2.0
• Alternate diagnosis at least as likely
(-2) – Intermediate 2.0 - 6.0
– High > 6.0
• DVT likely if > 2

Prophylaxis recommendations

• Risk stratification based on Caprini score (Chest 2012)


– Caprini score
• Composite score based on overall health (age, malignancy) and comorbidities,
thrombotic risk factors, bleeding risk, mobility

Risk Caprini Score VTE Incidence Prophylaxis


Very Low 0 0.5% Ambulation
Low 1-2 1.5% SCDs
Moderate 3-4 3% SCDs,
LMWH/UFH
High 5+ 6% LMWH/UFH,
SCDs, ± stockings

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IVC Filters
Indications – ACCP Guidelines
• DVT • PE
– Acute proximal lower extremity – Acute PE with AC contra-
– Contra-indication to AC indication
• Bleeding diathesis
• Periop
– Prophylactic
• Severe trauma
• Recurrent VTE
– Including TBI, SCI, long
• VTE through AC therapy bone/pelvic fractures
• Bleeding complications • High risk
• AC therapy complication • Prolonged immobilization
• Fall risk
• Poor compliance
~20-40% still placed without clear indication based on request/preference[8]

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IVC Filter Types


Bard Günther
Tulip

ALN OptEase

IVC Filter Types [9,10]


Permanent Retrievable
• Older patients • Younger patients, temporary
• Short life expectancy requirement
• Can be permanent
• Long-term or life long
– Long-term safety data still
thrombotic risk lacking
• Need to be removed in 3-18
month interval
• 80-90% retrieval success rate
• Rare reports of major
complications
*Class I evidence lacking with heavy reliance on clinical judgment.

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Gentleman with progressive callosal lesion on serial MRI scans


and found to have multiple PE’s identified on CT chest abd
pelvis for metastatic disease – conundrum how to biopsy or treat

2/17/2015

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3/25/2015

5/12/2015

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5/13/2015

IVC Filter 5/15/15


Stereotactic biopsy off A/C 5/18/15 GBM
Started Lovenox 40 QD POD#2
Also started ASA 81 QD cardiac POD#2
Recommended full A/C but went to hospice

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Let’s look at some specific cases:

56 yr old RH F with metastatic renal cell carcinoma


to the lungs and the brain
On Coumadin for LL DVT and PE

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11/2013

The patient was offered SRS for the brain lesions

Few days later: The patient had focal seizure at work

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Patient admitted at outside institution:

3 wks later: patient was seen at Radiation-Oncology Clinic at LUMC

C/O HA

Exam: unremarkable

On Therapeutic Lovenox

Patient sent to ER and admitted to Neurosurgery

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Protamine was used for reversal of Lovenox

HA improved after steroids

Patient was offered SRS

2 days later: Cerebral angiogram was done

Negative

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15 days later: Patient was treated by SRS for the R frontal lesions
2 days later: patient presented to ER with RLE pain and dyspnea

Patient admitted to Oncology and Heparin drip was started for a day
& transitioned to Lovenox

Patient discharged 2 days later

2 days later: HA, L hemiparesis; transferred from OSH

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Patient taken to OR emergently after reversal of Lovenox by protamine

A day later

Family withdraw care and patient was terminally extubated

• AB - Fresh MI with stent/AC and New ICH


• 76 y/o RH M w PMH HTN, HL, Depression. Patient
transferred from OSH with AMS on PPD#1 PCI w LAD stent
on ASA/Prasurgrel/therapeutic Lovenox. CT head showed
L frontal IPH.

• Exam:
– AOX3
– R Hemiparesis
– L full strength

• Troponin I: 7.8

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On Admission

Increase in size within 6 hours: Exam stable

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Stable after size 6 hours from the last scan

I don’t know what was done surgically in this case.

The issues are:

1) If surgery done when do we restart A/C?


2) If no surgery do we allow A/C to continue unabated?
3) Should we do surgery simply to allow A/C restart sooner
even if surgery not needed for the mass itself?

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• JI – Patient had LP on SQ Heparin – went paraplegic


• 61 y/o LH F w h/o Raynaud’s, hypothyroidism who presented
to the hospital with 2 weeks of progressive weakness, tingling
in the fingers and toes with proximal progression. Heparin SQ
5000u BID for DVT prophylaxis
• LL weakness has progressed dramatically after LP
• Exam:
– Bilateral LL 0/5
– DTR 0
– No clonus/diminished rectal tone

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• Patient underwent emergent T10-L1 decompression and


evacuation of anterior epidural hematoma.

• No reversal strategy used.

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• Restarted SQ heparin prophylaxis on POD#3


• Venous duplex negative POD#1

9 months postop

Paraplegic in wheelchair

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• Thoughts on AC for elective surgery


• Natural decay is best
• Would we ever reverse a patient for
convenience reasons for elective surgery?
– Probably not
– Unless a drug holiday would increase their risk and
an ultrashort window is needed – rarely the case –
and if so we would bridge/not reverse
– We’d rather change the surgical date in such cases,
like my friend Mr. EB

• I haven’t shown you any TSOAC bleed cases.


– We haven’t seen much of this problem yet
– Blood levels are better controlled
– Penetration is lower for now
• But we do need reversal agents
– For emergency non-bleed cases
– And we need to know the dosing and
pharmacokinetics

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SH 1247052
77 yo RH F PMH of DVTs and possible PEs on Xarelto admitted to trauma after fall down stairs with CT head
demonstrating a left cerebral intraparenchymal hemorrhage with left posterior subdural and 6mm MLS. GCS 13 on
arrival. 2188 units of Kcentra administered on admission.
• PMH/PSH: Baseline Dementia, DM, Bone Cancer, Thrombocytopenia, PE, Hypothyroidism
• Home Meds: alendronate, ASA81, donepezil, fexofenadine, insulin, hydroxyurea, lantus, synthroid, xarelto,
simvastatin, vesicare
• Allergies: Amoxicillin
• SH: Denies tobacco use, Denies alcohol use, Denies illicits. Lives at home with daughter who is at bedside. Retired
legal secretary.
• FH: noncontributory
• ROS: Negative except for as specified above.
Recs:
- ICU with Q1 hour neuro checks. Contact Neurosurgery for changes in neurologic exam.
- Please avoid hypo-osmolar and dextrose containing fluids as these can exacerbate cerebral edema and ischemia.
- Repeat CT head 6 hours after initial scan. Repeat CT head sooner if there is deterioration in neurologic exam
- Avoid hypotension
- Keppra for seizure ppx x 7 days
- Discussed prognosis and potential intervention with daughter at bedside. Daughter states that the patient would not want
a undergo surgical intervention given the poor prognosis.
- Maintain normal body temperature
- Total fluids 83ml / hr

Cranial Imaging

Initial 6 hours

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Cranial Imaging

18 hours 42 hours

Classes and mechanisms of A/C drugs


How do we shut off for emergencies:
ASA
Clopidrigel
Vitamin K antagonists
NOAC’s
How do we shut off for elective surgery:
ASA
Clopidrigel
Vitamin K antagonists
NOAC’s
Who needs a bridging strategy?
When is it safe to restart A/C postop?
How do we restart A/C:
Bridge
Bolus dose
Maintenance dose rampup
How do we screen and prophylax for DVT and PE?
Who needs an IVC filter? What type?

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Strive for continuous self-improvement!

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Thank you.

• Any questions?

References
1. Gordon JL, Fabian TC, Lee MD, et al. Anticoagulant and antiplatelet medications encountered in
emergency surgery patients: a review of reversal strategies. J Trauma Acute Care Surg.
2013;75(3):475-86.
2. Grandhi R, Harrison G, Voronovich Z, et al. Preinjury warfarin, but not antiplatelet medications,
increases mortality in elderly traumatic brain injury patients. J Trauma Acute Care Surg.
2015;78(3):614-21.
3. Campbell PG, Sen A, Yadla S, et al. Emergency reversal of antiplatelet agents in patients presenting
with an intracranial hemorrhage: a clinical review. World Neurosurg. 2010;74(2-3):279-85.
4. Yorkgitis BK, Ruggia-Check C, Dujon JE. Antiplatelet and anticoagulation medications and the surgical
patient. Am J Surg. 2014;207(1):95-101.
5. Levi M, Eerenberg E, Kamphuisen PW. Bleeding risk and reversal strategies for old and new
anticoagulants and antiplatelet agents. J Thromb Haemost. 2011;9(9):1705-12.
6. Schulman S, Hwang HG, Eikelboom JW, et al. Loading dose vs. maintenance dose of warfarin for
reinitiation after invasive procedures: a randomized trial. J Thromb Haemost. 2014;12(8):1254-9.
7. Owaidah T, AlGhasham N, AlGhamdi S, et al. Evaluation of the usefulness of a D dimer test in
combination with clinical pretest probability score in the prediction and exclusion of Venous
Thromboembolism by medical residents. Thromb J. 2014;12(1):28.
8. Patel G, Panikkath R, Fenire M, et al. Indications and appropriateness of inferior vena cava filter
placement. Am J Med Sci. 2015;349(3):212-6.
9. Berczi V, Bottomley JR, Thomas SM, et al. Long-term retrievability of IVC filters: should we abandon
permanent devices? Cardiovasc Intervent Radiol. 2007;30(5):820-7.
10. Kaufman JA, Kinney TB, Streiff MB, et al. Guidelines for the use of retrievable and convertible vena
cava filters: report from the Society of Interventional Radiology multidisciplinary consensus
conference. Surg Obes Relat Dis. 2006;2(2):200-12.

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References cont.
11. Buesing KL, Mullapudi B, Flowers KA. Deep Venous Thrombosis and Venous Thromboembolism
Prophylaxis. Surg Clin North Am. 2015;95(2):285-300.
12. Majeed A, Meijer K, Larrazabal R, et al. Mortality in vitamin K antagonist-related intracerebral
bleeding treated with plasma or 4-factor prothrombin complex concentrate. Thromb Haemost.
2014;111(2):233-9.
13. Mavrakanas TA, Samer C, Fontana P, et al. Direct oral anticoagulants: efficacy and safety in patient
subgroups. Swiss Med Wkly. 2015;145:w14081.
14. McCoy CC, Lawson JH, Shapiro ML. Management of anticoagulation agents in trauma patients. Clin
Lab Med. 2014;34(3):563-74.
15. Moussouttas M. Challenges and controversies in the medical management of primary and
antithrombotic-related intracerebral hemorrhage. Ther Adv Neurol Disord. 2012;5(1):43-56.
16. Ortel TL. Perioperative management of patients on chronic antithrombotic therapy. Hematology
Am Soc Hematol Educ Program. 2012;2012:529-35.
17. Spyropoulos AC. Bridging therapy and oral anticoagulation: current and future prospects. Curr Opin
Hematol. 2010;17(5):444-9.
18. Suryanarayan D, Schulman S. Potential antidotes for reversal of old and new oral anticoagulants.
Thromb Res. 2014;133 Suppl 2:S158-66.
19. Thiele T, Sümnig A, Hron G, et al. Platelet transfusion for reversal of dual antiplatelet therapy in
patients requiring urgent surgery: a pilot study. J Thromb Haemost. 2012;10(5):968-71.
20. Yasaka M, Okada Y. [Management of intracranial hemorrhage during anticoagulant therapy with
warfarin or novel anticoagulants]. Rinsho Shinkeigaku. 2012;52(11):1113-6.

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