Neurocritical Care - Continuum 2021

OCTOBER 2021
Neurocritical Care
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VOL. 27 NO. 5
Guest Editor: Katharina M. Busl, MD, MS, FAAN
1170 Editor’s Preface

Editor-in-Chief: Steven L. Lewis, MD, FAAN
REVIEW ARTICLES
1172 Management of Cerebral Edema, Brain Compression,

and Intracranial Pressure
Eric M. Liotta, MD, MS
1201 Subarachnoid Hemorrhage

Sherry Hsiang-Yi Chou, MD, MSc, FNCS, FCCM
1246 Intracerebral Hemorrhage

Christa O’Hana S. Nobleza, MD, MSCI
1278 Moderate and Severe Traumatic Brain Injury

Christopher P. Robinson, DO, MS
1301 Posterior Reversible Encephalopathy Syndrome and Reversible

Cerebral Vasoconstriction Syndrome as Syndromes of
Cerebrovascular Dysregulation
Aneesh B. Singhal, MD, FAAN, FANA, FAHA
1321 Seizures, Status Epilepticus, and Continuous EEG in the Intensive

Care Unit
Eric S. Rosenthal, MD
1344 Neuromuscular Disorders in the Intensive Care Unit

DENOTES CONTINUUM
Torrey Boland Birch, MD
AUDIO INTERVIEW
DENOTES VIDEO 1365 Acute Neurologic Manifestations of Respiratory Viruses

CONTENT Michael A. Pizzi, DO, PhD
1382 Neurologic Complications in the Postoperative Neurosurgery

Patient
Aarti Sarwal, MD, FNCS, FAAN, FCCM, RPNI
Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

1405 Neurologic Outcome Prediction in the Intensive Care Unit
Carolina B. Maciel, MD, MSCR
1430 Palliative Care and Shared Decision Making in the Neurocritical

Care Unit
Claire J. Creutzfeldt, MD
1444 Brain Death/Death by Neurologic Criteria Determination

Ariane Lewis, MD; Matthew P. Kirschen, MD, PhD
SELF-ASSESSMENT AND CME
1164 Learning Objectives and Core Competencies
1465 Instructions for Completing Postreading Self-Assessment and CME

Test and Tally Sheet
1467 Postreading Self-Assessment and CME Test
1479 Postreading Self-Assessment and CME Test—Preferred Responses
1492 Update
1494 Errata
1496 Index
List of Abbreviations (Back Cover)

CONTRIBUTORS
Katharina M. Busl, MD, MS, Sherry Hsiang-Yi Chou, MD,

FAAN, MSc, FNCS, FCCM
Guest Editor Associate Professor; Chief,
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Associate Professor, Neurology Division of Neurocritical Care,

and Neurosurgery Chief, Ken and Ruth Davee Department
Division of Neurocritical Care, of Neurology, Northwestern
University of Florida College University Feinberg School of
of Medicine; Medical Director, Medicine, Chicago, Illinois
Neurosciences Intensive Care
Relationship Disclosure: Dr Chou serves on
Unit, University of Florida the board of directors of the Neurocritical
Health Shands Hospital, Care Society, on an advisory board for CSL
Behring, and on the editorial board of Stroke.
Gainesville, Florida Dr Chou receives research/grant support
from the National Institute of Neurological
Relationship Disclosure: Dr Busl serves as a
Diseases and Stroke (R21NS113037) and
consultant for Guidepoint Global, LLC and
the National Institutes of Health/National
Techspert.io Ltd.
Center for Advancing Translational Sciences
(UL1 TR001857).
Unlabeled Use of Products/Investigational
Use Disclosure: Dr Busl reports
no disclosure.
Use Disclosure: Dr Chou reports
no disclosure.
Torrey Boland Birch, MD

Associate Professor, Department Claire J. Creutzfeldt, MD
of Neurological Sciences; Associate Professor of
Director, Neurocritical Care Neurology, University
Fellowship Program, Rush of Washington, Seattle,
University Medical Center, Washington
Chicago, Illinois
Relationship Disclosure: Dr Creutzfeldt
Relationship Disclosure: Dr Birch serves on serves on the board of directors of the
an advisory board for Gift of Hope Organ & International Neuropalliative Care Society
Tissue Donor Network and has served as a and on the editorial board of Neurology and
consultant for the legal firm Rhoades McKee PC. receives research/grant support from the
National Institute of Neurological Disorders
Unlabeled Use of Products/Investigational and Stroke (K23 NS099421).
Use Disclosure: Dr Birch reports
no disclosure. Unlabeled Use of Products/Investigational
Use Disclosure: Dr Creutzfeldt reports no
disclosure.
1166 O C TO B ER 2 0 2 1

Matthew P. Kirschen, MD, PhD Carolina B. Maciel, MD, MSCR
Assistant Professor, University Assistant Professor of Neurology
of Pennsylvania Perelman and Neurosurgery, University
School of Medicine; Associate of Florida, Gainesville,
Director, Pediatric Neurocritical Florida
Care, Children’s Hospital
Relationship Disclosure: Dr Maciel serves
of Philadelphia, Philadelphia, on the editorial boards of Critical Care
Pennsylvania Explorations, eNeurologicalSci, and
Neurocritical Care ON CALL.
Relationship Disclosure: Dr Kirschen has
received research/grant support from the Unlabeled Use of Products/Investigational
Neurocritical Care Society. Use Disclosure: Dr Maciel reports
no disclosure.
Use Disclosure: Dr Kirschen reports no
disclosure.
Christa O’Hana S. Nobleza,
MD, MSCI
Ariane Lewis, MD Associate Professor of
Professor, Departments of Neurology, Division of
Neurology and Neurosurgery; Neurosciences Critical Care,
Director of Neurocritical Care, University of Mississippi,
NYU Langone Medical Center, Jackson, Mississippi
New York, New York Relationship Disclosure: Dr Nobleza reports
no disclosure.
Relationship Disclosure: Dr Lewis serves as a
deputy editor for Neurology and Seminars in Unlabeled Use of Products/Investigational
Neurology. Use Disclosure: Dr Nobleza reports
no disclosure.
Use Disclosure: Dr Lewis reports
no disclosure.
Michael A. Pizzi, DO, PhD
Assistant Professor of
Eric M. Liotta, MD, MS Neurology and Neurosurgery,
Associate Professor of Division of Neurocritical Care,
Neurology and Surgery–Organ University of Florida,
Transplantation, Northwestern Gainesville, Florida
University Feinberg School
Relationship Disclosure: Dr Pizzi reports no
of Medicine, Chicago, Illinois disclosure.
Relationship Disclosure: Dr Liotta serves on Unlabeled Use of Products/Investigational

the editorial board of Critical Care Explorations Use Disclosure: Dr Pizzi reports
and has received personal compensation for no disclosure.
a speaking engagement from Penumbra, Inc
and research/grant support from the National
Institutes of Health (L30 NS098427).

Use Disclosure: Dr Liotta reports
no disclosure.
C O N T I N U U M J O U R N A L .C O M 1167

CONTRIBUTORS (CONTINUED)
Christopher P. Robinson, Aarti Sarwal, MD, FNCS, FAAN,

DO, MS FCCM, RPNI
Assistant Professor of Professor, Department of
Neurology and Neurosurgery, Neurology; Section Chief,
University of Florida College Neurocritical Care; Medical
of Medicine, Director, Neurocritical Care
Gainesville, Florida Unit, Wake Forest School of
Medicine, Winston-Salem,
Relationship Disclosure: Dr Robinson has
provided legal consulting for Thompson North Carolina
and Evangelo PA.
Relationship Disclosure: Dr Sarwal has served
Unlabeled Use of Products/Investigational as a consultant for Lungpacer Medical Inc;
Use Disclosure: Dr Robinson reports has received personal compensation for
no disclosure. speaking engagements for the American
Physical Therapy Association, the Neurocritical
Care Society, and the Society of Critical
Care Medicine; and has received research/
Eric S. Rosenthal, MD grant support from the Clinical Translational
Assistant Professor, Harvard Science Institute (supported by the National
Center for Advancing Translational Sciences)
Medical School; Director, and the National Institutes of Health
Neurosciences Intensive (UL1TR001420).
Care Unit, Massachusetts Unlabeled Use of Products/Investigational
General Hospital, Use Disclosure: Dr Sarwal discusses
Boston, Massachusetts the unlabeled/investigational use of
dexmedetomidine, gabapentinoids,
muscle relaxants, and nerve blocks for
Relationship Disclosure: Dr Rosenthal
postoperative headaches; steroids
serves on scientific advisory boards for
for retraction edema; and intraarterial
Ceribell, Inc and UCB, Inc and has received
verapamil, nicardipine, and nimodipine for
personal compensation for speaking
catheter-induced vasospasm.
engagements from UCB, Inc. Dr Rosenthal
receives research/grant support from
Moberg Analytics, Inc (DoD W81XWH-18-
DMRDP-PTCRA) and the National Institutes
of Health/National Institute of Neurological
Diseases and Stroke (1R01NS117904,
1R01NS113541, 1K23NS105950, U54NS100064,
DoD W81XWH-BAA-15-1).

Use Disclosure: Dr Rosenthal discusses
the unlabeled/investigational use of IV
injection of ketamine, midazolam, and
propofol for the treatment of seizures.
1168 O C TO B ER 2 0 2 1

Aneesh B. Singhal, MD, FAAN,
FANA, FAHA
Associate Professor of
Neurology, Harvard Medical
School; Vice Chair of Neurology,
Director, Comprehensive Stroke
Center, Massachusetts
General Hospital,
Boston, Massachusetts
Relationship Disclosure: Dr Singhal
has served as a consultant for Deck
Therapeutics and Omniox; received
research/grant support from the National
Institutes of Health/National Institute
of Neurological Disorders and Stroke
(R01NS105875, U10NS086729, U01NS095869)
and publishing royalties/honoraria from
MedLink, LLC and UpToDate, Inc; and
provided expert legal testimony on posterior
reversible encephalopathy syndrome
and reversible cerebral vasoconstriction
syndrome. Dr Singhal’s wife is an employee
of Biogen.

Use Disclosure: Dr Singhal discusses
the unlabeled/investigational use of
glucocorticoids, intraarterial vasodilator
therapy, and nimodipine calcium channel
blockers for the treatment of posterior
reversible encephalopathy syndrome
and reversible cerebral vasoconstriction
syndrome.
Self-Assessment and CME Test Writers
Nuri Jacoby, MD Allyson R. Zazulia, MD

Associate Professor of Professor of Neurology and
Neurology, SUNY Downstate Radiology, Associate Dean for
Health Sciences University; Continuing Medical Education,
Attending Neurologist, Washington University,
Maimonides Medical Center, St. Louis, Missouri
Brooklyn, New York
Relationship Disclosure: Dr Zazulia reports
Relationship Disclosure: Dr Jacoby no disclosure.
has received the Faculty Innovation in
Education Award from the American Board Unlabeled Use of Products/Investigational
of Psychiatry and Neurology. Use Disclosure: Dr Zazulia reports
no disclosure.
Use Disclosure: Dr Jacoby reports
no disclosure.
C O N T I N U U M J O U R N A L .C O M 1169

EDITOR’S PREFACE
Critical Conversations
This issue of Continuum is devoted to the diagnosis and management
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of patients with neurologic disorders in the intensive care unit

(ICU), and particularly in the neurocritical care unit. To accomplish
this important task, I am so pleased that Dr Katharina M. Busl
accepted my invitation to serve as guest editor and enlisted such
outstanding expert contributors to guide us through the diagnosis and management
of the large variety of critical neurologic illnesses and the counseling of patients and
families affected by them.
The issue begins with the article by Dr Eric M. Guillain-Barré syndrome, myasthenia gravis, and
Liotta, who updates us on the most current ICU-acquired weakness.
pathophysiologic principals to inform the Dr Michael A. Pizzi next discusses the acute
management of cerebral edema, brain compression, neurologic manifestations of respiratory viruses,
and intracranial pressure. In the next article, with special attention to the neurologic complications
Dr Sherry Hsiang-Yi Chou discusses the of COVID-19, currently a common reason for
epidemiology, clinical presentation, diagnosis, and admission to or comorbidity of patients in an ICU.
current management of patients with subarachnoid Dr Aarti Sarwal then reviews the diagnosis and
hemorrhage. Dr Christa O’Hana S. Nobleza next management of neurologic complications occurring
reviews the diagnosis and management of patients in postoperative neurosurgery patients, including
presenting with nontraumatic intracerebral patients who have undergone craniotomy
hemorrhage. Dr Christopher P. Robinson then procedures, endovascular and other vascular
discusses the current principles of management to procedures, and spinal procedures.
improve the outcome of patients with moderate and The next two articles in the issue delve into the
severe traumatic brain injury. critical humanistic aspects involved in the care of
Dr Aneesh B. Singhal next discusses the patients who are neurocritically ill. First, Dr Carolina
pathophysiology, diagnosis, and management of two B. Maciel discusses the important considerations and
interrelated syndromes of cerebrovascular caveats in neurologic outcome prediction in the ICU.
dysregulation often seen in our hospitalized patients, This is followed by the article by Dr Claire J.
including in the ICU: posterior reversible Creutzfeldt, who reviews the concepts of palliative
encephalopathy syndrome and reversible cerebral care, communication, and shared decision making in
vasoconstriction syndrome. In the article that daily practice in the neurocritical care unit.
follows, Dr Eric S. Rosenthal reviews the diagnosis In the final review article of the issue, Drs Ariane
and acute management of patients with seizures and Lewis and Matthew P. Kirschen discuss the
status epilepticus in the ICU as well as the use of determination of brain death/death by neurologic
continuous EEG in the ICU. Dr Torrey Boland Birch criteria, including discussion of the recently
then reviews the diagnosis and management of published consensus criteria of the World Brain
neuromuscular disorders in the ICU, including Death Project.
1170 OCTOBER 2021

After reading the issue and taking the Postreading This issue is included in a pilot program of
Self-Assessment and CME Test written by Drs Nuri Continuum issues read aloud. Different from
Jacoby and Allyson R. Zazulia and edited by Continuum Audio, these are recordings read
Dr Joseph E. Safdieh, Associate Editor and Associate verbatim from the print articles by Dr Michael
Editor of Self-Assessment and CME, readers may Kentris, a neurologist at the Clinical Neuroscience
earn up to 20 AMA PRA Category 1 CreditsTM toward Institute in Dayton, Ohio. The audio files are
self-assessment CME or, for Canadian participants, a available to all Continuum subscribers in the AAN’s
maximum of 20 hours toward the Self-Assessment Online Learning Center at continpub.com/CME.
Program (Section 3) of the Maintenance of I encourage you to listen and submit the survey with
Certification Program of the Royal College of your feedback on this pilot.
Physicians and Surgeons of Canada. Additional credit We would also like to remind all readers
can be obtained by listening to Continuum Audio of the Continuum mobile experience at
interviews associated with this and other Continuum ContinuumJournal.com. The streamlined website
issues, available to all subscribers, and completing allows you to simply and easily navigate content
tests on the Continuum Audio web platform or mobile from any Continuum issue on your mobile phone
app. Continuum Audio is also accredited by the Royal as well as read full-text articles and access tables
College of Physicians and Surgeons of Canada. and figures wherever you are and whenever you
need them, including at the point of care.
My sincere thank you to Dr. Busl for her
remarkable and devoted guest editorship of this
I am so pleased that Dr Katharina M. issue, for enlisting such outstanding expert authors,
Busl accepted my invitation to serve and for providing such an extensive and inclusive
as guest editor and enlisted such group of topics that will enhance our state-of-the-art
outstanding expert contributors to diagnosis and management of critical neurologic
illness and counseling of patients and their families.
guide us through…the large variety
of critical neurologic illnesses and —STEVEN L. LEWIS, MD, FAAN
EDITOR-IN-CHIEF
the counseling of patients and
families affected by them. © 2021 American Academy of Neurology.
CONTINUUMJOURNAL.COM 1171

REVIEW ARTICLE

Management of Cerebral
C O N T I N UU M A UD I O
I NT E R V I E W A V AI L A B L E
ONLINE
Edema, Brain
Compression, and
Intracranial Pressure
By Eric M. Liotta, MD, MS
ABSTRACT
PURPOSE OF REVIEW: This article reviews the pathophysiology and management
of cerebral edema, brain compression, and elevated intracranial pressure
(ICP). It also provides a brief introduction to the concept of the glymphatic
system and select cellular contributors to cerebral edema.
RECENT FINDINGS: Cerebral edema and brain compression should be treated

in a tiered approach after the patient demonstrates a symptomatic indication
to start treatment. All patients with acute brain injury should be treated
with standard measures to optimize intracranial compliance and minimize
risk of ICP elevation. When ICP monitors are used, therapies should target
CITE AS: maintaining ICP at 22 mm Hg or less. Evidence exists that serial clinical
CONTINUUM (MINNEAP MINN)
2021;27(5, NEUROCRITICAL CARE):
examination and neuroimaging may be a reasonable alternative to ICP
1172–1200. monitoring; however, clinical trials in progress may demonstrate advantages
to advanced monitoring techniques. Early decompressive craniectomy and
Address correspondence to
hypothermia are not neuroprotective in traumatic brain injury and should be
Dr Eric M. Liotta, Northwestern
University Feinberg School of reserved for situations refractory to initial medical interventions. Medical
Medicine, Ken and Ruth Davee therapies that acutely lower plasma osmolality may lead to neurologic
Department of Neurology,
Division of Stroke and
deterioration from osmotic cerebral edema, and patients with acute brain
Neurocritical Care, 625 N injury and renal or liver failure are at elevated risk.
Michigan Ave, Ste 1125, Chicago,
IL 60611, eric.liotta@
SUMMARY: A tiered approach to the management of cerebral edema and
northwestern.edu.
brain compression can reduce secondary brain injury when implemented
RELATIONSHIP DISCLOSURE: according to core physiologic principles. However, our knowledge of the
Dr Liotta serves on the editorial
board of Critical Care
pathophysiology of acute brain injury is incomplete, and the conceptual
Explorations and has received framework underlying decades of clinical management may need to be
personal compensation for a revised in response to currently evolving discoveries regarding the
speaking engagement from
Penumbra, Inc and research/ pathophysiology of acute brain injury.
grant support from the National
Institutes of Health
(L30 NS098427).
INTRODUCTION
T
UNLABELED USE OF he management of cerebral edema, elevated intracranial pressure
PRODUCTS/INVESTIGATIONAL
USE DISCLOSURE:
(ICP), and brain compression from space-occupying lesions is central
Dr Liotta reports no disclosure. to the care of patients with acute brain injury. Although these entities
often coexist, they are distinct, and differences in injury mechanism
© 2021 American Academy and clinical presentation refine the management. Historically,
of Neurology. management strategies have been rooted in a few core physiologic principles, as
1172 OCTOBER 2021

discussed later in the article: the Monro-Kellie doctrine and intracranial KEY POINTS
compliance, the relationship between ICP and cerebral perfusion pressure
● Cerebral edema is a major
(CPP), cerebral autoregulation and the coupling of cerebral blood volume to cause of secondary brain
cerebral metabolism, and the movement of water between tissues driven by injury through compression
osmotic gradients. Moreover, a rather limited number of therapeutic of brain structures,
interventions have been based on these physiologic principles; hyperosmolar distortion and herniation of
brain tissue, and
therapy and supportive medical care—along with selective use of analgesics, compromise of cerebral
anesthetics, CSF diversion, and occasional surgical decompression or induced blood flow through
hypothermia—remain the core interventions for cerebral edema, elevated ICP, increased intracranial
and brain compression. These core interventions are rather blunt instruments in pressure.
that they do not distinguish between or specifically target the multitude of ● Clinicians should be
cellular mechanisms underlying cerebral edema formation, and they are aware of four forms of
principally used after cerebral edema or elevated ICP has already developed. cerebral edema: vasogenic,
However, the management of cerebral edema may be at a turning point. Recent cytotoxic, hydrostatic, and
osmotic. Vasogenic and
discoveries concerning the anatomy of the brain and the cellular mechanisms
cytotoxic edema are the
dictating cerebral fluid movement may result in future therapies that target most frequently
specific cerebral edema mechanisms. This article reviews the current concepts encountered.
important for the clinical understanding and management of cerebral edema,
elevated ICP, and brain compression. The article concludes by introducing the ● Vasogenic edema results
from dysfunction of the
recently discovered glymphatic system and select cellular mechanisms that may blood-brain barrier, the
come to change the conceptual framework and interventions by which cerebral physical and metabolic
edema and ICP are clinically managed. barrier between the brain
and the systemic circulation.
It is associated with brain
CEREBRAL EDEMA tumors, cerebral abscesses,
The term cerebral edema essentially denotes an increase in brain water content and posterior reversible
that leads to brain volume expansion. Cerebral edema may occur either focally or encephalopathy syndrome.
diffusely and may be encountered after any type of primary injury to the brain as
well as in some systemic medical conditions, such as acute or acute-on-chronic
liver failure.1,2 Identifying cerebral edema is clinically important because it is a
major cause of secondary brain injury (following a variety of primary insults)
through compression of brain structures, distortion and herniation of brain
tissue, and compromise of cerebral blood flow through increased ICP.3 Clinically,
cerebral edema is indirectly measured by its appearance on imaging studies (such
as low attenuation on CT, increased T2 signal on MRI, or tissue shifts) or, when
cerebral edema is sufficiently advanced, by the development of increased ICP
when invasive monitoring is available. The qualitative identification of cerebral
edema and delineation of its pattern on imaging studies may also be useful when
a differential diagnosis for acute neurologic dysfunction is not immediately
apparent from history and physical examination (CASE 1-1). Furthermore,
identifying the dominant type of cerebral edema based on neuroimaging pattern
and injury mechanism can guide initial treatment strategies to minimize
secondary brain injury. Clinicians should be aware of four forms of cerebral
edema: vasogenic, cytotoxic, hydrostatic, and osmotic. Vasogenic and cytotoxic
edema are the most frequently encountered, and their mechanisms have received
the most attention.2
Vasogenic edema (FIGURE 1-2) results from dysfunction of the blood-brain
barrier, the physical and metabolic barrier between the brain and the systemic
circulation that is formed by endothelial cells, the tight junctions between
endothelial cells, astrocytes, and pericytes. Blood-brain barrier dysfunction
results in extravasation of ions and macromolecules from the plasma; these ions

CEREBRAL EDEMA, BRAIN COMPRESSION, AND INTRACRANIAL PRESSURE
CASE 1-1 A 58-year-old woman presented to the emergency department comatose

after being found unresponsive by her neighbors, who were unable to
provide additional history. Her initial systolic blood pressures were
140 mm Hg to 150 mm Hg. A head CT demonstrated hypoattenuation of the
bilateral posterior white matter in a pattern consistent with severe
posterior reversible encephalopathy syndrome (PRES) (FIGURE 1-1A).4
Subsequent T2-weighted/fluid-attenuated inversion recovery (FLAIR) MRI
demonstrated hyperintense signal consistent with vasogenic edema in the
posterior white matter and involvement of the brainstem (FIGURE 1-1B).
Diffusion-weighted imaging (DWI) MRI also revealed hyperintensity
(FIGURE 1-1C) with corresponding hypointensity on apparent diffusion
coefficient MRI (FIGURE 1-1D), suggesting cytotoxic edema involving the left
parietal, occipital, and medial temporal cortex. Three hours after
presentation, the patient developed sustained systolic hypertension to
220 mm Hg and required nicardipine infusion for blood pressure control.
EEG confirmed nonconvulsive status epilepticus with seizures arising from
the left medial temporal lobe. She improved neurologically after treatment
of status epilepticus and intermittent severe hypertension.
FIGURE 1-1
Imaging of the patient in CASE 1-1. A, Axial head CT shows hypoattenuation of the bilateral
posterior white matter in a pattern consistent with posterior reversible encephalopathy
syndrome (PRES). B, Axial fluid attenuated inversion recovery (FLAIR) MRI shows
hyperintense signal consistent with vasogenic edema in the posterior white matter and
involvement of the brainstem. C, Axial diffusion-weighted MRI shows hyperintensity,
suggesting cytotoxic edema involving the left parietal, occipital, and medial temporal
cortex that is confirmed by axial apparent diffusion coefficient MRI hypointensity (D).
COMMENT This case demonstrates that cerebral edema patterns can be useful in
directing the initial management of patients with undifferentiated coma.
Bilateral posterior-predominant vasogenic edema raised suspicion for
PRES, even in the initial absence of significant hypertension. Although
empiric seizure management and EEG were initiated in response to the
patient’s CT scan, the presence of cortical DWI hyperintensity could have
alerted the clinician to the possibility of cytotoxic edema from status
epilepticus.
1174 OCTOBER 2021

FIGURE 1-2
A 30-year-old man presented with severe headaches and left-sided face, arm, and leg
numbness and was found to have a right hemispheric grade 3 anaplastic astrocytoma. Axial
noncontrast head CT (A) and fluid-attenuated inversion recovery (FLAIR) MRI (B) show the
typical pattern of vasogenic edema expected with a brain tumor. Signal abnormality extends
along the white matter and appears to respect the boundary with the gray matter, creating a
fingerlike appearance. The tumor can be appreciated encased by surrounding edema. An
element of brain compression in the form of right lateral ventricle compression is seen.
and macromolecules generate an osmotic pressure, which, combined with

vascular hydrostatic pressure, results in net movement of water into the brain.2
The resulting water expands the extracellular space and collects preferentially in
the subcortical white matter, giving an appearance of hypoattenuated white
matter on CT and hyperintense white matter on T2-weighted MRI without
diffusion restriction and sparing of the cortical and deep gray matter. Vasogenic
edema is classically associated with brain tumors, cerebral abscesses, and
posterior reversible encephalopathy syndrome (PRES). An important advance in
the understanding of vasogenic edema was the observation that frank
blood-brain barrier disruption visible on microscopy is not necessary. Abnormal
transcellular transport across endothelial cells and degradation of endothelial
tight junctions by proteolytic enzymes, such as matrix metalloproteinase-9, can
contribute to vasogenic edema by the passage of ions, proteins, and water from
the plasma despite a blood-brain barrier that appears intact on microscopy.1,2
Cytotoxic edema (FIGURE 1-3) results from derangements in cellular
metabolism with resulting alterations in ionic gradients and movement of water
into the brain tissue. It is important to note that this article and most clinicians
use the term cytotoxic edema to refer to brain swelling that results from failure of
cellular metabolism; basic scientists use the term differently. When brain cells
die, they lose the ability to maintain normal ionic gradients; as a result, ions and
water move from the extracellular space to the intracellular space and the brain
cells expand. This process, called true cytotoxic cellular edema by basic scientists, is
a redistribution of fluid without a net increase in tissue volume. As a result of this
process, the extracellular space develops an ion deficiency. If the extracellular

space is then exposed to a fluid source,

such as vascular blood flow or CSF,2,5 ions
and water can flow down an ionic gradient
from the fluid source to the extracellular
space; this results in expansion of the
extracellular space that, combined with
the previous fluid redistribution, causes
a net increase in brain tissue volume
through the process of ionic edema. The
clinical term cytotoxic edema refers to the
combined process of true cytotoxic
cellular edema and ionic edema resulting
in tissue swelling. These semantics are
useful to remind clinicians that ultimately
FIGURE 1-3 all brain swelling requires the brain to be
A 66-year-old man was admitted to the perfused with an external source of new
medical floor for pulmonary symptoms fluid. Since cytotoxic edema affects both
related to COVID-19. During the white and gray matter, cytotoxic edema
hospitalization, he developed
new-onset atrial fibrillation. The next appears as CT hypoattenuation of both
day, he experienced acute-onset left white and gray matter; on MRI, T2
hemiparesis and was found to have hyperintensity affecting both white and
acute occlusion of the right middle gray matter is seen, accompanied by
cerebral artery. Axial noncontrast head
CT obtained 5 hours after neurologic
hyperintensity on diffusion-weighted
symptom onset shows subtle imaging (DWI), representing true
hypoattenuation involving the white cytotoxic cellular edema. Cytotoxic edema
and gray matter of the right middle is classically associated with ischemic
cerebral artery territory consistent with
early cytotoxic edema.
stroke and acute liver failure. Additionally,
cytotoxic edema predominates in
hypoxic-ischemic brain injury, and
traumatic brain injury (TBI) and intracerebral hemorrhage include components
of both cytotoxic and vasogenic cerebral edema. Although cellular death often
occurs, cellular metabolic stress that impairs normal ionic homeostasis—as can
be seen with prolonged seizures (CASE 1-1), liver failure, or various toxic
exposures—is sufficient to result in cytotoxic edema.
Although it may be clinically useful to identify whether cytotoxic or vasogenic
edema predominates and attribute each to particular diseases, these distinctions
are somewhat artificial. Vasogenic edema may compromise local blood flow or
increase the brain’s exposure to toxic substances that result in cytotoxic edema.
Meanwhile, cytotoxic processes can predispose to vasogenic edema by involving
the cells composing the blood-brain barrier or by precipitating inflammation-
mediated blood-brain barrier injury. Although TBI, ischemic stroke, and liver
failure were each historically believed to result in only one form of edema,
modern literature demonstrates that each represents a mixture of vasogenic and
cytotoxic edema.1,2,6
Hydrostatic cerebral edema results from displacement of CSF from the
ventricular space into the brain interstitium; this occurs as a consequence of
hydrocephalus when increased hydrostatic pressure pushes CSF through the
ependymal lining. Radiographically, hydrostatic cerebral edema appears as CT
hypoattenuation beneath the ependymal surface and tends to concentrate at the
horns of the ventricles. Some, particularly older, literature will also use the term
1176 OCTOBER 2021

hydrostatic cerebral edema to refer to edema in the context of severe hypertension; KEY POINTS
this is likely a conceptual oversimplification of hydrostatic pressure and does not
● Cytotoxic edema results
account for the blood-brain barrier injury and cytotoxic injury that occurs with from derangements in
severe acute hypertension. Osmotic cerebral edema occurs when an osmotic cellular metabolism with
gradient develops between the brain tissue and serum that favors entry of water resulting alterations in ionic
into the brain. This form of cerebral edema may be underrecognized clinically, in gradients and movement of
water into the brain tissue.
part because it is called by a variety of other names, such as rebound edema (after
Cytotoxic edema is
rapid weaning of hyperosmolar therapy), water intoxication, or dialysis classically associated with
disequilibrium syndrome (after renal replacement therapy, particularly in ischemic stroke and acute
patients with brain injuries).7-9 CASE 1-2 demonstrates the development of acute liver failure.
osmotic cerebral edema as a contributor to neurologic deterioration in a patient
● Hydrostatic cerebral
who was critically ill with severe liver failure.8 Clinically significant osmotic edema results from
cerebral edema most often occurs in the setting of concurrent vasogenic or displacement of CSF from
cytotoxic cerebral edema because blood-brain barrier and astrocyte dysfunction the ventricular space into
result in reduced ability to regulate brain volume in the face of an osmotic the brain interstitium; this
occurs as a consequence of
challenge.1 Osmotic cerebral edema may be difficult to appreciate on hydrocephalus when
neuroimaging because the volume increase is distributed across the entire brain.8 hydrostatic pressure pushes
At this time, quantitative neuroimaging assessments of cerebral edema are not CSF through the ependymal
widely available clinically. However, research approaches are available to lining.
quantify cerebral edema using MRI and CT imaging techniques.1,8,10
● Osmotic cerebral edema
occurs when an acute
INTRACRANIAL PRESSURE, CEREBRAL PERFUSION, AND osmotic gradient develops
BRAIN COMPRESSION between the brain and
serum favoring water entry
Conceptually, the intracranial compartment can be thought of as a rigid box
into the brain. Patients with
(the skull) with a balloon attached to the side, which represents the anatomic brain injuries receiving
reservoir where CSF and blood can be displaced from the skull. The rigid box medical interventions that
has a fixed volume and contains three compartments: vascular blood, brain reduce serum osmolality,
tissue, and CSF. This foundational concept is known as the Monro-Kellie such as dialysis, are at
particular risk for acute
doctrine. Pathologic processes result in an increased volume of these deterioration from this
compartments or introduce space-occupying lesions that compress the other edema.
compartments (eg, a hematoma). As material is introduced into the box, some
of the box’s contents can be displaced to the balloon, which acts as a pressure ● Rapid identification and
treatment of osmotic
buffer. At first, when the balloon is empty, the addition of material to the cerebral edema by returning
system results in only small increases in pressure. However, as the balloon serum osmolality to prior
becomes filled with displaced material, the same increase in volume results in levels may be lifesaving.
progressively larger pressure increases. When the balloon is full, it takes on a
● The intracranial
rigid nature and additional volume in the system results in exponential
compartment can be
pressure increases. The relationship between volume and pressure thought of as a rigid box with
represented by progressively filling the balloon in this scenario describes the a balloon attached to the
property of intracranial compliance. CSF, being lower in pressure than venous side. The balloon buffers
or arterial blood, functions as the primary buffer responsible for intracranial volume added to the box
and minimizes pressure
compliance; CSF can be displaced from the skull to the spinal cisterns and increases until the balloon is
cranial nerve sheaths, which function as an intracranial compliance reserve to full. The balloon represents
buffer ICP. To a lesser extent, compression of venous and then arterial intracranial compliance.
structures with displacement of blood from the skull provides an additional
compliance reserve; incidentally, displacement of arterial blood risks
exacerbating brain injury through cerebral ischemia. Once intracranial
compliance is exhausted, ICP increases exponentially. In patients with greater
degrees of cerebral atrophy, as might occur with advanced age or chronic
diseases such as cirrhosis, the ratio of CSF to brain is larger and, therefore, is a

greater buffer against elevated ICP. The clinician should appreciate that
monitoring ICP is insensitive to detecting cerebral edema (and other
space-occupying pathology) before it progresses to severe levels because of
intracranial compliance (FIGURE 1-5); failure to recognize this is, in part,
responsible for the historical misperception that patients with hepatic
encephalopathy from acute-on-chronic liver failure do not manifest cerebral
edema.1 It remains unknown whether cerebral edema that does not progress to
elevated ICP (so-called low-grade cerebral edema) is benign. However, data
CASE 1-2 A 26-year-old man presented with fulminant liver failure from
acetaminophen overdose. He developed hyperammonemia to
264 μmol/L, progressive encephalopathy, and cerebral edema on serial
neuroimaging. He was started on hypertonic saline and was initiated on
continuous renal replacement therapy with close serum osmolality
monitoring to reduce ammonia levels while maintaining steady serum
osmolality. The patient received a liver transplant on hospital day 6. Brain
CT on hospital day 7 demonstrated improving cerebral edema
(FIGURE 1-4A). On hospital day 8, the transplant abdominal incision could
not be closed because of fluid overload. To address this, the patient was
treated with a session of hemodialysis using sodium modeling (sodium
concentration of dialysate decreases during hemodialysis session) rather
than a constant isoosmolar sodium concentration dialysate. Three hours
into the hemodialysis session, the patient was noted to have fixed dilated
pupils and no longer withdrew from noxious stimulation. His serum
osmolality had decreased from 354 mOsm/kg to 300 mOsm/kg. Emergent
CT demonstrated worsened cerebral edema with brain volume increase
of 35 mL (FIGURE 1-4B). The patient received 180 mL of 23.4% hypertonic
saline over 90 minutes, with increase in serum osmolality to 348 mOsm/kg,
after which his pupils were again briskly reactive and he withdrew from
noxious stimulation. Repeat CT (FIGURE 1-4C) demonstrated brain volume
reduction of 40 mL compared to the previous CT (FIGURE 1-4B). The patient
was discharged to acute rehabilitation 2 weeks later. Six months later, the
patient was living independently at home and working part-time.
1178 OCTOBER 2021

from stroke and TBI suggest that cerebral edema, independent of elevated ICP, is
a mechanism of secondary brain injury.11-13
In addition to clinical intuition from neuroimaging and neurologic
examination, the status of intracranial compliance can be qualitatively assessed
from the waveform recorded on invasive ICP monitors. With each heartbeat, a
small bolus of arterial volume enters the skull; this process results in a
characteristic waveform on the ICP monitor. The normal waveform has three
peaks: P1 (cardiac systole), P2 (displaced intracranial contents meeting resistance
FIGURE 1-4
Imaging of the patient in CASE 1-2. Axial noncontrast head CT shows improving cerebral edema
following liver transplantation (A), emergent CT imaging obtained after an acute neurologic
deterioration the following day demonstrates worsened cerebral edema compared to the
prior CT (B) and improved cerebral edema on repeat imaging after treatment with hypertonic
saline (C). All three CT scans are shown with the same center: 42 width, 55 window. The
greater cerebral edema of panel B can be visually appreciated by the brain’s darker
(hypodense) appearance.
Acute onset of cerebral edema and clinical brain herniation may occur in the COMMENT
setting of hemodialysis and preexisting brain injury. Although this scenario
has been termed dialysis disequilibrium syndrome, this case illustrates an
example of acute osmotic cerebral edema related to a rapid reduction in
serum osmolality relative to brain osmolality. In addition to dialysis, medical
interventions such as infusion of large volumes of hypotonic fluids and rapid
weaning of osmotic agents may also lead to osmotic cerebral edema,
particularly in patients with concurrent acute brain injury and other forms of
cerebral edema. Measurement of serum osmolality is prudent in the patient
with brain injuries with renal failure, liver failure, or shock because serum
osmolality may be unexpectedly elevated. Hypertonic saline may be
administered in these scenarios to ensure that reductions in serum
osmolality are performed in a gradual manner and with close clinical
monitoring. This case illustrates that severe neurologic deterioration from
osmotic cerebral edema can be reversed with good patient outcome by
rapidly recognizing the deterioration and acting to return serum osmolality to
previous levels.

FIGURE 1-5
Intracranial compliance curves demonstrating the relationship between intracranial volume
and pressure changes and compensatory mechanisms in patients with normal baseline brain
volume and patients with baseline atrophy because of advanced age or chronic illness.
CSF = cerebrospinal fluid.
Reprinted with permission from Liotta EM, Kimberly WT, Neurosci Lett.1 © 2020 Elsevier BV.
from the structures that form the compliance reserve), and P3 (dicrotic wave
from aortic valve closure). Normally, P1 is greater than P2, which is greater than
P3. As compliance is initially compromised, P2 progressively becomes greater
than P1. When compliance is more severely compromised, P1 and P2 begin to
merge (FIGURE 1-6). These waveform changes can occur before the
demonstration of ICP values that exceed the normal range (typical normal is
7 mm Hg to 15 mm Hg, with an upper limit of 20 mm Hg) and should suggest that
elevated ICP may be detected in the near future. This waveform morphology
should not be confused with ICP Lundberg waves. Lundberg waves (FIGURE 1-7)
refer to intermittent nonsustained increases in ICP that are apparent when
continuous ICP measurement is trended over minutes to hours.14,15 Lundberg C
waves are characterized by an ICP up to 25 mm Hg and pressure oscillations at 4
to 8 times per minute; Lundberg C waves may be seen in normal physiology and
are likely due to cardiac and respiratory cycles. Lundberg B waves oscillate at 0.5
to 2 waves per minute over up to 5 minutes, and ICP is increased 20 mm Hg to
30 mm Hg above baseline; these waves are likely due to vasomotor instability
when cerebral perfusion is compromised. Lundberg B waves are a sign of
impaired intracranial compliance. Lundberg A waves (called plateau waves) are
always pathologic and reflect critically exhausted intracranial compliance with
elevated risk for brain herniation and death. Lundberg A waves are characterized
by rapid increases in ICP from baseline to 50 mm Hg to 80 mm Hg; they typically
last 5 to 20 minutes but may persist over hours. Lundberg A waves are believed to
1180 OCTOBER 2021

KEY POINTS
● CSF functions as the

primary buffer responsible
for intracranial compliance.
CSF can be displaced to the
spinal cisterns and cranial
nerve sheaths. Once
intracranial compliance is
exhausted, intracranial
pressure increases
exponentially.
● Lundberg A waves reflect

critically exhausted
intracranial compliance with
elevated risk for brain
herniation. Lundberg A
waves are characterized by
rapid increases in
FIGURE 1-6 intracranial pressure to
Intracranial pressure waveforms associated with individual heartbeats. Normal waveform 50 mm Hg to 80 mm Hg
shows P1 exceeds P2, which exceeds P3. With compromised intracranial compliance P2 lasting 5 to 20 minutes.
exceeds P1. With critically low compliance, P1 and P2 merge.
FIGURE 1-7
Lundberg intracranial pressure waves. C waves may be seen in normal physiology and are
likely related to cardiac and respiratory cycles, and intracranial pressure (ICP) may increase
to 25 mm Hg. B waves likely occur because of impaired cerebral perfusion and suggest
impaired intracranial compliance. B waves occur as 0.5 to 2 waves per minute with ICP
increasing 20 mm Hg to 30 mm Hg above baseline. A waves (also known as plateau waves) are
rapid increases in ICP to 50 mm Hg to 80 mm Hg that typically last 5 to 20 minutes. A waves
reflect critically exhausted intracranial compliance.

occur from cycles of cerebral vasodilation precipitated by episodes of reduced

cerebral perfusion in the setting of greatly impaired compliance.15 Although the
occurrence of Lundberg A waves should trigger a rapid reassessment of available
interventions, the transient self-resolving nature of Lundberg B and C waves
suggests that not every ICP increase necessitates specific intervention. Treatment
of every ICP increase over 20 mm Hg, however brief, would result in
overtreatment and risk exposing the patient to treatment side effects with little
benefit. The Brain Trauma Foundation guidelines recommend an ICP treatment
threshold of 22 mm Hg, given that higher values are associated with increased
mortality. Generally, ICP treatment algorithms reserve interventions for ICP
above threshold for at least 10 minutes to avoid treating elevations that might
resolve spontaneously.16 The 22 mm Hg threshold is based on a population-level
association between ICP above this threshold and mortality. An evolving
literature suggests the possibility that optimal ICP thresholds may vary between
patient subgroups, different time points after acute brain injury, and even within
individual patients.17
Cerebral perfusion pressure (CPP) is a concept closely related to ICP. CPP is
the pressure supplying arterial perfusion to the brain and is calculated by
subtracting the ICP from the mean arterial blood pressure. Avoiding low CPP
reduces the risk of secondary ischemic brain injury; however, the CPP
calculation assumes that the pressure resisting vascular perfusion is equivalent
throughout the cranium, which may not be the case in areas of focal brain
compression. A long-standing therapeutic recommendation for CPP has been
50 mm Hg to 70 mm Hg, the normal CPP range.18 However, the latest Brain
Trauma Foundation guidelines recommended revising the CPP goal to 60 mm
Hg to 70 mm Hg.16 Although data from prior randomized studies failed to
demonstrate a neurologic outcome difference between CPP thresholds of 50 mm
Hg versus 70 mm Hg,19 subsequent observational data suggested that patients
who had any time with CPP below 50 mm Hg experienced a lower rate of survival
than patients who had no time with CPP below 60 mm Hg.16,20 Therefore, a
wider margin against CPP below 50 mm Hg seems reasonable. These guidelines
continue to advise against aggressive attempts to achieve CPP greater than
70 mm Hg, which has been associated with greater risk for acute respiratory
distress syndrome (ARDS).16 Numerous studies in the literature have taken
opposing positions regarding whether ICP- or CPP-focused treatment algorithms
are superior. No definitive study has supported one approach, and consensus
guidelines recommend clinicians attend to both ICP and CPP goals.16,18
The normal brain is capable of regulating vasoconstriction and vasodilation to
maintain a constant cerebral blood flow over a mean arterial blood pressure of
about 50 mm Hg to 150 mm Hg through cerebral autoregulation.21 Beyond the
blood pressure bounds of cerebral autoregulation, cerebral blood flow becomes a
passive pressure-dependent process. In the acute brain-injured state, it is possible
for the normal physiologic responses of cerebral autoregulation to exacerbate
injury. For example, during cerebral hypoperfusion, the normal physiologic
response is cerebral vasodilation; however, in a patient with compromised
intracranial compliance, the increased blood volume from vasodilation may lead
to greater ICP elevation with subsequent decrease in CPP, which actually
worsens cerebral ischemia. In this scenario, using vasopressors to augment CPP
may allow vasoconstriction that reduces cerebral blood volume and leads to
improved ICP and cerebral perfusion. However, excessive CPP could lead to
1182 OCTOBER 2021

exacerbation of vasogenic edema in areas of blood-brain barrier dysfunction, KEY POINTS
which would increase brain volume and worsen ICP. Because of variable
● The Brain Trauma
impairment of both global and regional cerebral autoregulation after acute brain Foundation recommends
injury,21 the relationship between ICP, CPP, and cerebral blood volume can be treatment for intracranial
complex and difficult to predict. These scenarios often require therapeutic pressure greater than 22 mm
trials to evaluate response. Although approaches exist to assess the integrity of Hg. Intracranial pressure
should be elevated for
cerebral autoregulation and estimate individualized optimal CPP goals,21 these
about 10 minutes before
techniques remain unproven at a level to justify widespread use. treatment to avoid
Currently the only way to determine ICP and CPP is through invasive overtreatment of
measurement. The two most common ICP monitors are intraparenchymal spontaneously resolving
intracranial pressure
sensors and external ventricular drains, (EVDs), which have the added benefit of
elevations.
being able to therapeutically drain CSF and are considered the gold standard ICP
monitor. Noninvasive techniques, such as optic nerve sheath ultrasound and ● Cerebral perfusion
transcranial Doppler ultrasound, have been investigated as means of estimating pressure is calculated by
ICP.22,23 Although they may have utility in some scenarios, the confidence subtracting the intracranial
pressure from the mean
intervals for ICP estimates from noninvasive techniques remain too wide to arterial blood pressure.
substitute for invasive measurement.22,23 Currently, ICP monitoring is not The latest Brain Trauma
routine in the management of hemorrhagic or ischemic stroke, brain tumors, or Foundation guidelines
meningitis, although intracerebral hemorrhage guidelines suggest ICP recommended revising
the cerebral perfusion
monitoring might be considered in patients who are comatose, those with pressure goal to 60 mm Hg
evidence of herniation, or those with significant intraventricular hemorrhage or to 70 mm Hg.
hydrocephalus.18 There is a trend away from the use of ICP monitors in patients
with acute liver failure because of concerns about hemorrhagic complications ● Currently, intracranial
pressure monitoring is not
from monitor placement, observational data demonstrating no overall survival
routine in the management
benefit, and an association with worse outcome in some subgroups.8,24,25 of hemorrhagic or ischemic
However, ICP monitoring is routinely used in TBI. The Brain Trauma stroke, brain tumors, or
Foundation guidelines recommend ICP monitoring for patients who either have meningitis but may be
abnormal CT scans of the head and are comatose after resuscitation or have considered in select cases
of coma, herniation, or
normal CT scans with two or more of the following: age older than 40 years, hydrocephalus occurring in
motor posturing, or systolic blood pressure below 90 mm Hg. This these diseases.
recommendation is based on a high incidence of elevated ICP in patients meeting
these criteria (about 60%) rather than a proven mortality or neurologic outcome ● Intracranial pressure
monitoring should be
benefit from ICP monitoring.16,26 In fact, the highest level evidence in this area, considered in patients who
the BEST:TRIP (Benchmark Evidence from South American Trials: Treatment of are comatose after
Intracranial Pressure) trial, demonstrated no mortality, functional, or cognitive traumatic brain injury with
outcome difference between severe TBI management based on ICP monitoring abnormal CT scans of the
head or normal CT scans
compared to clinical assessments from physical examination and
with two or more of the
neuroimaging.16,27 The clinical assessment group did have a significantly longer following: age older than
interval during which they received brain-specific treatments (median 4.8 days 40 years, motor posturing,
compared to 3.4 days), although this benefit required invasive monitor or systolic blood pressure
below 90 mm Hg.
placement and ICP monitors carry a small but non-negligible risk of infection or
hemorrhage.27,28 The BEST:TRIP trial stirred controversy in the neurocritical
care community because it was received by many in a polarized fashion: some
cited it as a justification to abandon ICP monitoring all together, whereas others
disregarded the results as having no generalizability outside the specific context
in which the trial was conducted. In this author’s opinion, an assessment of the
BEST:TRIP trial that balances these viewpoints may be of greater utility in
guiding the clinical application of ICP monitoring and future avenues of research.
First, BEST:TRIP should not be used as a reason to abandon ICP monitoring
given the large body of literature supporting clinical utility. On the other

TABLE 1-1 Brain Herniation Syndromesa,b
Herniation
syndrome Mechanism Notable clinical findings
Falcine Supratentorial lesion; medial displacement of Leg weakness; because of reduced likelihood of
the cerebral hemisphere against the falx; compression or displacement of the diencephalon,
cingulate gyrus displaced under the falx midbrain, or brainstem, mental status is less
affected than in other herniation syndromes
Lateral Supratentorial lesion; focal lesion that laterally Depressed consciousness proportionate to degree
diencephalon displaces the diencephalon of displacement: 3-5 mm drowsy, 6-8 mm stupor,
displacement ≥9 mm coma; vertical gaze palsy if the dorsal
midbrain is compressed; pituitary stalk avulsion with
diabetes insipidus in severe casesc
Uncal transtentorial Supratentorial lesion; unilateral medial temporal Enlarged sluggish pupil is an early sign, followed by
lobe (uncus) laterally displaced to compress ipsilateral fixed and dilated pupil, progressive
ipsilateral cranial nerve III; midbrain directly cranial nerve III palsy, contralateral and/or
compressed or laterally displaced ipsilateral hemiplegia, flexor or extensor posturing,
and stupor/coma; ipsilateral hemiplegia is from
midbrain displacement with contralateral cerebral
peduncle compression against the Kernohan
tentorial notch
Central-descending Supratentorial lesion; bilateral medial temporal Bilateral pupil dilation followed by cranial nerve III
transtentorial lobe (uncus) laterally displaced or caudal palsies if due to bilateral uncal herniation; if due to
displacement of supratentorium against direct diencephalon compression, small minimally
diencephalon reactive pupils with roving eye movements giving
way to midposition pupils; flexor followed by
extensor posturing and stupor/coma
Rostrocaudal Supratentorial lesion; downward displacement Signs of brainstem infarction secondary to shearing
deterioration of the midbrain and pons of medial perforating branches of the basilar artery,
which is tethered to the circle of Willis
Upward-ascending Infratentorial lesion; upward displacement of Vertical gaze palsy followed by stupor/coma;
transtentorial cerebellum through tentorial incisura with dorsal intracranial pressure monitor may report low
midbrain compression, seen with combination intracranial pressure; cerebral aqueduct
of excessive supratentorial CSF diversion or compression may result in acute hydrocephalus
robust hyperosmolar therapy and posterior
fossa lesions that were not treated by surgical
posterior fossa decompression
Tonsillar Infratentorial or severe supratentorial lesion; Development of hydrocephalus, cranial nerve

downward displacement of the cerebellar palsies, and stupor/coma from brainstem
tonsils through the foramen magnum with compression; quadriparesis from compression of
cervicomedullary junction compression medullary pyramids; Cushing reflex of
hypertension, bradycardia, slow respirations; can
progress to respiratory arrest

a
Data from Posner JB, et al, Oxford University Press.31
b
Irreversible injuries following brain herniation: Brain herniation may lead to compression of venous drainage with venous infarction and possible
hemorrhagic conversion. Compression of arterial structures against dural reflections may lead to arterial infarcts, particularly compression of the
posterior cerebral arteries during uncal or central herniation or compression of the anterior cerebral, pericallosal, or callosomarginal arteries during
subfalcine herniation. Brain compression and displacement may also lead to shearing of penetrating arterioles, resulting in Duret hemorrhages,
particularly seen in the brainstem.
c
Brain herniation may result in diabetes insipidus because of injury to the hypothalamic-pituitary axis with loss of antidiuretic hormone expression.
Diabetes insipidus results in the production of a large volume (>3 mL/kg/h for multiple hours) of dilute (specific gravity ≤1.005) urine that can result
in severe hypovolemia and hypernatremia. Diabetes insipidus should be treated with volume resuscitation, administration of antidiuretic hormone,
and discontinuation of hyperosmolar therapy to avoid exacerbation of hypernatremia.
1184 OCTOBER 2021

extreme, this expertly designed and executed trial should not be disregarded KEY POINTS
through excessive criticism because it failed to confirm preconceived expectations.
● Although intracranial
The unexpected results of the BEST:TRIP trial likely demonstrate that our pressure monitoring does
knowledge of acute brain injury, cerebral edema, and ICP management remains not have a proven outcome
incomplete. In addition, BEST:TRIP suggests that ICP monitoring is ultimately only benefit, it still has
a clinical tool and other approaches can be used to guide therapies to similar effect. considerable clinical utility.
However, clinicians could
Before placing an ICP monitor or initiating therapy for cerebral edema,
also consider alternative
clinicians should first consider whether the mechanism of injury and available strategies, including clinical
clinical data suggest that ICP elevations or secondary brain injury due to cerebral assessment and serial
edema are likely to occur. In the case of ICP monitoring or obtaining serial neuroimaging.
neuroimaging, the clinician should consider how the information is likely to
● Normal intracranial
change management. Patients who are not comatose may not benefit from ICP pressure values should not
monitoring or specific ICP-directed therapies and could be harmed by side be comforting when in
effects. Patients with space-occupying injuries that are not severely distorting conflict with other
critical brain structures may only need supportive care and neurologic concerning clinical data.
Significant pressure
monitoring. Patients who are stuporous or comatose with possible diffuse gradients may exist in the
cerebral edema, as can be seen in encephalitis or toxic-metabolic exposures skull, and brain herniation
(eg, liver failure, diabetic ketoacidosis, or toxic leukoencephalopathies), may can occur with normal
represent a challenging decision because diffuse edema can be hard to appreciate intracranial pressure
monitor readings.
visually until it is severe; assessing the response to a trial of hyperosmolar therapy
may be helpful in such patients.8,29 On the other hand, a normal ICP value should
not be comforting when in conflict with other concerning clinical data, such as an
unexplained deterioration of the neurologic examination or radiographic
progression of brain distortion. The intracranial space is not a perfect sphere
filled with a homogeneous fluid, and the brain does not behave as a newtonian
fluid.30 Furthermore, the dural reflections and bony curvature of the middle
cranial fossa can facilitate the creation of pressure gradients within the skull. In
fact, pressure gradients of 30 mm Hg have been recorded between the middle
and posterior fossae, and gradients of 20 mm Hg have been recorded between the
ventricular fluid and the posterior fossa.30 Even EVDs may fail to detect significant
pressure gradients, especially if focal lesions prevent the free communication of
CSF. Brain herniation, the displacement of brain structures into adjacent cranial
compartments with compression of those compartments and structural brain
distortion, can occur as a result of these pressure gradients (TABLE 1-1).31
Life-threatening brain herniation may occur even if an ICP monitor reports a
normal pressure. Therefore, monitoring for brain herniation is dependent on serial
neurologic examinations and potentially serial neuroimaging.
Numerous monitoring technologies have been used for acute brain injury,
such as cerebral microdialysis, near-infrared spectroscopy, automated
pupillometry, and brain tissue oxygenation. Although ample literature may be
available to justify the use of these technologies in institutional management
protocols, most of these technologies lack sufficient evidence to advocate for
their widespread standardized use.32 The BOOST3 (Brain Oxygen Optimization
in Severe TBI, Phase 3) trial is currently investigating the efficacy of ICP plus
brain tissue oxygen monitoring compared to ICP monitoring alone in TBI.33 The
trial has attracted enthusiasm, and BOOST2 (Brain Tissue Oxygen Monitoring in
Traumatic Brain Injury [TBI]) provided promising preliminary data in favor of
brain tissue oxygenation monitoring,34 although cautious interpretation is
warranted given that the ICP monitoring–only group had significantly more
frequent severe brain compression.35

TREATMENT OF CEREBRAL EDEMA, BRAIN COMPRESSION, AND

ELEVATED INTRACRANIAL PRESSURE
In the patient presenting with an acute brain injury, the treatment of cerebral
edema, brain compression (by diffuse or focal processes), and elevated ICP
should begin with establishing an understanding of the severity and likely
trajectory of the injury based on history, mechanism, physical examination, and
review of emergent neuroimaging. This will suggest the pace at which
interventions may need to be introduced and allow preparations to be made if the
need for high-tier interventions seems likely. All patients with acute brain injury
TABLE 1-2 Tiers of Intracranial Pressure and Cerebral Edema–Directed Therapiesa
Tier Therapies
Zero, standard Supportive medical care (airway, breathing, circulation)

measures for all
patients at risk of Analgesia for comfort
intracranial pressure
Sedation to tolerate medical interventions (Richmond Agitation and Sedation Scale score 0 to -2)37
elevation
Avoid fever (normothermia 36 °C to 37 °C [96.8 °F to 98.6 °F])
Avoid constipation/abdominal distension
Head at 30- to 45-degree elevation
Head midline; avoid jugular vein compression
Isotonic or hyperosmolar fluids targeting normal serum sodium (>135 mmol/L)
Steroids for select conditionsb
One Mannitol or hypertonic saline for symptom-directed or osmolality/sodium level goal
CSF diversion, drain 5-10 mL if external ventricular drain in place
Selective consideration of surgical decompression or lesion resection
Mild hyperventilationc
Two Hypertonic saline if refractory to mannitol; consider higher osmolality goal
Sedation and analgesia for deeper Richmond Agitation and Sedation Scale goal
Reconsider surgical decompression as lifesaving measure
Mild hyperventilationc
Three Patient determined not to be a surgical candidate
Sedation/barbiturate titrated to intracranial pressure goal or EEG burst suppression
Moderate hypothermia (core temperature 32 °C to 34 °C [89.6 °F to 93.2 °F])
Moderate hyperventilationd
CSF = cerebrospinal fluid; EEG = electroencephalogram.

a
Data from Venkatasubramanian C, et al, Neurocrit Care.36
b
Brain tumors, cerebral abscess, meningitis, neuroinflammatory conditions (eg, acute demyelinating encephalomyelitis [ADEM]).
c
As a temporizing measure (PaCO2 30 mm Hg to 35 mm Hg or 5 mm Hg below baseline); wean after use.
d
As temporizing measure (PaCO2 25 mm Hg to 35 mm Hg or 10 mm Hg below baseline); wean after use.
1186 OCTOBER 2021

should first receive systemic resuscitation (airway, breathing, circulation) and KEY POINTS
supportive medical care followed by standard ICP-directed measures (tier zero
● Intracranial
interventions), as discussed below. It is vital for neurologists to be aware of and pressure–targeted therapy
advocate for the correction of systemic physiologic derangements because should follow a tiered
conditions such as shock or severe metabolic disturbance can contribute to approach in which therapies
secondary brain injury. Possible indications for early surgical intervention should from higher tiers are
introduced after ensuring
be identified, and then multidisciplinary discussions should delineate potential
optimization of lower-tier
surgical versus medical treatment options. ICP-targeted (and cerebral interventions.
edema/compression-targeted) therapy should follow a tiered approach
(TABLE 1-236,37), in which therapies from higher tiers are introduced after ● Systemic resuscitation
ensuring optimization of lower-tier interventions. Institutional treatment and goal-directed
supportive medical care are
algorithms improve the consistency of care and patient outcomes,38 and ideally critical to avoid secondary
these algorithms should be developed and regularly reviewed by a brain injury. Numerous
multidisciplinary team. Many example algorithms are available from clinical studies have demonstrated
trials or professional societies that may be adapted to individual that hypotensive and
hypoxic episodes are
institutional settings.27,39 associated with worse
Clinical brain herniation (TABLE 1-1) and severe or sustained elevation of outcome.
intracranial pressure represent neurologic emergencies that should be treated
with the same urgency afforded to a cardiac code situation. Although brain
herniation often contributes to death or severe disability, it is possible for
patients to have an acceptable functional outcome after brain herniation if
effective interventions are rapidly implemented (CASE 1-2). Rapid initiation of
empiric interventions to improve intracranial compliance, such as acute
hyperosmolar therapy and hyperventilation (discussed further below), are
indicated in an attempt to reverse the brain herniation. Efforts to identify the
precipitating factors leading to brain herniation should be initiated concurrently
with empiric therapeutic interventions. In some cases, recent clinical events may
suggest a possible precipitant; for example, brain herniation could be
precipitated by an acute decline in serum osmolality associated with initiating
renal dialysis or administering hypotonic fluids, dysfunction of an EVD, or even
fever in patients with severely compromised intracranial compliance. Emergent
neuroimaging should also be pursued to identify structural causes of brain
herniation that could justify surgical intervention. A clinician should accompany
the patient in transport to emergent neuroimaging to continue directing attempts
at reversing the brain herniation.
Supportive Medical Care and Standard Intracranial Pressure–Directed

Measures (Tier Zero)
Systemic resuscitation and goal-directed supportive medical care are critical to
avoid secondary brain injury. Numerous studies have demonstrated that
hypotensive and hypoxic episodes are associated with worse outcome in patients
with TBI; in fact, TBI guidelines recently emphasized this point by revising
systolic blood pressure goals from greater than 90 mm Hg to greater than
100 mm Hg for patients 50 to 69 years of age and 110 mm Hg for patients 15 to 49
and older than 70 years of age.16 On the other hand, excessive hypertension could
contribute to hematoma expansion or vasogenic edema in patients with acute
brain injury. In addition, all patients at risk for cerebral edema and increased ICP
should be treated with tier zero interventions (TABLE 1-2). These interventions
are aimed at optimizing intracranial compliance and avoiding ICP exacerbation.
Elevating the head of bed to 30 degrees and avoiding jugular vein compression

from causes such as neck rotation or tight cervical collars facilitates venous
drainage. Severe constipation and other causes of abdominal distension can raise
abdominal pressure and oppose the displacement of CSF to the lumbar cistern; in
patients with traumatic injury or shock, unrecognized intraabdominal
hypertension can contribute to elevated ICP. Even small intracranial volume
changes induced by untreated pain, agitation, and fever could lead to elevated
ICP in the patient with compromised intracranial compliance.
Selective Corticosteroids (Tier Zero)

Corticosteroids are most commonly used to treat vasogenic edema resulting from
intraaxial or extraaxial brain tumors. Corticosteroids are believed to improve
tumor-induced blood-brain barrier permeability through upregulation of tight
junction proteins and inhibition of cytokine-induced blood-brain barrier
disruption.40 Because of their numerous side effects, steroids should be reserved
for the treatment of significant symptoms that are referrable to the peritumoral
edema rather than the tumor itself. For acute edema treatment, 10 mg to 20 mg
IV dexamethasone may be administered, followed by maintenance doses of
4 mg/d to 24 mg/d, given orally or intravenously; it is common practice to divide
the maintenance dose 4 times daily, although twice-daily dosing is acceptable
practice.40,41 The clinician should monitor for adverse effects such as
hyperglycemia, gastric distress, and adrenal insufficiency with corticosteroid
weaning, and the lowest effective dose of steroids should be used to minimize
these adverse effects.41 It has classically been taught that steroids should be
withheld before biopsy of new tumors because steroids may reduce the
diagnostic yield for lymphoma; however, recent studies suggest this is
infrequently the case.42 Dexamethasone may be tapered over weeks following
surgical or radiation tumor therapy; however, in palliative situations,
dexamethasone doses may need to be increased to address neurologic symptoms
from progressive edema. Bevacizumab, a monoclonal antibody against vascular
endothelial growth factor (VEGF), has relatively recently begun to be used for
symptomatic peritumoral edema refractory to steroids40; the effect begins within
a few days, which limits bevacizumab’s utility in the acute setting, and a poorly
defined risk of intracerebral hemorrhage exists.
The role of corticosteroids for treating vasogenic edema from cerebral abscesses
or meningitis is less clear. For abscesses, steroids are generally reserved for severe
cases of edema because of concerns that steroids might reduce antibiotic penetration
or increase the risk of intraventricular rupture of periventricular abscesses.43 In
meningitis, multiple lines of evidence have suggested neurologic (principally
reduced hearing loss) and possible mortality benefits from corticosteroids,
especially in some subgroups such as in patients with Streptococcus pneumoniae
meningitis.44 In contrast, the CRASH (Corticosteroid Randomisation After
Significant Head Injury) trial demonstrated that patients with severe TBI treated
with 48 hours of methylprednisolone had significantly increased mortality. As
such, steroids are contraindicated in the treatment of TBI.16,45 Steroids are not
used in the management of cerebral edema from hemorrhagic or ischemic stroke
because current evidence suggests no benefit and potential harm.44,46
Osmotic Therapy (Tiers One and Two)

Mannitol and hypertonic saline are the main osmotic agents used to treat cerebral
edema and work primarily by generating an osmolar gradient between the brain
1188 OCTOBER 2021

and plasma. Hypertonic saline is available in concentrations ranging from 2% to KEY POINTS
23.4% and may be given by bolus or continuous infusion. For bolus dosing,
● Because of their
150 mL to 500 mL of 3% saline over 15 to 30 minutes or 30 mL of 23.4% saline over numerous side effects,
10 minutes is common; faster administration of 23.4% saline risks acute right steroids should be reserved
heart failure from fluid overload. Concentrations lower than 7.5% saline can be for the treatment of
given by peripheral lines in a large vessel with close monitoring to avoid vascular significant symptoms that
are referrable to peritumoral
injury and tissue necrosis by extravasation. Although central venous access is
edema rather than the tumor
preferred for saline concentrations of 7.5% or more, 23.4% boluses by itself.
intraosseous cannulation (placing a sturdy needle through cortical bone into the
medullary cavity of a bone for medication infusion, often using a power motor ● Steroids are
drill to facilitate insertion) can be considered in life-threatening circumstances in contraindicated in the
treatment of traumatic brain
which establishing central venous access would cause delay; transient injury because of increased
self-resolving hypotension can occur in about one-fourth of 23.4% saline boluses mortality.
given by intraosseous cannula infusion compared to 8% to 17% of 23.4% saline
boluses given by central venous catheter infusion.47 Typical guidance is to avoid
serum sodium greater than 160 mmol/L; however, this advice is not based on
high-quality data and individual risks and benefits should be considered.44
Targeting serum sodium up to 170 mmol/L in many patients with diffuse cerebral
edema from liver failure has resulted in good neurologic outcomes in select
cases.8,29 Hypertonic saline may produce hyperchloremic metabolic acidosis and
appears to increase the risk of acute kidney injury when serum sodium
approaches 160 mmol/L or serum chloride approaches 115 mmol/L44; use of
hypertonic saline buffered in acetate might reduce this risk.
Mannitol is an osmotic diuretic that is delivered by a filtered peripheral IV
catheter as a 20% solution at a bolus dose of 0.5 g/kg to 2 g/kg, depending on the
severity of the indication. Mannitol is typically redosed as boluses every 4 to
6 hours guided by serum osmolality measurements. Practice has shifted away
from continuous mannitol infusion because a small portion (approximately 10%)
of mannitol appears to leak across the blood-brain barrier, which may create an
increased risk for rebound edema when mannitol therapy is weaned after
continuous or prolonged use. Typical guidance is to avoid serum osmolality
greater than 320 mOsm/kg or an osmolar gap (measured minus calculated
osmolality) greater than 20 mOsm/kg. This guidance is largely based on classic
teachings that exceeding these thresholds increases the risk of acute kidney
injury, but a 2020 guideline statement was unable to identify evidence to support
these thresholds.44 Since hypovolemia and renal failure are risks of mannitol
therapy, the clinician should monitor for these complications but may decide that
cautiously exceeding the classic thresholds is beneficial. Additionally, the strong
diuretic effect of mannitol is frequently underappreciated by those less familiar
with its use. When transferring patients from remote emergency departments,
concurrent saline infusion should be considered if mannitol therapy is given
before transport to prevent dramatic hypovolemia from mannitol-induced
diuresis. However, both mannitol and hypertonic saline appear to be effective in
treating elevated ICP in patients with anuric end-stage renal disease, suggesting
neither therapy requires diuresis to be effective.48 In addition, the serum osmolar
gap does correlate with mannitol levels such that a large gap likely indicates that
mannitol is still present and therapeutically active; monitoring the osmolar gap
may inform the clinician whether or not to redose mannitol. Since mannitol is
primarily eliminated by urinary excretion but is cleared by hemodialysis, the
clinician should expect mannitol to have a delayed elimination in patients with

renal failure pending receipt of renal replacement therapy, which should be

initiated with caution to avoid rapid osmolar shifts and exacerbation of ICP.
The selection of osmotic agent for the individual patient is most often based on
practitioner preference and the patient’s volume status, with hypertonic saline
used for those needing volume expansion and mannitol used for those needing
diuresis. In urgent situations, the osmotic agent should be dictated by availability
and familiarity at the treating institution. Many emergency departments do not
stock and are not familiar with hypertonic saline but are familiar with mannitol.
No high-quality evidence indicates that either hypertonic saline or mannitol
improves mortality or neurologic outcome or that one agent is superior to the
other agent.44 However, a body of literature suggests that hypertonic saline may
have quicker onset and more durable ICP reduction and may be effective when
mannitol has failed.44 This literature likely explains a general trend toward greater
use of hypertonic saline. Furthermore, Koenig and colleagues49 reported that 23.4%
hypertonic saline boluses could clinically reverse transtentorial herniation, an effect
more frequent when serum sodium increased greater than 5 mmol/L. However,
the reversal of cerebral herniation is likely not a threshold effect and may differ
between underlying disease states; this article author’s group observed that
volumetric cerebral edema reduction was linearly related to acute osmolality
increase in a cohort with severe hepatic encephalopathy.8,29 Incidentally, the
magnitude of cerebral edema reduction affected by aggressive osmotic therapy is
small; approximately 15 mL of cerebral edema reduction was sufficient to
meaningfully improve neurologic examination scores in this cohort, consistent with
the exponential nature of intracranial compliance during severe cerebral edema.8,29
Osmotic therapy should be reserved for symptomatic clinical deterioration
that is likely to benefit from improved intracranial compliance and should not be
used prophylactically. In fact, prophylactic mannitol has been associated with
harm.44 The primary utility of osmotic therapy is to temporize intracranial
compliance until more definitive therapy occurs, such as surgical intervention, or
until enough time has passed that cerebral edema begins to abate. It has long been
recognized that the brain’s astrocytes begin to accumulate idiogenic osmoles
(such as amino acids, polyols, and methylamines) to reequilibrate brain-plasma
osmolality and normalize brain volume in response to osmotic therapy.50 More
recent literature suggests that premature osmotic therapy could actually
predispose to greater cerebral edema formation in patients who are vulnerable
through increased blood-brain barrier permeability and upregulation of
aquaporin-4 (AQP4) water channel expression on astrocyte end feet.51
Consistent with this hypothesis, this article author’s group recently observed that
spontaneous hyperosmolality at hospitalization for severe liver failure was
strongly associated with encephalopathy severity and altered CSF composition.51
Therefore, initiating osmotic therapy before it is needed for intracranial
compliance may actually promote an earlier development and greater magnitude
of edema through increased blood-brain barrier permeability; this may
ultimately obligate clinicians to maintain a higher osmolality later in the disease
course than might otherwise be needed.
The ideal approach to initiating and escalating osmotic therapy is debatable,
without strong evidence favoring one approach.44 Therapy might be titrated to
clinical symptoms or to a serum sodium or osmolality goal and accomplished by
bolus dosing of mannitol or hypertonic saline with or without continuous
hypertonic saline infusion. Bolus therapy to achieve a symptomatic goal and then
1190 OCTOBER 2021

maintaining serum osmolality with continuous 3% saline infusion (0.5 mL/kg/h KEY POINTS
to 1 mL/kg/h) along with serial sodium and osmolality measurements is one
● In urgent situations, the
approach; this might avoid rebound osmotic edema because of decline in serum osmotic agent used to treat
osmolality between boluses concurrent with accumulation of brain cerebral edema or elevated
idiogenic osmoles. intracranial pressure should
be dictated by availability
and familiarity. Many
CSF Diversion and Decompressive Surgery (Tiers One and Two)
emergency departments do
In patients with symptomatic hydrocephalus, CSF diversion is a first-line not stock and are not
therapy. However, in cases of complex brain injury mechanisms, the familiar with hypertonic
contribution of hydrocephalus to the clinical presentation is not always clear and saline but are familiar with
mannitol.
practitioners may have differing opinions on neuroimaging findings. In these
cases, a multidisciplinary discussion may be helpful. CSF diversion by an EVD, ● Osmotic therapy should
without concurrent surgical decompression of the posterior fossa, should be be reserved for patients
avoided as the sole therapy in patients with hydrocephalus from compressive with cerebral edema or
lesions in the posterior fossa because of the risk of upward herniation.18 elevated intracranial
pressure and with
Surgical intervention may be considered as a tier one therapy in select patients symptomatic clinical
with impaired intracranial compliance because of focal compressive lesions. For deterioration that is likely to
example, in patients 60 years of age and younger with malignant middle cerebral benefit from improved
artery infarcts who neurologically deteriorate despite medical therapy, intracranial compliance and
should not be used
decompressive craniectomy within 48 hours of stroke is recommended to prophylactically.
improve mortality and functional outcome.52 Patients older than 60 years of age
with similar malignant infarcts appear to have a mortality but not functional ● Initiating osmotic therapy
outcome benefit from early decompressive craniectomy. In patients with before it is needed for
intracranial compliance may
posterior fossa lesions causing brainstem compression or obstructive
actually promote an earlier
hydrocephalus, posterior fossa decompression is considered first-line therapy.18 development and greater
In contrast, decompressive craniectomy with or without hematoma evacuation magnitude of edema
has not proved to improve functional outcomes in patients with supratentorial through increased
intracerebral hemorrhage and is currently considered a lifesaving measure when blood-brain barrier
permeability; this may
patients deteriorate despite medical management.18 ultimately obligate clinicians
In patients with impaired intracranial compliance because of multifocal brain to maintain a higher
injuries such as severe TBI, decompressive craniectomy is a tier two measure osmolality later in the
based on data from the DECRA (Early Decompressive Craniectomy in Patients disease course than might
otherwise be needed.
With Severe Traumatic Brain Injury) and RESCUEicp (Randomised Evaluation
of Surgery With Craniectomy for Uncontrollable Elevation of Intracranial ● In patients 60 years of age
Pressure) clinical trials. DECRA found that early bifrontal decompressive and younger with malignant
craniectomy in severe TBI resulted in improved ICP but worse neurologic middle cerebral artery
infarcts who neurologically
outcome compared to standard care.53 A criticism of DECRA was that patients
deteriorate despite medical
were randomly assigned before ICP had proved to be sufficiently refractory to therapy, decompressive
medical therapy, and the trial essentially investigated surgical intervention as tier craniectomy within 48 hours
one therapy. RESCUEicp required ICP to be higher and for a more prolonged of stroke is recommended
to improve mortality and
period before randomization, testing decompressive craniectomy as a tier two
functional outcome.
intervention. RESCUEicp demonstrated improved survival from decompressive
craniectomy and higher rates of severe disability and vegetative state compared ● In patients with posterior
to continued medical therapy but noted no improvement in the rate of good fossa lesions causing
outcome.54 DECRA and RESCUEicp suggest that for diffuse brain injury, brainstem compression or
obstructive hydrocephalus,
decompressive craniectomy is a tier two option that can improve survival, but posterior fossa
decision makers should understand the expected outcome is for most survivors decompression is
to face severe disability. considered first-line
Minimally invasive surgical techniques currently in development may have therapy.
implications for ICP management in select diseases (CASE 1-3). The 2019

CASE 1-3 A 62-year-old man with a history of moyamoya syndrome, remote right
middle cerebral artery watershed infarct, and left external carotid to
internal carotid artery bypass surgery 1 month prior presented with acute
onset of headache, right-sided hemiplegia, and lethargy. Head CT
(FIGURE 1-8A) showed a large left lobar hemorrhage with brain
compression. Hypertonic saline was initiated for symptomatic brain
compression, and serum sodium was increased to 155 mmol/L. The
patient was taken for urgent hematoma evacuation by minimally invasive
endoscopic approach, which succeeded in removing the majority of the
hematoma (FIGURE 1-8B). The patient returned to the intensive care unit
with modest improvement in lethargy. Hypertonic saline infusion was
discontinued with the expectation that intracranial compliance had
sufficiently improved.
The following morning the patient was noted to be stuporous, and his
serum sodium was 150 mmol/L. Repeat head CT showed worsened
cerebral edema and brain compression comparable in severity to his
preoperative neuroimaging (FIGURE 1-8C). The patient clinically improved
after increasing serum sodium to 157 mmol/L but ultimately progressed to
brain death 4 days later.
FIGURE 1-8
Imaging of the patient in CASE 1-3. Axial head CT shows a large left lobar hemorrhage with
brain compression (A), the majority of which was removed through a minimally invasive
endoscopic approach (B). Repeat imaging the following day shows worsened edema and
brain compression comparable in severity to preoperative imaging (C).
COMMENT This case illustrates the use of minimally invasive endoscopic evacuation of
a hematoma in an attempt to improve intracranial compliance. The series of
CT scans illustrates that brain compression did improve after hematoma
evacuation, but considerable brain compression remained and the
hematoma cavity failed to collapse. Ultimately, intracranial compliance was
not improved enough to allow reduction in osmotic therapies, and, in fact,
cerebral edema and brain compression progressed despite hematoma
evacuation. This case illustrates that although minimally invasive surgical
procedures are becoming more common for acute brain injury, they are not
a panacea; close monitoring and intensive medical interventions will remain
critical.
1192 OCTOBER 2021

MISTIE-III (Minimally Invasive Surgery Plus Rt-PA for ICH Evacuation Phase KEY POINT
III) trial investigated whether evacuation of supratentorial intracerebral
● Therapeutic hypothermia
hemorrhage using a minimally invasive catheter approach could improve may be used for refractory
outcome compared to standard care.55 MISTIE-III demonstrated improved intracranial pressure
survival in the surgical arm but did not demonstrate improved functional elevation, but prophylactic
outcome. However, the technique appeared to reduce brain compression and, in hypothermia does not
improve outcome in severe
the subgroup with more technically successful hematoma evacuations, appeared
traumatic brain injury and
to have a potential functional outcome benefit. MISTIE-III has stimulated might be harmful.
interest in a variety of minimally invasive hematoma evacuation techniques that
could have implications for improving intracranial compliance by reducing
hematoma volume.
Anesthetics for Metabolic Suppression (Tiers Two and Three)

Anesthetics can be used for cerebral metabolic suppression, which will reduce
cerebral blood volume and improve ICP while maintaining adequate
oxygenation. Increasing sedation with propofol or benzodiazepines can be used
as a tier two ICP approach. For refractory ICP elevation, pentobarbital is the
mainstay approach. Although strong evidence suggests that pentobarbital
effectively lowers ICP, no high-quality evidence has proven that pentobarbital
improves patient outcomes.16 Pentobarbital may be started as a 5 mg/kg to
15 mg/kg infusion over 30 to 120 minutes followed by maintenance infusion of
1 mg/kg/h to 4 mg/kg/h.36 Pentobarbital is then titrated to ICP goals and
continuous EEG of at least 50% suppression. The doses of barbiturate in these
infusions can cause cardiac suppression and vasoplegia, requiring vasopressor
support, and can also cause paralytic ileus, immunosuppression, and bone
marrow suppression. IV pentobarbital and phenobarbital include propylene
glycol; thus, the osmolar gap should be monitored since propylene glycol
accumulation can lead to severe lactic acidosis, acute renal failure, and shock.
High-dose barbiturates can suppress brainstem function, including pupillary
function, and mimic brain death. Since pentobarbital can take days to clear
(half-life 15 to 50 hours), caution should be exercised during prognostication.
Weaning pentobarbital can be fraught with both withdrawal seizures and ICP
elevation recurrence, particularly if weaning is done too rapidly. Phenobarbital
can be started to facilitate pentobarbital weaning and allow long-term
barbiturate weaning and should be considered in advance when anticipating
prolonged weaning periods.
Induced Hypothermia (Tier Three)

Hypothermia to 32 °C to 34 °C (89.6 °F to 93.2 °F) has been shown to be effective
for refractory ICP elevation but has not demonstrated improved patient
outcomes.16 In 2015, the results from the Eurotherm3235 (European Study of
Therapeutic Hypothermia [32-35 °C] for Intracranial Pressure Reduction After
Traumatic Brain Injury) trial demonstrated that early initiation of hypothermia
for ICP control after TBI was associated with worse functional outcome and
greater mortality than standard care, despite the need for fewer medical
ICP-directed interventions. The POLAR-RCT (Prophylactic Hypothermia Trial
to Lessen Traumatic Brain Injury-Randomized Clinical Trial) reported results in
2018 and demonstrated no difference in neurologic outcome or mortality
between prehospital initiation of prophylactic hypothermia and standard care
with normothermia; interestingly, prophylactic hypothermia did not lead to

lower ICP and was associated with more frequent pneumonia.56 Nevertheless,
hypothermia remains a tier three option for refractory ICP. Hypothermia is
typically achieved with surface or intravascular cooling devices. An antishivering
protocol is needed because shivering prevents effective temperature
management and can increase cerebral metabolism and systemic hypercarbia,
which leads to counterproductive ICP elevation. Antishivering interventions
include surface counterwarming (heated air blankets on the arms and legs),
magnesium, buspirone, meperidine, sedatives, and paralytic medications.
Therapeutic hypothermia requires close monitoring of electrolytes and
cardiovascular status. During induction, severe hypokalemia, significant
diuresis, and skin necrosis (due to peripheral vasoconstriction and pressure
from external cooling pads) may occur. Rewarming should occur slowly
(≤0.1 °C [0.18 °F] per hour) with close monitoring because of rebound
hyperkalemia and potential distributive shock from peripheral vasodilation.
Hyperventilation (Tiers One Through Three Transient Rescue Therapy)

Hyperventilation can be very effective at reducing ICP, but its utility as a
management strategy is limited.44 Hyperventilation reduces ICP by causing
cerebral vasoconstriction. In patients experiencing an ICP crisis, cerebral
vasoconstriction can contribute to cerebral ischemia, which may then contribute
to further cerebral edema and impairment of intracranial compliance. As such,
hyperventilation should primarily be used as a transient emergency intervention
to bridge a patient to a more definitive therapy. Furthermore, the benefits of
hyperventilation are expected to be time limited because the brain will
eventually buffer the pH change induced by hyperventilation and the cerebral
vascular caliber will return to baseline. Hyperventilation PaCO2 targets of 25 mm
Hg to 35 mm Hg are typically suggested; however, this guidance does not account
for patients who may have chronic carbon dioxide retention from pulmonary
disease. Hyperventilation should be gradually weaned after it is used because a
sudden increase in PaCO2 will lead to an acute increase in cerebral blood volume,
which could precipitate ICP elevation.
THE GLYMPHATIC SYSTEM AND CELLULAR TARGETS FOR CEREBRAL

EDEMA TREATMENT
The discovery of the brain’s glymphatic (glial-lymphatic) system (FIGURE 1-957)
and meningeal lymphatic vessels in the past decade represents potential
therapeutic implications for a number of neurologic disorders, including acute
brain injury and cerebral edema.58-60 The glymphatic system consists of
perivascular spaces through which CSF flows in to the brain, driven by the
pulsations of the arterial wall.61 CSF exits these perivascular spaces into the brain
parenchyma in a process facilitated by AQP4 water channels on astrocyte end
feet.62 Within the brain parenchyma, the CSF mixes with interstitial fluid and
fluid that influxes across the blood-brain barrier and moves by bulk flow through
the brain to be collected in perivascular spaces around venules. This process
appears to be responsible for the clearance of waste products, including amyloid-β,
and may also be involved in distributing metabolites and signaling molecules
through the brain.58 Furthermore, the rate of fluid flow through the glymphatic
system appears to be under circadian control and is further upregulated by sleep
or anesthesia. When the glymphatic system is downregulated while awake, a
greater portion of CSF appears to drain directly to meningeal and cervical
1194 OCTOBER 2021

KEY POINTS
● Hyperventilation should
primarily be used as a
transient intervention to
bridge a patient to a more
definitive intracranial
pressure therapy because it
can induce cerebral
ischemia.
● The glymphatic system

consists of perivascular
spaces through which CSF
flows into the brain, driven
by the pulsations of the
arterial wall and facilitated
by aquaporin-4 channels on
astrocyte end feet.
FIGURE 1-9
The glymphatic system. Pial arteries in the subarachnoid space are surrounded by CSF and
become penetrating arteries upon entering the brain parenchyma. Penetrating arteries are
surrounded by CSF in perivascular (Virchow-Robin) spaces. Arterial wall pulsations drive CSF
into the brain along perivascular spaces. As penetrating arteries become arterioles and
capillaries, the CSF-filled perivascular spaces narrow and finally disappear, but the
extracellular matrix of the basal lamina provides a perivascular conduit for continued CSF
flow around arterioles and capillaries. Aquaporin-4 (AQP4) water channels on astrocyte end
feet surrounding the perivascular space facilitate entry of CSF into the brain parenchyma.
CSF mixes with interstitial fluid in the brain and moves by bulk flow through the brain
parenchyma to perivenous spaces. Fluid drains from perivenous spaces out of the brain by
meningeal and cervical lymphatics, along cranial and spinal nerves, and possibly through
arachnoid granulations.
Reprinted with permission from Jessen NA, et al, Neurochem Res.57 © 2015, Springer Science Business
Media.
lymphatics.62 Although many features of glymphatic function remain under

debate or entirely unknown, the observation of this system by many
independent groups has resulted in its existence being widely accepted. The
glymphatic system likely went unrecognized until recent times because of
the absence of high-resolution in vivo imaging and because the perivascular
spaces collapse after death and may be obliterated with postmortem tissue
preparation.62

The precise processes by which glymphatic function might contribute to

cerebral edema formation are yet to be fully delineated, but several lines of
evidence suggest a critical role. Recently, CSF was demonstrated to be the source
of fluid influx responsible for early brain swelling after ischemic stroke.5 In a
mouse model of ischemic stroke, accelerated CSF influx into the brain
parenchyma along perivascular spaces was observed within minutes of stroke.
This CSF influx followed the wave of spreading depolarization that occurred
with the loss of ionic gradients during cellular death and appeared to be the result
of parenchymal and pial arteriole vasoconstriction precipitated by the spreading
depolarization.5 Interestingly, the magnitude of CSF influx was reduced in
AQP4-deficient mice. The authors acknowledged that this process would not
completely explain cerebral edema formation after ischemic stroke but proposed
that it could also contribute to cerebral edema formation in other diseases in
which spreading depolarizations have been observed, such as subarachnoid
hemorrhage, intracerebral hemorrhage, and TBI.5 Glymphatic dysfunction in
clearing toxic substances, such as reactive oxygen and nitrogen species and
inflammatory cytokines, could also contribute to cerebral edema. For example,
reactive oxygen and nitrogen species might lead to cerebral edema through
activation of ionic transporters (ie, the Na-K-Cl cotransporter 1), activation of
intracellular protein kinase signaling cascades, blood-brain barrier disruption by
activation of matrix metalloproteinases, or failure of oxidative phosphorylation
through mitochondrial membrane pore formation and depolarization.1,63
Furthermore, accumulation of brain cytokines, including tumor necrosis factor-α
and transforming growth factor beta, from local and systemic inflammation can
exacerbate vasogenic edema through disruption of blood-brain barrier tight
junction proteins and upregulation of metalloproteinases.1
Given its prominent role in facilitating fluid movement through the brain,
AQP4 might be an intuitive target for developing new cerebral edema therapies.
For example, AQP4 membrane expression is increased after hypoxic central
nervous system injury, and inhibiting this increased expression with
trifluoperazine reduced edema and improved functional outcome in a rat
model.64 However, although AQP4-deficient mice demonstrate reduced
cerebral edema in models of cytotoxic edema (cerebral ischemia and acute
liver failure), cerebral edema is worse in AQP4-deficient models of vasogenic
edema (tumors, subarachnoid hemorrhage, and abscesses).1,6 Since most
acute brain injury involves a mixture of cerebral edema types that evolve at
different points in the disease, the pathophysiology around AQP4 and cerebral
edema evolution will likely need greater clarification before AQP4 is an
actionable therapeutic target.
Modifying the function of ion cotransporters and ion channels could also
represent a therapeutic approach for cerebral edema. Na-K-Cl cotransporter 1
plays a prominent role in ionic hemostasis and water transport, and its activity is
upregulated shortly after TBI and during acute liver failure. In addition to
contributing to cytotoxic edema, Na-K-Cl cotransporter 1 also appears to be
involved in the regulation of AQP4 and metalloproteinases with implications for
blood-brain barrier integrity.1,6 Although bumetanide has shown promise in
animal models as a Na-K-Cl cotransporter 1 inhibitor, clinical data do not yet
support therapies directed at this cotransporter for cerebral edema management.
In contrast, clinical data are available to support the sulfonylurea receptor-
1–transient receptor potential melastatin 4 (SUR1-TRPM4) ion channel as a
1196 OCTOBER 2021

therapeutic target. The SUR1-TRPM4 channel regulates inorganic cation KEY POINT
transport in the brain. SUR1-TRPM4 is unique in that it is not normally expressed
● CSF influx along
in the brain but is upregulated following brain injury with intracellular ATP perivascular spaces may
depletion, promoting channel opening, cellular depolarization, and cytotoxic provide the source of early
edema with the potential for vasogenic edema if endothelial cells are involved.6 cerebral edema after acute
Therefore, therapies directed at SUR1-TRPM4 would have the theoretic ischemic stroke.
benefit of being selective for injured cells. Glyburide (glibenclamide) binds the
SUR1 portion of SUR1-TRPM4 and blocks the channel’s function. Glyburide is
also an indirect inhibitor of matrix metalloproteinase-9, which could have
implications for blood-brain barrier integrity and vasogenic edema. The phase 2
GAMES-RP (Glyburide Advantage in Malignant Edema and Stroke – Remedy
Pharmaceuticals) trial demonstrated reduced brain compression and matrix
metalloproteinase-9 levels in patients with severe anterior circulation stroke at
risk for malignant cerebral edema who were treated with IV glyburide; however,
the trial was underpowered to demonstrate a mortality or functional outcome
benefit.65 A randomized clinical trial of 66 patients with severe TBI
demonstrated a reduced rate of contusion expansion but no difference in clinical
outcome in patients who received oral glyburide.66 Glyburide is currently being
investigated in a clinical trial of TBI67 and a phase 3 trial of large hemispheric
ischemic stroke.68
The few specific cellular targets discussed here by no means represent the
extent of agents and mechanisms that are being investigated for potential
therapeutic effect on cerebral edema6; however, even this partial list suggests
that our current therapeutic approach to cerebral edema is far from optimized.
The list of potential therapies will likely continue to grow as our understanding of
the mechanisms underlying cerebral edema deepens.
CONCLUSION
Cerebral edema, brain compression, and elevated ICP represent major causes of
secondary brain injury that contribute to morbidity and mortality in neurocritical
care. The current management of these conditions is based primarily on core
physiologic principles and a limited number of interventions that have
nonspecific effects on cerebral edema and brain compression. Over time, our
knowledge of how to implement these interventions has been refined, but
unexpected results from clinical trials suggest that our knowledge of acute brain
injury pathophysiology remains incomplete. As our understanding of the
glymphatic system and the cellular mechanisms of fluid regulation in the brain
improves, we may learn how to better implement existing therapies and may
identify new therapies that address specific cerebral edema mechanisms. We
may also find that our classic conceptual models of cerebral edema and ICP are
overly simplistic approximations in need of revision.
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1200 OCTOBER 2021

Subarachnoid REVIEW ARTICLE

Hemorrhage CONTINUUM AUDIO
INTERVIEW AVAILABLE
ONLINE
By Sherry Hsiang-Yi Chou, MD, MSc, FNCS, FCCM
ABSTRACT
PURPOSE OF REVIEW: Subarachnoid hemorrhage (SAH) remains an important
cause of mortality and long-term morbidity. This article uses a case-based
approach to guide readers through the fundamental epidemiology and
pathogenesis of SAH, the approach to diagnosis and management, the
results of clinical trials and evidence to date, prognostic considerations,
controversies, recent developments, and future directions in SAH.
RECENT FINDINGS: Historically, management of SAH focused on prevention

and treatment of subsequent cerebral vasospasm, which was thought to
be the primary cause of delayed cerebral ischemia. Clinical and
translational studies over the past decade, including several therapeutic
CITE AS:
phase 3 randomized clinical trials, suggest that the pathophysiology of C O N T I N U U M ( M I N NE AP M I N N )
SAH-associated brain injury is multiphasic and multifactorial beyond large 2 0 21 ; 27(5, NEUROCRITICAL CARE):
1201–1245.
vessel cerebral vasospasm. The quest to reduce SAH-associated brain
injury and improve outcomes is shifting away from large vessel cerebral
vasospasm to a new paradigm targeting multiple brain injury mechanisms, Dr Sherry Hsiang-Yi Chou,
including early brain injury, delayed cerebral ischemia, microcirculatory Division of Neurocritical Care,
Department of Neurology,
dysfunction, spreading cortical depolarization, inflammation, and the Northwestern Feinberg School
brain-body interaction in vascular brain injury with critical illness. of Medicine, Ste 1150, 625 N
Despite multiple negative randomized clinical trials in search of Michigan Ave, Chicago, IL 60611,
sherry.chou@northwestern.
potential therapeutic agents ameliorating the downstream effects after edu.
SAH, the overall outcome of SAH has improved over recent decades, likely
RELATIONSHIP DISCLOSURE:
related to improvements in interventional options for ruptured cerebral
Dr Chou serves on the board of
aneurysms and in critical care management. Emerging clinical evidence directors of the Neurocritical
also suggests potential harmful impact of historic empiric treatments Care Society, on an advisory
board for CSL Behring, and on
for SAH-associated vasospasm, such as prophylactic induction of the editorial board of Stroke.
hypertension, hypervolemia, and hemodilution (triple H therapy). Dr Chou receives research/
With decreasing mortality, long-term SAH survivorship and efforts to grant support from the National
Institute of Neurological
reduce chronic morbidity and to improve quality of life and Diseases and Stroke
patient-centered outcome are growing areas of unmet need. Despite (R21NS113037) and the National
existing guidelines, significant variabilities in local and regional practices Institutes of Health/National
Center for Advancing
and in scientific terminologies have historically limited advancement in Translational Sciences
SAH care and therapeutic development. Large global collaborative efforts (UL1 TR001857).
developed harmonized SAH common data elements in 2019, and studies
UNLABELED USE OF
are under way to examine how existing variabilities in SAH care impact PRODUCTS/INVESTIGATIONAL
long-term SAH outcomes. USE DISCLOSURE:
Dr Chou reports no disclosure.
SUMMARY: Although the overall incidence and mortality of SAH is decreasing

with advances in preventive and acute care, SAH remains a major cause of © 2021 American Academy
of Neurology.

SUBARACHNOID HEMORRHAGE
long-term morbidity in survivors. Significant variabilities in care settings

and empiric treatment protocols and inconsistent scientific terminologies
have limited advancement in patient care and therapeutic clinical studies.
Large consensus efforts are under way to introduce clinical guidelines and
common data elements to advance therapeutic approaches and improve
patient outcome.
INTRODUCTION
A
cute bleeding into the subarachnoid space can have multiple
etiologies (TABLE 2-11–3), but by far the most common and most
severe form is nontraumatic spontaneous subarachnoid
hemorrhage (SAH). This article focuses on adults with
nontraumatic SAH. SAH is rare in children, and the etiologies
are different from those in the adult population. In children under 15 years of age,
the most common cause of nontraumatic SAH is cerebral arteriovenous
malformation.
SAH is the least common type of stroke (1% to 6% of all strokes). However, it
disproportionately affects a younger population and leads to extensive long-term
morbidity in addition to having higher mortality.4,5 SAH is responsible for more
than 27% of life-years lost before age 65 and leads to disproportionately high
societal health care costs and economic impact.4,6 In particular, aneurysmal SAH
from the rupture of intracerebral aneurysms is the deadliest form of SAH, with a
case-fatality rate up to 51% and long-term disability in one-third to one-half of all
survivors. The most common cause of spontaneous SAH is a ruptured cerebral
aneurysm (85%). Approximately 10% to 15% of patients with SAH do not have an
identifiable bleeding source; of these, approximately 38% have nonaneurysmal
perimesencephalic SAH, which is a benign variant of SAH with generally
excellent prognosis.1-3 The incidence of aneurysmal SAH is approximately
30,000 per year in the United States and 6.1 per 100,000 person-years
worldwide,7 with females affected 1.6 times more often than males.8
The American Heart Association (AHA)/American Stroke Association (ASA)
SAH guidelines from 20125 and Neurocritical Care Society guidelines from 20119
are the most recent clinical guidelines for SAH management, with an updated
iteration of guidelines by the Neurocritical Care Society currently under
development.
EPIDEMIOLOGY, RISK FACTORS, AND SCREENING

Although the primary risk of SAH comes from having an intracranial aneurysm,
the incidence of unruptured intracranial aneurysms in the population far exceeds
that of SAH10; only an estimated 0.3% of all unruptured intracranial aneurysms
rupture per year, suggesting that not all unruptured intracranial aneurysms
rupture and lead to SAH and that not all unruptured intracranial aneurysms
may require acute intervention.11,12 Data from a 2020 study suggest that
patients with extracranial aneurysms have a higher prevalence of intracerebral
aneurysms.13
Risk factors associated with rupture of an existing unruptured intracranial
aneurysm may include hypertension, age, larger aneurysm, and aneurysm
location and shape, whereas data on the impact of ethnic origin and family
history are limited.14-18 Aneurysms that are growing or causing clinical symptoms
1202 OCTOBER 2021

Differential Diagnosis of Subarachnoid Hemorrhage in Adults TABLE 2-1
Primary subarachnoid hemorrhage (SAH)1

◆ Aneurysmal SAH (85%): SAH due to rupture of intracerebral aneurysm
◆ Nonaneurysmal SAH (perimesencephalic SAH) (10%): SAH with no evidence of cerebral
aneurysm or other vascular malformations
◆ SAH due to other vascular malformations (5%): SAH due to bleeding from cerebral or
spinal arteriovenous malformation, dural arteriovenous fistula, arterial dissection,
moyamoya disease, or other malformation
Secondary SAH etiologies2
◆ Trauma
◆ Reversible cerebral vasoconstriction syndrome
◆ Posterior reversible encephalopathy syndrome (PRES)
◆ Cerebral amyloid angiopathy
◆ Pituitary apoplexy
◆ Cerebral vasculitis
◆ Primary intracerebral hemorrhage with secondary extension to subarachnoid space
◆ Cerebral venous sinus thrombosis
◆ Tumor/neoplasm
◆ Coagulopathy
◆ Sympathomimetic recreational drug use
◆ Heavy alcohol use
◆ Septic emboli to brain from endocarditis
◆ Iatrogenic injury to cerebral vasculature
Pseudo-SAH on imaging3
◆ CT
◇ Anoxic brain injury
◇ Spontaneous intracranial hypotension
◇ Iatrogenic (eg, secondary to cerebral arterial thrombectomy)
◆ Fluid-attenuated inversion recovery (FLAIR) MRI
◇ Supplemental oxygen
◇ CSF pulsation
◇ Contrast (gadolinium) leakage (eg, in broken blood-brain barrier or with renal failure)
◇ Insufficient suppression, patient motion
CSF = cerebrospinal fluid; CT = computed tomography; MRI = magnetic resonance imaging.

are generally referred for expeditious repair, although this has not been studied
in a prospective clinical trial. For asymptomatic or nongrowing unruptured
intracranial aneurysms, the preventive treatment strategy is less clear, as
currently available aneurysm treatment modalities carry a 6% risk of
complications resulting in permanent disability or death.19,20 Generally, larger
asymptomatic unruptured intracranial aneurysms are referred for neurosurgical
or endovascular treatment because they are thought to be at higher risk for
rupture, with the average size of a ruptured cerebral aneurysm being 6 mm to
7 mm.21 However, because smaller unruptured intracranial aneurysms have
much higher baseline population prevalence than larger unruptured intracranial
aneurysms, small cerebral aneurysms account for most cases of SAH.22
Currently, the multicenter PROTECT-U (Prospective Randomized Open-label
Trial to Evaluate Risk faCTor Management in Patients With Unruptured
Intracranial Aneurysms) trial is actively enrolling patients who do not qualify for
preventive unruptured intracranial aneurysm interventions.12 PROTECT-U
examines the risk for aneurysm rupture or aneurysm growth in patients treated
with 100 mg/d aspirin plus intensive systolic blood pressure control to less
than 120 mm Hg compared to standard care.
The incidence of SAH increases with age and peaks in the fifth and sixth
decades, is higher in females, and is more common in African American,
Hispanic, Japanese, and Finnish populations.1,4,5,14 The global incidence of SAH
has fallen since 1998 by approximately 0.6% per year.23 Genetically, approximately
10% of individuals with autosomal dominant polycystic kidney disease have
asymptomatic unruptured intracranial aneurysms.24 Autosomal dominant
polycystic kidney disease accounts for 0.3% of all SAH cases.25 Although familial
clustering is seen in SAH, variabilities in genetic loci account for only 5% of the
hereditary risk of SAH, suggesting that familial clustering may also be related to
shared environmental risk factors. The risk in first-degree relatives of patients
with SAH is 3 to 7 times higher than in the general population, but second-degree
relatives have risks similar to that of the general population.26 Although several
genetic polymorphisms have been linked to higher risk for intracranial aneurysms,
no predominant genetic risk factor has been identified for either unruptured
cerebral aneurysm or for SAH. Currently, no clinical genetic screening tests are
recommended for SAH or unruptured cerebral aneurysm risk determination.27
Epidemiologic studies of familial clustering of cerebral aneurysms and SAH
suggest that environmental factors may be more important than genetic factors in
familial cases.28 The International Study of Unruptured Intracranial Aneurysms
found that people with two or more first-degree relatives with cerebral aneurysm
or SAH are at increased risk for aneurysmal SAH, particularly when the affected
probands are siblings.17,29-31 Based on this, the AHA/ASA SAH guidelines suggest
screening be considered in those with two or more first-degree relatives with
aneurysm or SAH.27
Potentially modifiable risk factors for SAH include hypertension, smoking,
heavy alcohol use, and sympathomimetic recreational drug (eg, cocaine) use.32
Although no prospective clinical trials have proven that modifying these risk
factors indeed lowers SAH risk, these preventive measures are generally
recommended in clinical practice. Nonmodifiable SAH risk factors include age,
female sex, family history, ethnicity/nation of origin, and a history of SAH.
Over the past 2 to 3 decades, the SAH case-fatality rate has decreased by 17% to
50% worldwide,33 likely a result of multiple factors, including advances in
1204 OCTOBER 2021

stroke systems of care, diagnostic accuracy, surgical techniques, and critical care KEY POINTS
support. For many years, the global incidence of SAH did not change, and no
● Subarachnoid
preventive measures for SAH had been identified. However, a 2019 hemorrhage (SAH) is the
meta-analysis found a declining worldwide incidence for SAH, possibly because least common type of stroke
of cardiovascular risk prevention measures, such as hypertension control and syndrome (1% to 6% of all
smoking cessation.7 Despite these advances, SAH remains a highly deadly and strokes) but leads to
significant morbidity and
morbid disease, with 30-day mortality as high as 35%.33,34 The overall mortality
disproportionately high
of SAH may be underestimated, as patients with SAH who are found dead or societal health care costs
who die before hospital arrival may not receive the diagnosis. and economic impact.
CLINICAL PRESENTATION AND DIAGNOSIS ● The incidence of SAH

increases with age and
Patients with SAH can present with a variety of symptoms and signs, peaks in the fifth and sixth
including non-neurologic organ dysfunction (TABLE 2-235,36). The classic SAH decades; is higher in
presentation is characterized by the sudden development of a severe headache, females; and is more
often referred to as thunderclap headache or the worst headache of life, which common in African American,
Hispanic, Japanese, and
can be associated with nausea, vomiting, meningismus, altered mental status, Finnish populations.
loss of consciousness, seizure, or seizurelike events (CASE 2-1A), or in some cases
patients may develop acute focal strokelike deficits associated with bleeding into ● Although familial
intraparenchymal or subdural spaces.37 Approximately 70% of patients with clustering is seen in SAH,
most cases of SAH are
SAH present with sudden headache. A subset of patients with SAH may
sporadic. People with two or
experience a sentinel headache that precedes SAH diagnosis by days to weeks. more first-degree relatives
Although many suspect a sentinel headache represents a minor rupture of with cerebral aneurysm or
cerebral aneurysm before SAH, the pathophysiology and clinical significance of SAH are at increased risk for
aneurysmal SAH. The
sentinel headaches are not yet fully understood.38
American Heart
Association/American
What Headaches Suggest the Presence of Subarachnoid Hemorrhage? Stroke Association
Acute SAH constitutes approximately 1% to 4% of all emergency department visits guidelines recommend
for acute headaches.39 The decision whether to pursue invasive diagnostics to rule screening in those with two
or more first-degree
out a rare but lethal headache etiology is often a diagnostic dilemma, particularly in relatives with aneurysm
patients with acute headache and no other neurologic symptoms. The Ottawa SAH or SAH.
Rule is a decision rule validated for use in the emergency department to screen for
SAH in patients with acute headache who are neurologically intact (TABLE 2-3).40,41 ● The classic SAH
presentation is
Implementation of the Ottawa SAH Rule in practice has reduced the total number characterized by the sudden
of lumbar punctures done while retaining 100% sensitivity for SAH. development of a severe
Delayed or missed diagnosis of aneurysmal SAH is common, particularly in headache, often referred to
patients in good clinical condition at presentation.39,42 Incorrect or delayed as the worst headache of
life, which can be
diagnosis of aneurysmal SAH has profound consequences, leading to increased
associated with nausea,
rates of aneurysm rebleeding, unfavorable outcome, and death.43 Aneurysmal vomiting, meningismus,
SAH from a ruptured cerebral aneurysm or other bleeding cerebral vascular altered mental status, loss
malformation is a neurologic emergency that requires immediate diagnosis and of consciousness, seizure or
seizurelike events, and
rapid transfer to a high-volume center. The most common diagnostic error leading
acute focal strokelike
to missed or delayed diagnosis of aneurysmal SAH is the failure to obtain a deficits.
head CT.43
Subarachnoid Hemorrhage Clinical and Radiographic Severity Scores

The initial clinical severity of SAH presentation also varies from very mild to
critical. SAH clinical severity is most commonly measured using the Hunt and
Hess Scale44 or the World Federation of Neurological Surgeons Scale
(WFNSS),45 or both (TABLE 2-4). The Hunt and Hess Scale and WFNSS were
initially developed in 1968 and 1988 to predict surgical risk and mortality in SAH.

Although surgical techniques and critical care management for SAH have
advanced significantly since that time, epidemiologic studies consistently show
that SAH clinical severity scores remain the strongest predictors of SAH functional
outcome.46 The best timing of WFNSS or Hunt and Hess Scale assessment has
been a subject of debate, particularly as initial SAH presentations can be
confounded by acute hydrocephalus or other potentially reversible conditions in
which patients’ neurologic functions improve following emergent resuscitative
measures such as external ventricular drain (EVD) insertion. Recent data now
suggest that a postresuscitation WFNSS is more predictive of final SAH
outcome.47,48
TABLE 2-2 Aneurysmal Subarachnoid Hemorrhage Presenting Symptoms and Signs
Symptoms
◆ Worst headache of life: sudden onset of severe headache
◆ Sentinel headache: a new headache without other associated subarachnoid hemorrhage
symptoms that is later followed by life-threatening aneurysm rebleeding, leading to
diagnosis of aneurysmal subarachnoid hemorrhage (40%)35
◆ A change in headache characteristics: patients with a history of headaches may develop a
new headache that is different in quality and severity from their baseline headache
syndrome
◆ Nausea, often with vomiting
◆ Sudden loss of consciousness, transient syncope
◆ Acute onset or progressive altered mental status
Neurologic examination findings
◆ Altered mental status
◆ Abnormal Glasgow Coma Scale score
◆ Focal cranial nerve palsies and ophthalmoplegia (eg, third nerve palsy from posterior
communicating artery aneurysm, sixth nerve palsy from increased intracranial pressure)
◆ Meningismus: neck stiffness, photophobia
◆ Terson syndrome: intraocular extension of subarachnoid blood36
◆ Acute hemiparesis or hemiplegia due to focal intracerebral hematoma from aneurysm
rupture
◆ Bilateral leg weakness and abulia due to mass effect from hematoma in the interhemispheric
fissure
◆ Seizure or seizurelike events
◆ Focal neurologic deficits
Systemic manifestations
◆ Acute hypertension
◆ Cardiac arrhythmia
◆ Cardiac arrest
◆ Hypotension/shock from neurogenic stunned myocardium
◆ Hypoxia from aspiration, respiratory depression, or neurogenic pulmonary edema
1206 OCTOBER 2021

Patients with SAH can also present with a broad range of radiologic bleeding KEY POINTS
severity, from a thin layer of subarachnoid blood to extensive and thick
● SAH is a neurologic
hematomas involving all basal cisterns with extension into the intraventricular, emergency that requires
intracerebral, and, at times, subdural spaces. The Fisher Scale is an original SAH immediate diagnosis and
radiographic severity scale developed in the 1980s to predict the risk of delayed rapid transfer to a
cerebral vasospasm.49 Since then, additional scales have been developed that high-volume center.
Delayed or missed diagnosis
have better predictive value for subsequent vasospasm and where vasospasm
of SAH is common and often
risks consistently increase with incremental increase in radiologic severity score, associated with severe
which was not the case with the original Fisher Scale. Currently, the most consequences, including
commonly used radiographic SAH severity scores are the modified Fisher Scale50 death and severe morbidity.
The most common
and the Hijdra Scale51 (TABLE 2-5).
diagnostic error leading to
missed or delayed diagnosis
Diagnostic Imaging of SAH is the failure to
Noncontrast head CT is the most common modality that identifies the obtain a head CT scan.
presence of acute blood in the subarachnoid space. TABLE 2-6 summarizes
● Diagnostic head CT is
key characteristic appearance features of aneurysmal SAH on head CT. Of most sensitive for SAH in the
patients with classic CT findings for aneurysmal SAH, 85% have a ruptured first 6 to 12 hours following
cerebral aneurysm, 5% have other cerebrovascular malformations, and 10% aneurysm rupture. For
have no cerebrovascular malformations identified and are classified as having subacute or chronic phases
of SAH, MRI with gradient
nonaneurysmal or perimesencephalic SAH. Other secondary etiologies of recalled echo,
SAH include trauma, reversible cerebral vasoconstriction syndrome, cerebral susceptibility-weighted
amyloid angiopathy, vasculitis, cerebral venous sinus thrombosis, or bleeding imaging, or fluid-attenuated
into the subarachnoid space because of systemic conditions (such as inversion recovery
sequences has superior
coagulopathy), infectious conditions (such as septic brain emboli from
sensitivity compared to
endocarditis), or toxic-metabolic etiologies (such as cocaine use) (TABLE 2-1). noncontrast head CT.
Secondary SAH has different CT characteristics and tends to be present in the
high cerebral convexity and not centered around the basal cisterns as in ● In cases of negative or
aneurysmal SAH.2,3 equivocal imaging and high
clinical suspicion for SAH,
Head CT is the go-to modality because of ease of access and rapidity of lumbar puncture to evaluate
diagnostic results. It is most sensitive for SAH in the first 6 to 12 hours following for CSF xanthochromia is
aneurysm rupture, with a sensitivity of 93% to 100%. Diagnostic sensitivity by recommended.
head CT degrades over time, declining to 60% at 7 days post-SAH.52 In the first
● After initial resuscitation
6 hours of SAH, MRI may be slightly superior to head CT in detecting the and stabilization of a patient
presence of SAH.52 For subacute or chronic phases of SAH, MRI with gradient with SAH, a key next step is
recalled echo (GRE), susceptibility-weighted imaging (SWI), or fluid- to rapidly identify and
attenuated inversion recovery (FLAIR) sequences have superior sensitivity secure the bleeding source
to minimize the risk for
compared to noncontrast head CT.53
aneurysm rerupture.
Cerebral CT angiography is
Lumbar Puncture and CSF Analysis often the first-line imaging
In cases of negative or equivocal imaging and high clinical suspicion for SAH, modality, with 90% to 97%
sensitivity in detecting an
lumbar puncture for diagnostic CSF analysis can assist in the diagnosis of acute
intracranial aneurysm.
SAH, although the value of lumbar puncture has been questioned.54 The classic Digital subtraction
diagnostic criterion is presence of xanthochromia on laboratory angiography with
spectrophotometry analysis. It is important to note that xanthochromia, three-dimensional
particularly if evaluated visually and not by spectrophotometry, may not be reconstructions remains the
gold standard diagnostic
apparent in the hyperacute phase of SAH. In addition to CSF analysis, lumbar modality for cerebral
puncture offers the opportunity to measure an opening pressure as a surrogate aneurysms.
for intracranial pressure (ICP). It is recommended that a closing pressure be
measured after CSF sampling through a lumbar puncture, particularly if the
opening pressure is abnormal.

CASE 2-1A A 46-year-old woman suddenly collapsed with jerking movements and
vomiting. She was brought to the emergency department 30 minutes
later. The patient was in good health except for high blood pressure and
cigarette smoking. She took no medications, had no history of
recreational drug use, and had never had seizures before. On arrival at the
emergency department, she was urgently intubated and given a 2000 mg
IV levetiracetam load. Emergent head CT (FIGURE 2-1) demonstrated
diffuse subarachnoid hemorrhage (SAH). She was emergently transferred
to a comprehensive stroke center. Before transfer, she had intact
brainstem reflexes and was spontaneously moving all limbs.
On arrival at the comprehensive stroke center, her heart rate was
105 beats/min in sinus rhythm. Her blood pressure was 180/110 mm Hg,
and her temperature was 38 °C (100.4 °F). She was intubated, and oxygen
saturation was 98% on 100% FIO2. Urine pregnancy test was negative, and
finger stick glucose was 110 mg/dL. On train-of-four testing (peripheral
nerve stimulator test for depth of neuromuscular blockade), she had 4/4
twitches, suggesting no residual effect of the pharmacologic paralytic
agent. On examination, the patient was in a cervical spine immobilization
collar. After her propofol drip was stopped for 20 minutes, she remained
obtunded. She grimaced symmetrically and slowly withdrew all four
extremities to deep noxious stimuli. Her pupils were 5 mm, equal, and
reactive. When her eyes were held open, she had forced downward gaze.
Corneal, cough, and gag responses were present but diminished. She had
bilateral spontaneously upgoing toes, hyperactive deep tendon reflexes
without clonus, and increased tone in bilateral lower extremities.
Emergent CT head demonstrated acute obstructive hydrocephalus
with dilated temporal horns of the lateral ventricle, dilated third
ventricle, acute blood in the distal cerebral aqueduct and fourth
ventricle, and evidence of transependymal CSF flow (FIGURE 2-2).
An external ventricular drain (EVD) for acute obstructive
hydrocephalus was emergently placed. Upon insertion, the patient had
an elevated CSF opening pressure of greater than 25 cm H2O. CSF was
slowly drained through an open EVD set at 20 mm Hg above the midbrain,
FIGURE 2-1
Initial imaging of the patient in CASE 2-1A. Axial noncontrast head CT shows acute
subarachnoid hemorrhage with intraventricular extension (A), with focal clot in the
interhemispheric fissure (B), perimesencephalic cistern (C), and fourth ventricle (D).
1208 OCTOBER 2021

after which the patient’s intracranial pressure (ICP) returned to 18 mm Hg.
The EVD was clamped for continuous ICP monitoring and only opened for
ICP greater than 20 mm Hg. Acute hypertension was treated with a
continuous IV labetalol drip titrated to maintain systolic blood pressure at
less than 140 mm Hg to minimize the risk for cerebral aneurysm rerupture.
Follow-up CT demonstrated reduced acute hydrocephalus, and CT
angiography suggested the presence of an anterior communicating artery
cerebral aneurysm. The patient was then taken for urgent digital
subtraction angiography, which confirmed the presence of an anterior
communicating artery cerebral aneurysm with intramural thrombosis
(FIGURES 2-3). The aneurysm was successfully coil embolized (FIGURES 2-4).
FIGURE 2-2
Follow-up imaging of the patient in CASE 2-1A. Axial noncontrast head CT shows the presence
of basilar subarachnoid blood with dense clot filling the fourth ventricle (A, solid arrow
points to the fourth ventricular clot, dotted arrow points to the prepontine subarachnoid
hemorrhage). Compared with initial imaging, the patient now has dilated temporal horns
of the lateral ventricles (B, C, solid arrows in B point to temporal horns) with evidence of
transependymal CSF flow (C, dotted arrow), dilated third ventricle (C, solid arrow), and
acute clot in the cerebral aqueduct (B, dotted arrow).
FIGURE 2-3
Imaging of the patient in CASE 2-1A. Digital subtraction angiography lateral (A) and magnified
transorbital oblique views (B) with internal carotid artery (ICA) contrast injection
demonstrate the presence of an anterior communicating artery cerebral aneurysm
(A, B, solid arrow) with partial intramural thrombosis (dotted arrow).
ACA = anterior cerebral artery; MCA = middle cerebral artery. CONTINUED ON
PAGE 1210

CONTINUED FROM
PAGE 1209
FIGURE 2-4
Imaging of the patient in CASE 2-1A. Successful endovascular coil embolization of the
anterior communicating artery cerebral aneurysm (A) in magnified transorbital oblique
view with internal carotid artery (ICA) contrast injection, with no further contrast filling in
the coiled aneurysm (solid arrow) on frontal view cerebral angiography with ICA contrast
injection (B).
ACA = anterior cerebral artery; MCA = middle cerebral artery.
COMMENT This case illustrates the classic hyperacute clinical presentation, initial triage,
differential diagnosis, and emergent treatment of acute aneurysmal SAH,
including the prehospital phase. The initial presentation of aneurysmal SAH
can often mimic seizure, acute stroke, trauma from fall/collapse, or
cardiopulmonary emergencies and can easily be misdiagnosed.
Life-threatening hyperacute complications from this phase of SAH include
acute hydrocephalus, aneurysm rerupture, and SAH-associated acute
extra–central nervous system organ dysfunctions, such as acute respiratory
failure. Early and accurate diagnosis of aneurysmal SAH and emergent transfer
to a high-volume center with neurosurgical, endovascular, and neurocritical
care support can improve the patient’s chances for survival and favorable
outcome.
Vessel Imaging to Identify Source of Bleeding

Once a patient is identified as having clinical and radiographic findings
suggestive of aneurysmal SAH and following acute stabilization of airway,
breathing, and spontaneous circulation as well as intracranial pressure, acute
hydrocephalus, or mass effect on the brain, a key next step is to rapidly identify
and secure the bleeding source. For those without contraindications, cerebral
CT angiography (CTA) is often the first-line vessel imaging modality because
it can be rapidly obtained together with the initial hyperacute diagnostic head
CT. Cerebral CTA has 90% to 97% sensitivity in detecting an intracranial
aneurysm compared to digital subtraction angiography (DSA) with three-
dimensional reconstructions, which remains the gold standard diagnostic
1210 OCTOBER 2021

modality for cerebral aneurysms. A negative CTA is insufficient to rule out the
presence of a bleeding aneurysm in patients with aneurysmal SAH, particularly
when the bleeding aneurysm is smaller than 4 mm.55 When cerebral aneurysms
are detected on CTA, patients often still proceed to DSA, which is also a
potential therapeutic modality for endovascular treatment of the bleeding
aneurysm.
Perimesencephalic Subarachnoid Hemorrhage

Patients with no aneurysms found on DSA with three-dimensional
reconstructions are often referred to as having “angio-negative” SAH. A large
proportion of these patients may have a CT pattern of perimesencephalic SAH, in
which the presence of subarachnoid blood is isolated to the perimesencephalic or
prepontine cisterns and no vascular malformations are found on DSA or other
diagnostics. The population incidence of perimesencephalic SAH is
approximately 0.5 per 100,000 person-years. This is thought to be a
nonaneurysmal benign variant of primary SAH for which prognosis is generally
excellent (CASE 2-2).56,57 Unlike aneurysmal SAH, perimesencephalic SAH
affects men more often than women.58 Approximately 10% of perimesencephalic
pattern SAHs are due to rupture of posterior circulation aneurysms. For
perimesencephalic pattern SAH, cerebral CTA and three-dimensional DSA have
similar sensitivity in detecting an aneurysm, and whether DSA is needed
following a negative CTA remains controversial.
Of patients with a classic aneurysmal pattern of bleed on CT and negative
initial DSA, between 4% and 25% may later be diagnosed with a vascular
malformation on repeat DSA or develop life-threatening rebleeding.56,59 A repeat
DSA days to weeks later can detect an aneurysm in 7% to 14% of these patients.60
Many centers will perform repeat DSA in patients with SAH with negative
initial DSA to minimize the risk of missing an acute bleeding source. Overall,
approximately 15% of patients with primary SAH do not have a bleeding
source identified on imaging.61 FIGURE 2-6 summarizes a clinical algorithm for
the acute diagnosis and evaluation of SAH.
The Ottawa Subarachnoid Hemorrhage Rulea,b TABLE 2-3
Investigate if one or more high-risk variables present:

◆ Age ≥40 years
◆ Neck pain or stiffness
◆ Witnessed loss of consciousness
◆ Onset during exertion
◆ Thunderclap headache (reaching maximum intensity within 1 minute of onset)
◆ Limited neck flexion on examination
a
Data from Perry JJ, et al, CMAJ.40
b
The Ottawa Subarachnoid Hemorrhage Rule applies to patients older than 15 years of age with new severe
nontraumatic headache reaching maximum intensity within 1 hour.

HYPERACUTE STABILIZATION AND MANAGEMENT CONSIDERATIONS

Hyperacute life-threatening complications that can occur shortly after initial
aneurysm bleeding include acute cardiopulmonary failure,62-65 acute
hydrocephalus, diffuse cerebral edema66,67 and aneurysm rebleeding.68,69 These
events may occur in the prehospital phase, during initial evaluation and
treatment in the emergency department, during acute interhospital transfer,
or shortly after admission to the ICU. Acute symptomatic hydrocephalus can
develop within minutes to days of aneurysm rupture and occurs in 20% of
patients with SAH. Timely insertion of an external ventricular catheter for acute
symptomatic hydrocephalus is lifesaving. TABLE 2-770 summarizes possible
etiologies and clinical features of these hyperacute life-threatening events with
aneurysmal SAH and resuscitative options.
Cardiopulmonary Dysfunction and Cardiac Arrest With Aneurysmal

Subarachnoid Hemorrhage
Patients with aneurysmal SAH can present in extremis, including presenting in
cardiopulmonary arrest,62-65 or may present with milder initial symptoms but
then acutely deteriorate, often because of aneurysm rerupture or acute
hydrocephalus. It is important to recognize aneurysmal SAH as a potential
etiology in patients presenting with cardiac arrest, as delayed diagnosis is
associated with high mortality. Although patients who present in cardiac arrest
from aneurysmal SAH often have poor-grade SAH and high associated mortality
and morbidity, a large 2020 multicenter cohort study showed good outcome is
possible, and up to 25% patients with aneurysmal SAH who survived cardiac
arrest were discharged to home after index aneurysmal SAH admission.64
Within the first week of SAH, acute left ventricular dysfunction is observed in
up to 30% of patients, in whom severe cases can lead to significant reduction in
ejection fraction and cardiogenic shock.71 This phenomenon, often referred to as
neurogenic myocardial stunning or stress cardiomyopathy, is thought to be secondary
to the sudden catecholamine surge following cerebral aneurysm rupture, leading
TABLE 2-4 Commonly Used Subarachnoid Hemorrhage Clinical Severity Grading

Scales
World Federation of Neurological

Grade Hunt and Hess Scale44 Surgeons Scale45
Glasgow Coma Scale (GCS) score of 15,
1 Asymptomatic or mild headache, minimal or no nuchal rigidity
motor deficit absent
Moderate to severe headache, nuchal rigidity, and no neurologic

2 GCS score of 13-14, motor deficit absent
deficit other than cranial nerve palsy
Mild alteration in mental status (confusion, lethargy), with or without

3 GCS score of 13-14, motor deficit present
mild focal neurologic deficit
GCS score of 7-12, motor deficit absent or

4 Stupor and/or hemiparesis
present
GCS score of 3-6, motor deficit absent or

5 Comatose and/or decerebrate rigidity and/or no motor response
present
1212 OCTOBER 2021

Commonly Used Subarachnoid Hemorrhage Radiologic Severity Grading TABLE 2-5
Scales
Grade Fisher Scale49 Modified Fisher Scale50 Hijdra Scale51,a
0 NA No subarachnoid hemorrhage No blood in the cistern or ventricle

(SAH) or intraventricular
hemorrhage (IVH)
1 No SAH or IVH Localized or diffuse thin SAH, Small amount of blood in cistern,
with no IVH sedimentation of blood in the
posterior part of ventricle
2 Diffuse deposition of thin layers of Localized or diffuse thin SAH, Moderate amount of blood in
subarachnoid blood with vertical layers of with IVH cistern, ventricle partly filled with
blood (interhemispheric fissure, insular blood
cistern, ambient cistern) <1 mm thick
3 Vertical layers of blood (interhemispheric Localized or diffuse thick SAH, Cistern completely filled with
fissure, insular cistern, ambient cistern) ≥1 mm with no IVH blood, ventricle completely filled
thick or localized clots (defined as >3 5 mm) with blood
4 Intracerebral or intraventricular clots with Localized or diffuse thick SAH, NA

diffuse SAH or no subarachnoid blood with IVH
NA = not applicable.
a
Hijdra Scale grades each of the 10 cisterns and each of the four ventricles.
Characteristic CT Appearance of Aneurysmal Subarachnoid Hemorrhage TABLE 2-6
CT features Aneurysm locations
Preponderance of subarachnoid blood in the basal All

cisterns
Subarachnoid blood along the sylvian fissure More common with middle cerebral artery aneurysms
Subarachnoid blood in the interhemispheric fissure More common with anterior communicating artery or anterior
cerebral artery aneurysms
Subarachnoid blood in the interpeduncular cistern All
Subarachnoid blood in prepontine area, fourth ventricular Posterior circulation aneurysms

outlet, and foramen magnum
Focal anterior temporal lobe intracerebral hematoma More common with middle cerebral artery aneurysms
Focal frontal lobe intracerebral hematoma More common with anterior communicating artery or anterior
cerebral artery aneurysms
Concomitant subdural hematoma without associated head A less typical presentation of aneurysmal subarachnoid
trauma hemorrhage
Focal subarachnoid blood in the prepontine area Perimesencephalic subarachnoid hemorrhage with no
cerebrovascular malformations identified
CT = computed tomography.

CASE 2-2 A 55-year-old man with a history of type 2 diabetes and chronic back pain
presented to the emergency department after developing a sudden
severe headache originating from the posterior neck and radiating to the
top of his head. His headache was much improved by the time he arrived
at the emergency department. He had no other neurologic symptoms. His
neck had been manipulated by a chiropractor earlier in the day. The
patient had no history of alcohol or tobacco use. He took metformin daily
and naproxen occasionally for pain.
On examination, his temperature was 36.2 °C (97.2 °F), blood pressure
was 154/87 mm Hg, heart rate was 81 beats/min, respiratory rate was
22 respirations/minute, and arterial blood oxygen saturation was 98% on
room air. He was alert and oriented. Cranial nerves, sensation, and
strength were all intact. His laboratory values were within normal
parameters except for glucose of 298 mg/dL. Urine toxicology screen
was negative.
Emergent head CT without IV contrast demonstrated acute
subarachnoid hemorrhage (SAH) in the premedullary, prepontine, and
perimesencephalic cisterns (FIGURES 2-5A through 2-5C). Subarachnoid
blood further extended into the suprasellar, sylvian, and the
quadrigeminal cisterns (FIGURE 2-5D), which is atypical for benign
nonaneurysmal SAH. CT angiography was not performed because the
patient had a contrast allergy. After adequate premedication, the patient
underwent diagnostic digital subtraction angiography (DSA) with
three-dimensional reconstruction, on which no cerebrovascular
abnormalities were detected. Specifically, no intracranial aneurysm or
vertebral artery dissection was seen.
The patient was admitted to the neurocritical care unit and started on a
clevidipine drip to target systolic blood pressure of less than 140 mm Hg
to minimize the risk for rebleeding. He was monitored with neurologic
checks every 2 hours, started on nimodipine 60 mg orally every 4 hours
for prevention of delayed cerebral ischemia, and underwent daily
transcranial Doppler ultrasound to monitor for cerebral vasospasm. He
underwent MRI of brain and cervical spine and MR angiography (MRA) of
the head and neck to evaluate for the presence of occult vascular
abnormalities. Other than mild disk degeneration, facet hypertrophy, and
foraminal stenosis, MRI and MRA detected no abnormalities.
The patient remained in the neurocritical care unit under close
monitoring for the next 7 days. He remained neurologically intact except
for headache and neck pain treated with oral acetaminophen. He
remained on an IV clevidipine drip intermittently for hypertension control
and required insulin for control of hyperglycemia. The patient underwent
repeat DSA on postbleed day 7 after adequate premedication for
contrast allergy. Once again, no cerebral aneurysm or other vascular
abnormalities were detected. Strict blood pressure control to a systolic
blood pressure less than 140 mm Hg with continuous IV antihypertensive
medication was no longer indicated, and he was weaned off clevidipine.
He remained stable and was discharged to home the next day.
1214 OCTOBER 2021

FIGURE 2-5
Imaging of the patient in CASE 2-2. Axial noncontrast head CT shows acute subarachnoid
hemorrhage in the premedullary (A), prepontine (B), and perimesencephalic cisterns (C).
Higher and more diffuse subarachnoid blood extension to the suprasellar and sylvian
cisterns and posterior extension in the quadrigeminal cistern (D) is an atypical feature for
classic benign subarachnoid hemorrhage and raises concern for a possible underlying
vascular malformation. Red arrows point to the acute blood clot in the subarachnoid space.
This case illustrates the presentation and relatively benign clinical course COMMENT
of nonaneurysmal SAH. In addition to the classic CT appearance of
perimesencephalic SAH, this patient had some atypical CT features
concerning for a possible underlying aneurysmal source for the bleed.
Although most nonaneurysmal SAHs have a benign clinical course, in
atypical cases, patients can develop delayed cerebral vasospasm, delayed
hydrocephalus, or even rebleeding from an occult cerebral aneurysm not
visualized on the initial DSA. A common practice is to closely monitor these
patients in a neurocritical care setting for these rare complications for
several days and to perform a second DSA to confirm the absence of
cerebral vascular malformation.

FIGURE 2-6
Algorithm for subarachnoid hemorrhage (SAH) investigation.
CTA = computed tomography angiography; DSA = digital subtraction angiography; LP = lumbar puncture;
MRI/A = magnetic resonance imaging/angiography; PRES = posterior reversible encephalopathy syndrome.
Reprinted with permission from MacDonald RL, Schweizer TA, Lancet.1 © 2016 Elsevier Ltd.
to myocardial cell contraction band necrosis.72,73 Echocardiography may show

diffuse or cardiac regional wall motion abnormality/hypokinesis with systolic
dysfunction. A classic appearance of neurogenic stunned myocardium is left
ventricle apical akinesis leading to ballooning of the apex during systole, often
referred to as takotsubo cardiomyopathy as the left ventricular shape resembles
that of a Japanese octopus trap (CASE 2-3). With appropriate critical care support,
the myocardial stunning often improves over days to weeks, with recovery of left
ventricular systolic function.
On ECG, patients often have QTc prolongation followed by T-wave
abnormalities, and some will eventually develop a deeply inverted T wave, often
referred to as cerebral T wave. Troponin elevation is common and seen in up to
30% of patients with SAH. Timely diagnosis and treatment of neurogenic
myocardial stunning is important as the reduced cardiac output can directly
affect cerebral perfusion, and patients are at increased risk for cardiac
arrhythmias, including malignant rhythms such as ventricular tachycardia and
fibrillation, which may lead to secondary insults to the acutely injured brain. The
presence of QTc prolongation, troponin elevation, and neurogenic stunned
myocardium have all been shown to predict unfavorable SAH outcomes.74
Acute pulmonary dysfunction and hypoxic respiratory insufficiency are
common after SAH and have multiple etiologies, including respiratory depression
and poor airway protection because of coma or altered consciousness, lung injury
1216 OCTOBER 2021

Hyperacute Life-threatening Complications of Aneurysmal Subarachnoid TABLE 2-7
Hemorrhage and Management Considerations
Clinical condition Etiology and clinical features Hyperacute management
Respiratory Inability to protect airway because of coma/ Assess adequacy of airway, breathing,
insufficiency62,63 obtundation from acute intracranial pressure (ICP) oxygenation, and ventilation
elevation, hematoma mass effect, diffuse cerebral
If clinically indicated, intubate and initiate
edema, hydrocephalus, or seizure
mechanical ventilation
Acute aspiration from vomiting and altered mental
For nonintubated patients: close monitoring for
status from acute subarachnoid hemorrhage (SAH)
delayed onset respiratory failure
Hypoxia from neurogenic pulmonary edema
Hemodynamic Acute hypertension secondary to SAH-associated Assess adequacy of systemic circulation and
instability, sympathetic surge and high ICP tissue perfusion In patients presenting in cardiac
including arrest or shock, resuscitate to establish return of
Acute neurogenic cardiac arrhythmia and/or
presenting in spontaneous circulation
cardiac arrest
cardiac arrest64,65
Consider and treat neurogenic causes for shock
Reduced cardiac output and/or cardiogenic shock
and cardiac arrhythmia in acute hemodynamic
secondary to neurogenic stunned myocardium
resuscitation
Acute Acute blood in the subarachnoid space and/or Emergent CSF diversion by inserting external
hydrocephalus70 intraventricular hemorrhage extension can lead to ventricular drain can be lifesaving; in cases in
acute obstructive hydrocephalus which the CSF space is compartmentalized
because of hematoma obstruction, more than
Symptoms of acute hydrocephalus include
one external ventricular drain may be necessary
decreasing levels of consciousness, impaired
to adequately alleviate acute hydrocephalus
upgaze, sixth nerve palsies; end-stage symptoms
include respiratory depression, bradycardia, and
hypertension (the Cushing response)
Aneurysm Rebleeding from ruptured cerebral aneurysm is Tightly control blood pressure and avoid extreme
rebleeding often lethal, with associated mortality rate up to blood pressure peaks; guideline
60% recommendations are to keep systolic blood
pressure <160 mm Hg; practice variations exist,
Highest rebleeding risk is within first 72 hours of
and many centers may target a lower blood
aneurysm rupture (up to 23%); after the first month,
pressure threshold in patients with a ruptured
rebleeding risk drops down to 3% per year
and unsecured cerebral aneurysm
Risk factors include poor-grade SAH, hypertension,
Timely obliteration of bleeding aneurysma
large aneurysm, and possibly the use of antiplatelet
agents Short-term use of antifibrinolytic drug
(ε-aminocaproic acid) may be safe but does not
reduce rebleeding rate; prolonged use
(>72 hours) is associated with increased
thrombotic complications
Global cerebral Acute global cerebral edema on SAH presentation Presence of global cerebral edema may lead to
edema and ICP occurs in 8-29% of patients and is associated with ICP elevation and abnormal cerebral perfusion
elevation66,67 mortality and poor outcome and metabolism.
No clinical trial data exist to guide management
specifically in SAH; consider osmotic therapy to
reduce edema and normalize ICP; a cerebral
perfusion pressure–driven or other multimodal
monitoring goal-directed management protocol
for diffuse cerebral edema is reasonable

a
See TABLE 2-10 for further guideline recommendations from the American Heart Association/American Stroke Association and the Neurocritical
Care Society.

CASE 2-3 A 70-year-old woman with a history of hypertension and smoking was
found unresponsive in a bathroom. Emergency medical services found
her obtunded with minimal respiratory effort and a weak pulse; she was
emergently intubated and brought to the emergency department.
On arrival, her blood pressure was 75/50 mm Hg, her temperature was
36.8 °C (98.2 °F), and her heart rate was 110 beats/min with intermittent
premature ventricular contractions. Finger stick glucose was 220 mg/dL.
Urine toxicology screen was negative. Her extremities were cold and
clammy. Her oxygen saturation was 92% on 80% FIO2. Significant
laboratory values included elevated creatinine at 2.1 mg/dL, elevated
blood lactate of 3.5 mmol/L, elevated cardiac troponin at 5.5 ng/mL, and
leukocytosis at 17,000 cells/mm3. ECG showed QTc prolongation and
T-wave inversion without active ischemic changes. Bedside ultrasound
showed significantly reduced left ventricular contractility with apical
akinesis and ballooning consistent with takotsubo cardiomyopathy. Lung
ultrasound showed pulmonary edema. An emergent central venous
catheter was inserted, and norepinephrine infusion was started to
maintain a mean arterial pressure greater than 65 mm Hg.
Following hemodynamic resuscitation and without sedative
medications, the patient’s neurologic examination demonstrated no
response to noxious stimuli, sluggishly reactive pupils at 4 mm, forced
downward gaze, limited vertical and horizontal eye movements on
oculocephalic maneuvers, diminished corneal responses, and absent
cough and gag reflexes. Emergent head CT revealed diffuse thick
subarachnoid hemorrhage (SAH) with extension into all ventricles (FIGURE 2-7).
The patient was diagnosed with World Federation of Neurological
Surgeons Scale grade 5, modified Fisher Scale grade 4 acute SAH.
A large right frontal external ventricular drain (EVD) was urgently
inserted, and CSF squirted out under high opening pressure. The patient
was taken for digital subtraction angiography, which showed a large
basilar tip aneurysm that was successfully coil embolized (FIGURE 2-8). The
patient was subsequently admitted to the neurocritical care unit and
received continuous vasopressor support for cardiogenic shock and
mechanical ventilation for hypoxic respiratory failure. She remained
obtunded and only grimaced sluggishly and sluggishly withdrew
extremities to noxious stimuli.
Over the next 5 days, the patient’s neurologic examination showed no
improvement. Continuous EEG showed diffuse low-amplitude slowing
with no epileptiform discharges. Her EVD was intermittently occluded
from blood clots and had to be replaced twice. Her intracranial pressure
remained below 20 mm Hg except for transient periods when the EVD
was occluded. Troponin peaked at 15 ng/mL. She developed systemic
inflammatory response syndrome, with persistent fever requiring
1218 OCTOBER 2021

targeted temperature management with acetaminophen plus continuous
surface cooling. Infectious workup found acute gram-positive
pneumonia, and the patient was appropriately covered with
broad-spectrum antibiotics. She had persistent acute kidney injury with
oliguria and rising serum creatinine. Given the patient’s progressive
multiorgan failure, high-grade SAH, and known wishes, her family
transitioned her to comfort-focused care and she was compassionately
extubated.
FIGURE 2-7
Imaging of the patient in CASE 2-3. Axial noncontrast head CT shows extensive dense
(“thick” in modified Fisher Scale) acute subarachnoid hemorrhage involving multiple
cisterns (A) with extensive intraventricular extension from the lateral ventricles (B) through
the fourth ventricle (C, D). Yellow arrow points to a large-bore external ventricular drain
that terminates in the right lateral ventricle, inserted for emergent CSF diversion.
This case illustrates a classic presentation of posterior circulation COMMENT

aneurysm rupture leading to high-grade SAH with associated acute
cardiopulmonary failure, neurogenic stunned myocardium with takotsubo
pattern on echocardiogram, and cardiogenic shock. This patient’s hypoxic
respiratory failure was likely caused by a combination of cardiogenic and
neurogenic pulmonary edema. With extensive intraventricular blood
extension, intermittent obstruction and clotting of even a large-bore EVD
can occur, further complicating acute management of hydrocephalus.
High-grade SAH increases a patient’s risk for multiorgan dysfunction with
SAH.
CONTINUED ON
PAGE 1220

CONTINUED FROM
PAGE 1219
FIGURE 2-8
Cerebral angiography frontal view with
left vertebral artery contrast injection
of the patient in CASE 2-3 demonstrates
the presence of a large basilar tip
aneurysm (A), which was successfully
coil-embolized (B, C). The solid red
arrow points to the basilar tip
aneurysm, and the dashed red arrow
points to coiled aneurysm, which is no
longer filling with contrast.
1220 OCTOBER 2021

from acute aspiration from nausea/vomiting, pulmonary ventilation/perfusion KEY POINTS
mismatch from calcium channel blocker use, cardiogenic pulmonary edema from
● The most common cause
neurogenic myocardial stunning, or, in rare cases, primary neurogenic of spontaneous SAH is a
pulmonary edema. To date, the precise mechanism of primary neurogenic ruptured cerebral aneurysm
pulmonary edema remains poorly understood, and treatment remains supportive (85%). Approximately 10% to
care.75 Timely diagnosis and treatment of acute respiratory insufficiency in SAH 15% of patients with SAH do
not have an identifiable
is important to minimize further brain injury due to hypoxia.
bleeding source; of these,
approximately 38% have
Aneurysm Rebleeding and Timing of Aneurysm Surgery nonaneurysmal
Rerupture of the bleeding cerebral aneurysm following aneurysmal SAH is perimesencephalic SAH,
which is a benign variant of
associated with very high mortality and morbidity. Short-term use of an
SAH with generally
antifibrinolytic drug (ε-aminocaproic acid) may be safe but does not reduce the excellent prognosis.
rebleeding rate. Prolonged use (>72 hours) is associated with increased
thrombotic complications.76 Endovascular and open neurosurgical obliteration of ● Hyperacute
the bleeding aneurysm effectively reduces the risk for aneurysm rebleeding. life-threatening
complications that can
The best timing for aneurysm obliteration must balance the urgency to minimize occur shortly after initial
rebleeding risk against the risks of aneurysm intervention, as aneurysm aneurysm bleeding include
treatment itself is associated with cerebral ischemia and may potentiate acute cardiopulmonary
SAH-associated brain injury when the injured brain is more vulnerable (refer to failure, acute
hydrocephalus, diffuse
the section on early brain injury).68,69 The cumulative rebleeding risk of a cerebral edema, and
ruptured cerebral aneurysm is highest within the first 72 hours of aneurysm aneurysm rebleeding.
rupture (8% to 23%). Aneurysm obliteration has generally moved to within
72 hours of rupture since a clinical trial showed no outcome difference between ● Acute symptomatic
hydrocephalus can develop
aneurysm treatment within 3 days of rupture compared to delaying treatment
within minutes to days of
after 7 days.77 Guidelines from the AHA/ASA, the Neurocritical Care Society, aneurysm rupture and
and the European Stroke Organization all recommend aneurysm obliteration as occurs in 20% of patients
early as feasible to minimize rebleeding risk. Currently, there are significant with SAH. Timely insertion of
global practice variabilities on timing of aneurysm obliteration across centers.78 an external ventricular
catheter for acute
The data on the benefit of aneurysm obliteration within 24 hours compared with symptomatic hydrocephalus
24 to 72 hours after bleeding are mixed, with one study showing possible worse is lifesaving.
outcome for aneurysms treated within 24 hours of rupture.68,79,80
● Acute cardiopulmonary
dysfunction is common in
Aneurysm Treatment Approaches SAH and often requires
Following acute stabilization of a patient with aneurysmal SAH, the next most critical care resuscitation
important step is to secure the bleeding cerebral aneurysm. Surgical and and support. In severe
endovascular options for aneurysm occlusion have improved significantly in cases, SAH may present
with cardiac arrest. It is
recent decades and continue to evolve rapidly. The treatment approach often
important to recognize
depends on aneurysm location, morphology, patient characteristics, and risk aneurysmal SAH as a
profiles. This is often a collaborative decision made by physicians with open and potential etiology in patients
with endovascular expertise. General consensus is that, if amenable, endovascular presenting with cardiac
arrest, as delayed diagnosis
approaches are preferred for posterior circulation aneurysm locations such as a
is associated with high
basilar tip aneurysm. ISAT (the International Subarachnoid Aneurysm Trial) mortality.
compared endovascular coiling to open surgical clipping in patients in whom the
treating physicians felt that either approach would be appropriate. ISAT found
that endovascular coiling is associated with higher odds of survival without
disability at 1 year after SAH, and this risk reduction lasts for at least 7 years.81 The
endovascular approach is associated with a slightly higher rate of aneurysm
recurrence; the long-term risk of recurrent SAH is low with either the
endovascular or open surgical approach, although slightly higher with the
endovascular approach.82

FIGURE 2-9
Early brain injury mechanisms in aneurysmal subarachnoid hemorrhage. Hemorrhage into various compartments (subarachnoid,
intraventricular, intracerebral, subdural) can cause brain shift, increased intracranial pressure, herniation, Duret brainstem hemorrhages,
and death. Systemic effects of subarachnoid hemorrhage include cardiac and pulmonary complications. Brain injury from this
condition initially is due to transient global ischemia and effects of the hemorrhage. Delayed neurologic complications can ensue.
MMPs = matrix metalloproteinases.
Reprinted with permission from MacDonald RL, Schweizer TA, Lancet.1 © 2016 Elsevier Ltd.
1222 OCTOBER 2021

Since ISAT, endovascular techniques have evolved further, and newer devices KEY POINTS
such as flow-diverting stents and web devices have made it possible to treat
● Neurogenic myocardial
aneurysms that had not been amenable to endovascular or surgical approaches. stunning with acute left
Treatment of ruptured and unruptured cerebral aneurysms has been shifting ventricular dysfunction
toward the endovascular approach, but open surgical approaches are still used, occurs in up to 30% of
particularly in cases requiring hematoma evacuation for mass effect, prior patients with SAH and can
lead to reduced cardiac
incomplete aneurysm obliteration, or distal aneurysms. BRAT (the Barrow
output and cardiogenic
Ruptured Aneurysm Trial), performed 1 decade after ISAT, randomly assigned shock. A classic appearance
eligible patients to endovascular coil embolization or microsurgical clipping. The of neurogenic stunned
BRAT study found the endovascular arm had fewer poor outcomes at 1 year, myocardium is left ventricle
apical akinesis leading to
but a substantial number of patients randomly assigned to the endovascular arm
ballooning of the apex
crossed over to the surgical clipping arm, suggesting surgical clipping remains during systole, often
an important alternative therapy.83 referred to as takotsubo
cardiomyopathy. Timely
SUBARACHNOID HEMORRHAGE–ASSOCIATED BRAIN INJURY appropriate critical care
support is important to
A prominent clinical feature of aneurysmal SAH is that a subset of patients will maintain adequate perfusion
develop progressive neurologic deterioration and accrue brain injury despite the to the brain and body in
successful obliteration of the bleeding cerebral aneurysm and critical care patients with SAH with
support. Historically, this clinical neurologic deterioration has been thought to be neurogenic stunned
myocardium.
caused by cerebral vasospasm and subsequent ischemic injury to the brain.
Multiple terminologies have been used to refer to this phenomenon, including ● Acute pulmonary
delayed cerebral ischemia (DCI). Much of the basic and clinical investigation on dysfunction and hypoxic
aneurysmal SAH in past decades was focused on prevention of cerebral respiratory insufficiency are
common after SAH and have
vasospasm and DCI as a means to improve overall patient outcome and reduce
multiple etiologies. Timely
morbidity and mortality. In the past decade, a series of large, well-powered, diagnosis and treatment of
multicenter, randomized controlled trials testing various agents that had showed acute respiratory
promising preclinical and early clinical signals in effectively reducing cerebral insufficiency in SAH is
important to minimize
vasospasm failed to demonstrate outcome benefit despite angiographic
further brain injury due to
improvement. A paradigm shift has since begun in the approach to hypoxia.
understanding SAH-associated brain injuries and neurologic dysfunction, which
is likely a complex multiphasic process involving multiple different ● Aneurysm rerupture in
pathophysiologic mechanisms. SAH leads to high mortality
and morbidity. Timely
obliteration of a bleeding
Phase 1: Early Brain Injury (0 to 72 Hours) aneurysm by endovascular
Early brain injury begins at the time of acute cerebral aneurysm rupture, which or microsurgical techniques
can lead to sudden transient ICP elevation, transient global ischemia, and a very effectively reduces the
risk of rerupture.
cascade of pathologic processes leading to injury and cell death (FIGURE 2-9).84,85 Endovascular treatment of
Included in early brain injury is any direct brain tissue damage by an bleeding aneurysms is
intracranial hematoma secondary to aneurysm rupture. Systemically, early brain associated with higher
injury is associated with multiple hyperacute extra–central nervous system acute survival and better
outcomes and, when
organ dysfunctions (TABLE 2-7) and a systemic inflammatory response
possible, is the preferred
syndrome characterized by tachycardia, fever, tachypnea, and leukocytosis.86 treatment modality.
However, some aneurysms
Phase 2: Delayed Cerebral Ischemia (3 to 21 days) may not be amenable to
endovascular approaches
DCI (FIGURE 2-1087) is an SAH-associated brain injury process that typically
and may require
develops 3 to 21 days following aneurysm rupture and remains one of the microsurgical clipping.
strongest predictors of poor outcome in patients with SAH who survived initial
bleeding.87,88 The term ischemia is misleading, as emerging evidence suggests that
ischemia is only one of the many pathophysiologic processes involved in this
phase of SAH-associated brain injury. Numerous overlapping terminologies with

FIGURE 2-10
Delayed cerebral ischemia pathophysiology in aneurysmal subarachnoid hemorrhage.
Reprinted with permission from MacDonald RL, Nat Rev Neurol.87 © 2013 Springer Nature Limited.
variable definitions have been used in the literature to denote this second phase
of brain injury and its clinical and possible associated radiologic features, leading
to further confusion.89 In 2019, a multidisciplinary international panel convened
to establish common data elements for SAH to standardize naming and definition
of SAH-associated terminologies and facilitate research advancement.90,91
TABLE 2-8 summarizes common SAH-associated brain injuries and their
definitions as used in recent large clinical trials.92
The clinical diagnosis of DCI is often challenging and involves a process
of exclusion. A number of cohort studies have identified various different
risk factors for DCI, but by far the most consistent and strongest predictor
for DCI is the initial SAH clinical severity. The diagnosis of DCI in patients
with high-grade SAH is even more difficult, as many patients may already
demonstrate significant neurologic impairment or are sedated, limiting the
sensitivity of clinical neurologic examination in screening for ongoing brain
injury.93 Significant practice variabilities exist in the diagnosis and monitoring
for DCI, from clinical examination to a combination of clinical and
diagnostic monitoring.
CEREBRAL VASOSPASM. A key feature in aneurysmal SAH is that up to 70% of all

patients may subsequently develop cerebral vasoconstriction visible on DSA,
typically between 3 and 21 days following initial aneurysm rupture. As
summarized in FIGURE 2-10, current data suggest that large vessel cerebral
1224 OCTOBER 2021

vasospasm is one of the many processes that contribute to DCI in aneurysmal
SAH. However, as ischemia from large vessel vasospasm is currently the only
potentially clinically reversible etiology of DCI, the intensive care unit
monitoring protocol for DCI is largely focused on early detection of
cerebral vasospasm.
Similar to DCI, the concept of cerebral vasospasm is also plagued with
multiple and overlapping terminologies and definitions (TABLE 2-8).
Angiographic vasospasm usually refers to large vessel cerebral vasospasm visible
on DSA with various degrees of severity. In SAH clinical trials, angiographic
vasospasm is most commonly defined as reduction of cerebral artery diameter by
more than two-thirds of its baseline caliber.92 It is important to note that
angiographic vasospasm may or may not be clinically symptomatic, and the
severity of angiographic narrowing is not well correlated with clinical symptoms
or SAH outcome. Although some degree of vasoconstriction/vasospasm is visible
angiographically in up to 70% of patients with SAH, only 30% of all patients with
SAH develop clinical symptoms attributable to ischemia from vasospasm visible
on angiography. A common terminology used for this is symptomatic vasospasm,
which is often used interchangeably with DCI or clinical deterioration due to
DCI, among many others. Unlike angiographic vasospasm, the presence of
symptomatic vasospasm is associated with DCI and poor outcome following
SAH.94,95 It important to note that in the SAH literature, symptomatic vasospasm
and DCI often have overlapping definitions and may be referring to the same
clinical phenomenon.
Terminologies and Definitions in Subarachnoid Hemorrhage–Associated Brain Injury TABLE 2-8
Terminology Definition
Clinical deterioration caused by delayed The occurrence of focal neurologic impairment (such as hemiparesis, aphasia,
cerebral ischemia apraxia, hemianopia, or neglect) or a decrease of at least 2 points on the Glasgow
Coma Scale score (either on the total score or on one of its individual
components) lasting at least 1 hour, not immediately apparent after aneurysm
occlusion, and cannot be attributed to other causes by clinical, radiographic, or
laboratory investigations
Cerebral infarction due to delayed The presence of cerebral infarction on CT or MRI of the brain within 6 weeks of
cerebral ischemia subarachnoid hemorrhage (SAH) or proven at autopsy, not present on CT or MRI
between 24 and 48 hours after aneurysm occlusion
Delayed ischemic neurologic deficit92 A decrease of ≥2 points on the modified Glasgow Coma Scale score or an
increase of ≥2 points on the abbreviated National Institutes of Health Stroke Scale
score lasting for at least 2 hours
Angiographic cerebral vasospasm Constriction of cerebral arteries visible on diagnostic cerebral angiography
following SAH; in most recent large clinical trials, vasospasm is defined as
reduction of cerebral arterial diameter by more than two-thirds from baseline92;
not clearly associated with delayed cerebral ischemia or SAH functional outcome
Symptomatic cerebral vasospasm Patients with SAH develop clinical symptoms attributable to ischemia from visible
vasospasm on angiography
CT = computed tomography; MRI = magnetic resonance imaging.

CASE 2-1B Following successful endovascular aneurysm coil embolization, the

patient in CASE 2-1A was admitted to the neurocritical care unit. She arrived
intubated with oxygen saturation of 96% on 80% FIO2 and positive
end-expiratory pressure (PEEP) of 5 cm H2O. Chest x-ray showed
evidence of gross aspiration. Bedside bronchoscopy successfully
removed gastric content, and her oxygenation improved. Off sedation,
the patient was able to open her eyes to voice and sluggishly follow
commands. Her brainstem reflexes were intact. She moved all
extremities equally with antigravity strength. She was started on
nimodipine 60 mg through a nasogastric tube every 4 hours for 21 days.
Because of clinical seizurelike activity at initial presentation, she was
continued on levetiracetam 1000 mg through a nasogastric tube 2 times a
day for seizure prophylaxis. She was also started on low-molecular-
weight heparin injections for venous thromboembolism prophylaxis.
On post–subarachnoid hemorrhage (SAH) day 2, the patient was
extubated successfully. She was oriented to self and place but not to
time and was intermittently drowsy. She began daily transcranial Doppler
ultrasound studies for monitoring of delayed cerebral vasospasm. IV
boluses were used to maintain euvolemia, measured by total fluid
balance and clinical assessment. Her mean arterial pressure was 70 mm
Hg to 80 mm Hg.
On post-SAH day 5, the patient became febrile to 38.5 °C (101.3 °F) with
leukocytosis. Chest x-ray, urinalysis, CSF analysis, and blood culture
were all negative. Venous duplex studies did not find any deep venous
thrombosis as the potential occult cause of fever, and she was started on
acetaminophen for fever control. She had no focal weakness but
appeared impulsive and delirious. She developed tachycardia, with heart
rate of approximately 100 beats/min to 110 beats/min, and hypertension
with systolic blood pressure 170 mm Hg to 180 mm Hg. The Lindegaard
ratios on transcranial Doppler were 2.9 on the left and 3.2 on the right
(normal reference <3), suggesting possible mild vasospasm in the right
middle cerebral artery.
The next morning, on post-SAH day 6, the patient remained febrile and
developed voluminous urine output at 400 mL/h to 600 mL/h, and plasma
sodium dropped to 132 mmol/L, consistent with cerebral salt wasting
syndrome. She then suddenly developed bilateral lower extremity plegia
with increased tone. Her intracranial pressure was 15 mm Hg. She was
immediately resuscitated with 30 mL/kg of 4 °C (39.2 °F) IV normal saline
(0.9% sodium chloride) bolus. Emergent head CT showed no new
hemorrhage or infarct. She was started on a norepinephrine infusion
through a subclavian central line to maintain systolic blood pressure at
180 mm Hg to 220 mm Hg and taken emergently for digital subtraction
angiography (DSA), which showed severe flow-limiting vasospasm in
multiple segments of bilateral anterior cerebral arteries (FIGURES 2-11) and
mild to moderate vasospasm of right middle cerebral artery M2 segments
(FIGURES 2-11A and 2-11B). She was treated with 10 mg intraarterial nicardipine
injections to both internal carotid arteries. Subsequently, the patient’s
new neurologic deficits resolved. She remained on a norepinephrine drip
to maintain systolic blood pressure at 180 Hg mm to 220 mm Hg. For
1226 OCTOBER 2021

high-volume urine output and hyponatremia consistent with cerebral salt
wasting syndrome, she was treated with hourly IV fluid boluses to replace
urinary fluid loss and to maintain even to 500 mL positive total body fluid
balance. She was started on fludrocortisone, and her polyuria improved.
FIGURE 2-11
Imaging of the patient in CASE 2-1B. Panels A and C are cerebral angiography images from post–
subarachnoid hemorrhage (SAH) day 6. Panels B and D are cerebral angiography images from
day of initial presentation with SAH. Anterior-posterior view of right internal carotid artery
(ICA) injection from emergent digital subtraction angiography (DSA) following acute
deterioration on post–SAH day 6 (A) demonstrates severe vasospasm (solid red arrows) in
distal A1 and throughout subsequent segments of the right anterior cerebral artery (ACA) with
significantly delayed arterial filling in the ACA territory compared to DSA obtained on day of
admission (B). Calibers of M2 branches of the right middle cerebral artery (MCA) are also
reduced (dashed red arrow) compared to DSA from day of admission, consistent with mild to
moderate vasospasm. Oblique view of left ICA injection from emergent DSA following acute
deterioration on post–subarachnoid hemorrhage day 6 (C) demonstrates severe vasospasm
(solid red arrows) with sausage appearance in A2 branch and diffuse vasospasm of its distal
segments (dashed red arrows) of the left ACA with delayed arterial filling in the ACA territory
compared to DSA obtained on day of admission (D). CONTINUED ON
PCA = posterior cerebral artery. PAGE 1228

CONTINUED FROM
PAGE 1227 On post-SAH day 8, the patient again acute bilateral lower extremity
developed weakness, DSA showed persistent severe bilateral anterior
cerebral artery vasospasm treated with angioplasty of the proximal
anterior cerebral arteries and intraarterial nicardipine infusion through
both internal carotid arteries. Postendovascular rescue, the patient’s
new neurologic deficits resolved.
Over the next few days, the patient continued on supportive therapy
for symptomatic cerebral vasospasm, including fluid resuscitation to
maintain euvolemia, induced hyperdynamic therapy to maintain systolic
blood pressure at 180 mm Hg to 240 mm Hg, continued CSF diversion,
and targeted temperature management to maintain euthermia
(temperature target 36.5 °C to 37.5 °C [97.7 °F to 99.5 °F]). The patient
did not develop any further acute neurologic symptoms, and her clinical
condition gradually improved, with less fever and resolving polyuria, and
she became more alert and oriented. The patient was gradually weaned
off the norepinephrine drip provided she had no new neurologic
deterioration. Her external ventricular drain was removed, and she was
able to transfer out of the intensive care unit on post-SAH day 17. She
had significant deconditioning and protein malnutrition following the
prolonged critical illness and required physical therapy for strength and
coordination training. On post-SAH day 20, she was discharged to home.
COMMENT This case illustrates the classic presentation, disease course, clinical
monitoring, and treatment considerations for severe symptomatic cerebral
vasospasm following aneurysmal SAH. This case also illustrates how
transcranial Doppler as a screening modality may not detect all clinically
significant vasospasm, particularly in more distal segments of cerebral
arteries such as the severe A2 segment vasospasm in this case. This patient
had refractory cerebral vasospasm requiring repeated endovascular
rescue therapy and induced hyperdynamic therapy with inotropic
vasopressors such as norepinephrine to maintain cerebral perfusion. In this
case, timely diagnosis of symptomatic vasospasm with rapid resuscitation
to correct hypovolemia from cerebral salt wasting and endovascular
rescue therapy likely prevented sustained delayed cerebral ischemia, and
the patient had a relatively good outcome at hospital discharge. Many
patients with favorable outcome at hospital discharge (modified Rankin
Scale score of <3) still experience significant disabling symptoms, which
can include headaches, cognitive and memory dysfunction, mood disorder,
sexual dysfunction, mental and physical fatigue, sleep disorders, and
anosmia, even at 1 year following SAH.97 Long-term follow-up, consultation
with the physical medicine and rehabilitation team, and targeted therapy
are important for continued care of survivors of aneurysmal SAH.
1228 OCTOBER 2021

Transcranial Doppler (TCD) ultrasound monitoring of cerebral artery flow KEY POINTS
velocity is commonly used as a low-risk noninvasive tool to monitor for the
● A prominent clinical
presence of cerebral vasospasm following acute SAH. TCD has reasonable feature of SAH is that a
sensitivity and specificity to detect vasospasm in the circle of Willis cerebral subset of patients will
arteries, particularly the proximal segments of the middle cerebral artery develop progressive
(MCA) and internal carotid artery (ICA). TCD is less reliable in detecting neurologic deterioration and
additional brain injury
vasospasm in the anterior cerebral artery (ACA) branches and posterior
despite the successful
circulation arteries.96 The Lindegaard ratio, defined as the ratio of mean MCA obliteration of the bleeding
flow velocity divided by mean ICA flow velocity, is typically used to diagnose cerebral aneurysm and
vasospasm in the MCA when the ratio is above 3. However, it is important to critical care support. Brain
injury following SAH is
note that the sensitivity and specificity of TCD for detecting cerebral
multiphasic and caused by
vasospasm is operator dependent, that different laboratories may use multiple pathophysiologic
different threshold values for cerebral vasospasm, and that some patients do processes, including
not have adequate temporal bone windows to allow detection of TCD signals. ischemia from vasospasm.
When using TCD to monitor cerebral vasospasm, results must be interpreted
● Early brain injury
with clinical correlation, and negative TCD studies do not rule out the following SAH begins at the
presence of vasospasm or the risk for symptomatic DCI (CASE 2-1B). More time of acute cerebral
advanced modes of TCD have been used to detect cerebral autoregulation aneurysm rupture when
dysfunction and microemboli in SAH and DCI, but the use of these techniques sudden intracranial pressure
elevation causes transient
remains experimental at this time.98,99 DSA remains the gold standard for global cerebral ischemia and
diagnosis of large- and medium-caliber cerebral artery vasospasm. brain tissue damage by
In patients at high risk for severe angiographic vasospasm or those who have intracranial hematoma.
known angiographic vasospasm, the acute onset of neurologic symptoms
● Delayed cerebral
attributable to ischemia corresponding to the vascular territory at risk likely
ischemia is an
represents acute cerebral hypoperfusion that may lead to permanent cell death if SAH-associated brain injury
perfusion is not rapidly restored. This forms the basis of many empiric treatment process that typically
protocols for symptomatic vasospasm/DCI, such as hemodynamic augmentation develops 3 to 21 days
to enhance cerebral blood flow and endovascular rescue therapy in acute following aneurysm rupture
and remains the strongest
symptomatic vasospasm. No high-quality clinical trial data are available to guide predictor of poor outcome.
management in these clinical scenarios. As a result, significant variabilities in The term ischemia is
management approaches exist, and this remains one of the most debated areas of misleading, as many
SAH management. different pathophysiologic
mechanisms contribute to
Common forms of acute endovascular rescue therapy involve intraarterial this phase of brain injury.
infusion of a vasodilatory drug, such as nicardipine or verapamil, and balloon
angioplasty.9,87 These interventions have not been studied in large
randomized clinical trials, and their global efficacy remain unknown. Use of
endovascular therapy is very much dependent on local practice patterns at
each center. These interventions can be associated with significant
procedure-related complications. Current expert recommendations suggest
reserving these for patients with clinically symptomatic vasospasm rather
than empirically treating all patients with angiographic or TCD evidence of
vasospasm.5,9 It is important to note that in patients with severe clinical grade
SAH who have severe disorders of consciousness or already have a severe
neurologic deficit from early brain injury, their poor baseline examination
makes the diagnosis of symptomatic vasospasm difficult and highly variable
between clinicians. Some centers use advanced multimodal monitoring
techniques or imaging modalities, such as CT or magnetic resonance perfusion
studies, to assist in treatment decision making. Currently, no systematic
study data on these approaches are available, and their use remains
experimental.

PREVENTION AND TREATMENT OF DELAYED CEREBRAL ISCHEMIA BEYOND TREATMENT

OF ANGIOGRAPHIC VASOSPASM. To date, the only therapeutic agent with Class I
evidence for decreasing risk of poor outcome in SAH is nimodipine started
within 96 hours of initial hemorrhage and continued at 60 mg every 4 hours for
21 consecutive days.100 A common misconception is that nimodipine exerts
therapeutic benefit through reducing cerebral vasospasm. In a randomized
clinical trial, the rate of angiographic vasospasm was similar between treatment
arms, whereas the nimodipine arm had a reduced rate of DCI.
Numerous other therapeutics, such as fasudil, cilostazol, intrathecal
fibrinolytics, and intrathecal vasodilators such as nicardipine, have been
evaluated in smaller clinical trials and meta-analyses and are thought to
demonstrate possible efficacy in protection against DCI and improve aneurysmal
SAH outcome. Although more data are needed and only low-grade evidence
supports the use of these agents, some centers empirically use these agents for
TABLE 2-9 Randomized Controlled Clinical Trials of Delayed Cerebral Ischemia

Therapeutics
Mechanism of
Agent action Dose studied Result
Nimodipine (1983)102 Calcium channel 60 mg orally every Reduced severe disability/death

blocker 4 hours for 21 days post–subarachnoid hemorrhage
(SAH); no change in incidence of
vasospasm
Nicardipine (1992)103,104 Calcium channel 0.075 mg/kg/h IV for Reduced incidence of

blocker 14 days symptomatic and angiographic
vasospasm; no difference in SAH
outcome
Tirilazad mesylate (1992-1999)105-107 Free radical Multiple doses were Reduced incidence of
scavenger studied symptomatic vasospasm and
infarct; no change in outcome
Clazosentan (2011) CONSCIOUS-2 Selective 5 mg/h for 14 days Reduced need for endovascular
(Clazosentan in Reducing endothelin-1b rescue therapy for vasospasm;
Vasospasm-related Morbidity and receptor antagonist no difference in SAH outcome
All-cause Mortality in Adult Patients
With Aneurysmal Subarachnoid
Hemorrhage Treated by Surgical
Clipping)92
Magnesium (2012) MASH-2 (Magnesium Multiple 64 mmol/d IV infusion No difference in SAH outcome
for Aneurysmal Subarachnoid mechanisms
Hemorrhage)108
Simvastatin (2014) STASH (Simvastatin in Multiple 40 mg/d orally for No difference in SAH outcome at
Aneurysmal Subarachnoid mechanisms 21 days 6 months
Hemorrhage)109
Intrathecal nimodipine (2020) NEWTON2 Calcium channel Extended release Trial stopped early because of
(Study of EG-1962 Compared to blocker 600 mg nimodipine futility; no difference in rate of
Standard of Care Oral Nimodipine in bound to angiographic vasospasm or poor
Adults With Aneurysmal Subarachnoid microparticle SAH outcome
Hemorrhage)101
1230 OCTOBER 2021

DCI treatment or prevention. Meanwhile, several therapeutics have been tested KEY POINTS
in large well-powered multicenter randomized clinical trials and showed no
● Multiple overlapping
efficacy in improving SAH functional outcome, although some reduced the terminologies used to
incidence of angiographic vasospasm.92 The 2020 NEWTON2 (Study of EG-1962 describe secondary
Compared to Standard of Care Oral Nimodipine in Adults With Aneurysmal neurologic deterioration and
Subarachnoid Hemorrhage) randomized clinical trial on intrathecal nimodipine brain injury lead to
confusion over clinical
to improve SAH outcome was stopped early following interim analysis
entities and monitoring
demonstrating futility.101 TABLE 2-9102-109 summarizes the large randomized approaches. Consensus
clinical trial evidence in DCI prevention to date. common data elements and
Intravascular hypovolemia is associated with DCI and unfavorable neurologic definitions for clinical
deterioration due to delayed
outcomes in aneurysmal SAH.87 Hypovolemia is a particular concern in
cerebral ischemia, cerebral
aneurysmal SAH as a subset of patients develop SAH-associated cerebral salt infarction due to delayed
wasting syndrome, in which rapid natriuresis may lead to acute intravascular cerebral ischemia,
hypovolemia and hyponatremia. Historically, inducing intravascular angiographic cerebral
hypervolemia as part of the hypervolemic, hypertensive, and hemodilutional vasospasm, and
symptomatic cerebral
(Triple H) therapy was used to support patients with DCI or cerebral vasospasm vasospasm are available and
or even used prophylactically before clinical evidence of DCI or vasospasm was should be used to minimize
seen. Studies have since shown that prophylactic use of Triple H therapy is not confusion.
associated with any improved SAH outcome but increases cardiopulmonary
● Up to 70% of all patients
complications and is not recommended in modern neurocritical care practice.87 with aneurysmal SAH may
Current guidelines by the Neurocritical Care Society and the AHA/ASA subsequently develop
recommend avoiding hypovolemia and maintaining intravascular euvolemia in visible cerebral
aneurysmal SAH (TABLE 2-10110). vasoconstriction on digital
subtraction angiography
between 3 and 21 days
ACUTE COMPLICATIONS OF SUBARACHNOID HEMORRHAGE AND following initial aneurysm
CRITICAL CARE MANAGEMENT CONSIDERATIONS rupture, but only 30% will
Acute SAH is a critical illness that often leads to multiorgan dysfunction in develop clinical symptoms
attributable to ischemia
addition to brain injury. Optimal neurocritical care requires support and
from vasospasm.
optimization of both acute brain dysfunction and systemic dysfunctions that Symptomatic vasospasm is
may secondarily worsen brain injury processes. After patients with SAH survive associated with delayed
the hyperacute period and aneurysm intervention and while their brains are cerebral ischemia and
susceptible to DCI, patients with SAH often develop some, if not all, of the unfavorable SAH outcome,
whereas angiographic
following complications commonly seen during acute SAH course. These vasospasm is not.
common complications and their management recommendations per the latest
AHA/ASA and Neurocritical Care Society guidelines are summarized in TABLE 2-10.
Seizures and Nonconvulsive Status Epilepticus

The clinical presentation of acute onset of aneurysm rupture or rerupture can
include seizurelike symptoms (CASE 2-1A). Given the emergent and critical
onset of these symptoms, confirmatory testing with EEG is often impractical
when these symptoms are present. Up to 26% of patients with aneurysmal
SAH may present with seizurelike symptoms at onset.5,9 Although no
high-level evidence exists to support clinical efficacy, many clinicians empirically
load anticonvulsants during hyperacute resuscitation until the patient is stabilized.
Clinicians may choose to continue anticonvulsant use until the bleeding cerebral
aneurysm is surgically obliterated based on the assumption that seizures may
cause rapid spikes in blood pressure and increase the risk for aneurysm rebleed.
Following successful obliteration of the bleeding aneurysm, discontinuation of
anticonvulsants can be considered. It is important to note that nonconvulsive
seizures and nonconvulsive status epilepticus are seen in up to 18% of comatose

TABLE 2-10 Summary of Key Management Recommendations from the American Heart
Association/American Stroke Association and Neurocritical Care Society
Guidelinesa
Treatment American Heart Association/

decision American Stroke Association5,b Neurocritical Care Society,9,c
Hospital/system Low-volume hospitals (eg, fewer than 10 Patients with SAH should be treated at high-volume
characteristics subarachnoid hemorrhage [SAH] cases per centers (moderate quality of evidence, strong
year) should consider early transfer of patients recommendation).
with SAH to high-volume centers (eg, more than
High-volume centers should have appropriate
35 SAH cases per year) with experienced
specialty neurointensive care units, neurointensivists,
cerebrovascular surgeons, endovascular
vascular neurosurgeons, and interventional
specialists, and multidisciplinary neurointensive
neuroradiologists to provide the essential elements of
care services (Class I, Level B).
care (moderate quality of evidence, strong
After discharge, it is reasonable to refer recommendation).
patients with SAH for a comprehensive
evaluation, including cognitive, behavioral, and
psychosocial assessments (Class IIa, Level B).
Aneurysm Surgical clipping or endovascular coiling of the Early aneurysm repair should be undertaken, when
treatment ruptured aneurysm should be performed as possible and reasonable, to prevent rebleeding (high
early as feasible in the majority of patients to quality of evidence, strong recommendation).
reduce the rate of rebleeding after SAH (Class I,
An early, short course of antifibrinolytic therapy prior
Level B).
to early aneurysm repair (begun at diagnosis and
For patients with ruptured aneurysms judged to continued up to the point at which the aneurysm is
be technically amenable to either endovascular secured or at 72 hours postictus, whichever is shorter)
coiling and neurosurgical clipping, endovascular should be considered (low quality of evidence, weak
coiling should be considered (Class I, Level B). recommendation).
Complete obliteration of the aneurysm is Delayed (more than 48 hours after the ictus) or
recommended whenever possible (Class I, prolonged (more than 3 days) antifibrinolytic therapy
Level B). Stenting of a ruptured aneurysm is exposes patients to side effects of therapy when the
associated with increased morbidity and risk of rebleeding is sharply reduced and should be
mortality (Class III, Level C). avoided (high quality of evidence, strong
recommendation).
For patients with an unavoidable delay in
obliteration of aneurysm, a significant risk of
rebleeding, and no compelling medical
contraindications, short-term (less than
72 hours) therapy with tranexamic acid or
aminocaproic acid is reasonable to reduce the
risk of early aneurysm rebleeding (Class IIa,
Level B).
Blood pressure Between the time of SAH symptom onset and Treat extreme hypertension in patients with an
control aneurysm obliteration, blood pressure should unsecured, recently ruptured aneurysm. Modest
be controlled with a titratable agent to balance elevations in blood pressure (mean blood pressure of
the risk of stroke, hypertension-related less than 110 mm Hg) do not require therapy.
rebleeding, and maintenance of cerebral Premorbid baseline blood pressures should be used
perfusion pressure (Class I, Level B). to refine targets and hypotension should be avoided
(low quality of evidence, strong recommendation).
The magnitude of blood pressure control to
reduce the risk of rebleeding has not been
established, but a decrease in systolic blood
pressure to less than 160 mm Hg is reasonable
(Class IIa, Level C).
CONTINUED ON PAGE 1233
1232 OCTOBER 2021

CONTINUED FROM PAGE 1232

Intravascular Maintenance of euvolemia and normal Intravascular volume management should target
volume status circulating blood volume is recommended to euvolemia and avoid prophylactic hypervolemic
prevent delayed cerebral ischemia (Class I, therapy. In contrast, there is evidence for harm from
Level B). aggressive administration of fluid aimed at achieving
hypervolemia (moderate quality of evidence, strong
recommendation).
Cardiopulmonary No recommendations given. Baseline cardiac assessment with serial enzymes, ECG,
complications and echocardiography is recommended, especially in
patients with evidence of myocardial dysfunction (low
quality of evidence, strong recommendation).
Monitoring of cardiac output may be useful in patients
with evidence of hemodynamic instability or
myocardial dysfunction (low quality of evidence,
strong recommendation).
Seizures The use of prophylactic anticonvulsants may be Routine use of anticonvulsant prophylaxis with
considered in the immediate posthemorrhagic phenytoin is not recommended after SAH (low quality
period (Class IIb, Level B). of evidence, strong recommendation).
The routine long-term use of anticonvulsants is If anticonvulsant prophylaxis is used, a short course
not recommended (Class III, Level B). (3–7 days) is recommended (low quality of evidence,
weak recommendation).
Continuous EEG monitoring should be considered in
patients with poor-grade SAH who fail to improve or who
have neurologic deterioration of undetermined etiology
(low quality of evidence, strong recommendation).
Fever treatment Aggressive control of fever to a target of During the period of risk for delayed cerebral ischemia,
normothermia by use of standard or advanced control of fever is desirable; intensity should reflect
temperature modulating systems is reasonable the individual patient’s relative risk of ischemia (low
in the acute phase of SAH (Class IIa, Level B). quality of evidence, strong recommendation).
Surface cooling or intravascular devices are more
effective and should be employed when antipyretics
fail in cases where fever control is highly desirable
(high quality of evidence, strong recommendation).
Glucose control Careful glucose management with strict Hypoglycemia (serum glucose of less than 80 mg/dL)
avoidance of hypoglycemia may be considered should be avoided (high quality of evidence, strong
as part of the general critical care management recommendation).
of patients with SAH (Class IIb, Level B).
Serum glucose should be maintained below 200 mg/dL
(moderate quality of evidence, strong recommendation).
Deep vein Heparin-induced thrombocytopenia and deep Measures to prevent deep vein thrombosis should be
thrombosis vein thrombosis are relatively frequent employed in all patients with SAH (high quality of
prophylaxis complications after SAH. Early identification evidence, strong recommendation).
and targeted treatment are recommended, but
The use of unfractionated heparin for prophylaxis
further research is needed to identify the ideal
could be started 24 hours after undergoing aneurysm
screening paradigms (Class I, Level B).
obliteration (moderate quality of evidence, strong
recommendation).


Delayed cerebral Oral nimodipine should be administered to all Oral nimodipine (60 mg every 4 hours) should be
ischemia patients with SAH (Class I, Level A). administered after SAH for a period of 21 days (high
quality of evidence, strong recommendation).
Maintenance of euvolemia and normal
circulating blood volume is recommended to The goal should be maintaining euvolemia, rather than
prevent delayed cerebral ischemia (Class I, attempting hypervolemia (moderate quality of
Level B). evidence, strong recommendation).
Prophylactic hypervolemia or balloon Transcranial Doppler may be used for monitoring and
angioplasty before the development of detection of large artery vasospasm with variable
angiographic spasm is not recommended (Class sensitivity (moderate quality of evidence, strong
III, Level B). recommendation).
Transcranial Doppler is reasonable to monitor Digital subtraction angiography is the gold standard
for the development of arterial vasospasm for detection of large artery vasospasm (high quality of
(Class IIa, Level B). evidence, strong recommendation).
Perfusion imaging with CT or MRI can be useful Patients clinically suspected of delayed cerebral
to identify regions of potential brain ischemia ischemia should undergo a trial of induced
(Class IIa, Level B). hypertension (moderate quality of evidence, strong
recommendation).
Induction of hypertension is recommended for
patients with delayed cerebral ischemia unless Endovascular treatment using intraarterial vasodilators
blood pressure is elevated at baseline or and/or angioplasty may be considered for
cardiac status precludes it (Class I, Level B). vasospasm-related delayed cerebral ischemia
(moderate quality of evidence, strong
Cerebral angioplasty and/or selective
recommendation).
intraarterial vasodilator therapy is reasonable in
patients with symptomatic vasospasm,
particularly those who are not responding to
hypertensive therapy (Class IIa, Level B).
Anemia and The use of packed red blood cell transfusion to Patients should receive packed red blood cell
transfusion treat anemia might be reasonable in patients transfusions to maintain hemoglobin concentration
with SAH who are at risk of cerebral ischemia. above 8–10 g/dL (moderate quality of evidence, strong
The optimal hemoglobin goal is still to be recommendation).
determined (Class IIb, Level B).
Hyponatremia The use of fludrocortisone acetate and Fluid restriction should not be used to treat
hypertonic saline solution is reasonable for hyponatremia (weak quality of evidence, strong
preventing and correcting hyponatremia (Class recommendation).
IIa, Level B).
Early treatment with hydrocortisone or
fludrocortisone may be used to limit natriuresis and
hyponatremia (moderate quality of evidence, weak
recommendation).
Mild hypertonic saline solutions can be used to
correct hyponatremia (very low quality of evidence,
strong recommendation).
CT = computed tomography; ECG = electrocardiogram; EEG = electroencephalogram; MRI = magnetic resonance imaging.
a
Reprinted with permission from Suarez JI, Continuum (Minneap Minn).110 © 2015 American Academy of Neurology.
b
American Heart Association/American Stroke Association recommendations follow the American Heart Association Stroke Council’s methods of
classifying the level of certainty of the treatment effect and the class of evidence.
c
For the Neurocritical Care Society’s guidelines, the quality of the data was assessed and recommendations developed using the Grading of
Recommendations, Assessment, Development, and Evaluation (GRADE) system.
1234 OCTOBER 2021

SAH patients and they are associated with unfavorable outcome.111,112 As a result, KEY POINTS
experts recommend continuous EEG studies in patients with high-grade SAH who
● Transcranial Doppler
remain comatose or encephalopathic following resuscitation. Currently, no data (TCD) ultrasound is a
are available on whether continuous EEG or anticonvulsant use affects SAH common modality used to
outcome. For more information on the use of continuous EEG in the management monitor for the
of SAH, refer to the article “Seizures, Status Epilepticus, and Continuous EEG in development of vasospasm.
TCD has adequate sensitivity
the Intensive Care Unit” by Eric S. Rosenthal, MD,113 in this issue of Continuum.
to detect vasospasm in the
Following obliteration of bleeding cerebral aneurysms, cohort studies circle of Willis vessels but is
suggest that in patients who did not present with seizurelike events, less reliable for distal vessel
discontinuation of anticonvulsants is safe, not associated with increased segments and posterior
circulation vessels. The
seizures, and, in fact, may be associated with more favorable SAH outcome and
sensitivity and specificity of
improved neurocognitive recovery, particularly with the use of phenytoin.114-116 TCD are operator and
Currently, very limited data are available on whether acute anticonvulsant use laboratory dependent. TCD
impacts the risk for developing long-term epilepsy, which occurs in 2% of results must be interpreted
survivors of SAH.1 with clinical correlation.
Negative TCD studies do not
rule out the presence of
Fever and Systemic Inflammatory Response Syndrome clinically significant
Fever is a common symptom in patients with hemorrhagic brain injuries. vasospasm.
Following SAH, up to 70% of patients develop fever during the acute
● In patients with acute
clinical course, which may be infectious, noninfectious/inflammatory, or neurologic deterioration
central/neurogenic in etiology.5,9 Febrile symptoms often parallel the onset of attributable to ischemia
DCI and overall critical illness severity; in patients with severe-grade SAH with from vasospasm, accepted
multiorgan dysfunction, it may be difficult to rule out infectious etiologies. Fever empiric treatments include
hemodynamic augmentation
is associated with higher SAH clinical severity and worse outcome, and small
to increase blood pressure
studies of targeted temperature management strategies suggest there may be a and endovascular rescue
signal toward improved SAH outcome.117 Current guidelines recommend fever therapy such as intraarterial
control, although larger clinical trials are still needed to determine whether and vasodilator infusion and
cerebral angioplasty.
how much fever control may be beneficial in SAH.
Prophylactic use of these
Systemic inflammatory response syndrome, characterized by a combination interventions is associated
of two or more clinical features of tachycardia, tachypnea, fever or hypothermia, with increased
and leukocytosis or leukopenia, is a clinical syndrome initially defined to capture complications and morbidity
inflammatory response to acute systemic disease such as sepsis. Systemic and is not recommended.
inflammatory response syndrome is prevalent in the clinical course of acute SAH ● To date, the only
and is associated with higher initial SAH severity, larger hematoma, and therapeutic agent with Class
unfavorable outcomes. Whether systemic inflammation exerts independent I evidence for decreasing
effects on worsening SAH-associated brain injury is currently unknown and is an the risk of poor outcome in
SAH is nimodipine started
area of active investigation.86 within 96 hours of the initial
hemorrhage and continued
Chronic Shunt-dependent Hydrocephalus for 21 consecutive days.
A subset of patients with SAH who required EVDs for CSF diversion may fail to
● A common misconception
wean from CSF drainage and require long-term CSF diversion via various types
is that nimodipine exerts
of shunting devices. The timing and method of EVD weaning following SAH and therapeutic benefit through
the threshold to convert to long-term CSF shunting are highly variable between reducing cerebral
centers. General risk factors for developing shunt-dependent hydrocephalus vasospasm. In a randomized
following SAH include older age, high clinical SAH grade, the need for EVD clinical trial, nimodipine use
reduced delayed cerebral
placement, a larger amount of SAH blood, and intraventricular hemorrhage.118 ischemia but had no impact
Although various small studies have investigated whether medications (such as on the rate of radiographic
dexamethasone) or other management strategies can prevent progression to vasospasm.
chronic shunt-dependent hydrocephalus following SAH,119 insufficient clinical
evidence is available to support any prophylactic strategy.

Hyponatremia
Hyponatremia is common following SAH and can occur at different stages of the
acute clinical course from different pathophysiologic processes. The two most
common causes of hyponatremia following SAH are the syndrome of
inappropriate secretion of antidiuretic hormone (SIADH) and cerebral salt
wasting syndrome.120 Accurate diagnosis of SIADH versus cerebral salt wasting
is very important in critical care support of patients with SAH at risk for DCI, as
these syndromes impact hemodynamic physiology differently and require
divergent treatment approaches.
The two syndromes cannot be distinguished by laboratory features; both
conditions have low serum sodium, high urine sodium, low serum osmolality,
and high urine osmolality. The most important distinguishing feature between
SIADH and cerebral salt wasting is the patient’s intravascular volume status.
Cerebral salt wasting can rapidly lead to clinically significant intravascular
hypovolemia, whereas SIADH occurs in a euvolemic state. One possible
distinguishing feature between cerebral salt wasting and SIADH is polyuria,
which is often present with cerebral salt wasting. Without timely diagnosis and
treatment, urinary loss of fluid and salt in cerebral salt wasting continues despite
intravascular hypovolemia and can lead to or worsen brain ischemia and
symptomatic DCI (CASE 2-1B). The focus in critical care management of cerebral
salt wasting in SAH is to restore and maintain intravascular euvolemia with
fluid resuscitation. Use of hypertonic solutions in cerebral salt wasting may not
sufficiently correct intravascular hypovolemia even if it restores serum sodium
to normal values. In some cases, cerebral salt wasting can present with very
high urine output of more than 500 mL/h, making it difficult to maintain
intravascular volume even with aggressive IV fluid resuscitation. Adding
fludrocortisone (0.1 mg to 0.3 mg 2 times a day) is reasonable in clinically
significant cerebral salt wasting. In a small randomized trial of cerebral salt
wasting due to tuberculous meningitis, fludrocortisone use resulted in earlier
normalization of serum sodium, although it did not impact outcome.121 No
randomized clinical trial data are available on fludrocortisone use in SAH. In
patients with SAH with active cerebral salt wasting and high urine output, it is
important to closely monitor and titrate treatment to intravascular volume status
and serum sodium in real time.
As discussed earlier in this article, intravascular hypovolemia can significantly
worsen brain injury and neurologic dysfunction in SAH, and an important principal
in critical care support of patients with acute SAH at risk for DCI is to strictly
maintain intravascular euvolemia. This can lead to the diagnostic challenge of
distinguishing cerebral salt wasting from SIADH, as successful critical care support
means the patient is never allowed to achieve a hypovolemic state. Although
SIADH is typically treated with fluid restriction, this may not be an option in
patients with SAH at high risk for DCI. The use of hypertonic fluid with high
sodium content is a reasonable approach to correct moderate to severe
hyponatremia while maintaining a euvolemic state in SAH patients with SIADH.
Anemia
A large number of patients with SAH develop progressive anemia during their
acute hospital course.122,123 Given the concern that anemia may reduce
oxygen-carrying capacity and oxygen delivery to the brain, particularly at
high-risk periods such as during DCI, red blood cell transfusions have been
1236 OCTOBER 2021

studied in an attempt to reduce brain injury and improve SAH outcome. KEY POINTS
However, red blood cell transfusions may also have detrimental effects in SAH,
● No high-quality data
such as further depletion of nitric oxide. Although small clinical trials suggested support the use of fasudil,
transfusion may be safe in SAH,124 whether transfusion is beneficial in SAH cilostazol, intrathecal
and the optimal hemoglobin target are currently unknown.123 SAHaRA fibrinolytics, and intrathecal
(Aneurysmal Subarachnoid Hemorrhage—Red Blood Cell Transfusion and vasodilators for delayed
cerebral ischemia treatment
Outcome), a large multicenter randomized control trial comparing a liberal
or prevention in SAH.
versus a restrictive red blood cell transfusion strategy in SAH, is ongoing.125
● The use of hypervolemic,
Post–Subarachnoid Hemorrhage Headaches and Pain Control hypertensive, and
More than 70% of all patients with aneurysmal SAH experience severe headaches hemodilutional (Triple H)
therapy is associated with
that are at times refractory to multiple analgesic agents, including opioids.126 increased cardiopulmonary
Many patients report insufficient pain control following SAH, and a significant complications and is not
number continue to use opioids following hospital discharge. Chronic headaches recommended in modern
may continue for more than a year after SAH.127,128 Steroids are often used neurocritical care for SAH.
clinically as an adjunct therapy for SAH-associated headaches, although no ● Intravascular
high-level evidence is available for either efficacy or harm in this approach.129 hypovolemia is associated
Novel narcotic-sparing approaches using pterygopalatine fossa or occipital nerve with delayed cerebral
blockade have shown efficacy in small case series.130,131 Larger clinical trials are ischemia and unfavorable
SAH outcomes and should
needed to determine if these newer approaches effectively control
be avoided. Guidelines
SAH-associated headaches and reduce chronic narcotic use. recommend maintenance of
normal intravascular volume
PROGNOSIS AND LONG-TERM RECOVERY in critical care support
during the high-risk period
Prognostication of SAH outcome is rapidly evolving over time, with many
for delayed cerebral
advances in surgical techniques, endovascular options, and critical care ischemia.
capabilities. Mortality from SAH has steadily decreased over past decades,
although no randomized clinical trial has successfully identified a therapeutic ● Up to 26% of patients with
agent that improves SAH outcome since the original nimodipine trial.132 Whereas SAH may present with
seizurelike symptoms at
the original Hunt and Hess and World Federation of Neurological Surgeons onset. Nonconvulsive
studies found patients with grade 5 SAH almost uniformly had unfavorable seizures and nonconvulsive
outcomes, more modern studies from the past decade found that up to 39% of status epilepticus are seen
patients with grade 5 SAH can achieve favorable clinical outcome and good in up to 18% of patients with
SAH who are comatose, and
cognitive function.133-136 Although high SAH clinical grade and older age remain they are associated with
important predictors for unfavorable long-term outcome in SAH, clinicians must unfavorable outcome.
be mindful of the time evolution and imprecision of current SAH prognostic Continuous EEG studies are
tools, particularly in discussions regarding futility of care. Even patients with recommended in patients
with high clinical suspicion
SAH with severe disability at hospital discharge can make significant gains
for seizures. Prolonged
with neurorehabilitation and achieve a moderate level of functional empiric anticonvulsant use,
independence.137-139 With the exception of patients who present with neurologic particularly phenytoin, is
examinations concerning for imminent brain death, it is reasonable to offer associated with less
favorable outcome and
state-of-the-art critical care resuscitation and support early in the acute course of
neurocognitive dysfunction.
SAH should this be consistent with the patient’s values and wishes.
With the reduction in mortality and severe morbidity from SAH, more data ● Fever is common
are now emerging on long-term survivorship and the long-term impacts of SAH following SAH and is
on patient-centered quality-of-life measures. Even in patients who achieve a associated with higher SAH
clinical severity and
favorable outcome as defined by a modified Rankin Scale of 2 or lower, unfavorable outcome.
significant numbers of survivors of SAH are unable to return to work and Current guidelines
report subjective health impairment and chronic symptoms such as cognitive recommend fever control in
dysfunction, anxiety, depression, and, particularly, fatigue.140-142 Unlike patients at higher risk of
delayed cerebral ischemia.
other patients with stroke, patients with SAH have good long-term physical

KEY POINTS function and independence in activities of daily living. Despite this, long-term
disability impacting daily life is common even at 7 years post-SAH.143 Few
● Hyponatremia is common
following SAH and is most
existing clinical trials have examined the potential impact of acute and
commonly caused by the subacute SAH treatment strategies on these long-term patient-centered
syndrome of inappropriate outcome measures. Clinical studies on SAH survivorship are urgently needed
secretion of antidiuretic to understand the burden of long-term disability and to explore strategies to
hormone (SIADH) or cerebral
improve quality of life in survivors of SAH.
salt wasting syndrome. The
correct diagnosis of SIADH
versus cerebral salt wasting
is very important as CONCLUSION
treatment approaches are
SAH is a neurologic emergency that tends to affect patients who are younger and
divergent.
female, and it continues to cause significant mortality and long-term morbidity.
● Without timely diagnosis In addition to having a life-threatening initial presentation requiring urgent
and treatment, cerebral salt transfer to centers equipped to provide emergent surgical, endovascular, and
wasting syndrome can critical care interventions, patients with SAH develop multiorgan dysfunctions
rapidly lead to hypovolemia,
worsen brain ischemia, and
requiring prolonged neurocritical care support in high-volume centers. Although
cause symptomatic delayed no new single drug or intervention has demonstrated efficacy in improving SAH
cerebral ischemia. outcome, mortality and morbidity from SAH have steadily improved over time,
Treatment of cerebral salt and favorable outcome is possible even in patients initially presenting with severe
wasting should focus on
restoring and maintaining
clinical grade SAH. Keys to optimizing good outcome in SAH include the following:
intravascular euvolemia with
fluid resuscitation. u Timely and accurate initial recognition and diagnosis of SAH
u Expeditious acute resuscitation and stabilization of life-threatening organ dysfunctions
● Although SIADH is and timely obliteration of the bleeding aneurysm to avoid rebleeding
typically treated with fluid
restriction, this may not be u Minimizing additional brain injury with close monitoring and high-quality neurocritical care
an option in patients with support through the high-risk period for DCI
SAH at high risk for delayed u Timely recognition, correct diagnosis, and guideline-driven treatment of multiorgan
cerebral ischemia. Use of dysfunctions to optimize protection of the injured brain
hypertonic fluid with high
sodium content is a u Neurorehabilitation and future studies on long-term follow-up care to reduce the burden
reasonable approach to of long-term disability on SAH survivors
correct moderate to severe
hyponatremia while
maintaining a euvolemic
state in SAH patients with ACKNOWLEDGMENTS
SIADH. This work was supported by a grant from the National Institute of Neurological
Disorders and Stroke (R21NS113037). The author would like to thank Bradley A.
● A large number of
patients with SAH develop
Gross, MD, for his help with imaging.
progressive anemia.
Whether transfusion is
beneficial in SAH and the REFERENCES
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307-315. doi:10.1159/000508577

REVIEW ARTICLE
Intracerebral
Hemorrhage

ONLINE
By Christa O’Hana S. Nobleza, MD, MSCI
ABSTRACT
PURPOSE OF REVIEW: Nontraumatic intracerebral hemorrhage (ICH) is the
second most common type of stroke. This article summarizes the basic
pathophysiology, classification, and management of ICH and discusses the
available evidence on therapy for hematoma, hematoma expansion, and
perihematomal edema.
RECENT FINDINGS: Current available data on potential therapeutic options for

ICH are promising, although none of the trials have shown improvement in
mortality rate. The literature available on reversal of anticoagulation and
antiplatelet agents after an ICH and resumption of these medications is
also increasing.
SUMMARY: ICH continues to have high morbidity and mortality. Advances in

therapeutic options to target secondary brain injury from the hematoma,
hematoma expansion, and perihematomal edema are increasing. Data on
reversal therapy for anticoagulant-associated or antiplatelet-associated
ICH and resumption of these medications are evolving.
INTRODUCTION
N
ontraumatic intracerebral hemorrhage (ICH) is the second most
CITE AS: prevalent type of stroke in the world, with a prevalence of
CONTINUUM (MINNEAP MINN) 17.9 million globally,1 and it accounts for up to 20% of all strokes.2
1246–1277. Primary ICH, usually due to cerebral small vessel damage,
comprised 26.2% of the 11,931,000 global incident strokes in 2017.3
Address correspondence to The American Heart Association’s 2020 stroke statistics show that a persistent
Dr Christa O’Hana S. Nobleza,
2500 N State St, Jackson,
racial disparity of ICH exists, with higher age-adjusted incidence of first-ever
MS 39216, christaohana14md@ ICH in Blacks than in Whites.1 In women, late menopause, gestational
yahoo.com. hypertension, pregnancy-associated hypertensive disorders, preterm delivery,
and stillbirth increase risk for ICH.4
Dr Nobleza reports no In the United States, the mortality rate for ICH declined from 31.6% for the
disclosure. years 2005-2009 to 24% in 2012-2015.5 The overall burden of ICH on patients,
UNLABELED USE OF caregivers, and society encompasses not only the financial burden of health care
PRODUCTS/INVESTIGATIONAL but also impaired patient and caregiver quality of life, severe disability, caregiver
USE DISCLOSURE:
burnout, and post–intensive care syndrome.6,7
Dr Nobleza reports no
disclosure.
INTRACEREBRAL HEMORRHAGE CLASSIFICATION
© 2021 American Academy
ICH can be classified according to etiology, risk factors, or anatomic location. A
of Neurology. general classification subdivides ICH into primary (or spontaneous) and
1246 OCTOBER 2021

secondary (or nonspontaneous) ICH. Primary ICH comprises ICH due to KEY POINTS
cerebral small vessel damage, most commonly associated with hypertension or
● The American Heart
cerebral amyloid angiopathy (CAA), whereas secondary ICHs are those with Association’s 2020 stroke
associated known etiologies. The classification schemes may have implications statistics show that a
for both clinical management and patient outcomes; however, this has not been persistent racial disparity of
well established, and their application should still be individualized. intracerebral hemorrhage
(ICH) exists, with higher
Primary intraventricular hemorrhage (IVH) is a type of nontraumatic ICH
age-adjusted incidence of
that occurs mainly in the ventricles and adjacent ependyma without associated first-ever ICH in Blacks than
parenchymal ICH. It is much less common than other types of nontraumatic in Whites. In women, late
ICH, accounting for only 3.1% of all nontraumatic ICH.8 Primary IVH is usually menopause, gestational
hypertension, pregnancy-
idiopathic; however, 11.4% of patients with IVH have associated etiologies,
associated hypertensive
including hypertension, arteriovenous malformation (AVM), moyamoya disorders, preterm delivery,
disease, coagulopathy, and arteriovenous fistula. IVH in association with ICH has and stillbirth increase risk
a prevalence of 40%.9 The presence of IVH dictates the potential need for for ICH.
external ventricular drain and intraventricular thrombolysis.10 The 2017 CLEAR
● Classification schemes
III (Clot Lysis: Evaluating Accelerated Resolution of Intraventricular for ICH may have
Hemorrhage Phase III) trial10 and three meta-analyses on intraventricular implications for both clinical
fibrinolysis clinical trials11 showed that intraventricular fibrinolysis had a trend of management and patient
improved mortality with no significant increase in complication rates, but no outcomes; however, this has
not been well established,
difference was seen in the primary outcome measure (good functional outcome) and their application should
and more patients in the thrombolysis group survived in a severely dependent still be individualized.
state (modified Rankin Scale [mRS] score of 5). Potential complications analyzed
in IVH and intraventricular fibrinolysis studies include symptomatic rebleeding ● Hypertension can be
present in patients with
and ventriculitis. Hydrocephalus may also develop in association with IVH.
either lobar or nonlobar ICH,
Assessing for acute hydrocephalus on noncontrast head CT is important because although it is more
of its association with poor outcome in patients with ICH.12 Acute hydrocephalus prominent in those with
can be seen as dilatation of a part or all of the ventricles, whereas subtle signs nonlobar ICH.
such as rounding of frontal horn, sulcal effacement, and increase in temporal
horn width can be seen as well.13,14 Some common manifestations include
headaches, nausea, vomiting, double vision, blurred vision, gait difficulty,
upgaze impairment, personality changes, and seizures.
COMMON ETIOLOGIES OF INTRACEREBRAL HEMORRHAGE

This section discusses common etiologies of nontraumatic ICH that can be
encountered by neurologists.
Hypertensive Angiopathy
Hypertension is the most common cause of ICH, affecting up to 35 per 100,000
people per year (CASE 3-1).15 Hypertensive ICH is associated with chronic
changes in small cerebral vasculature resulting in arteriosclerotic changes that,
under pressure, lose the autoregulatory mechanism and become prone to
rupture.16 Proinflammatory cytokines such as interleukin (IL), tumor necrosis
factor-a, and vascular endothelial growth factor (VEGF) have been found to play
an important role in the cascade of secondary injury in ICH due to
hypertension.17 The most common locations associated with hypertensive ICH
include the basal ganglia, pons, cerebellum, and thalamus, although it may
involve the lobar areas as well. Usage of the term hypertensive ICH to refer only to
nonlobar ICH has recently been put into question as data are showing that
hypertension can be present in patients with either lobar or nonlobar ICH,
although it is more prominent in those with nonlobar ICH.18 Use of illicit or

INTRACEREBRAL HEMORRHAGE
CASE 3-1 A 49-year-old man with a history of hypertension presented to the

emergency department with a chief complaint of sudden severe
headache and acute-onset left-sided weakness.
His Glasgow Coma Scale (GCS) score was 14. Emergent head CT
revealed a 22-mL right frontal hemorrhage (FIGURE 3-1). His systolic blood
pressure was found to be 220 mm Hg. Hydralazine 10 mg IV was
administered. An hour later, while in the emergency department, the
patient deteriorated to a GCS score of 5 and was subsequently intubated.
A repeat CT head was obtained (FIGURE 3-2).
His systolic blood pressure remained around 200 mm Hg. Nicardipine
infusion was started with a target systolic blood pressure goal of less than
140 mm Hg. Neurosurgery was called to assess him for candidacy for
external ventricular drain placement. Mannitol 1 g/kg was administered
while awaiting central vascular access.
An external ventricular drain was placed in the emergency department
while waiting transfer to the neurocritical care unit. His examination was
unchanged after external ventricular drain placement. His systolic blood
pressure was better controlled after titration of the nicardipine infusion
to 10 mg/h. The patient was then admitted to the neurocritical care
service for close neurologic monitoring and further supportive care.
His course was further complicated by ventilator-associated
pneumonia and requirement of tracheostomy and gastrostomy tube
placement because of his persistent comatose state. Other workup
during the hospitalization included a CT angiogram, MRI with and without
contrast, and digital subtraction angiography; however, no tumor or
vascular malformation was found. The workup for his intracerebral
hemorrhage suggested that the likely etiology for the spontaneous lobar
ICH was hypertension.
Palliative care was consulted to discuss goals of care with the family.
The family wanted to give the patient a time-limited trial before further
considering transitioning goals of care to a palliative level of care. He was
eventually transferred to a long-term acute care facility. At the 90-day
visit, the patient was off the ventilator; however, he continued to be in a
vegetative state that required maintenance of tracheostomy and
gastrostomy tube.
1248 OCTOBER 2021

FIGURE 3-1
Imaging of the patient in CASE 3-1. Axial noncontrast CT head shows a right frontal lobar
hemorrhage (A) with associated intraventricular extension without evidence of
hydrocephalus (B, C).
FIGURE 3-2
Repeat imaging of the patient in CASE 3-1. Repeat axial noncontrast CT head shows
increased size of lateral (A, B), third (C), and fourth (D) ventricular hemorrhage with
hydrocephalus.
This case of hypertensive hemorrhage demonstrates hematoma expansion COMMENT

and worsening hydrocephalus because of the hematoma more extensively
involving the ventricular system. Underlying this gross worsening in imaging
is secondary brain injury occurring because of the inflammatory cascade
activated both focally and globally by the hematoma expansion. This
patient could have been a candidate for intraventricular thrombolysis after
the hematoma was found to be stable. For blood pressure control, IV
nicardipine was used. When the patient worsened, it was reasonable, as
seen in this case, to administer mannitol to manage increased intracranial
hypertension. Hypertonic saline is also an option, depending on
institutional policies in its administration (eg, central venous access
requirement). The patient was admitted to the neurocritical care unit for
close monitoring, but despite all the aggressive measures for this patient,
his functional status did not improve significantly.

recreational substances, such as cocaine, amphetamines, alcohol, or tobacco, and

diet (high saturated fat, high sodium, and high calorie) are common factors
associated with hypertension.1 Other unique contributors to hypertension
include climate, autumn season (specifically increased air pressure and higher
temperature on the day of the ictus),19 and licorice root, because of its active
component, glycyrrhizin.20 Hypertension as the etiology, elevated systolic blood
pressure on admission, and lower calcium levels all are associated with worse
outcome in ICH. It is recommended that blood pressure should be controlled
immediately after an ICH; however, how much or how quickly the blood
pressure should be lowered is still being debated.21 A long-term systolic blood
pressure goal of less than 130 mm Hg and diastolic blood pressure goal of less than
80 mm Hg may be ideal.15
Anticoagulant- and Antiplatelet-associated Intracerebral Hemorrhage

About one-third of patients presenting with ICH are taking anticoagulant or
antiplatelet medications, or both. The underlying theory for anticoagulant-
associated ICH is that it prolongs the hematoma formation but is not the direct
cause of it.22 The annual ICH rate increases from 0.3% to 0.6% in patients taking
anticoagulants, the majority of which are nontraumatic ICH with an associated
mortality rate of 40% to 65%.22 Although antiplatelet-associated ICH was not
found to have worse outcomes compared to the general ICH population, use of
combined antiplatelet and anticoagulant medications was associated with larger
ICH volume and worse functional outcome (mRS score of 4 to 6). Interestingly,
animal and human studies on warfarin-associated ICH revealed worse functional
outcomes as well as higher hematoma volumes compared to direct oral
anticoagulant–associated ICHs.23 Worth mentioning here is ICH associated with
the administration of IV recombinant tissue plasminogen activator (rtPA), which
is administered to up to 5.2% of patients with acute ischemic stroke.24 A more
in-depth discussion on ICH after IV rtPA is beyond the scope of this article;
however, it should be noted that symptomatic ICH, which is generally defined as
a neurologic deterioration (≥4 points on the National Institutes of Health Stroke
Scale score) that is attributed to the ICH, can occur in up to 11.3% of patients,25
depending on the timing of imaging, definition followed, imaging
characteristics, and whether mechanical reperfusion is considered. Because of
this, clinicians who make decisions regarding IV rtPA administration should be
aware of how to reverse IV rtPA as well.
The suspicion of potential medication-associated ICH should raise the level of
urgency in the management of patients with ICH because some patients may be
candidates for surgery if they receive timely reversal therapy; at times, reversal
therapy may be the only treatment that can be administered in addition to
supportive therapy. Important aspects in history taking for patients on
anticoagulant or antiplatelet medications include the dose, administration, and
last time the medication was taken. For patients who received IV rtPA, a high
index of suspicion is helpful if a patient deteriorates. Principles of airway,
breathing, and circulation assessment should be immediately applied followed by
an emergent CT head while preparing for possible reversal.
Cerebral Amyloid Angiopathy

Accumulation of amyloid β (Aβ) proteins along the cortical and leptomeningeal
vessel wall leading to degeneration is the common pathology involved in
1250 OCTOBER 2021

CAA-associated ICH, resulting in cerebral microbleeds and cortical superficial KEY POINTS
siderosis.26 The prevalence of CAA has been reported to be 5% of the population
● Hypertension as the
older than 65 years of age,27 with 14.7% of all spontaneous ICH likely associated etiology, elevated systolic
with CAA.28 Patients with CAA may be asymptomatic or may have a range of blood pressure on
symptoms, including having recurrent neurologic deficits in association with the admission, and lower
location of the ICH or catastrophic hemispheric hemorrhages. CAA-associated calcium levels all are
associated with worse
ICH can also present as progressive cognitive dysfunction followed by a sudden
outcome in ICH.
focal neurologic deficit, focal seizures, or transient ischemic attack–type events
(amyloid spells).13 MRI sequences such as gradient recalled echo (GRE), ● Important aspects in
susceptibility-weighted imaging (SWI), or T2* sequences are sensitive to history taking for patients on
susceptibility artifacts produced by hemosiderin manifesting as cerebral anticoagulant or antiplatelet
medications include the
microbleeds and macrobleeds. In the modified Boston criteria, the presence of dose, administration, and
ICH, cerebral microbleeds, or cortical superficial siderosis in lobar and cerebellar last time the medication was
areas in patients older than 55 years of age with no other etiology for ICH are taken.
commonly attributed to possible or probable CAA with a high sensitivity.14
● Differentiation of
However, in the setting of an older adult patient with concomitant hypertension, cerebral amyloid angiopathy
the presence of cerebral microbleeds on MRI may not fully distinguish a from hypertensive ICH has
hypertensive hemorrhage from CAA, especially if the ICH is located in deeper clinical implications that
structures. Differentiation of CAA from hypertensive ICH has clinical may affect future
antiplatelet and
implications that may affect future antiplatelet and anticoagulant medication risk
anticoagulant medication
assessments for these patients who are also at high risk for cardiovascular disease, risk assessments for these
since CAA carries a higher ICH recurrence risk29 (especially with the use of patients who are also at high
anticoagulants30) compared to hypertensive ICH, which has a low recurrence risk for cardiovascular
disease, since cerebral
risk of approximately 2% per year and does not carry an absolute
amyloid angiopathy carries a
contraindication for anticoagulants.31 Avoidance of long-term anticoagulants has higher ICH recurrence risk.
traditionally been suggested for patients with CAA15,31; however, more recent
data on resumption of anticoagulants in patients with lobar ICH indicate benefit ● Prior or known cerebral
for mortality, functional outcome, and stroke incidence.32 Antiplatelet agents are microbleeds are not
established to be a
generally not considered contraindicated in the setting of CAA,15 although an contraindication to the use
increased risk of recurrent ICH after lobar ICH has been reported in the general of IV recombinant tissue
population treated with antiplatelet therapy in a study of survivors of lobar plasminogen activator for
ICH.33 Prior or known cerebral microbleeds are not established as a acute ischemic stroke, and
MRI before thrombolysis
contraindication to the use of IV rtPA for acute ischemic stroke, and MRI before administration is not
thrombolysis administration is not recommended.34 recommended.
Vascular Malformation ● The most common clinical

presentation of
The most common vascular malformations that may cause ICH include AVMs
arteriovenous malformation
with or without associated arteriovenous fistula and cavernous malformations. is ICH followed by seizures.
Recognizing and diagnosing these as the etiology for ICH is important for
management. Increased suspicion of the presence of these vascular anomalies is
also important to guide diagnostic testing in ICH. The gold standard for the
diagnosis of AVMs and arteriovenous fistulas is digital subtraction angiography
(DSA). Cavernous malformations are usually diagnosed via MRI by their unique
popcornlike appearance on a T2-weighted sequence. Brain AVMs are tangled
dysplastic cerebral arteries and veins that meet at a vascular center without
intervening normal brain parenchyma. The overall incidence of AVMs ranges
from 1.10 per 100,000 to 1.42 cases per 100,000 patients.35 The most common
clinical presentation of AVM is ICH followed by seizures.36 Treatment options
for AVMs include microsurgical resection, embolization via endovascular
therapy, and stereotactic radiosurgery.35 Cavernous malformations account for

13% of cerebral vascular malformations37 and commonly present with seizures or

headaches in addition to ICH. Treatment may involve surgical treatment for
patients with symptomatic cavernous malformations38 and supportive care.
Other Etiologies of Intracerebral Hemorrhage

ICH can be found in up to 30% to 40% of patients with cerebral venous sinus
thrombosis (CVST) and should be ruled out, especially if the ICH distribution on
imaging is lobar or associated with an infarction that does not follow a typical
arterial distribution.39 The mechanism underlying the development of ICH in
CVST is primarily associated with the cerebral vein’s thrombosis causing venous
infarction and petechial hemorrhages, which then progresses to a parenchymal
hematoma.40 The incidence of CVST has increased from 0.2 to 0.5 per 100,000
person-years to 1.32 to 1.57 per 100,000 person-years, likely because of the use of
advanced imaging.41 The most common venous sinuses affected are the superior
sagittal sinus, lateral sinus, and sigmoid sinus,41 and the most common
presentation is throbbing, bandlike, burning, pounding, or thunderclap
headaches with acute to subacute and rarely chronic intermittent onset and
progression. It has been reported that ICH in the setting of CVST is considered a
risk factor for early seizures and death.41 Treatment remains anticoagulation
with unfractionated heparin or low-molecular-weight heparin, although the use
of non–vitamin K antagonist oral anticoagulants42 has also been recently
reported. For severe CVST unresponsive to anticoagulation, endovascular
therapy may be an option41; however, this is still not always available. The overall
prognosis of CVST is good with improved diagnosis and early treatment;
however, patients can still develop severe disability and death, especially in
severe cases.
Moyamoya disease is a chronic, progressive, spontaneous cerebrovascular
occlusive disease characterized by stenosis at the terminal portion of the internal
carotid artery and an associated vasculature that is usually described as netlike at
TABLE 3-1 Common Genetic Loci and Association With Spontaneous Intracerebral
Hemorrhagea
Association with spontaneous intracerebral

Genetic loci hemorrhage
APOE, COL4A1, COL4A2, CD36, TIMP1, TIMP2, MMP2, MMP9, Increased susceptibility to spontaneous intracerebral
KCNK17, CR1, STYK1, ACE, 1q22, CETP hemorrhage
FGA Thr312Ala, LIMK1, KCNK17 Protective against spontaneous intracerebral

hemorrhage
APOE ε2, ε4, ε2/ε3, GPX1 Lobar spontaneous intracerebral hemorrhage
APOE ε4, 1q22, COL4A2, TIMP1, TIMP2, MMP2, MMP9, ACE Deep spontaneous intracerebral hemorrhage
COL4A1, TIMP1, TIMP2, ACE Vascular integrity
Loci 17p12, gp130 (G/A), von Willebrand factor (rs216321), LIMK1, Hematoma expansion, admission level of consciousness,
APOE ε2, CFH Y402H, KCNK17 and functional outcomes
a
Data from Wahab KW, et al, J Neurol Sci.51
1252 OCTOBER 2021

the base of the brain or stenosed internal carotid arteries, which can be either KEY POINTS
unilateral or bilateral.43 Its diagnosis requires CT angiography (CTA), DSA, or
● Approximately 30% of
MRI/magnetic resonance angiography (MRA). Moyamoya disease is more patients with moyamoya
common in East Asia; in the United States, the reported incidence is 0.086 per disease can present with an
100,000,44 with a pattern of bimodal age distribution peaks in the first and ICH because of friable
fourth decades. Although moyamoya disease commonly presents with an collateral vessels that may
have formed micro and/or
ischemic event, approximately 30% of patients with moyamoya disease can
false aneurysms. Herpes
present with an ICH because of friable collateral vessels that may have formed simplex virus, varicella-
micro and/or false aneurysms.45 zoster virus, syphilis, and
Herpes simplex virus, varicella-zoster virus, syphilis, and severe acute severe acute respiratory
syndrome coronavirus 2
respiratory syndrome coronavirus 2 (SARS-CoV-2)46 infections have been
(SARS-CoV-2) infections
implicated as causes of ICH, with the primary pathology of vasculitic infiltration have been implicated as
of the blood vessels. Vascular irregularity is a common characteristic in imaging causes of ICH, with the
studies.47 More recently, endotheliopathy in SARS-CoV-2 infection was primary pathology of
proposed as a cause of ICH in patients affected, with prevalence reported to be vasculitic infiltration of the
blood vessels.
21.7% of all cases of cerebrovascular disease with COVID-19 (n = 23) in a cohort
of 1683 patients with COVID-19.46 ● Solid or hematologic
Vasculitis of the central nervous system (CNS), another potential etiology of malignancy can cause ICH
ICH, remains a diagnostic challenge because of its protean manifestations. because of vasculature
involvement, primary brain
Primary angiitis of the CNS is unique in that the patient only has vasculitis in the tumor, or metastatic
brain; a brain biopsy is usually required for definitive diagnosis.48 The use of disease.
black blood MRI sequences is increasing, especially in vasculitis, revealing vessel
wall contrast enhancement in 85% of patients with suspected vasculitis.48 ICH
was considered a “minor” neuroradiologic feature of vasculitis in a narrative
review that analyzed publications from 2002 to 2019, although it was seen in
20.5% of all patients included in the study48 and can be recurrent. Of note,
systemic vasculitis may also present with ICH49; this is usually differentiated
from primary angiitis of the CNS by its association with other constitutional
symptoms and serum markers, such as elevated erythrocyte sedimentation rate,
C-reactive protein, and antinuclear antibodies.
Solid or hematologic malignancy can cause ICH due to vasculature
involvement, primary brain tumor, or metastatic disease. Note that patients with
malignancies are hypercoagulable and are sometimes taking anticoagulant or
antiplatelet therapies as an outpatient. ICH can also be the initial presentation of
solid brain tumors50 or hematologic malignancies.
ROLE OF GENETICS
Genomic studies have evolved in the past decade, and their role in unraveling
pathomechanisms and therapy for ICH is increasing.51 TABLE 3-1 presents the
various genetic variants associated with nontraumatic ICH identified in a
systematic review.51 Their application in the clinical setting is limited to research
and providing guidance on the underlying pathophysiology and etiology of ICH.43
PATHOPHYSIOLOGY OF PERIHEMATOMAL EDEMA AND

INFLAMMATORY CASCADE
Thirty percent of patients with ICH may have hematoma expansion within the
first 6 hours of ICH occurrence,52 whereas up to 12% may have hematoma
expansion between 1-hour and 20-hour noncontrast head CTs.53 The insult from
the intracerebral hematoma after the onset of ICH may result in secondary brain
injury from the mass effect of the hematoma, hematoma expansion, or the

inflammatory cascade that ensues as reflected by perihematomal edema and

perihematomal expansion rate.54
An inflammatory reaction after ICH has implicated release of inflammatory
cytokines and chemokines after the focal brain injury in ICH.55 Immediately after
the hemorrhage, damage to neuronal cells and the release of damage-associated
molecular patterns (DAMPs) start a cascade of proinflammatory changes that
have been shown to last between 7 and 25 days in hemorrhagic stroke.56
Proinflammatory changes may persist beyond weeks and may be associated with
cognitive dysfunction after ICH.55 The focal mechanism of inflammation
involves DAMPs and subsequent increase in excitotoxicity, oxidative stress,
mitochondrial disturbances, thrombin activation, and hemoglobin and iron
release in the area of the hematoma. DAMPs induce adenosine, heat shock
protein, high mobility group box 1, and IL-33,57 and, together with
thromboinflammatory changes,58 cause immune cell recognition that activates
intracellular signaling pathways that subsequently activates microglia.59
Microglia activation releases cytokines and chemokines that also communicate
with astrocytes to recruit immune cells from the periphery.60 These peripheral
immune cells increase cytokines and produce reactive oxygen species and matrix
metalloproteinases in addition to their direct effect on the breakdown of the
blood-brain barrier.61 As the peripheral immune cells cross the blood-brain
barrier, platelet dysregulation and endothelial cell activation ensue, which cause
damage to the blood vessels and brain parenchyma and inflammation. All of
these changes are thought to contribute to edema expansion, which has been
shown to be associated with worse clinical outcomes.55
The global inflammatory cascade is thought to be activated via a similar
pathway through DAMPs. It is likely initiated by the hematoma mass effect that
may cause some mechanical injury to the contralateral hemisphere, which is seen
as intracranial injury that starts activation of DAMPs.55 Studies have shown
microglia activation in remote areas of the brain after an ICH.62 Evidence of
increased mRNA levels for IL-1β, IL-6, transforming growth factor β, tumor
necrosis factor-α, and IL-27 has been found in the contralateral hemisphere up to
7 days postictus.63
TABLE 3-2 History Data Important for Patients With Intracerebral Hemorrhage
◆ Age
◆ Current medications with timing of last intake, if possible: anticoagulants, antiplatelet
medications, antihypertensive medications, stimulants, weight-loss drugs
◆ Past medical history: recent trauma or operations, known comorbidities, past intracerebral
hemorrhage, liver or renal disease, hematologic or solid tumor malignancies
◆ Alcohol and illicit substance use
◆ Last known well, symptom onset and progression
◆ Family history of intracerebral hemorrhage
◆ Functional baseline
◆ Review of systems: blurring of vision, chest pain, headache, nausea, vomiting, dizziness,
fever, loss of appetite
1254 OCTOBER 2021

HISTORY AND PHYSICAL EXAMINATION KEY POINTS
Acute ischemic stroke, seizures, and ICH can present similarly, with an acute
● The insult from the
focal deficit or alteration in mental status often the main symptom. Because of intracerebral hematoma
this, prehospital system protocols have been established that emphasize elements after the onset of ICH may
of history and physical examination that should be obtained by emergency result in secondary brain
medical services to guide receiving clinicians on the potential diagnosis of the injury from the mass effect
of the hematoma,
patient being transported to the emergency department. Patients with acute
hematoma expansion, or the
neurologic change should be called into the emergency systems as stroke alerts. inflammatory cascade that
Several unique points in the history are important specifically for patients with ensues as reflected by
ICH to guide receiving clinicians on what they should prepare in advance in the perihematomal edema and
perihematomal expansion
emergency department for the arriving patients (TABLE 3-2). Unique features
rate. An inflammatory
that make it likely to be ICH rather than an ischemic stroke include symptoms reaction after ICH has
progressing after onset, associated headache, dysarthria, systolic blood pressure implicated release of
of 165 mm Hg or greater, diastolic blood pressure of 95 mm Hg or greater, inflammatory cytokines and
disturbance of consciousness, conjugate eye deviation, dysarthria, and upper chemokines after the focal
brain injury in ICH.
limb paralysis, with the last two features having the highest point value in the
Japan Urgent Stroke Triage (JUST) score.64 Improvement of symptoms after ● Patients with acute
onset, history of a cerebral infarction, and arrhythmia make it less likely to be neurologic change should be
ICH.64 This is demonstrated in CASE 3-1 with a patient who was hypertensive and called into the emergency
systems as stroke alerts.
had a focal neurologic deficit and an acute decline in consciousness with
associated headache. ● A nationwide US sample
Included in history taking is inquiry into the comorbid conditions of the showed mortality was higher
patient, such as hypertension, diabetes, renal failure, chronic obstructive in patients with ICH with
coagulopathy, liver disease,
pulmonary disease, congestive heart failure, obesity, and coagulopathy. A
acquired immunodeficiency
nationwide US sample showed mortality was higher in patients with syndrome, and congestive
coagulopathy, liver disease, acquired immunodeficiency syndrome (AIDS), and heart failure and,
congestive heart failure and paradoxically significant lower in those with paradoxically, significantly
hypertension, obesity, and hypothyroidism.5 Chronic alcohol use is associated lower in those with
hypertension, obesity, and
with hypertensive ICH, whereas the association of binge alcoholic consumption hypothyroidism.
with ICH is still unclear.65
● Immediate diagnosis of
DIAGNOSTIC CONSIDERATIONS ICH is important to be able
to institute measures to
Immediate diagnosis of ICH is important to be able to institute measures to stabilize the patient and, it is
stabilize the patient and, it is hoped, prevent hematoma expansion. Immediately hoped, prevent hematoma
after medical stabilization, neuroimaging should be done. The initial diagnostic expansion.
modality of choice is a noncontrast head CT. If the facility is capable, CTA should
● The initial diagnostic
be considered in some patients to exclude obvious vascular etiologies of ICH,
modality of choice for ICH is
especially for patients with associated risk factors for vascular lesions as an a noncontrast head CT.
etiology of the ICH, such as female sex, age younger than 65 years old,
nonsmoker, lobar ICH, IVH, and absence of hypertension or coagulopathy.15 The
sensitivity and specificity of CTA is high for vascular abnormalities with the
advantage of being noninvasive.66 DSA can still be considered if high clinical
suspicion remains or the noninvasive studies suggest a vascular lesion,15 for
example, in a young adult who is not hypertensive and presents with a cortical or
lobar hemorrhage with an unrevealing CTA. As part of the workup for etiologies
in the nonemergent setting, MRI with and without contrast and MRA can be
considered. Imaging features that are important to review specifically for ICH
include hematoma volume, presence of perihematomal edema, midline shift,
presence of IVH, location of the hemorrhage (infratentorial or supratentorial,
cortical versus subcortical), presence of signs of hydrocephalus, and evidence of

FIGURE 3-3
ABC/2 measurement and ICH Score calculation.
GCS = Glasgow Coma Scale; ICH = intracerebral hemorrhage; IVH = intraventricular hemorrhage.
TABLE 3-3 Six-point Approach to Radiologic Herniation Syndromea
Clinical information
◆ Directs image reviewer to potential area of interest and affected regions
◆ Includes history and physical examination
Anatomic landmarks
◆ Distinct known structures that are common reference points for measurements,
comparison, and locating other structures
Direction of mass effect
◆ In association with where the primary lesion is, the direction of force of the mass effect
assists in identifying directly and indirectly affected structures
Displayed structure
◆ Used to classify herniation type or syndrome
Indirect signs
◆ Analyzes other structures that may be affected by the herniated structure
Herniation-related complications
◆ Complications from herniation may be from compression of other structures, such as
adjacent brain parenchyma, tracts, blood vessels, or ventricles, which may result in
additional clinical deficit, areas of infarctions, or hydrocephalus
a
Modified with permission from Riveros Gilardi B, et al, Radiographics.73 © 2019 Radiological Society of
North America.
1256 OCTOBER 2021

herniation. Several radiologic signs, such as the black hole sign, swirl sign, or KEY POINTS
blend sign, and other findings can be associated with poor outcome.67 Hematoma
● The presence of
volume on noncontrast head CT is calculated by the ABC/2 method, where A is herniation is an important
the largest hematoma diameter, B is the diameter perpendicular to A, and C is the radiologic feature that
approximate number of CT slices with hemorrhage multiplied by the slice should be recognized and
thickness, which can vary from 3 mm to 10 mm68 with π estimated as 3 correlated with the clinical
examination of the patient.
representing an ellipsoid model.69 The ICH volume has been shown to predict
mortality in ICH.70 FIGURE 3-3 demonstrates an example of the application of ● Noncontrast head CT
ICH Score with ICH volume calculation. indicators of herniation
Perihematomal edema is another radiographic marker that has been a include midline shift,
therapeutic target of several trials; however, no trials have shown improvement hydrocephalus, or new
areas of infarction adjacent
in functional outcome.71 Imaging features such as hematoma volume, to displaced structures.
intraventricular hemorrhage, and perihematomal edema have been shown to be
associated with patient outcome.72
The location of the hemorrhage will also guide diagnostic and therapeutic
options for patients with ICH. For example, in an older adult with a
supratentorial cortical ICH, MRI may be helpful to determine the extent and
distribution of cerebral microbleeds, whereas CTA may be needed in a younger
patient with a subcortical supratentorial ICH who has a drug screen positive for
cocaine to rule out cocaine-induced vascular changes and determine the need for
aggressive management of blood pressure. A supratentorial cortical hemorrhage
in a young patient who is not hypertensive and has no other indications of
vasculopathy should lead the clinician to proceed with a DSA and/or MRI with
and without contrast for further workup of the ICH.
The presence of herniation is an important radiologic feature that should be
recognized and correlated with the clinical examination of the patient. Common
locations of herniation include subfalcine, uncal, descending or ascending
transtentorial, and tonsillar.73 A six-point approach has been suggested for the
radiologic assessment of herniation (TABLE 3-3).73 Consequences of herniation as
discovered by noncontrast head CT include midline shift, hydrocephalus, or new
areas of infarctions adjacent to displaced structures.
MANAGEMENT CONSIDERATIONS
The management of ICH is complex and involves coordination of care along the
health care continuum as well as integration of the management of the acute
brain injury and other organ system issues. TABLE 3-4 lists the diagnostic tests to
be considered in the management of ICH and their relevance.
Intracerebral Hemorrhage Systems of Care

Coordination of care for patients with ICH is important to ensure the proper
standards along the continuum and transition of care for these patients. Patients
presenting from the community with a suspected stroke should be brought to a
hospital with the capability of emergent brain imaging. TABLE 3-5 lists important
aspects of ICH systems of care, and FIGURE 3-4 depicts an algorithm for decision
making in ICH. Increasing data suggest that step-down units or intermediate care
units can be safe alternatives for patients with ICH.74 Deterioration (early
<24 hours and late 1 to 7 days) not resulting from hematoma expansion and
associated poorer outcome occur in as many as 17.3% of patients.75 Comorbidities
are highly prevalent, may manifest in the acute period of ICH, and will require
close primary care and potentially subspecialty follow-up, such as from

TABLE 3-4 Diagnostic Tests to Be Considered in the Management of Intracerebral

Hemorrhage
Tests Rationale Comments
Neuroimaging Exclude ischemic stroke Location of ICH may guide

further neuroimaging beyond
Assess intracerebral hemorrhage (ICH)
emergent noncontrast head CT
characteristics
and CT angiography
Evaluate for signs of high intracranial pressure or
herniation
Evaluate for potential for hematoma expansion
Evaluate need for external ventricular drain
Blood tests
Complete blood cell count White blood cell count demonstrates evidence of Elevated white blood cell count
underlying infection has been shown to be
associated with worse outcome
Red blood cell count demonstrates concurrent
systemic bleeding
Platelet count guides need for transfusion
Electrolytes Guide replacement of electrolytes as part of Patients may come in with

supportive care concomitant indicators of
hypovolemia
Guide hyperosmolar therapy
Renal function (blood urea nitrogen Guide risk assessment for ICH Patients with a history of
[BUN]/creatinine) chronic kidney disease are
Guide supportive care
prone to ICH; kidney disease
has also been associated with
poor outcome in ICH
Glucose Guide supportive care and need for feeding Elevated glucose has been
shown to be associated with
worse outcome
Coagulation studies (prothrombin Guide reversal and factor replacement Vitamin K antagonist–
time, international normalized ratio associated hemorrhages have
[INR] and activated partial been found to be associated
thromboplastin time) with worse outcomes
Cardiac-specific troponin May detect concomitant active cardiac ischemia Elevated troponin levels are
associated with worse outcomes
Alcohol level Risk assess complications from alcohol abuse that Is a risk factor for ICH
may affect management, such as liver cirrhosis,
platelet dysfunction, and alcohol withdrawal
Urinalysis and urine drug screen Guide differential diagnosis of etiology for
intracerebral hemorrhage
Exclude pregnancy
Exclude proteinuria associated with pregnancy
Other
ECG Demonstrate concurrent cardiac strain or ischemia
CT = computed tomography; ECG = electrocardiogram.
1258 OCTOBER 2021

hypertension specialists, cardiologists, nephrologists, and endocrinologists.
Nonetheless, not every patient with ICH requires intensive care unit (ICU) level
of care. Admitting patients to a step-down unit rather than the ICU had reported
advantages of decreasing ICU and hospital length of stay significantly.74 The
most important factors to consider in patient selection for step-down unit
admission are lack of infratentorial involvement and lack of IVH at least in the
third or fourth ventricles.
Emergent/Intensive Care Management Considerations

This section discusses the immediate management considerations for patients
presenting with an ICH.
MEDICAL STABILIZATION. Mechanical ventilation is required in up to 30% of

patients with ICH.76 Postintubation interventions initiated in the emergency
department, including appropriate tidal volume, proper endotracheal tube
position confirmed by chest radiography, assessing arterial blood gas values,
orogastric or nasogastric tube insertion for decompression, urethral catheter
insertion, utilization of quantitative capnography, and early sedative
administration, have been found to improve outcomes of in-hospital mortality
and likelihood of home discharge77 and should be considered by the consulting
neurologist. Initial blood tests for the workup of a patient with an acute
neurologic deficit should proceed (TABLE 3-4).
BLOOD PRESSURE MANAGEMENT. Blood pressure control is recommended upon

confirmation of the diagnosis of ICH, although the timing and target blood
pressure remain controversial.15,21 TABLE 3-678-80 summarizes several trials on
blood pressure management that have recently been published. Systolic blood
pressure has been found to be associated with hematoma volume.81 Hematoma
expansion occurs in up to 38% of patients with ICH82 and represents a
therapeutic target and an outcome measure.21 However, although it seems
implicit that lowering blood pressure might reduce hematoma expansion, the
relationship between the degree of lowered blood pressure and hematoma
expansion is still not fully elucidated, nor has a clear effect of blood
pressure–lowering strategies to mitigate hematoma expansion been shown. The
Important Points to Consider in Intracerebral Hemorrhage Systems of Care TABLE 3-5
◆ Emergent alert systems for stroke apply for intracerebral hemorrhage (ICH)
◆ Patients with a suspected stroke/ICH should be brought to the nearest hospital with
emergent brain imaging capabilities
◆ Simultaneous assessment and stabilization should be done immediately upon arrival
◆ Emergent brain imaging should follow
◆ Neurosurgical consultation should be done when ICH is confirmed
◆ Admission team is hospital dependent (eg, neurology, neurosurgery, neurocritical care teams
as primary team)
◆ Admission should be in a hospital area capable of frequent neurologic checks (eg,
neurocritical care unit, general intensive care unit, stroke unit)

2015 American Heart Association (AHA)/American Stroke Association (ASA)

recommendation is to reach a systolic blood pressure goal of less than 140 mm Hg.15
INTERACT2 (The Second Intensive Blood Pressure Reduction in Acute Cerebral
Haemorrhage Trial) showed a benefit from intensive treatment of blood pressure
in terms of improved functional outcome and health-related quality of life,
although a difference in death or severe disability was not detected.78 The
ATACH-II (Antihypertensive Treatment of Acute Cerebral Hemorrhage-II)
trial comparing lowering of systolic blood pressure within 4.5 hours to either
110 mm Hg to 139 mm Hg (treatment) or 140 mm Hg to 179 mm Hg (standard)21
did not find a significant difference for death or disability between the groups
but found that 7-day renal adverse events were higher in the treatment group
compared to the standard group (9.0% compared to 4.0%, P=.002). The trial was
stopped at 1000 participants because of futility. Critical assessment of the results
from INTERACT2 and ATACH-II raises the question of whether selection (eg,
large versus smaller ICH and deep versus lobar) might shed light not only on
the mechanism by which blood pressure lowering might exert its effect but also
the individual patients for whom it might work best. The SAMURAI (Stroke
Acute Management With Urgent Risk-factor Assessment and Improvement)
ICH study showed that reaching the target systolic blood pressure of less than
160 mm Hg within 38 minutes from ictus decreased the odds of hematoma
expansion.83 A study analyzing the effect of the hospital’s change in blood
FIGURE 3-4
Approach to the management of intracerebral hemorrhage from prehospital to the
neurocritical care unit.
ABC = airway, breathing, circulation; CT = computed tomography; CTA = computed tomography
angiography; ICH = intracerebral hemorrhage; NSTEMI = non–ST segment myocardial infarction;
SIADH = syndrome of inappropriate secretion of antidiuretic hormone; STEMI = ST segment elevation
myocardial infarction.
1260 OCTOBER 2021

pressure control protocol based on INTERACT1 and INTERACT2 found a KEY POINTS
significant difference in the proportion of patients with hematoma expansion
● Blood pressure control is
(defined as increase in lesion size no less than 10% or presence of more recommended upon
hemorrhagic lesions) in the aggressive blood pressure reduction group compared confirmation of the
to control (13.9% compared to 21.1%, P=.018), without a significant increase in diagnosis of ICH, although
kidney dysfunction.84 In their multivariate logistic regression analysis, the study the timing and target blood
pressure remain
authors determined that intensive blood pressure control was inversely
controversial.
associated with hematoma expansion after controlling for age, sex, baseline
National Institutes of Health Stroke Scale score and Glasgow Coma Scale score.84 ● Increased blood pressure
Another post hoc analysis to determine whether ultra-early intensive blood variability, defined as the
pressure lowering less than 2 hours from symptom onset would improve mean of the absolute
differences between two
outcomes showed that the intensive treatment group had less hematoma consecutive blood pressure
expansion and improved functional outcome at 90-day follow-up.85 In addition variations, variation of blood
to early blood pressure control, the role of blood pressure variability and the pressure during a period of
influence on patient outcomes after ICH is currently being studied. Increased time, or coefficient of
variation, in patients with
blood pressure variability, defined as the mean of the absolute differences between ICH has been found to be
two consecutive blood pressure variations, variation of blood pressure during a associated with worsening
period of time, or coefficient of variation,86 in patients with ICH has been found to neurologic status and poor
be associated with worsening neurologic status and poor outcome.87 Care should outcome.
be taken to prevent blood pressure variability as much as possible.
The current recommendation for systolic blood pressure goal in ICH is less than
140 mm Hg for patients presenting with systolic blood pressure between 150 mm Hg
and 220 mm Hg who have no other contraindication to intensive blood pressure
control.15 Note that no recommendation has been made on the specific medication
to be used to control blood pressure.15 Considerations in selection of medication
are usually dependent on potential side effects, patient comorbidity, allergy
history, refractoriness of the blood pressure, and availability of the medication.
REVERSAL OF COAGULOPATHY. Reversal of antiplatelet or anticoagulant

medications for patients with ICH is emergent. Common anticoagulants and
reversal agents are presented in TABLE 3-7. All patients with ICH associated with
antiplatelet or anticoagulation should be monitored in an ICU (FIGURE 3-4).
AHA/ASA guidelines recommend demonstration of ICH stability before
restarting antiplatelet medications when necessary to restart.15 Routine platelet
transfusions for patients who were on antiplatelet medication before ictus are not
recommended because of higher death and dependence at 90 days88 but can be
considered (as can desmopressin) for patients who will undergo neurosurgical
intervention or those demonstrating ongoing bleeding in the setting of potential
neurosurgical intervention.
Activated partial thromboplastin time, international normalized ratio (INR), and
prothrombin time should be monitored frequently to make certain the coagulopathy
is controlled. Thromboelastometry, a cheap, readily available, and easy-to-use test of
coagulation function, assesses hemostatic components such as platelets, fibrinogen,
coagulation factors, and erythrocytes by analyzing the interaction of the components,
coagulation times, clot strength, and lysis. The 2015 AHA/ASA guidelines for ICH
recommend specific reversal agents only for warfarin and heparin.15 The antiplatelet
medications most commonly used include aspirin, clopidogrel, dipyridamole, and
cilostazol. Glycoprotein IIb/IIIa antagonists are another group of medications that
carry risk of ICH. For antiplatelets, desmopressin 0.4 mcg/kg IV is recommended by
guidelines; however, the level of evidence is low.89

TABLE 3-6 Landmark Clinical Trials on Blood Pressure Management in Intracerebral

Hemorrhage
Research question Primary

Trial answered Comparison groups outcome Result Remarks
ATACH-II Is intensive blood Intensive blood 90-day No difference in Higher rate of

(Antihypertensive pressure control pressure lowering mortality or outcome of renal adverse
Treatment of (systolic blood pressure (systolic blood severe death or events in
Acute Cerebral 110-139 mm Hg) superior pressure goal disability disability in patients under
Hemorrhage-II)21 to standard treatment 110-139 mm Hg) (modified intensive group intensive
(systolic blood pressure compared to Rankin Scale compared to treatment
140-179 mm Hg) while standard treatment [mRS] score standard within 7 days
using nicardipine in (systolic blood 4-6) treatment
Subgroup
patients with pressure
Intensive analysis on
intracerebral 140-179 mm Hg)
treatment was patients with
hemorrhage (ICH) in within 4.5 hours
NOT superior in spot sign or
terms of death or after symptom
terms of other imaging
disability? onset using IV
decreasing markers of
nicardipine, blood
death and hematoma
pressure target
disability expansion did
maintained for
not show
24 hours
benefit
Stopped for
futility
No difference in
ordinal
distribution of
mRS score
Decreased
perihematomal
edema
expansion rate
in intensive
group with
deep ICH
1262 OCTOBER 2021

Research question Primary

Trial answered Comparison groups outcome Result Remarks
INTERACT2 (The What is the effect of Target systolic 90-day death No difference In a
Second Intensive early intensive blood blood pressure and moderate between the prespecified
Blood Pressure pressure lowering <140 mm Hg or severe two groups in ordinal shift
Reduction in (systolic blood compared to disability (mRS terms of main analysis of the
Acute Cerebral pressure <140 mm Hg) systolic blood score of 3-6) outcome mRS score,
Haemorrhage versus conservative pressure functional
Trial)78 guideline-based blood <180 mm Hg; outcomes were
pressure lowering antihypertensive better in the
(systolic blood pressure not specified; intensive group
of <180 mm Hg) on death patients are to compared to
and dependency at remain below the the
90 days among patients blood pressure nonintensive
with ICH? target for 7 days group
Serious adverse
events were
similar between
the two groups
ICH ADAPT Is cerebral blood flow in 39 patients Perihematomal Intensive group Within 2 hours,
(Intracerebral acute ICH unaffected by assigned to systolic relative did not the <150 mm Hg
Hemorrhage blood pressure blood pressure cerebral blood significantly target group
Acutely reduction? target of <150 mm flow lower had a
Decreasing Hg compared to 36 perihematomal significantly
Arterial Pressure patients assigned cerebral blood lower mean
Trial)79 to systolic blood flow compared systolic blood
pressure target of to the <180 mm pressure
<180 mm Hg Hg target group
Rapid blood Is lowering the blood 21 patients each Clinical decline No significant Secondary
pressure pressure to mean arterial assigned to a (National difference in outcomes
reduction in acute pressure <110 mm Hg standard target Institutes of early neurologic included mRS
intracerebral within 8 hours of ICH blood pressure Health Stroke deterioration score at 90 days
hemorrhage: safe and feasible? with mean arterial Scale [NIHSS] and 24-hour
feasibility and pressure score decrease hematoma
safety80 110-130 mm Hg ≥2 points within enlargement;
compared to 48 hours) no significant
aggressive blood difference was
pressure goal of found between
mean arterial the two groups
pressure <110 mm
Hg, with mean
arterial pressure
control sustained
for 24 hours
IV = intravenous.

Other Pharmacologic Therapeutic Considerations

The multicenter TICH-2 (Tranexamic Acid for Hyperacute Primary
IntraCerebral Haemorrhage-2) trial showed that tranexamic acid use within
8 hours of ICH occurrence did not result in improved functional outcome,
although the tranexamic acid cohort had a lower proportion of patients with
hematoma expansion at day 2 compared to placebo.90 Thromboembolic events
and arterial occlusion were not significantly higher in the tranexamic acid group.
STOP-AUST (The Spot Sign and Tranexamic Acid On Preventing ICH
Growth–AUStralasia Trial), a prospective double-blind randomized
placebo-controlled phase 2 trial of adult patients with ICH less than 70 mL with
positive spot sign, also did not show a significant difference in terms of
hematoma expansion between the intervention and control groups.91
Deferoxamine emerged as a potential target for ICH therapy because of its
potential for neuroprotection as an iron chelator.92 A prospective multicenter
double-blind randomized placebo-controlled phase 2 clinical trial randomly
assigning participants to deferoxamine or placebo showed that deferoxamine
was safe, but it did not increase the chance of a good functional outcome at
90 days.93
Intracranial Pressure Management

Intracranial hypertension, defined as intracranial pressure greater than 20 mm
Hg, has a prevalence of up to 67% in patients with ICH,94 with lower admission
Glasgow Coma Scale score, presence of a greater than 6 mm midline shift, age,
hematoma volume, and presence of hydrocephalus correlated with intracranial
hypertension. For more information, refer to the article “Management of
Cerebral Edema, Brain Compression, and Intracranial Pressure” by Eric M.
Liotta, MD, MS,95 in this issue of Continuum. Prophylactic hyperosmolar therapy
is not recommended as it does not improve outcomes.96 The agents most
commonly used are hypertonic saline and mannitol, with the common goal to
TABLE 3-7 Common Anticoagulants and the Corresponding Reversal Agents
Anticoagulant/antiplatelet/antifibrinolytic Reversal agent options
Vitamin K antagonists warfarin, acenocoumarol, phenprocoumon, Three-factor or four-factor prothrombin complex

dicoumarol, tecarfarin, and fluindione concentrate, vitamin K
Dabigatran, argatroban, bivalirudin Idarucizumab
Rivaroxaban Andexanet alfa, prothrombin complex concentrate
Apixaban Andexanet alfa, prothrombin complex concentrate
Heparin Protamine, andexanet alfa
Fondaparinux Andexanet alfa, prothrombin complex concentrate
Enoxaparin Andexanet alfa, protamine
Antiplatelet agents Desmopressin acetate
IV recombinant tissue plasminogen activator (rtPA) Cryoprecipitate, fresh frozen plasma, platelets,
tranexamic acid, aminocaproic acid
1264 OCTOBER 2021

increase the osmotic gradient across the blood-brain barrier and to shift water KEY POINTS
into the intravascular space. For use in ICH, 2020 cerebral edema
● Prophylactic
recommendations from the Neurocritical Care Society suggest hypertonic saline hyperosmolar therapy is not
as the hyperosmolar agent preferred over mannitol, with the caveat that the recommended in patients
quality of evidence for this is very low.96 Clinicians should consider the available with ICH as it does not
IV access for administration of hyperosmolar therapy as well as the potential improve outcomes.
adverse effects of the hyperosmolar agents.
● American Heart
Association/American
Seizure Prophylaxis Stroke Association
The role of seizure prophylaxis for ICH is controversial, and current AHA/ASA guidelines do not
guidelines do not recommend it.15 Although one study reported lower risk of recommend seizure
prophylaxis in ICH.
seizures for patients with ICH placed on seizure prophylaxis with newer
antiseizure medications, more studies are needed to prospectively evaluate their ● The target temperature
benefit.97 A meta-analysis on seizure prophylaxis and short- and long-term for patients with ICH in
outcomes of patients with ICH found no association between seizure prophylaxis consensus guidelines is
36.5 °C to 37.5 °C (97.7 °F
and improved functional outcome and mortality; however, most studies to 99.5 °F).
analyzed were retrospective studies.98 Early seizures in patients with ICH have
an incidence rate of 4.3%, whereas late seizures have an incidence rate of 2.3%,
with an overall incidence of post-ICH seizures of 6.6% in a cohort of 1920
patients with ICH.99 Patients who have had a seizure should be treated
accordingly.15 The threshold for ordering EEG or continuous EEG for patients
with ICH in a comatose state should be low because up to 8.8% of patients with
ICH may have nonconvulsive status epilepticus.100 Lobar involvement and
craniotomy increase the risk of nonconvulsive status epilepticus.100 Risk factors
for acute seizure development in patients with ICH include younger age,
nonhypertensive ICH, cortical involvement, and a high National Institutes of
Health Stroke Scale score.99 Post-ICH–associated epilepsy was found to develop
in 15.7% of patients with ICH with initial post-ICH seizures, with the ICH volume
being an independent predictor associated with recurrent seizures.99 Very scant
data are available on whether patients with acute symptomatic seizures require
lifelong antiseizure medications or whether and when they can safely be weaned
off antiseizure medications.
Other Supportive Measures

Hyperthermia worsens outcomes101 and increases perihematomal edema.
Decreasing temperature to lower than 37.5 °C (99.5 °F) and responsiveness to
antihyperthermic treatment may have benefit in decreasing perihematomal
edema.102 The target temperature in consensus guidelines is 36.5 °C to 37.5 °C
(97.7 °F to 99.5 °F) for patients with ICH.103
The effect of glucose level on outcomes in patients with ICH continues to be
controversial. A subanalysis of the INTERACT2 trial found that 51% of the
patients had hyperglycemia at baseline, and these patients also had significantly
more occurrence of early neurologic deterioration, death, and nonfatal adverse
events.104 Based on older studies associating hyperglycemia with poor outcomes,
the AHA/ASA guidelines for ICH recommend avoidance of both hyperglycemia
and hypoglycemia.15
Up to 50% of patients with stroke have concomitant dysphagia,105 which
increases the risk of malnutrition, dehydration, and aspiration. The AHA/ASA
guidelines recommend dysphagia screening for any patient with ICH before oral
intake.15 Nutritional considerations in patients with ICH include early initiation

CASE 3-2 A 53-year-old man with a history of hypertension was found unconscious
by his wife in the bathroom 1 hour after eating dinner. When emergency
medical services arrived, he was found to have sonorous breathing, fixed
and dilated pupils, and extensor posturing. He had a Glasgow Coma Scale
score of 4 (eyes, 1; voice, 1; motor, 2). He was intubated immediately for
airway protection and transferred to the nearest Level 1 trauma center.
Upon arrival in the emergency department, his blood pressure was
found to be 180/100 mm Hg. IV nicardipine was immediately started, and
a neurosurgery consult was called. Mannitol was also administered, and
noncontrast head CT obtained (FIGURE 3-5). The patient was immediately
taken for Level 1 surgery for posterior decompression and hematoma
evacuation.
After surgery, the patient was admitted to the neurocritical care unit.
After 2 weeks of hospitalization, he did not have meaningful functional
change. His Glasgow Coma Scale score remained at 4. After multiple
family meetings with the primary team and the palliative care team in the
2 weeks following admission, the family decided to transition to a
palliative level of care and not proceed with tracheostomy and
gastrostomy tube placement since they felt the patient would not want
to continue in his current state.
FIGURE 3-5
Imaging of the patient in CASE 3-2. Axial noncontrast head CT shows bilateral cerebellar
hemorrhage (A, B) and obstructive hydrocephalus (C, D).
COMMENT The poor clinical examination and severity of the cerebellar intracerebral
hemorrhage in this patient did not preclude his candidacy for
decompressive craniectomy after stabilization. This case highlights that
continued engagement with the family is important after the acute period
as decision making on tracheostomy, gastrostomy, and transitions of care
are needed. Although no score can accurately determine the future
functional outcome of the patient, the lack of improvement and a higher
likelihood of prolonged recovery helped the family decide on what the
patient would probably have wanted using the principle of substituted
judgment.
1266 OCTOBER 2021

of feeding via oral intake or enteral feeding as soon as possible. If prolonged
dysphagia is likely, enteral feeding via a temporary gastrostomy may be
warranted.105
Neurosurgical Management Considerations

Neurosurgical management of ICH usually includes external ventricular drain
placement for CSF diversion, intracranial pressure monitoring, and hematoma
evacuation. The most readily available neurosurgical treatment is external
ventricular drain placement with or without thrombolysis administration. In
association with the CLEAR III trial, a subsequent study analyzed the efficacy
and safety of intraventricular fibrinolysis with lumbar drain placement to
prevent shunt dependency for patients with ICH and IVH, and results showed
0% of the patients in the treatment group needed a permanent shunt compared
to 43.8% in the control group needing a permanent shunt.106
The AHA/ASA ICH guidelines recommend carefully selecting patients for
neurosurgical intervention; however, the level of evidence is not high.15
Hematoma volume reduction as a surgical target may decrease midline shift and
intracranial pressure and potentially decrease the neurotoxic and
proinflammatory effects of the hematoma, which may subsequently decrease the
likelihood of secondary brain injury.107 Neither of the main trials on
supratentorial ICH evacuation, STICH (Surgical Trial in Intracerebral
Haemorrhage) and STICH II, showed improvement in outcome, but the trials
provided insight on subgroup selections that may benefit from early surgery.
Considerations in Restarting Antiplatelet or Anticoagulation After an TABLE 3-8

Intracerebral Hemorrhage
◆ For patients with a spontaneous lobar intracerebral hemorrhage (ICH) or those with multiple
cerebral microbleeds without strong indications for anticoagulants (eg, mechanical heart
valves or cardiac thrombus), especially warfarin, waiting 4-8 weeks is recommended15,31
◆ In patients with nonlobar ICH with strong indications for anticoagulation, anticoagulants may
be considered15
◆ For patients with indications for antithrombotics after an anticoagulant-associated ICH,
aspirin monotherapy may be safe within days of the ICH15
◆ Factors that should be considered before restarting oral anticoagulants include, but are not
limited to, the severity of ICH, presence of cerebral microbleeds, lobar ICH, no reversible
cause of bleeding, older age, bleeding with adequately or underdosed direct oral
anticoagulant, difficult to control hypertension, chronic alcohol abuse, need for dual
antiplatelet therapy28,31
◆ Scoring systems that weigh bleeding risk versus thrombotic risk are available and should be
used with caution
◆ Because the studies on direct oral anticoagulants showed lower risk of ICH compared to
vitamin K antagonists, it has been recommended to consider switching to a direct oral
anticoagulant after an ICH if anticoagulation is needed114
◆ Ongoing clinical trials to increase information on anticoagulant or antiplatelet use after ICH
include A3ICH (Avoiding Anticoagulation After IntraCerebral Haemorrhage),115 ASPIRE
(Anticoagulation in ICH Survivors for Stroke Prevention and Recovery),116 and APACHE-AF
(Apixaban After Anticoagulation-associated Intracerebral Haemorrhage in Patients With
Atrial Fibrillation),117 among others

TABLE 3-9 Intracerebral Hemorrhage Prognostic Scores Comparison
FUNC (Functional Outcome in

Intracerebral Modified Patients with Primary
Intracerebral Hemorrhage Grading Intracerebral Intracerebral Hemorrhage)
Hemorrhage Score122 Scale123 Hemorrhage Score124 Score125
Original Patients who Primary ICH confirmed Nontraumatic ICH; 142 ICH with functional status data
population presented with by CT head; 378 patients included at 90 days; final cohort was a
tested intracerebral patients included total of 629 patients
hemorrhage (ICH)
(ICD-9 code 431) who
primarily presented in
the study institutions;
152 patients included
Excluded Transfers from outside Traumatic ICH Traumatic ICH Secondary ICH from vascular
patients clinic or hospital abnormality, tumor, trauma or
ischemic stroke, vasculitis,
anticoagulation, or
coagulopathy
Primary In-hospital and 30-day In-hospital and 30-day In-hospital and 30-day 90-day functional outcome
outcome mortality mortality mortality
measured
Secondary None Good functional Functional outcome None

outcome outcome (Glasgow measured by modified
measured Outcome Scale score Rankin Scale score at
4 and 5) at 30 days 30 days after ICH with
good outcome being
modified Rankin Scale
score ≤2
Score Glasgow Coma Scale Glasgow Coma Scale National Institutes of Glasgow Coma Scale score
components score score Health Stroke Scale
<9 = 0
score
3-4 = 2 3-8 = 3
≥9 = 2
21-40 = 2
5-12 = 1 9-12 = 2
11-20 = 1
13-15 = 0 13-15 = 1
0-10 = 0
Hematoma volume Hematoma volume Hematoma volume Hematoma volume

≥30 mL = 1 Infratentorial ≥30 mL = 1 >60 mL = 0
<30 mL = 0 >20 mL = 3 <30 mL = 0 30-60 mL = 2
10-20 mL = 2 <30 mL = 4
<10 mL = 1
Supratentorial
>70 mL = 3
40-70 mL = 2
<40 mL = 1
1268 OCTOBER 2021


Hematoma location Hematoma location Hematoma location Hematoma location
Infratentorial = 1 Infratentorial = 2 Infratentorial = 1 Infratentorial = 0
Supratentorial = 0 Supratentorial = 1 Supratentorial = 0 Deep =1
Lobar = 2
Age Age Age Age

≥80 years = 1 ≥65 = 3 ≥80 = 1 ≥80 = 0
<80 years = 0 45-64 = 2 <80 = 0 70-79 = 1
<45 = 1 <70 = 2
Intraventricular Intraventricular Intraventricular Cognitive impairment

hemorrhage hemorrhage hemorrhage
Yes = 0
Yes = 1 Yes = 2 Yes = 1
No = 1
No = 0 No = 1 No = 0
Total score 0-6 5-13 0-6 0-11
Score Each increase in point Score of 5 had the Each point increase is Score of 11 indicates high
interpretation is associated with an lowest probability of associated with an likelihood of functional
increase in 30-day dying; scores ≥10 increase in 30-day independence (0-4 = 0%;
mortality (0, 13%, 26%, showed 87% mortality 5-7 = 1-20%; 8 = 21-60%;
72%, 97%, and 100% for in-hospital and 30-day 9-10 = 61-80%; and 11 = 81-100%)
those with ICH Score mortality and higher,
of 0 to 5, respectively) and 0% to 4% had good
functional outcome
Strengths Most validated; can be Higher sensitivity than Better than the ICH Collected pre-ICH cognitive
easily applied; ICH Score in predicting Score for predicting impairment by proxy interview
applicable to both in-hospital (78.2% good outcome and Informant Questionnaire on
supratentorial and compared to 63.8%, Cognitive Decline in the Elderly
infratentorial ICH P<.05) and 30-day
Can be done at bedside
mortality (78.5%
compared to 64.4%, Needs information from the
P<.05) initial patient evaluation and CT
scan only
Analysis done to control for ICH
survivors to control for the
effect of withdrawal of care on
functional outcome


Limitations Did not account for Did not account for Did not account for Requires assessment of pre-ICH
withdrawal of care; withdrawal of care withdrawal of care; cognitive impairment
only analyzed 30-day less accurate than the
mortality; no ICH Score in
functional outcome predicting mortality;
several patients with
missing data points;
not widely validated
Remarks Use data at the time of Use data at the time of Study to determine if Functional independence =
presentation; hospital arrival; ICH the ICH Score can Glasgow Outcome Scale
hematoma volume volume measured by predict morbidity and score ≥4
measured by ABC/2 ABC/2 method mortality at 30 days
Useful for goals-of-care
method; their cohort and if modification can
discussion regarding likelihood
did not have a patient improve the
of survival with recovery of
with ICH Score of 6 prediction; National
function, not just survival or
mortality
Stroke Scale score
found to be predictive
of both 30-day
mortality and good
outcome, not Glasgow
Coma Scale score
CT = computed tomography; ICD-9 = International Classification of Diseases, Ninth Revision.
However, further clinical trials are needed to firmly establish the role of early
surgery for supratentorial ICH.108 Minimally invasive neurosurgical approaches
include making a small cranial opening with a smaller intraparenchymal incision
with the goal of reducing parenchymal manipulation and decreasing procedure
time and anesthesia exposure with the concomitant advantage of faster hematoma
evacuation compared to external ventricular drain alone.109 Several minimally
invasive neurosurgical devices and approaches are currently available to achieve
the goal of hematoma evacuation. Trials are ongoing to determine whether the
specific minimally invasive neurosurgical device is a factor that contributes to
patient outcomes.109 The MISTIE III (Minimally Invasive Surgery Plus Rt-PA for
ICH Evacuation Phase III) trial involved using minimally invasive neurosurgery
combined with image-guided rigid catheter insertion targeted toward the middle
two-thirds of the hematoma, with the intervention group receiving 1 mg rtPA
every 8 hours for up to nine doses.71 Although the study did not show
improvement in the proportion of patients with good functional outcome (mRS
score of 0 to 3) at 365 days, it showed a lower rate of mortality in the treatment
group compared to the standard treatment cohort.110 Other minimally invasive
neurosurgery trials are currently ongoing using end-port–mediated evacuation
and stereotactic aspiration, both of which require a small craniotomy with the
main difference of the advantage of visualization in the latter approach.109
1270 OCTOBER 2021

Cerebellar hemorrhage (CASE 3-2), which accounts for up to 10% of all ICH, KEY POINTS
has a 30-day mortality of up to 38%.111 In patients with cerebellar ICH, low Glasgow
● Neurosurgical
Coma Scale score (<8), obstructed quadrigeminal cistern, and hydrocephalus were management of ICH may
independent predictors of in-patient mortality and poor functional outcome at include external ventricular
discharge.112 Expert consensus incorporated in the AHA/ASA guideline drain placement for CSF
recommends consideration for hematoma evacuation for ICH greater than 3 cm or if diversion, intracranial
pressure monitoring, and
signs of herniation with or without hydrocephalus are seen.15 However, in analyzing
hematoma evacuation.
the effect of surgical hematoma evacuation in these patients and the association with
outcomes, a 2019 meta-analysis including 578 patients revealed that hematoma ● In patients with
evacuation did not result in improved functional outcome but was associated with cerebellar ICH, low Glasgow
improved survival at 3 and 12 months.113 It is generally difficult to conduct a Coma Scale score (<8),
obstructed quadrigeminal
trial on surgical evacuation in cerebellar ICH because of the lack of clinical cistern, and hydrocephalus
equipoise, which makes forgoing intervention ethically challenging. were independent
predictors of in-patient
Resumption of Antithrombotic or Anticoagulant Medications After an mortality and poor
functional outcome at
Intracerebral Hemorrhage discharge.
Recommendations for restarting anticoagulation involve meticulous analysis of
the benefits of anticoagulation and the risk of ICH recurrence. TABLE 3-8 lists ● Recommendations for
considerations in the shared decision making for restarting anticoagulants restarting anticoagulation
after ICH involve meticulous
or antiplatelets.114-117
analysis of the benefits of
anticoagulation and the risk
Palliative Care Considerations in Intracerebral Hemorrhage of ICH recurrence.
Palliative care measures are instituted in 6.2% to 16.2% of patients with ICH in
the United States.118,119 The length of stay for patients with ICH who received ● Prognostic scoring
systems for ICH should only
palliative care were significantly shorter compared to those who did not,118,119 be used to provide guidance
and hospital costs averaged $4753 less for those who received palliative care in evaluating the risk of ICH
compared to those who did not.119 The AHA recommendations on palliative care intervention and in research
for stroke states that all patients and families affected by this disease with but not to precisely predict
outcome. It is recommended
subsequent effect in their daily function and quality of life should be provided to delay any change in goals
with (at least) primary palliative care services120 (ie, a non–palliative care of care for patients with ICH
specialist administering palliative care services that include support for the who did not have
patient and family and symptom management). Involvement and use of treatment-limiting orders on
admission, because early
palliative care were found to have increased from 4.3 % in 2007 to 16.2% in 2011 treatment limitations in ICH
in patients with ICH in a study analyzing the Nationwide Inpatient Sample.119 are associated with
increased mortality in some
OUTCOMES AND PROGNOSTICATION patients who could have
survived with good
High mortality and severe disability continue to be associated with ICH; thus,
functional outcome.
futility and prognostication are commonly discussed when caring for ICH. Up to
37 clinical prognostic scales for ICH are available, but some do not account for the
effect of withdrawal of care or surgical intervention.121 TABLE 3-9 shows a
comparison of the most validated prognostic scoring systems for ICH, including
their limitations.122-125 These scores should only be used to provide guidance in
evaluating the risk of ICH intervention and in research but not to precisely
predict outcome. It is recommended to delay any change in goals of care for
patients with ICH who did not have treatment-limiting orders on admission,15
because early treatment limitations in ICH are associated with increased
mortality in some patients who could have survived with good functional
outcome.126 An individualized approach is recommended for treating patients
with ICH, and self-fulfilling prophecies should be avoided when it comes to
prognostication during goals-of-care discussion.

CONCLUSION
This article summarizes the important basic foundations of acute ICH and the
considerations for its assessment and management along the patient care
continuum. Emergent stabilization, blood pressure control, reversal of
anticoagulation, neurosurgical consultation, and medical stabilization remain the
mainstays of ICH therapy.
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REVIEW ARTICLE

Moderate and Severe
ONLINE
Traumatic Brain Injury
By Christopher P. Robinson, DO, MS
ABSTRACT
PURPOSE OF REVIEW: Traumatic brain injury (TBI) encompasses a group of
heterogeneous manifestations of a disease process with high neurologic
morbidity and, for severe TBI, high probability of mortality and poor
neurologic outcomes. This article reviews TBI in neurocritical care, hence
focusing on moderate and severe TBI, and includes an up-to-date review
of the many variables to be considered in clinical care.
RECENT FINDINGS: With advances in medicine and biotechnology,

understanding of the impact of TBI has substantially elucidated the
distinction between primary and secondary brain injury. Consequently,
care of TBI is evolving, with intervention-based modalities targeting
multiple physiologic variables. Multimodality monitoring to assess
intracranial pressure, cerebral oxygenation, cerebral metabolism, cerebral
blood flow, and autoregulation is at the forefront of such advances.
SUMMARY: Understanding the anatomic and physiologic principles of acute

brain injury is necessary in managing moderate to severe TBI. Management
is based on the prevention of secondary brain injury from resultant
trauma. Care of patients with TBI should occur in a dedicated critical
care unit with subspecialty expertise. With the advent of multimodality
monitoring and targeted biomarkers in TBI, patient outcomes have a higher
CITE AS: probability of improving in the future.
C O N T I N U U M ( M I N N E AP M I N N )
2 02 1 ; 27(5, NEUROCRITICAL CARE):
1278–1300.
Address correspondence to INTRODUCTION
T
Dr Christopher P. Robinson, raumatic brain injury (TBI) is a leading cause of major disability and
1149 Newell Dr, Gainesville,
FL 32610, christopher.robinson@
death worldwide. In addition, the socioeconomic burden of TBI is
neurology.ufl.edu. increasing substantially because of its large burden on the health care
system, including acute care, rehabilitation, and permanent
Dr Robinson has provided legal
neurologic disability.1 The global incidence of TBI continues to
consulting for Thompson and increase annually in both low- to middle-income countries and high-income
Evangelo PA. countries, with varying causation. Vehicular injury remains the largest causative
UNLABELED USE OF agent in lower-income countries, whereas falls are an ever-increasing etiology in
PRODUCTS/INVESTIGATIONAL higher-income countries as populations age.2 TBI accounts for more than
USE DISCLOSURE:
2.5 million emergency department visits annually, with an average incidence of
Dr Robinson reports no
disclosure. 242 per 100,000 to 317 per 100,000 per year.3,4 Worldwide, mild TBI accounts
for 81% of all cases, with the remaining 19% moderate and severe TBI.5 Case
fatality rates range from 0.9 per 100 to 7.6 per 100 persons overall, with fatality
of Neurology. rates ranging from 29 per 100 to 55 per 100 patients in severe TBI.3,6,7 TBI-related
1278 OCTOBER 2021

disability accounts for the societal and economic burden of the disease, with KEY POINTS
nearly 12 million people affected in the United States and Europe.3
● Traumatic brain injury
TBI is an umbrella term for a heterogeneous group of disease processes with (TBI) is a leading cause of
multiple intracranial pathologies, including cerebral contusions, epidural death and disability
hemorrhage, subdural hemorrhage, subarachnoid hemorrhage, skull fractures, worldwide.
diffuse axonal injury, and cerebral edema (FIGURE 4-1). It is these multiple
● The leading cause of TBI
pathologies that lead to the various sequelae of injury appreciated in TBI. This
in low- to middle-income
article discusses moderate and severe TBI, as they are most relevant to the countries is vehicular
neurologist in the acute and critical care setting, and includes an overview of the trauma, whereas the leading
pathology, presentation, management, prognostication, and pediatric cause of TBI in high-income
considerations. countries is falls.
● TBI is a heterogeneous
CLASSIFICATION OF TRAUMATIC BRAIN INJURY group of diseases with
The classification systems of TBI include the three broad categories of clinical, multiple chemical and
radiographic, and mechanistic domains aimed at providing prognostic guidance biomechanical pathologies.
in the acute care setting (CASE 4-1). The clinical classification system is the most
● Acute classifications for
well-known and commonly used diagnostic tool of TBI severity and is based moderate and severe TBI
on cumulative admission Glasgow Coma Scale (GCS) scoring using eye, motor, exist within the clinical,
and verbal scales (TABLE 4-1). Mild TBI is characterized by a GCS score of 13 to radiographic, and
mechanistic domains.
15, moderate TBI is characterized by a GCS score of 9 to 12, and severe TBI is
characterized by a GCS score of 8 or less. Both moderate and severe TBI are ● Clinical classification of
characterized as higher-grade injuries, typically requiring care in a specialized TBI describes mild,
neurocritical care unit.8 It should be noted, however, that the clinical moderate, and severe levels
of injury based on
presentation Glasgow Coma
Scale score.
FIGURE 4-1
Radiographic heterogeneity of traumatic brain injury on axial noncontrast head CTs. A, Right
parietal epidural hemorrhage and midline frontal contusion. B, Right frontal subdural
hemorrhage with subfalcine herniation. C, Diffuse cerebral edema with diffuse axonal injury.
D, Bifrontal contusions with left hemispheric subdural hematoma and midline shift.
E, Depressed skull fracture with pneumocephalus. F, Diffuse subarachnoid hemorrhage with
intraventricular hemorrhage and frontal contusions and right frontal skull fracture.

MODERATE AND SEVERE TRAUMATIC BRAIN INJURY
CASE 4-1 An 18-year-old man with no significant past medical history was brought
to the emergency department as a Level 1 trauma alert. The report from
emergency providers revealed that the patient was swinging on a rope
swing when he slipped and fell 20 feet. He was found submerged face
first in the water among large tree roots.
On initial examination, the patient was noted to have a large head
laceration and an agonal breathing pattern. Clinical vital signs in the field
included blood pressure of 100/40 mm Hg and arterial oxygenation of
88%. The patient was emergently intubated, resuscitated with IV fluids,
and transferred to a tertiary trauma center for care.
Initial neurologic examination revealed a large left frontal laceration
with notable depression. The patient showed no eye opening or motor
movement in any extremity to central or localized noxious stimulus.
Pupillary examination revealed bilaterally fixed pupils, with the right
pupil measuring 8 mm and the left pupil measuring 6 mm. Corneal
reflexes were absent, as were cough and gag reflexes. Oculocephalic
reflexes were deferred because of cervical collar placement. A head CT
was obtained and showed evidence of a depressed skull fracture, left
temporal intracranial hemorrhage, and midline shift of 10 mm. (FIGURE 4-2).
FIGURE 4-2
Imaging of the patient in CASE 4-1. Axial noncontrast head CT shows severe traumatic brain
injury with tentorial subdural hemorrhage (A), cerebral edema and uncal herniation
(B, C), and depressed skull fracture with intracranial hemorrhage and midline shift (D).
COMMENT Clinical classification and early recognition of traumatic brain injury is

imperative. Classification systems rely on clinical, radiographic, and
mechanistic domains. In this case, the patient’s neurologic examination is
consistent with a Glasgow Coma Scale score of 3 T, with the T indicating
the patient was intubated (eyes, 1; voice, 1 T; motor, 1), classifying the injury
as severe. Radiographic Marshall CT classification of the lesion is
consistent with nonevacuated mass lesion VI. The mechanistic
classification of the injury is described as penetrating based on imaging
and mechanism of injury. Classification of such lesions allows for early and
acute management and provides objective data to aid in prognosis for the
practitioner.
1280 OCTOBER 2021

classification system has limitations because of medical confounders in acute
resuscitation, such as paralytics, anesthetics, and sedatives.
Radiographic classification schemes (such as the Marshall and Rotterdam CT
classification of traumatic brain injury scores) apply descriptive radiographic
CT findings, including appearance of the basal cisterns, degree of midline shift,
and intracranial mass lesions, to predict 6-month outcomes (TABLE 4-2, TABLE 4-3,
and TABLE 4-4).9,10 Limitations of these classification systems include broad
categorization of intracranial lesions (hemorrhage versus axonal injury) and
prognostication based upon a snapshot in time. Such limitations should be
considered when using these tools.
The mechanistic classification scheme describes various etiologies of TBI,
including closed head injury, penetrating head injury, crash injury (vehicular
injury), or blast injury (militarized injury). Descriptive analysis of the
mechanistic cause of TBI can provide valuable prognostic information as it
relates to mortality and outcomes.11 Several validated prognostic tools using large
patient samples, such as the Corticosteroid Randomisation After Significant
Head Injury (CRASH) and International Mission on Prognosis and Analysis of
Clinical Trials (IMPACT) prognostic models, are available for objective
assessment and prognostication.12
A final and important consideration in the acute classification of TBI should be
the impact of extracranial or systemic traumatic injuries, as such pathologies may
result in worsening hypoxemia, coagulopathy, hypotension, and secondary
brain injury.
PATHOLOGIC FEATURES OF TRAUMATIC BRAIN INJURY

Although TBI is classically described based on clinical severity, it is a
heterogeneous disease with multiple subtypes reliant on individualized
underlying pathology. In a broad sense, TBI is dichotomized pathologically into
primary and secondary injury. Primary injury results from an initial impact and
Clinical Classification Grading Scale for Traumatic Brain Injury TABLE 4-1
Mild
◆ Glasgow Coma Scale score = 14

OR
Glasgow Coma Scale score = 15 plus EITHER brief loss of consciousness (<5 minutes) OR
amnesia
Moderate
◆ Glasgow Coma Scale score = 8-13
OR
Loss of consciousness ≥5 minutes
OR
Focal neurologic deficit
Severe
◆ Glasgow Coma Scale score = 3-8

direct traumatic injury to the skull or intracranial structures. Such injuries lead to
intracranial hemorrhage, focal contusions, cerebral edema, skull fractures, and
diffuse axonal injury. As a result of primary injury, diffuse activation of multiple
complex biochemical and cellular processes occurs, resulting in the pathologic
mechanisms and heterogeneity of secondary injury in TBI (FIGURE 4-3).13 Several
different types of head injury may result in moderate or severe TBI clinically;
however, the underlying secondary mechanisms of injury may vary widely in
pathology. Such pathologies include oxidative stress, free radical formation,
calcium-mediated damage, proapoptotic expression, and astrocytic
inflammation.8 For example, a patient with a focal cerebral contusion may
develop significant inflammation or apoptosis, whereas a patient with diffuse
axonal injury may develop significant calcium-related damage. Such effects
typically occur concomitantly and develop or intensify throughout the duration
of disease. It is these complex secondary reactions that lead to the potentiation
and worsening of elevated intracranial pressure (ICP), decreased cerebral blood
flow (CBF), cerebral hypoxemia, and cerebral edema.13
DIAGNOSIS OF TRAUMATIC BRAIN INJURY

The diagnosis of TBI is based on a set of clinical factors, including GCS score, loss
of consciousness, impaired short-term memory, and focal neurologic deficits.
Upon a patient’s arrival at the acute care setting, it is imperative that a brief
neurologic examination be performed concurrently with CT evaluation to assess
structural damage and the need for neurosurgical intervention. Neurologic
examination remains a cardinal feature in the diagnosis of TBI and is the
preferred method of assessment, in addition to radiographic findings, to
determine deterioration and the need for intervention. Rapid assessment should
include evaluation of pupillary function and other brainstem reflexes and a
motor examination of central and peripheral responses to pain with descriptive
documentation of findings related to the GCS score. An abnormal pupillary
examination or posturing related to rostrocaudal decompensation should be a
clue to the need for rapid intervention. CT is the preferred radiographic modality
for diagnosis based on its ultra-early ability to detect acute blood products and
TABLE 4-2 Marshall CT Classification Scale for Traumatic Brain Injurya
Category Definition 6-Month mortality
Diffuse injury I No visible intracranial pathology 10%
Diffuse injury II Cisterns patent; shift 0-5 mm and/or lesions present; no lesion >25 cm3 13%
3
Diffuse injury III Cisterns compressed or absent; shift 0-5 mm; no lesion >25 cm 33%
Diffuse injury IV Midline shift >5 mm; no lesion >25 cm3 56%
Evacuated mass lesion V Any lesion surgically evacuated 35%
Nonevacuated mass lesion VI High- or mixed-density lesion >25 cm3; not surgically evacuated 91%
CT = computed tomography.
a
Data from Marshall LF, et al, Lancet Neurol.9
1282 OCTOBER 2021

bony abnormalities. Intracranial mass lesions secondary to TBI occur quite
frequently in moderate to severe TBI but are also seen in up to 15% of patients
with a GCS score of 13 to 14.14 It is therefore recommended that all patients
presenting to the acute care setting with a GCS score of 14 or less should undergo
cranial imaging. After diagnosis and stabilization, a follow-up CT is recommended
6 hours later because of the risk of delayed progression of intracranial
hemorrhages.15 New intracranial lesions in an otherwise normal-appearing CT
can appear in up to 20% of patients,16,17 and between 25% and 45% of preexisting
intracranial lesions will enlarge on subsequent studies.18 CT angiography should
also be considered in patients with moderate or severe TBI, particularly when
due to blunt traumatic injury. MRI studies are not usually performed in the
acute care setting because of their complex setup and length and concerns of
hemodynamic instability and airway compromise. MRI is classically reserved for
the subacute setting when clinically relevant diffuse axonal injury is suspected.
INVASIVE INTRACRANIAL AND HEMODYNAMIC MONITORING

Conservation of cerebral homeostasis via assessment and management of cerebral
perfusion pressure (CPP) is a safe and effective strategy to reduce mortality
and improve outcome in TBI.19 Continuous invasive hemodynamic monitoring
should therefore be considered for all patients with moderate to severe TBI. CPP
is defined as the difference between the mean arterial pressure (MAP) and the
ICP and is the target variable for cerebral autoregulatory homeostasis.20 The
Rotterdam CT Classification Scorea TABLE 4-3
Score element Points
Basal cisterns
Normal 0
Compressed 1
Absent 2
Midline shift
No shift or shift ≤5 mm 0
Shift >5 mm 1
Epidural mass lesion
Present 0
Absent 1
Intraventricular blood or traumatic subarachnoid hemorrhage
Absent 0
Present 1
Sum score: calculate the sum of all variables and add 1 point to the total +1
a
Data from Maas AIR, et al, Neurosurgery.10

generally accepted target CPP to provide value in outcome is between 60 mm Hg

and 70 mm Hg and is dependent on the patient’s autoregulatory function.21
The use of intracranial monitoring for elevations in ICP is typically reserved
for patients with severe TBI. Current guidelines recommend the placement of an
intracranial monitor in all patients with an abnormal CT scan and a GCS score
between 3 and 8 following resuscitation or, conversely, in patients with a similar
GCS score and a normal CT scan with two of the following characteristics: age
older than 40 years, systolic blood pressure less than 90 mm Hg, or motor
posturing on examination.21,22 The use of ICP monitoring and ICP-directed
therapy in this cohort is recommended to reduce early TBI-related mortality,
and the latest recommendations suggest an ICP threshold of 22 mm Hg.21,22
The duration of ICP elevation in the setting of TBI should also be an
important consideration for management, and it follows a heterogeneous
pattern similar to that of its underlying pathology. Patients with severe TBI
may display one of four distinct patterns in ICP elevation: early elevation
(<72 hours), late elevation (>72 hours), bimodal elevation (<72 and >72 hours),
or continuous elevation.23 These patterns allow for clinical distinction of
peak swelling times in individual patients. Such knowledge is imperative
for forming treatment algorithms and determining the duration of
monitoring.
The use of intracranial monitoring for decreases in brain tissue oxygen tension
(PbtO2) is an evolving concept in the management of TBI. Cerebral oxygenation
delivery and consumption relies on several factors, including the cerebral
metabolic rate of oxygen consumption (CMRO2) and cerebral oxygen
diffusion.24 Monitoring of PbtO2 requires invasive neuromonitoring much like
ICP. Current recommendations for target therapy suggest that a PbtO2 less than
20 mm Hg is correlative to the ischemic threshold of CBF at 18 mL/100 g/min.25
Attempts are therefore made to preserve cerebral oxygenation at greater than
20 mm Hg. At present, the literature suggests that monitoring of PbtO2 is safe.26
Its utility as an adjunctive treatment modality to improve outcomes is currently
being investigated in the multicenter BOOST3 (Brain Oxygen Optimization in
Severe TBI, Phase 3) trial.27 Although not validated in patients with moderate or
TABLE 4-4 Six-Month Mortality Based on Rotterdam CT Classification Scorea
Score Mortality
1 1%
2 2%
3 10%
4 57%
5 72%
6 80%
a
Data from Maas AIR, et al, Neurosurgery.10
1284 OCTOBER 2021

FIGURE 4-3
Pathologic heterogeneity of secondary brain injury in traumatic brain injury.
Data from Maas AIR, et al, Lancet Neurol.8
severe TBI, PbtO2 monitoring may be of use in the future, independent of ICP, as
small prospective studies have shown improvements in both mortality and
6-month outcomes.28
Other invasive intracranial measurements, including cerebral microdialysis,
jugular bulb arteriovenous oxygen content difference, and pressure-reactivity
index, exceed the scope of this article but are used at some centers in the
management of both moderate and severe TBI and likely will become more
developed concepts in the future.
With advances in bioinformatic and precision medicine, the use of
multimodality monitoring in the treatment of TBI has gained favor.
Multimodality monitoring includes the real-time monitoring of multiple
physiologic parameters, including ICP, CPP, CBF, PbtO2, cerebral
autoregulation, EEG, cerebral metabolism, cardiac output, and systemic
oxygenation. Formal guidelines currently exist for the implementation and use of
multimodality monitoring in the neurocritical care unit.29
CRITICAL CARE MANAGEMENT OF MODERATE AND SEVERE

TRAUMATIC BRAIN INJURY
Moderate and severe TBI are acute care diseases that require expert
multidisciplinary treatment within intensive care units (ICUs) equipped to
treat neurologic illness. Established in 1986, the Brain Trauma Foundation has

TABLE 4-5 Clinical Standardization Guidelines for Moderate to Severe Traumatic Brain
Injurya
Tier 0
◆ Maintain euvolemia
◆ Cerebral perfusion pressure >60 mm Hg
◆ PCO2 35-40 mm Hg
◆ SaO2 >90%
◆ Serum sodium >135 mmol/L
◆ Serum glucose >60 mg/dL and <180 mg/dL
◆ Hemoglobin >7 g/dL
◆ Normothermia
◆ Evacuate intracranial mass lesions
◆ Head of bed 30 degrees
Tier 1
◆ Adjust head of bed
◆ Ensure normothermia
◆ Titrate sedation to intracranial pressure
◆ Standard-dose hyperosmolar therapies
◆ CSF drainage if external ventricular drain available
◆ Consider EEG to rule out nonconvulsive seizures
◆ If intracranial pressure persistently >25 mm Hg, consider repeat CT
Tier 2
◆ High-dose hyperosmolar therapy
◆ Adjust PCO2 to 30-35 mm Hg
◆ Increased sedation to intracranial pressure target
◆ Vasopressor trial for increased cerebral perfusion pressure (70 mm Hg)
◆ Neuromuscular paralysis
Tier 3
◆ Adjust temperature to 35 °C to 37 °C (95 °F to 98.6 °F)
◆ Sedative bolus dosing
◆ Decompressive craniectomy
◆ Barbiturate coma
CSF = cerebrospinal fluid; CT = computed tomography; EEG = electroencephalogram.

a
Data from Carney N, et al, Neurosurgery.21
1286 OCTOBER 2021

developed evidence-based guidelines for the management of moderate to KEY POINTS
severe TBI.21 Extrapolated from these guidelines, a multitiered algorithmic
● Mechanistic classification
approach to patient care has been adopted to adequately minimize secondary of TBI includes closed head,
injury while reducing iatrogenic complications (TABLE 4-5) (CASE 4-2).30 penetrating head, crash, and
Tier 0 in the algorithm is aimed at primary prevention and prophylaxis of blast injuries.
secondary injury and is applied to all patients treated for TBI. Tiers 1 through 3
● Primary injury in TBI is
are aimed at interventions based on abnormalities in ICP, CPP, CBF, CMRO2,
defined as the initial
and cerebral autoregulation. The physiologic principles applied to the acute traumatic insult resulting in
management of TBI rely on underlying neuroanatomic knowledge, the hemorrhage, edema, and
principles of compartmentalization, and the Monro-Kellie doctrine. Specific axonal injury.
evidence for such interventions aimed at improving mortality and functional
● Secondary injury in TBI is
outcomes is discussed below. defined as injury related to
cellular and biochemical
Ventilator Management activation, including
Ventilator management in patients with moderate or severe TBI is an important inflammation, calcium
overload, free radical
physiologic concept that should be considered by all physicians. Intrathoracic formation, and blood-brain
pressure, oxygenation, and ventilation are all important for the neurologist to barrier breakdown.
understand as such factors have a direct role on ICP and CBF. It is common that
patients with higher-grade TBI have loss of airway reflexes and ventilatory drive. ● A severe TBI with Glasgow
Coma Scale score of 8 or
As such, the risk for aspiration with resulting hypoxia, and hyperventilation with
less with an abnormal CT
resulting hypercapnia, potentiates secondary brain injury. Ventilation in scan is an acute indication
particular is an important physiologic parameter used to augment CBF through for intracranial pressure
vasodilatory and constriction mechanisms in a direct fashion. As a result, monitoring.
decreases in ventilation produce hypercapnia and cerebral vasodilation with
● Neurocritical care for
subsequent increases in ICP. In the presence of mechanical ventilation with acute TBI follows a tiered
high-grade injuries, tight control of PCO2 within typical physiologic norms approach based on
(35 mm Hg to 45 mm Hg) is therefore necessary. The use of hyperventilation for consensus guidelines.
the treatment of acute elevations in ICP is, at times, appropriate in emergency
● Physiologic targets in the
situations; however, this should occur in a time-limited fashion so as not to risk
management of TBI include
cerebral ischemia from vasoconstriction and decreased CBF. In contrast, the use intracranial pressure,
of prophylactic hyperventilation in TBI with PCO2 targets less than 25 mm Hg is cerebral perfusion pressure,
not recommended because of this ischemic risk.21 Oxygenation targets with brain tissue oxygen tension,
and cerebral blood flow.
mechanical ventilation should remain within normal physiologic targets
(PaO2 >60 mm Hg) and, at times, can be augmented in specific patients with
intracranial PbtO2 monitoring. Finally, neurologists have a vital role in
determining long-term ventilatory strategies. Clinical acumen and objective
neurologic findings allow the clinician to assess anticipated neurologic burden
from the disease and assist in the decision for tracheostomy.
Hemodynamic Augmentation
CPP, CBF, and cerebral autoregulation play a critical role in the prevention of
secondary injury in patients with moderate and severe TBI. One singular isolated
episode of systolic hypotension (<90 mm Hg) in either the prehospital or acute
care setting is associated with worse functional outcomes and increased
mortality.31 Under normal physiologic circumstances, cerebral autoregulatory
mechanisms potentiate cerebral vasodilation or vasoconstriction to maintain an
adequate and constant CBF. In a patient with preserved autoregulation, CBF is
independent of systolic blood pressure and relies on cerebral myogenic,
neurogenic, and metabolic factors for maintenance. If such protective
autoregulatory mechanisms fail, CBF becomes completely dependent on systolic

blood pressure and any elevation in ICP can be deleterious. Given this intricate
dependence of autoregulation for perfusion and its subsequent pathology with
autoregulatory failure, maintenance of tight systolic blood pressure and MAP
goals is essential in preventing secondary injury. Current recommendations
aimed at reducing secondary injury suggest that patients 50 to 69 years of age
should maintain a systolic blood pressure greater than 100 mm Hg, and patients
15 to 49 years of age or older than 70 years of age should maintain a systolic blood
pressure greater than 110 mm Hg at all times.21
Reversal of Coagulopathy
Acute coagulopathy is a common finding in moderate or severe TBI, found in
between 7% and 63% of patients.32 Etiologic considerations of coagulopathy include
CASE 4-2 A 22-year-old woman with a severe traumatic brain injury (TBI) secondary
to a motor vehicle accident was admitted to the intensive care unit. A
head CT was obtained and showed evidence of diffuse cerebral edema
and bifrontal contusions (FIGURE 4-4). Her Glasgow Coma Scale score on
admission was 5 T (eyes, 1; voice, 1 T; motor, 3, decorticate posturing).
An intracranial pressure (ICP) monitor was emergently placed.
In the 24 hours following admission, the patient’s ICP fluctuated
between 15 mm Hg and 20 mm Hg. Tier 0/1 TBI interventions were
performed, including normothermia, normonatremia, head of bed
elevation, sedation, and cerebral perfusion pressure (CPP) greater than
60 mm Hg. The neurointensivist was acutely called to the bedside
because of a newly discovered 5-minute episode of ICP elevation of
30 mm Hg. Mean arterial pressure (MAP) at this time was 70 mm Hg.
Emergent tier 2 interventions were indicated, so the patient was given
hypertonic saline, hyperventilated to a PCO2 of 30 mm Hg, and given bolus
dose sedation. Her ICP subsequently decreased to 25 mm Hg with a
decrease in the MAP to 65 mm Hg. The decision was made to
simultaneously administer vasopressors to support CPP, which resulted
in improvement to a MAP of 90 mm Hg; however, her ICP was also noted
to increase to 30 mm Hg. Neuromuscular paralysis was initiated and
improved ICP to 20 mm Hg. Given concerns for the acute rise in ICP with
relative refractory features, repeat imaging was obtained and showed an
acute epidural hemorrhage in the right frontal lobe. The patient was
emergently taken to the operating room for urgent decompressive
craniectomy and hematoma evacuation.
1288 OCTOBER 2021

anticoagulant or antiplatelet medications, endogenous anticoagulation, or coexistent
systemic trauma, which is its own independent risk factor for coagulopathy. Rapidly
progressive hemorrhagic deterioration, delayed deterioration, and progressive
intracranial hemorrhage are all associated with coagulopathy in the acute setting.33
Independent of clinical worsening, the presence of coagulopathy on admission is a
powerful prognostic predictor, with 9 times increased risk of mortality and 30 times
increased risk of unfavorable outcome.32 Treatment of coagulopathy in TBI should
consist of acute reversal mechanisms aimed at the underlying cause. Abrupt reversal
of systemic pharmacologic anticoagulation should be considered with either fresh
frozen plasma or prothrombin complex concentrates. The use of platelet transfusion
or desmopressin for patients on antiplatelet therapy is controversial; it has definite
risks, and no definitive mortality benefit has been shown.34
FIGURE 4-4
Imaging of the patient in CASE 4-2. Axial noncontrast head CT shows right temporal
contusion (A), diffuse cerebral edema and bifrontal contusions (B, C), and diffuse
traumatic subarachnoid hemorrhage (D).
The patient in this case presented with an acute ICP crisis. Based on the COMMENT
guidelines for the management of an acute ICP crisis, a tiered approach to
treatment was initiated. As is standard, tier 0 and tier 1 interventions had
been employed before the time of crisis. With an acute rise in ICP,
determination of etiology and acute management to prevent secondary
injury are of vital importance. In this case, tier 2 interventions, including
hyperosmolar fluids, hyperventilation, and bolus dose sedation, were used.
Such interventions resulted in improvement of the ICP; however, the MAP
decreased, resulting in a decreased CPP, which was treated with
vasopressors with an improvement in perfusion pressures. However, the
increase in MAP also resulted in an increase in ICP, alerting the examiner to
impaired cerebral autoregulation. As CPP remained greater than 60 mm Hg
with vasopressor use, neuromuscular paralysis was instituted to reach the
target ICP of less than 22 mm Hg. As ICP goals were deemed appropriate,
etiologic concerns dictated repeat neuroimaging, which revealed acute
epidural hemorrhage. Emergent evacuation was indicated and performed.
The events related to acute ICP crisis in this case are common in the
neurocritical care unit, making it relatively clear that early recognition and
prompt management can decrease secondary brain injury.

Sedatives and Paralytics

Analgesics, anesthetics, sedatives, and paralytics are common interventions in
moderate and severe TBI aimed at reducing secondary brain injury. Medications
including propofol, midazolam, fentanyl, ketamine, and vecuronium are
common. Prevention of secondary injury through the use of such medications is
accomplished through several means, including reduction in CMRO2, reduction
in stimulus-induced ICP increases (ie, coughing), and reduction in free radical
oxygen formation.35 Although an effective strategy for targeted ICP therapy in
attempts to curb mortality, no singular sedative agent is more efficacious than
another, and no effective benefit on outcomes has been seen.36 Neurologists
should be very aware of such interventions because of the vast side effect profiles
of these medications. Complications include systemic hypotension, pulmonary
shunting, and depressed cardiac output leading to decreased perfusion pressure,
which can potentiate secondary brain injury. Sedative recommendations should
occur in conjunction with neurologic consultation in patients with TBI to ensure
safety and preservation of neurologic function. The use of barbiturates is also
a long-debated topic in the treatment of ICP and acute brain injury in TBI.
Trials investigating the use of barbiturates in TBI have assessed effective ICP
control, mortality, and 12-month outcomes. Data suggest that the use of
barbiturates in moderate or severe TBI lowers ICP values, has no effect on
mortality or functional outcomes, and results in systemic hypotension and
increased ICU length of stay.37-39 Increased ICU-related complications, such
as pneumonia and ileus, have also been associated with their use. Based on
these findings, neurologists should reserve the use of barbiturates for patients
whose ICP remains refractory to maximal medical interventions.21 The use of
neuromuscular paralytics in TBI is reserved for cases of refractory ICP and aims
at reducing the effective CMRO2.
CSF Drainage
The use of an external ventricular drain (EVD) as a means for CSF diversion
to treat elevated ICP in TBI relies on the physiologic principles of the
Monro-Kellie doctrine. The intracranial vault contents, including the brain
parenchyma, CSF, and arterial and venous blood, create a transcortical
pressure gradient commonly referred to as ICP. Based on the Monro-Kellie
doctrine, the use of CSF drainage attempts to reduce the relative pressure
exerted by CSF within the vault, effectively lowering ICP. Evidence to support
the use of CSF drainage to improve mortality and functional outcomes in TBI
is limited and of low quality.40 Although the effects of CSF drainage on
outcomes are limited, sufficient evidence is available to support patient
improvements in ICP, CPP, PbtO2, and cerebral metabolism.41 Although
potentially beneficial in mitigating secondary brain injury, EVD placement
and use is not without risk. Neurologists should be aware of the risks of tract
hemorrhage associated with drain placement and be vigilant in the assessment
of ventriculitis with acute neurologic deterioration. Ventriculitis resulting from
an EVD can occur in more than 20% of patients.42 Because of inflammation
caused by the drain itself and existing blood products within the ventricular
system, objective assessment of ventriculitis can be difficult. Classic findings of
bacterial infection, including CSF cell count, have limited diagnostic value. More
recently, CSF lactate and IL-6 have shown promise for diagnosing ventriculitis
when used in conjunction with CSF cell count.43,44 If concern for ventriculitis
1290 OCTOBER 2021

exists, empiric antibiotics should be administered and CSF cultures should KEY POINT
be obtained.
● Acute coagulopathy in TBI
is a powerful predictor of
Decompressive Craniectomy outcome and prognosis.
The use of decompressive craniectomy for the management of TBI has classically
been reserved for acute surgical lesions and cases of refractory ICP elevations.
The rationale for its use lies within the predescribed principles of
compartmentalization, ICP elevation, reduced cerebral blood flow, and
secondary brain injury. Primary decompressive craniectomy involves the acute
or early management of surgical lesions requiring evacuation, including epidural
and subdural hematomas and refractory ICP. Secondary decompressive
craniectomy refers to the late or delayed management of ICP refractory to
medical management. Two landmark trials (DECRA [Early Decompressive
Craniectomy in Patients With Severe Traumatic Brain Injury] and RESCUEicp
[Randomised Evaluation of Surgery with Craniectomy for Uncontrollable
Elevation of Intracranial Pressure]) evaluated the effectiveness of decompressive
craniectomy in early and late ICP elevations in TBI and compared mortality and
outcomes in each group. Findings from the DECRA trial suggested that an early
large bifrontal temporoparietal decompressive craniectomy decreased ICP values
but had no effect on mortality and increased unfavorable outcomes (vegetative
state).45 Findings from the RESCUEicp trial suggested that a smaller and later
unilateral decompressive craniectomy decreased ICP values, decreased
mortality, and provided an increased chance for functional independence.46
Based on this body of evidence, the current guidelines recommend late
decompressive craniectomy for refractory ICP to improve outcomes,
recommend against early decompressive craniectomy because of worsening of
outcomes, and suggest that both early and late decompressive craniectomy are
satisfactory interventions to reduce overall ICP burden.47
Other Interventions
Several other interventions aimed at reducing ICP and improving outcomes in
TBI have been explored, including the use of hypothermia to treat refractory ICP
to reduce secondary injury. Several studies exploring both prophylactic and
interventional hypothermia at multiple target temperatures have been
conducted. The current body of evidence suggests that hypothermia effectively
reduces ICP but does not improve outcomes.48,49
The use of glucocorticoids to reduce secondary injury in moderate to severe
TBI has also been explored. In the CRASH trial, which enrolled 10,000 patients to
placebo or intervention within 8 hours of presentation, mortality was higher in
the steroid arm at both 2 weeks and 6 months.50
GENERAL NEUROLOGIC MANAGEMENT OF MODERATE AND SEVERE

TRAUMATIC BRAIN INJURY
The neurologic care of patients with moderate or severe TBI typically occurs in
conjunction with other specialized services. The role of the neurologist is to aid in
the acute and subacute management of TBI to reduce secondary injury and
cognitive-behavioral burden and improve rehabilitation potential. Specific
evidence for such interventions, including seizure prophylaxis and management;
hyperosmolar therapies; and agitation, delirium, and behavior control, is
discussed in the sections that follow.

Seizure Prophylaxis and Management

Symptomatic seizures are a frequent manifestation and common cause of
secondary brain injury in both moderate and severe TBI. These symptomatic
seizures are classified in dichotomous fashion as either early posttraumatic
seizures (<7 days) or late posttraumatic seizures (>7 days). The total prevalence
of clinical posttraumatic seizures ranges from 2% to 12% in patients with
moderate or severe TBI, with subclinical electrographic seizures occurring in up
to 30%.51,52 The presence of early posttraumatic seizures in TBI significantly
increases the probability of posttraumatic epilepsy and risks potentiation of
secondary brain injury due to physiologic abnormalities.53 To reduce this burden,
a 7-day course of a prophylactic antiseizure drug is recommended in all patients
with severe TBI.54,55 In addition, continuous EEG should be considered for up to
72 hours in all patients with moderate or severe TBI to monitor for subclinical
events that may worsen outcome or potentiate ICP. At present, in the absence of
seizure occurrence, no data support the use of prophylactic antiseizure drugs
after 7 days as no long-term benefit in late posttraumatic seizure reduction has
been seen and little is known about the progression of symptomatic seizures as
they relate to the ictal-interictal continuum.56
Hyperosmolar Therapies
The effect of hyperosmolar therapies on mortality and functional outcomes in
TBI has long been a controversial topic. The aim is to effectively reduce ICP with
attempts to maintain adequate CPP and CBF while avoiding iatrogenic
complications. The ultimate goal of such interventions is to drive acute osmolar
change rather than maintain hypertonicity to allow effective reductions in edema
during emergent situations. Mannitol and hypertonic saline are usually first-line
interventions in the management of acute deterioration; the use of each carries
TABLE 4-6 Blunt Cerebrovascular Injury Grading Scalea
Injury grade Vascular injury description

1 Vessel luminal irregularity
OR
dissection with <25% stenosis
2 Vessel dissection
OR
intramural thrombus with ≥25% stenosis
3 Dissecting
OR
pseudoaneurysm
4 Complete vascular occlusion
5 Complete vessel transection with contrast extravasation
a
Data from Biffl WL, et al, J Trauma.65
1292 OCTOBER 2021

the risk of adverse events, specifically, hypovolemia and osmotic nephropathy KEY POINT
with mannitol use and acute renal injury, metabolic acidosis, and pulmonary
● Treatments for refractory
edema with hypertonic saline. Evidence for the use of hyperosmolar therapies in intracranial pressure include
the management of TBI has classically focused on effective reduction of ICP with hyperosmolar fluids,
secondary outcomes focused on CPP, mortality, and functional improvement. To sedation, neuromuscular
date, studies have shown effective, yet isolated, reductions of ICP and paralysis, and surgical
decompression.
radiographic edema, with no evidence to support improvement in mortality or
neurologic outcomes.57-61 A 2020 study compared the effects of bolus dosing of
hypertonic saline and mannitol on elevated ICP burden and duration.62 The
findings showed superiority of hypertonic saline compared to mannitol in
reducing ICP burden and associated cerebral hypoperfusion. Outcome measures
for mortality and functional outcomes were not assessed. The recently published
COBI (Continuous Hyperosmolar Therapy for Brain-Injured Patients) trial
aimed to assess these differences and found no significant improvement in
6-month functional outcomes.63 At present, the use of hyperosmolar therapies in
moderate or severe TBI should be reserved for emergent settings of elevated ICP
or reduced CPP because of lack of evidence supporting improvement in outcome
and risk of adverse effects with their use.
Blunt Cerebrovascular Injury

Blunt cerebrovascular injury, or traumatic vascular injury, occurs in 9% to 17% of
severe TBI cases and has systemic implications based on severity of injury and
respective treatment modality.8,64 All patients presenting with moderate or
severe TBI should undergo CT angiography as a screening measure for diagnosis.
The severity of blunt cerebrovascular injury is graded on a scale of 1 to 5 from
dissection with luminal irregularity (1) to complete vessel transection (5)
(TABLE 4-6).65 The presence of blunt cerebrovascular injury in the acute setting
significantly increases the patient’s risk for stroke. Ischemic stroke occurs in 11%
of patients with blunt cerebrovascular injury, and such risks increase with the
level of injury severity.66 At present, guidelines suggest the use of antithrombotic
or antiplatelet medications, dependent on cerebrovascular injury severity, for
secondary stroke prophylaxis.67 Discussion among the neurologist and the
treatment team is imperative to ensure adequate selection of therapy.
Endovascular intervention for higher-grade lesions, including pseudoaneurysm
formation, may be necessary, and neurosurgical consultation should be
considered.
Cerebral Venous Sinus Thrombosis

Cerebral venous sinus thrombosis (CVST) is a common complication of
moderate and severe TBI. Thrombosis within venous structures typically
presents along fracture lines and occurs in up to 26% of patients with severe
TBI.68 Clinicians should have high suspicion of venous injury when patients have
multiple skull fractures. Diagnosis of CVST is typically made by CT venography;
however, frequent recognition is made during screening CT angiography for
blunt cerebrovascular injury. The presence of CVST in TBI significantly increases
the risk of in-hospital mortality by 10% and should be considered in diagnosis
when patients present with worsening cerebral edema or new intracranial
hemorrhage.69 The treatment of CVST in TBI remains controversial. Given the
common presence of intracranial hemorrhage in TBI, anticoagulation is
commonly contraindicated. Interventions such as antiplatelet therapy and deep

venous thrombosis chemoprophylaxis can be considered, although no data exist

on their efficacy. In emergent situations, such as intracranial hemorrhage from
CVST, decompressive hemicraniectomy can be considered. Neurologists play a
vital role in this decision-making process and should weigh the potential risks
and benefits of any intervention for CVST in conjunction with the treatment
team.
Paroxysmal Sympathetic Hyperactivity

Paroxysmal sympathetic hyperactivity, defined as excessive sympathetic activity
after acute brain injury, includes paroxysms of symptoms such as tachycardia,
tachypnea, hyperthermia, hypertension, diaphoresis, and neurologic changes.70
Pathologically, paroxysmal sympathetic hyperactivity results from the loss of
inhibitory control of excitation, resulting in excessive sympathetic outflow.
Following TBI, paroxysmal sympathetic hyperactivity is a common occurrence,
with incidence between 8% and 10%.71 Although not an independent predictor of
morbidity or mortality, paroxysmal sympathetic hyperactivity is associated with
prolonged hospitalization and iatrogenic complications.72 Paroxysmal
sympathetic hyperactivity is often identified as “central fever” in patients with
TBI, and neurologists should be aware of this symptomatology as it manifests
with vital sign abnormalities but has its roots in a central neurologic disturbance.
The classic presentation of paroxysmal sympathetic hyperactivity occurs within 1
to 2 weeks following TBI, with paroxysms seen most commonly following
neurologic or noxious stimulation. The symptom-based Paroxysmal Sympathetic
Hyperactivity Assessment Measure is a tool that can be used to assess diagnostic
probability and for early identification of paroxysmal sympathetic
hyperactivity.73 The treatment of paroxysmal sympathetic hyperactivity
typically requires an individualized patient approach based on real-time
physiologic variables, including heart rate, respiratory rate, fever, and neurologic
examination, targeted at decreasing sympathetic drive. Multiple pharmacologic
agents are commonly needed to control paroxysms, including gabapentin,
bromocriptine, clonidine, propranolol, and opiates.74 The introduction of such
interventions should occur in a tiered manner with careful dose escalation and
assessment of response. For more information on paroxysmal sympathetic
hyperactivity, refer to the article “Autonomic Hyperactivity” by Alejandro A.
Rabinstein, MD, FAAN,75 in the February 2020 issue of Continuum.
Neurobehavioral Syndromes and Sleep-Wake Disorders

Neurobehavioral syndromes define a specific period of recovery following
moderate or severe TBI. Symptoms occur hours to weeks after emergence of
consciousness and include amnesia, agitation, impulsiveness, aggression,
delusions, and cognitive disturbance. The pathologic mechanisms behind such
disturbances relate to the secondary injurious effects of the catecholaminergic
and serotonergic systems in the brain.76 Several studies of pharmacologic efficacy
in neurobehavioral syndromes have been conducted, including the use of
propranolol, amantadine, sertraline, and atypical antipsychotics. Early initiation
of propranolol has shown improved survival and behavioral modification
following TBI, and the use of amantadine accelerates functional recovery,
reduces aggression, and improves cognitive outcomes.77,78 The use of sertraline
in neurobehavioral syndromes has been shown to reduce aggression, whereas the
use of neuroleptics such as olanzapine and quetiapine reduce the overall effects
1294 OCTOBER 2021

of neurobehavioral syndromes.79 α2-Adrenergic receptor agonists such as KEY POINTS
clonidine and dexmedetomidine have also been shown to reduce the severity of
● Early recognition and
neurobehavioral syndromes and provide neuroprotection in vitro.80,81 Further management of paroxysmal
prospective trials assessing the long-term benefit of these interventions are sympathetic hyperactivity
needed. following TBI can result in
Sleep-wake dysfunction is also a common sequela following TBI. Symptoms decreased length of stay
and decreased iatrogenic
such as insomnia and hypersomnia result from dysfunction within the reticulo-
complications.
hypothalamic-cortical system and can have lasting effects on functional quality
after injury. Insomnia and hypersomnias are reported in 30% to 60% of patients ● Management of
following TBI.82,83 Symptom-directed pharmacologic and cognitive-behavioral neurobehavioral syndromes
therapy are the mainstays of treatment for insomnia and parasomnias and following TBI is a key
component in improving
include the use of behavioral modifications and benzodiazepines.84 The use of long-term outcomes.
nonbenzodiazepines for the treatment of insomnia in TBI shows promise but
requires larger-scale studies to assess efficacy. The treatment of hypersomnias ● Determination of
following TBI includes the use of stimulants such as modafinil and prognosis of TBI is difficult
because of the
methylphenidate, which have shown significant improvements in daytime heterogeneity of the disease
sleepiness.84 and dynamic evolution of
pathologic processes.
PROGNOSIS IN TRAUMATIC BRAIN INJURY
● The management of
Prognostication in moderate and severe TBI remains difficult and complex.
refractory intracranial
Because of the heterogeneity and evolutionary pathology of TBI, creation of a pressure in pediatric
standardized approach to prognostication is difficult. In a 2019 study examining patients with TBI follows a
clinicians’ comfort with prognostication based on current TBI models, tiered approach similar to
assessments among neurologists, neurosurgeons, and intensivists were greatly that suggested for adult TBI,
with guidelines focused on
divided.85 At present, the CRASH and IMPACT models for prognostication in specific physiologic targets.
TBI are the most validated tools in the field. Each model aims to predict 6-month
outcomes following TBI based on objective data at a single point in time. The core
clinical predictors of outcome following admission for TBI in these models
include age, pupillary responses, and GCS motor score, which only accurately
predict 35% of all TBI outcomes.86 To attempt to reduce such variance, further
prognostic variables, including Marshall CT classification score, the presence of
subarachnoid hemorrhage, and laboratory values, were added to the outcome
prediction models. Although such objective measures improved the prediction
models, attempts to predict outcome at a single point in time remain difficult in
such a dynamic disease. Because of the risk of such confounding variables, the
recommended use of prognostic tools remains undefined in the current
guidelines. It is currently recommended that prognosis be attempted in the
context of real-time clinical care and objective data. At present, several clinical
validation studies into the use of biomarkers such as UCH-L1, S100B, and glial
fibrillary acidic protein (GFAP) for prognostication are ongoing.87 Further
research on models or data to support the dynamics of TBI are needed.
PEDIATRIC CONSIDERATIONS IN TRAUMATIC BRAIN INJURY

The worldwide incidence of pediatric TBI ranges between 47 per 100,000 and
280 per 100,000 children, with a similar pathologic distribution to the adult
population with 20% comprising moderate or severe TBI.88 The age of
distribution among the pediatric population follows a bimodal pattern (0 to
4 years and 15 to 18 years), with the leading injury mechanisms including motor
vehicle crashes, falls, and trauma.89 The acute care of pediatric patients with TBI
should include a dedicated pediatric ICU with dedicated specialists in brain

injury. Similar to the adult TBI algorithm, physiologic management aimed at the
reduction of secondary brain injury is essential. Target variables such as ICP,
CPP, CBF, and PbtO2 are common in the pediatric literature. The current
guidelines for the management of moderate or severe pediatric TBI are published
by the Society of Critical Care Medicine and follow a tiered approach similar to
that suggested for the adult population, with slight alterations in physiologic
norms based on age and weight.90
CONCLUSION
Moderate and severe TBI are a heterogeneous, dynamic, and ever-evolving
group of diseases. Current clinical practice standards rely on a set of
evidence-based guidelines aimed at the reduction of secondary brain injury.
Early recognition, expedited resuscitation, physiologic stabilization, and
rehabilitation are the critical elements necessary in attempts to reduce mortality
and improve functional outcomes. Prognostic estimation in TBI remains difficult
and relies on objective data, clinical acumen, and expertise. Future directions in
TBI should include implementation of precision medicine, studies improving
functional outcomes, and development of individualized prognostic tools to
better serve the patient.
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1300 OCTOBER 2021

Posterior Reversible REVIEW ARTICLE

Encephalopathy C O N T I N U UM A U D I O
INTERVIEW AVAILABLE
ONLINE
Syndrome and
Reversible Cerebral
Vasoconstriction
Syndrome as Syndromes CITE AS:
of Cerebrovascular 2021;27(5, NEUROCRITICAL CARE):

1301–1320.
Dysregulation Address correspondence to

Dr Aneesh Singhal, Department
of Neurology, 55 Fruit St,
Massachusetts General
By Aneesh B. Singhal, MD, FAAN, FANA, FAHA Hospital, Boston, MA 02114,
asinghal@mgh.harvard.edu.
Dr Singhal has served as a
ABSTRACT consultant for Deck
PURPOSE OF REVIEW: This article describes the causes, clinical and imaging Therapeutics and Omniox;
received research/grant
features, management, and prognosis of posterior reversible support from the National
encephalopathy syndrome (PRES) and reversible cerebral vasoconstriction Institutes of Health/National
syndrome (RCVS), in which the underlying pathophysiology is related to Institute of Neurological
Disorders and Stroke
reversible dysregulation of the cerebral vasculature. (R01NS105875, U10NS086729,
U01NS095869) and publishing
royalties/honoraria from
RECENT FINDINGS:PRES and RCVS are descriptive terms, each bringing
MedLink, LLC and UpToDate,
together conditions with similar clinical-imaging manifestations. Inc; and provided expert legal
Headache, visual symptoms, seizures, and confusion occur in both testimony on posterior
reversible encephalopathy
syndromes. RCVS is usually heralded by recurrent thunderclap syndrome and reversible
headaches, whereas encephalopathy and seizures are typical in PRES. cerebral vasoconstriction
In PRES, brain imaging shows reversible vasogenic edema that is syndrome. Dr Singhal’s wife is
an employee of Biogen.
typically symmetric and located in subcortical regions (mostly
posterior predominant). In RCVS, brain imaging is often normal; cerebral UNLABELED USE OF
angiography shows segmental vasoconstriction-vasodilatation
USE DISCLOSURE:
affecting the circle of Willis arteries and their branches. Aside from Dr Singhal discusses the
shared clinical features, significant imaging overlap exists. Both PRES unlabeled/investigational use of
glucocorticoids, intraarterial
and RCVS can be complicated by ischemic and hemorrhagic brain vasodilator therapy, and
lesions; angiographic abnormalities frequently occur in PRES and nimodipine calcium channel
vasogenic edematous lesions in RCVS. Common triggers (eg, blockers for the treatment of
posterior reversible
eclampsia, vasoconstrictive and chemotherapeutic agents) have been encephalopathy syndrome and
identified. Abnormal cerebrovascular tone and endothelial reversible cerebral
dysfunction may explain both syndromes. Management of these vasoconstriction syndrome.
syndromes includes the removal of identified triggers, symptomatic

treatment of headache or seizures, and moderate blood pressure © 2021 American Academy
of Neurology.

SYNDROMES OF CEREBROVASCULAR DYSREGULATION
control. Both syndromes are self-limited, with clinical recovery

occurring within days to weeks. Long-term deficits and mortality
are uncommon.
SUMMARY: PRES and RCVS have been well characterized and acknowledged
to have significant overlap. Advances in our understanding of
pathophysiology and risk factors for poor outcome are expected to
optimize the management of these not uncommon syndromes.
INTRODUCTION
P
atients with clinical and imaging features consistent with posterior
reversible encephalopathy syndrome (PRES) and reversible cerebral
vasoconstriction syndrome (RCVS) have been described in case
reports or case series since at least the 1960s. The first systematic
description of PRES in 1996 resulted from grouping several previously
described entities (eg, hypertensive and uremic encephalopathy, preeclampsia/
eclampsia, and encephalopathy associated with chemotherapy and immune
modulators) based on their common neuroimaging feature of posterior-
predominant, usually reversible, vasogenic cerebral edema.1 The evolution of
RCVS is similar: the term cerebral vasoconstriction syndromes was introduced
nearly 2 decades ago to group together entities with acute and reversible
segmental cerebral artery narrowing and dilatation, typically heralded by
thunderclap headaches (eg, postpartum cerebral angiopathy; cerebral
vasoconstriction associated with drugs, chemotherapeutic agents, and immune
modulators; Call or Call-Fleming syndrome; migraine angiitis; central nervous
system [CNS] pseudovasculitis; and benign angiopathy of the CNS).2,3 Over the
past few years, several prospective and retrospective cohort studies and review
articles have comprehensively characterized PRES4-6 and RCVS,7-14 leading to
their global recognition as cerebrovascular dysregulation syndromes that are
almost always reversible and self-limited in their clinical course. Additionally,
patients with features of both entities (the PRES/RCVS overlap syndrome) have
been described15-19 and similarities between PRES and RCVS in the form of
presenting symptoms, complications, and imaging findings have been
recognized,6,20 leading to the notion of a shared or overlapping pathophysiology.
Both syndromes are encountered frequently in the emergency department and
neurologic intensive care settings as well as on inpatient floors. This article
reviews the similarities of PRES and RCVS and differences in their triggers,
clinical-imaging features, pathophysiology, management, and outcomes.
EPIDEMIOLOGY
The past 2 decades have witnessed an explosion of published reports of PRES and
RCVS owing to their detailed characterization combined with easier recognition
because of the widespread use of CT and MRI brain and vascular imaging.
Previously considered rare, PRES and RCVS are now encountered routinely in
clinical practice, with each having their own International Classification of
Diseases, Tenth Revision (ICD-10) codes (PRES, I67.83; RCVS, I67.841).21
PRES affects individuals across all ages, although most commonly young or
middle-aged adults, and has a female preponderance. PRES has been reported
in 0.4% to 8% of adults and 2% to 25% of children undergoing solid organ or bone
1302 OCTOBER 2021

marrow transplantation and in up to 25% of patients with autoimmune disorders, KEY POINTS
infections, or end-stage renal disease.22,23 In children, PRES was observed in
● Reversible cerebral
0.4% of intensive care admissions and accounted for 0.04% of hospitalizations, vasoconstriction syndrome
with a mortality rate of 3.2%.24,25 (RCVS) predominantly
Reports on RCVS have included more than 1200 patients from different affects women, even after
geographic, racial, and ethnic backgrounds over the past 15 years alone.9-13,26-29 accounting for postpartum
cases.
The age range is 4 months to 82 years, with a mean age of 42 to 51 years in large
cohort studies. Female to male ratios range from 2:1 to 10:1 across cohort ● Brain imaging to
studies9-13,26-29; however, in children, a male predominance is seen.30,31 Affected investigate for posterior
males are younger, have onset with sexual activity more frequently (CASE 5-1), reversible encephalopathy
and have more benign outcomes than females.32 syndrome (PRES) is
warranted in patients with
altered mental status in
CLINICAL FEATURES high-risk clinical settings.
PRES can start acutely or subacutely or may be identified on neuroimaging
during the routine evaluation of tumors or encephalopathy. Most patients ● Cortical visual symptoms
are common in both PRES
present with confusion or an acute encephalopathy (TABLE 5-1). Generalized and RCVS.
tonic-clinic seizures or subclinical seizures (eg, occipital sharp waves on EEG)
develop in approximately two-thirds of patients. PRES should be considered in ● Although a single
any patient with unexplained altered sensorium, particularly in those who are thunderclap headache
carries a broad differential
hypertensive, have renal failure, are immunocompromised, or are receiving
diagnosis, recurrent
chemotherapy. Severe hypertension is usually present, although PRES can thunderclap headaches
develop in its absence.33 Patients without severe encephalopathy often recall occurring over a span of a
headaches and visual symptoms. The headache can be abrupt and severe few days are diagnostic for
(thunderclap) but more commonly is gradual, diffuse, and self-limited. Visual RCVS.
symptoms include blurriness, scotomas, and whiteout or blackout of vision,

suggesting cortical blindness. Vision usually recovers with resolution of
encephalopathy. Rare patients with complications of PRES, such as occipital
infarctions or brain hemorrhage, can develop irreversible visual symptoms or
other focal neurologic deficits such as hemiplegia. Spinal manifestations
have been described in a handful of cases, usually as cervical central cord edema
on MRI with or without spinal symptoms.
RCVS symptoms overlap with those of PRES (headache, seizures, visual
symptoms, encephalopathy); however, distinct differences are also seen
(TABLE 5-1). As highlighted in CASE 5-1, RCVS typically starts acutely with an
unusually severe explosive headache that reaches peak intensity within 1 minute
(thunderclap headache,34 similar to the headache of ruptured brain aneurysms
and other serious conditions discussed in the section on differential diagnosis).
Such headaches are different from a patient’s prior migraine headaches, if such a
history is present. Thunderclap headaches recur in approximately 85% to 90% of
patients, with an average of four recurrences spanning 1 to 4 weeks, usually
triggered by exertion or the Valsalva maneuver; however, their intensity and
frequency diminish over time.9,11 A minority of patients, usually women who are
pregnant, report milder and more gradual non-thunderclap headache or develop
RCVS in the absence of headache.9,35 Seizures are far less frequent in RCVS
than in PRES, are usually generalized tonic-clonic and self-limited, and do not
recur after resolution of RCVS except in rare patients with significant irreversible
cerebral injury. Visual symptoms are similar to those reported with PRES:
blurred vision, scotomas, and cortical blindness, frequently with elements of
Balint syndrome. Mild confusion at onset is frequent, usually associated with the
unbearable head pain, but significant or prolonged encephalopathy is uncommon.

Diffuse hyperreflexia is a common examination finding, probably reflecting

autonomic dysregulation and increased serotonergic activity. As with PRES,
focal neurologic deficits such as aphasia or hemiparesis can develop in patients
with ischemic or hemorrhagic cerebral complications of RCVS.
IMAGING FINDINGS
PRES lesions are best appreciated on T2/fluid-attenuated inversion recovery
(FLAIR) MRI sequences as symmetric hyperintense lesions that are usually located
posteriorly in the parietooccipital and frontal lobes (mostly in the cortical-
subcortical junctions) and the cerebellar hemispheres (TABLE 5-1). Three common
radiologic patterns have been described: the parietooccipital pattern, the
holohemispheric watershed pattern, and the superior frontal sulcus pattern
(FIGURE 5-2). Less commonly, lesions can involve the basal ganglia and brainstem.
PRES lesions reflect reversible vasogenic edema and hence appear hyperintense or
isointense on apparent diffusion coefficient (ADC) maps; they almost always
reverse within days to weeks. However, up to one-third of patients develop
heterogeneous lesions with areas of hypointensity (restricted diffusion, indicating
cytotoxic edema from brain ischemia, which is usually irreversible) within regions
CASE 5-1 A 46-year-old man developed a severe postcoital thunderclap headache.

Severe headaches recurred, and on day 3, he developed cortical
blindness and mild left hemiparesis. He had a history of migraine without
aura, hypertension, hyperlipidemia, and cannabis use.
CT angiography obtained at admission showed multifocal segmental
stenosis of the bilateral middle cerebral arteries (FIGURE 5-1A) and the
basilar, posterior cerebral, and superior cerebellar arteries (FIGURE 5-1B).
These abnormalities were also seen on brain magnetic resonance
angiography (MRA) (FIGURE 5-1C). Diffusion-weighted MRI (FIGURE 5-1D) and
apparent diffusion coefficient maps (FIGURE 5-1E) showed symmetric
lesions in the bilateral occipital lobes consistent with ischemic stroke. In
addition, brain MRI showed small infarctions in the bilateral cerebellar
hemispheres and in the right frontal lobe. Serologic tests and the results
of two CSF examinations showed no evidence of vasculitis or
subarachnoid hemorrhage.
The patient was treated with analgesics and verapamil. His deficits
resolved completely over a period of 3 weeks, and follow-up MRA
showed resolution of the cerebral arterial vasoconstriction (FIGURE 5-1F).
COMMENT This case is a classic example of reversible cerebral vasoconstriction

syndrome. A history of thunderclap headaches that recur within days is
virtually diagnostic for reversible cerebral vasoconstriction syndrome.
Cortical visual symptoms are common and correlate with the typical
symmetric ischemic lesions in the watershed territory of the middle and
posterior cerebral arteries.
Modified with permission from Calabrese LH, et al, Ann Intern Med.8 © 2007 The American College of
Physicians.
1304 OCTOBER 2021

of hyperintensity on ADC maps. Up to one-fourth of patients develop lobar
brain hemorrhage or convexity subarachnoid hemorrhage. Cerebral vascular
imaging in PRES reveals segmental arterial narrowing and dilatation (“sausage
on a string” appearance) identical to the angiographic abnormalities of RCVS
(CASE 5-2 and CASE 5-3) in approximately 50% of patients.17 Reversible
vasoconstriction of systemic arteries has not been described in PRES, unlike in
RCVS, as described below.
FIGURE 5-5 shows the types and frequencies of imaging findings in RCVS.
More than 70% of patients have normal brain MRIs with no parenchymal lesion,
despite the presence of widespread cerebral vasoconstriction. Linear or
dot-shaped lesions within the sulcal spaces are found in 20% to 40% of
patients, reflecting slow flow within abnormally dilated surface vessels.36,37
Although the initial brain imaging is usually normal, up to 70% of inpatients
go on to develop convexity subarachnoid hemorrhage, parenchymal
hemorrhage, ischemic stroke, or vasogenic brain edema (PRES) either in
isolation or in combination over the ensuing 2 weeks. Hemorrhagic lesions
tend to occur earlier than ischemic lesions.11,26,38,39 Similar to PRES, the
ischemic and edematous lesions of RCVS are usually located in the
FIGURE 5-1
Imaging of the patient in CASE 5-1. CT angiography obtained at admission shows multifocal
segmental stenosis of the bilateral middle cerebral arteries (A, arrows) and the basilar,
posterior cerebral, and superior cerebellar arteries (B, arrows). These abnormalities are also
seen on brain magnetic resonance angiography (MRA) (C, arrows). Diffusion-weighted
MRI (D) and apparent diffusion coefficient maps (E) shows symmetric lesions in the bilateral
occipital lobes consistent with ischemic stroke. Follow-up MRA (F) shows resolution of the
cerebral arterial vasoconstriction.
Reprinted with permission from Calabrese LH, et al, Ann Intern Med.8 © 2007 The American College
of Physicians.

posterior watershed and cortical-subcortical regions of the parietooccipital

and frontal lobes, rarely affect deep structures, and frequently involve the
cerebellar hemispheres. Transcranial Doppler ultrasound can show elevated
cerebral blood flow velocities40; however, the correlation between flow
velocities and multifocal narrowing of cerebral arteries is modest.
High-resolution vessel wall MRI often shows lack of arterial contrast
enhancement in RCVS.41,42 Cerebral angiographic studies in RCVS are (by
definition) abnormal, showing a smoothly tapered vasoconstriction and
vasodilation (“sausage on a string” appearance) with a centripetal
progression documented on serial imaging. Coexisting vascular lesions,
such as cervical artery dissection, unruptured aneurysms, cavernous
malformations, and fibromuscular dysplasia, are observed in approximately
20% of patients.43,44 Noncerebral arteries (extracranial carotid, retinal,
renal, mesenteric, coronary) are rarely affected and may resemble the
appearance of fibromuscular dysplasia.45 Rare cases of concomitant takotsubo
cardiomyopathy, presumably from coronary vasoconstriction, have been
reported.46
TABLE 5-1 Clinical and Imaging Features of Posterior Reversible Encephalopathy

Syndrome and Reversible Cerebral Vasoconstriction Syndromea
Posterior reversible Reversible cerebral

Feature encephalopathy syndrome vasoconstriction syndrome
Clinical
Encephalopathy 50-80% 10-15%
Seizures 60-75% 0-20%
Status epilepticus 5-15% Rare
Headache 50% 90-95%
Visual deficits 33% 30-40%
Focal neurologic deficit 10-15% 9-63%
Imaging
Vasogenic cerebral edema 100% 15-40%
Ischemic stroke 15-30% 33%
Lobar hemorrhage 10-25% 15%
Sulcal subarachnoid blood 3-8% 40%
Segmental vasoconstriction 30-70% 100%
Coexisting vascular lesion (eg, dissection, aneurysm) Uncommon 20%
Contrast enhancement 20% Uncommon
a
Data from Fugate JE, Rabinstein AA, Lancet Neurol4 and Rocha E, Singhal AB, Curr Treat Options Cardiovasc Med.14
1306 OCTOBER 2021

DIFFERENTIAL DIAGNOSIS KEY POINTS
The diagnosis of PRES is based on imaging features of vasogenic cerebral edema
● The word reversible in the
in the appropriate clinical setting. The differential diagnosis of imaging lesions term reversible cerebral
includes CNS infection, progressive multifocal leukoencephalopathy, vasoconstriction syndrome
demyelinating diseases, brain tumors such as glioblastoma or lymphoma, refers to the spontaneous
autoimmune or paraneoplastic encephalitis, cerebral vasculitis, and toxic reversibility of cerebral
angiographic abnormalities,
(eg, heroin) encephalopathy. These mimics can be excluded based on a careful
observed in 97% to 100% of
history and evaluation of the MRI lesions, serial brain imaging to confirm lesion cases. Patients who develop
reversibility, and, if warranted, by CSF examination. stroke as a complication can
For RCVS, the diagnostic approach should consider the main clinical have permanent clinical
deficits.
feature (thunderclap headache) and the main imaging feature (intracranial
arteriopathy). For thunderclap headache, it is important to consider whether ● Vasogenic edema
indicates disruption of the
blood-brain barrier, which is
central to the
pathophysiology of PRES.
● In RCVS, despite
widespread and often
severe intracranial artery
narrowing, brain
parenchymal imaging
typically remains normal at
onset.
● RCVS can be easily and

accurately diagnosed based
on clinical-imaging features
alone, for example by using
the RCVS2 score. Biomarkers
and advanced imaging
techniques such as
high-resolution vessel wall
MRI and invasive cerebral
angiography have limited
diagnostic utility.
FIGURE 5-2
Three radiologic patterns of posterior reversible encephalopathy syndrome (PRES) as seen
on axial fluid-attenuated inversion recovery (FLAIR) MRI. The dominant parietooccipital
pattern describes the involvement of only posterior brain (A-C). The holohemispheric
watershed pattern (D-F) describes the predominant involvement of the border zone
between the anterior, middle, and posterior cerebral artery territories in a linear pattern
spanning the frontal, parietal, and occipital lobes. The superior frontal sulcus pattern (G-I)
manifests as more isolated involvement of the superior frontal sulcus without extension into
the frontal pole.
Reprinted with permission from Fugate JE, Rabinstein AA, Lancet Neurol.4 © 2015 Elsevier Ltd.

the patient reports one headache or multiple headaches recurring within a

short time span. Single thunderclap headaches can be secondary to potentially fatal
conditions such as aneurysmal subarachnoid hemorrhage, pituitary apoplexy,
cervical artery dissection, meningitis, and cerebral venous sinus thrombosis.47
Hence, immediate brain and cerebrovascular imaging is indicated to exclude these
secondary etiologies. Lumbar puncture may then be considered to definitively
exclude meningitis or subarachnoid hemorrhage. If the evaluation is negative, the
differential diagnosis narrows to primary (idiopathic) thunderclap headache.
CASE 5-2 A 36-year-old woman developed severe headaches associated with

new-onset hypertension 10 days after the birth of twins by cesarean
delivery. Her initial brain MRI and CT examinations were normal.
Headaches persisted despite antihypertensive medications; a seizure
and an episode of aphasia and hemiparesis occurred. Repeat MRI on
postpartum day 18 (FIGURE 5-3A) showed hyperintense regions in both
parietooccipital lobes with elevated diffusion, findings consistent with
vasogenic edema. These clinical-imaging features were consistent with
posterior reversible encephalopathy syndrome (PRES). Magnetic
resonance angiography (MRA) of the circle of Willis (FIGURE 5-3B) showed
multifocal stenoses in the proximal anterior, middle, and posterior
cerebral arteries. This finding was consistent with postpartum angiopathy
(a condition included under the umbrella term reversible cerebral
vasoconstriction syndrome [RCVS]). MRI obtained on postpartum day 19
showed hyperintense lesions on fluid-attenuated inversion recovery
(FLAIR) (FIGURE 5-3C) and diffusion-weighted images (FIGURE 5-3D), a finding
consistent with ischemic stroke.
Despite multiple endovascular attempts to dilate the cerebral arteries
with intracerebral vasodilator injections, the patient showed clinical and
angiographic progression over the course of 1 week. A follow-up MRA
(FIGURE 5-3E) showed worsening of the multifocal cerebral arterial
stenosis, and FLAIR MRI showed bilateral cerebral infarction with edema
and hemorrhage (FIGURE 5-3F). The patient eventually died. On autopsy, the
cerebral arteries were normal with no evidence of inflammation.
COMMENT This case is a classic example of postpartum eclampsia with postpartum

angiopathy (ie, PRES with RCVS), which are interrelated conditions and
frequent causes of postpartum ischemic and hemorrhagic stroke. These
syndromes are difficult to predict or prevent. No proven treatment has
been established, although blood pressure control, magnesium
supplementation, and oral calcium channel blocker treatment are
considered important. Although 90% of patients will have a self-limited
course and recover within days to weeks, some patients (as in this case) will
have a progressive course, often with a fatal outcome. This case highlights
the potential risk for rebound vasoconstriction and reperfusion injury with
invasive angiography and intraarterial vasodilator therapy.
Modified with permission from Singhal AB, et al, N Engl J Med.18 2009 Massachusetts Medical Society.
1308 OCTOBER 2021

Many patients with primary thunderclap headache prove to have angiographic
changes of RCVS.48,49 In others, angiographic changes can be absent on initial
imaging but become evident later. Hence, primary thunderclap headache is
believed to lie within the spectrum of RCVS. In patients with multiple thunderclap
headaches that recur over a span of days, the pretest probability for RCVS
approaches 100%.10,50 Brain imaging is still indicated to investigate for
complications of RCVS, such as convexity (nonaneurysmal) subarachnoid
hemorrhage, lobar hemorrhage, or ischemic stroke.
FIGURE 5-3
Imaging of the patient in CASE 5-2. Axial fluid-attenuated inversion recovery (FLAIR)
MRI on day 18 after the delivery of twins shows hyperintense regions in both
parietooccipital lobes (A, arrows) that had elevated diffusion (not shown), findings
that are consistent with vasogenic edema and posterior reversible encephalopathy
syndrome (PRES). Magnetic resonance angiography (MRA) of the circle of Willis (B)
showed multifocal stenoses in the proximal anterior, middle, and posterior cerebral
arteries, consistent with postpartum angiopathy (a condition included under
reversible cerebral vasoconstriction syndrome [RCVS]). Hyperintense lesions are
shown on axial FLAIR (C, arrow) and diffusion-weighted images (D, arrow) from MRI
performed on postpartum day 19, a finding consistent with ischemic stroke. Axial
follow-up MRA (E) shows worsening of the multifocal cerebral arterial stenoses and
FLAIR image (F) shows bilateral cerebral infarction with edema and hemorrhage.
Reprinted with permission from Singhal AB, et al, N Engl J Med.18 © 2009 Massachusetts Medical Society.

The differential diagnosis of a new angiographically evident intracranial

arteriopathy includes RCVS, primary angiitis of the CNS, moyamoya disease,
intracranial atherosclerosis, and infectious vasculitis, among others.51 Before the
recognition of RCVS, many patients were misinterpreted as having primary
angiitis of the CNS and exposed to the risks of brain biopsy and lifelong
immunosuppression.52 Recent comparative studies have shown that RCVS can
be distinguished from primary angiitis of the CNS with nearly 100% accuracy
based on the character of headache (recurrent thunderclap in RCVS versus
gradual in primary angiitis of the CNS), MRI lesion patterns (symmetric
watershed infarcts in cortical-subcortical regions in RCVS versus scattered deep
CASE 5-3 A 49-year-old woman developed a severe headache reaching peak

intensity within seconds. Similar thunderclap headaches recurred twice
over the next 2 days and were associated with intermittent loss of central
vision. On day 4 after symptom onset, she developed a generalized
seizure.
She was hypertensive (230/130 mm Hg), and her neurologic
examination showed hyperreflexia. Urinalysis and toxicology screen
were unremarkable. Brain MRI showed vasogenic edema in the bilateral
parietooccipital regions (FIGURE 5-4A), consistent with posterior reversible
encephalopathy syndrome (PRES). Head CT angiogram (CTA) showed
smooth segmental narrowing of multiple intracranial arteries
(FIGURE 5-4B), which was confirmed on transfemoral cerebral angiography
(FIGURE 5-4C), consistent with reversible cerebral vasoconstriction
syndrome (RCVS).
Although the patient denied exposure to vasoconstrictive triggers,
further inquiry revealed that she had been consuming .45 kg (1 lb) of
licorice daily for 4 months. Licorice has vasoconstrictive effects, so it was
immediately discontinued. The patient was managed conservatively with
oral calcium channel blockers. Her headaches resolved, and a follow-up
CT/CTA after 3 months showed resolution of the edema and segmental
vasoconstriction (FIGURE 5-4D).
COMMENT This case is a classic example of PRES with RCVS. Note how careful history
taking was needed to uncover vasoconstrictive triggers.
Modified with permission from Chatterjee N, et al, Neurology.19 © 2010 American Academy of Neurology.
1310 OCTOBER 2021

infarcts in primary angiitis of the CNS), and cerebral angiographic appearance
(eg, smooth tapered narrowing and dilatation in RCVS versus an irregular
notched appearance in primary angiitis of the CNS).10,27 Early distinction is
critical since glucocorticoid therapy (the treatment for primary angiitis of the
CNS) is associated with worse outcomes in RCVS.26 The abrupt onset of RCVS
with excruciating headache makes it relatively straightforward to exclude other
intracranial arteriopathies that typically present subacutely or are incidentally
discovered during the evaluation of stroke. The recently developed RCVS2 score
(FIGURE 5-6) offers high sensitivity and 99% to 100% specificity to diagnose
RCVS in adults with a new intracranial arteriopathy based on clinical-imaging
FIGURE 5-4
Imaging of the patient in CASE 5-3. Axial fluid-attenuated inversion recovery (FLAIR) brain
MRI shows vasogenic edema in the bilateral parietooccipital regions (A, black arrows),
consistent with posterior reversible encephalopathy syndrome (PRES). Hyperintense
“dots” (A, red arrows), indicating slow flow within dilated segments of surface arteries,
are present in sulcal spaces. CT angiogram (CTA) shows smooth segmental narrowing of
multiple intracranial arteries (B, arrows), which is confirmed on transfemoral cerebral
angiography (C, arrows), consistent with reversible cerebral vasoconstriction syndrome
(RCVS). A follow-up CTA after 3 months shows resolution of segmental vasoconstriction
(D). Follow-up CT after 3 months (not shown) showed resolution of the lobar hemorrhages
and edema.
Reprinted with permission from Chatterjee N, et al, Neurology.19 © 2010 American Academy of Neurology.

information available on
admission. Hence, early
diagnosis can be made at the
bedside, without the need for
additional tests such as serial
imaging to confirm reversal
of arteriopathy.50
Based on the features
discussed, the astute clinician
should be able to easily and
accurately diagnose RCVS soon
after admission. CSF
examination, advanced 3T
contrast-enhanced MRI,41
biomarker levels (eg,
endothelin 1, circulating
microparticles),53,54 and
potentially risky invasive tests
such as intraarterial vasodilator
infusion55 and brain biopsy
have limited diagnostic utility.
The focus should be on
identifying potential
vasoconstrictive triggers
(TABLE 5-2) by careful history
FIGURE 5-5 taking and considering tests
Brain MRI findings in reversible cerebral such as calcium and
encephalopathy syndrome (RCVS). Representative magnesium levels, toxicology
axial brain images from patients with RCVS are shown
to highlight different lesion patterns. The numbers in
screening for illicit drugs, and
parentheses show the percentages of the lesion urine vanillylmandelic acid and
patterns; totals exceed 100% because of lesion 5-hydroxy-indoleacetic acid
combinations. A, No acute parenchymal lesion (24%). levels if symptoms suggest
Normal diffusion-weighted imaging (DWI), gradient
recalled echo (GRE), and fluid-attenuated inversion vasoactive tumors such as
recovery (FLAIR) images are shown. The hyperintense pheochromocytomas or
dot sign is present on the FLAIR image (far right, arrow). carcinoid tumors.
B, Border zone/watershed infarcts (25%). On the far
left, DWI shows typical symmetric posterior infarcts
that spare the cortical ribbon. In the middle and on PATHOPHYSIOLOGY
the far right, DWI shows widespread watershed The presence of cerebral
infarcts. C, Vasogenic edema (28%). Subcortical angiographic and cerebral
crescent-shaped T2-hyperintense lesions consistent
perfusion abnormalities,
with posterior reversible encephalopathy syndrome
(PRES) are seen on FLAIR image. D, Hemorrhagic vasogenic edema, and ischemic
lesions (42%). The two images on the left (GRE) show and hemorrhagic complications
simultaneous lobar and deep intraparenchymal implicates transiently impaired
hemorrhages. The two images on the right show
cerebral autoregulation in both
convexal subarachnoid hemorrhages on CT and GRE
MRI. E, Lesion combinations (28%). The two images syndromes. Indeed, cerebral
on the left show bilateral watershed infarcts on DWI, vasoreactivity was markedly
and the two images on the right show lobar as well abnormal in the acute phase of
as convexal subarachnoid hemorrhages on axial
FLAIR and CT, all in the same patient.
RCVS as compared to
Reprinted with permission from Singhal AB, et al, Ann controls,56 and cerebral
Neurol.10 © 2016 American Neurological Association. hypoperfusion is well
1312 OCTOBER 2021

KEY POINTS
● Thunderclap headache is
a neurologic emergency.
● Angiographic progression
in RCVS is often associated
with iatrogenic factors such
as glucocorticoid therapy,
exposure to
vasoconstrictive agents, or
changing levels of female
reproductive hormones as in
the postpartum state.
FIGURE 5-6
The RCVS2 score and distribution. A, The RCVS2 score. Histograms show the distribution of
RCVS2 scores; B, reversible cerebral vasoconstriction syndrome (RCVS) and non-RCVS; C,
individual intracranial arteriopathies.
TCH = thunderclap headache.
Reprinted with permission from Rocha EA, et al, Neurology.50 © 2019 American Academy of Neurology.
documented in PRES.4 The relationship between recurrent thunderclap

headache and the dynamic cerebral artery narrowing in RCVS is poorly
understood but may be linked to the trigeminovascular or serotonergic pathways
between the brainstem and cerebral vessels. Similarly, differential vascular
innervation of the anterior versus posterior circulation may explain the
preferential posterior cerebral involvement in PRES. Systemic hypertension,
conceivably from a central mechanism, appears important as a contributor to the
blood-brain barrier breakdown seen in both syndromes. A role for endothelial
dysfunction, endothelin 1, serotonin, cytokines, vascular endothelial growth
factor (VEGF), female reproductive hormone imbalance, enhanced oxidative
stress, genetic polymorphisms, circulating micro-RNAs, and autonomic
dysregulation have been implicated4,57-62 but require further investigation. No
genetic risks are known. It should be noted that many of the triggers and risk
factors for PRES and RCVS (TABLE 5-2) have vasoconstrictive underpinnings;
several factors are implicated on the basis of a temporal relationship, but
possible reporting biases may exist, and confirmatory epidemiologic studies
are lacking.
Underlying infection and a primary role for inflammation is exonerated by the
usually normal CSF examination results and pathologic studies of cerebral
arteries and brain tissue. Brain pathology in PRES has shown white matter
rarefaction, endothelial swelling, fibrinoid vascular necrosis, scattered
microinfarcts, gliosis, and hemosiderin deposition; however, in some cases,
reactive astrocytes and microglia and perivascular T lymphocytes have been

reported.63 Pathologic studies in RCVS are limited; however, no evidence for

inflammation has been seen.18
MANAGEMENT
The management of both RCVS and PRES requires an appreciation that both
are predominantly self-limited benign conditions. The key is to avoid
misdiagnosis and refrain from empiric treatment while focusing on symptomatic
treatment. No specific treatment or strategy has been proven to enhance the
resolution of vasogenic edema in PRES or of angiographic abnormalities in
RCVS. Similarly, no strategy has been established to prevent complications such
as ischemic or hemorrhagic stroke or the worsening of vasoconstriction. Removal
of the trigger (if identified), at least until clinical and imaging resolution, is
logical and important in both conditions.
In patients with PRES, appropriate triage to the intensive care setting or
inpatient floor depends on the patient’s clinical status (eg, presence of seizures,
encephalopathy, eclampsia) and level of hypertension. Experts agree that severe
hypertension should be treated, and fluctuations of blood pressure avoided. For
TABLE 5-2 Triggers and Conditions Associated With Reversible Cerebral

Vasoconstriction Syndrome
Trigger/Condition Examples
Headache disorders Primary thunderclap headache,a primary exertional headache, primary headache associated
with sexual activity, primary cough headache, migraine
Medications, blood products, Antimigraine medications (triptans,a ergot derivatives, isometheptene); cough and cold
over-the-counter agents suppressants (phenylpropanolamine, pseudoephedrine); antidepressants (selective
serotonin reuptake inhibitors [SSRIs] and serotonin norepinephrine reuptake inhibitors
[SNRIs])a; adrenergic agents (amphetamine derivatives,a phenylpropanolamine,
pseudoephedrine, phenylephrine, epinephrine, isometheptene, midodrine, ergotamine
tartrate, methylergonovine, lisuride, bromocriptine, cabergoline, methergine); blood
productsa (red blood cell transfusion, erythropoietin, interferon alfa, IV immunoglobulin
[IVIg]); hormonal agents (oral contraceptives, ovarian stimulation); chemotherapeutics and
immune modulatorsa (tacrolimus [FK-506], cyclophosphamide, cytarabine, interferon,
fingolimod, etanercept, tocilizumab, anastrozole); other (indomethacin, etoricoxib, Coffea
canephora robusta, nicotine patches, ma huang [Ephedra], atovaquone, isoflavones, licorice,a
khat leaves, Chinese herbal remedies, eucalyptus)
Illicit drugs Marijuana,a cocaine, ecstasy, lysergic acid diethylamide, amphetamine derivativesa
Pregnancy and puerperium Early puerperium, late pregnancy, eclampsia,a preeclampsia,a delayed postpartum eclampsia
Miscellaneous High altitude, cold water exposure, typhoons, severe grief, hypercalcemia, nifedipine
withdrawal, caffeine withdrawal, porphyria,a thrombotic thrombocytopenic purpura,
pheochromocytoma,a bronchial carcinoid tumor, unruptured saccular cerebral aneurysm,
head trauma, spinal subdural hematoma, cerebral venous sinus thrombosis, post–carotid
endarterectomy,a carotid glomus tumor, paraganglioma, neurosurgical procedures, repetitive
transcranial magnetic stimulation, systemic lupus erythematosusa
a
Factors that are also associated with posterior reversible leukoencephalopathy syndrome (PRES). In addition, PRES has been associated with
severe renal failure, infection, sepsis, autoimmune disorders, and malignancies.
1314 OCTOBER 2021

this purpose, arterial line monitoring of blood pressure and IV infusion of KEY POINTS
antihypertensive agents are often necessary. The choice of antihypertensive
● Accurate diagnosis of
agent has not been investigated, although most clinicians favor calcium PRES and RCVS rests on
channel blockers because of their vasodilatory effects. Blood pressure should be thorough evaluation of the
reduced gradually by approximately 25% every 3 to 4 hours. Care should be clinical setting, presenting
taken to avoid hypotension and worsening cerebral ischemia, especially in the symptoms, and
neuroimaging features.
face of cerebral hypoperfusion and concomitant RCVS.
In patients with severe preeclampsia or eclampsia, prompt delivery of the ● In RCVS, headaches are of
fetus is warranted and magnesium sulfate indicated for seizure treatment and extreme severity, often
prophylaxis. Patients with altered sensorium should be monitored with EEG for warranting opioid
subclinical status epilepticus and treated accordingly. Generalized tonic-clinic administration.
seizures are common at the onset of PRES but usually do not recur, so long-term
antiepileptic drugs are not warranted unless recurrent seizures develop from
irreversible brain injury. Most clinicians do not administer prophylactic
antiseizure medications to patients with PRES or RCVS, even in the presence of
structural brain lesions, unless the patient has recurrent seizures or concerning
EEG findings, in which case clinical judgment and follow-up EEG are used to
determine the appropriate duration of antiseizure prophylaxis.
Corticosteroids may precipitate PRES, are not associated with the extent of
vasogenic edema,64 and may worsen the situation in patients with concomitant
RCVS26 so are best avoided in PRES. Hyperglycemia is associated with worse
outcome and should be treated promptly. Symptomatic treatment of headache
and reassurance are important aspects of management. Patients with neurologic
deficits from stroke may require physical, speech, or occupational
rehabilitation therapy.
Despite the rather dramatic onset with thunderclap headache and cerebral
vasoconstriction, the vast majority of patients with RCVS do not have
parenchymal brain lesions or focal neurologic deficits. Many patients with
isolated thunderclap headache are discharged from the emergency department
only to return with recurrences, at which time cerebrovascular imaging reveals
vasoconstriction leading to the diagnosis of RCVS. It is reasonable to admit all
patients with RCVS for symptomatic treatment and monitoring until severe
headaches are controlled and recurrences start subsiding; this usually takes a few
days. Thunderclap headaches are brought on by exertion or Valsalva maneuver,
so bed rest, avoiding sexual activity, and laxatives should be considered.
Severe headaches may require nonsteroidal anti-inflammatory medications such
as indomethacin or ibuprofen and even opioid treatment. Patients with RCVS
with focal neurologic deficits and severe vasoconstriction or brain imaging
abnormalities should be admitted for longer periods. The highest risk of
hemorrhagic complications is in the first week and of ischemic complications
is in the second week. Appropriate triage to the inpatient floor rather than
the intensive care unit requires clinical discretion, assessment of blood
pressure lability, and whether poor outcome predictors such as exposure to
glucocorticoids or serotonergic vasoconstrictors26 are present. Daily
transcranial Doppler ultrasound is useful to monitor intracranial blood flow
velocities, although their sensitivity and specificity is limited and normal flow
velocities may not correlate with angiographic findings. The principles of blood
pressure and seizure management in RCVS are similar to those described above
for PRES. It is logical to be more aggressive with blood pressure control in
patients with RCVS with concomitant PRES. Calcium channel blockers

(eg, nimodipine, verapamil) should be offered because of their presumed

vasodilatory effects, but they are not shown to affect the time course of
vasoconstriction.11,40 However, they may reduce headache intensity, and most
clinicians administer these medications until the resolution of headache or
angiographic abnormalities.
Common missteps in RCVS management include the administration of
triptans, ergots, or other antimigraine vasoconstrictive medications for
headache; initiating glucocorticoids to cover for the possibility of cerebral
vasculitis; or undertaking brain biopsy or intraarterial vasodilator infusions to
exclude non-RCVS arteriopathies such as vasculitis.55 It should be noted that
intraarterial vasodilator infusions have short-lived effects and can induce
reperfusion injury.18 Despite case reports suggesting efficacy, no clear evidence
of benefit exists26; thus, this invasive procedure cannot be sanctioned for
routine diagnostic purposes and should be reserved as salvage therapy for
unambiguous clinical worsening.
PROGNOSIS
The outcome of both RCVS and PRES is usually excellent, with resolution of
clinical symptoms and imaging abnormalities within days to weeks in
approximately 80% to 90% of patients with PRES and in more than 90% of
patients with RCVS. Serial brain and cerebral vascular imaging is often pursued
to confirm reversal of brain parenchymal or angiographic abnormalities and
exclude mimics; however, its utility is becoming limited with ongoing recognition
of the self-limited natural history and the improving accuracy of early diagnosis.
With PRES, the average time to clinical resolution is less than 1 week; imaging
resolution may take longer. Long-term cognitive deficits and neurologic
symptoms such as reduced visual acuity or dizziness have been reported in 10%
to 20% of patients; however, these are usually minor and not debilitating.
Recurrent seizures can occur from underlying complications such as ischemic
or hemorrhagic stroke. Patients with hemorrhagic PRES have worse outcome, as
do patients with hyperglycemia, and longer time to resolution. Mortality
(eg, from progressive vasogenic edema or hemorrhagic stroke) has been reported
in 5% to 7% of patients; however, these patients are critically ill, and mortality
may not always be directly attributable to PRES. Recurrent PRES has been
reported in 5% to 10% of patients, usually associated with uncontrolled
hypertension or reexposure to immunosuppressant therapy.4 Removal of the
triggering chemotherapeutic or immunosuppressant therapy is advocated during
the acute phase, and alternative agents should be considered, if possible, after
resolution of PRES. Preeclampsia and eclampsia are associated with a higher
risk of future cardiovascular outcomes such as hypertension, coronary artery
disease, and stroke65; however, the long-term risk of all-cause PRES
remains unknown.
Approximately one-third of patients with RCVS develop ischemic or
hemorrhagic strokes, yet 90% become ambulatory by the time of discharge and
95% to 98% report complete resolution within 3 months.9-14 Thunderclap
headaches usually recur (average of four recurrences) over a span of days to
weeks and then subside. Their resolution does not parallel that of cerebral
angiographic abnormalities, which can take 2 to 3 months to resolve. Mortality
has been reported in 2.5% of inpatient series,10 and worse outcomes have been
associated with pregnancy and iatrogenic factors such as glucocorticoid
1316 OCTOBER 2021

treatment.26,66 Chronic headache and psychiatric symptoms, such as anxiety KEY POINTS
and depression, are frequent and associated with lower quality of life.67,68 As
● Intraarterial vasodilator
with PRES, removal of vasoconstrictive agents, including antimigraine therapy carries risks and
medications and antidepressants, is reasonable until resolution occurs. Patients should not be routinely used
with RCVS with long-term depression may require reexposure to serotonergic for the diagnosis of RCVS.
antidepressants, which appears safe since these agents have not been associated
● The time course of
with recurrent RCVS. Note that triptans should still be avoided since they are
resolution of the clinical and
contraindicated in patients with cerebrovascular disease. imaging abnormalities may
be dissociated in PRES and
RCVS.
CONCLUSION
PRES and RCVS are being diagnosed and reported with increasing frequency.
Emerging literature confirms a significant overlap in their clinical, imaging, and
angiographic features, suggesting a shared pathophysiology based on underlying
cerebral vasoconstriction and blood-brain barrier breakdown. Both syndromes
are self-limited and carry an excellent prognosis. Careful evaluation of clinical
and brain imaging features usually enables accurate early diagnosis, which is
critical since empiric therapies, including glucocorticoids to treat mimics such as
primary angiitis of the CNS, can worsen outcomes in PRES and especially RCVS.
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2013;14(1):94. doi:10.1186/1129-2377-14-94
48 Chen S-P, Fuh J-L, Lirng J-F, et al. Recurrent
primary thunderclap headache and benign CNS 61 Hsu WH, Wang SJ, Chao YM, et al. Urine
angiopathy: spectra of the same disorder? metabolomics signatures in reversible cerebral
Neurology 2006;67(12):2164-2169. doi:10.1212/01. vasoconstriction syndrome. Cephalalgia 2020;
wnl.0000249115.63436.6d 40(7):735-747. doi:10.1177/0333102419897621
49 Grooters GS, Sluzewski M, Tijssen CC. How often 62 Chen SP, Chang YA, Chou CH, et al. Circulating
is thunderclap headache caused by the microRNAs associated with reversible cerebral
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Headache 2014;54(4):732-735. 89(3):459-473. doi:10.1002/ana.25965
doi:10.1111/head.12256
63 Willard N, Honce JM, Kleinschmidt-DeMasters
50 Rocha EA, Topcuoglu MA, Silva GS, Singhal AB. BK. PRES: review of histological features.
RCVS2 score and diagnostic approach for J Neuropathol Exp Neurol 2018;77(2):100-118.
reversible cerebral vasoconstriction syndrome. doi:10.1093/jnen/nlx112
Neurology 2019;92(7):e639-e647.
64 Parikh NS, Schweitzer AD, Young RJ, et al.
doi:10.1212/WNL.0000000000006917
Corticosteroid therapy and severity of vasogenic
51 Singhal AB. Diagnostic challenges in RCVS, edema in posterior reversible encephalopathy
PACNS, and other cerebral arteriopathies. syndrome. J Neurol Sci 2017;380:11-15.
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65 Wu P, Haththotuwa R, Kwok CS, et al. 67 John S, Singhal AB, Calabrese L, et al. Long-term
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68 Boitet R, de Gaalon S, Duflos C, et al. Long-term
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doi:10.1001/archneurol.2011.811
1320 OCTOBER 2021

Seizures, Status REVIEW ARTICLE

Epilepticus, and C O N T I N U UM A U D I O
INTERVIEW AVAILABLE
ONLINE
Continuous EEG in the

Downloaded from http://journals.lww.com/continuum by +ZpA1co4Qt6hKOh5bX4Ic7hRsW++Cxq81G1146WlAFy1YfB8OltqGh0UEta2zTti8ILpuyLKmsgw63wfPZRTbEo+CrOYbcfUKsRUW+is83kqVZIjzdep+0C77ZQOlhp2KrTPrdW5sVvoyBmW4s5orA== on 11/10/2021
Intensive Care Unit

By Eric S. Rosenthal, MD
ABSTRACT
PURPOSE OF REVIEW: Thisarticle discusses the evolving definitions of seizures
and status epilepticus in the critical care environment and the role of
critical care EEG in both diagnosing seizure activity and serving as a
predictive biomarker of clinical trajectory. CITE AS:
RECENT FINDINGS:Initial screening EEG has been validated as a tool to 1321–1343.
predict which patients are at risk of future seizures. However, accepted
definitions of seizures and nonconvulsive status epilepticus encourage a Address correspondence to
Dr Eric S. Rosenthal, Department
treatment trial when the diagnosis on EEG is indeterminate because of of Neurology, Massachusetts
periodic or rhythmic patterns or uncertain clinical correlation. Similarly, General Hospital, 55 Fruit St,
recent data have demonstrated the diagnostic utility of intracranial EEG Lunder 644, Boston, MA 02114,
erosenthal@mgh.harvard.edu.
in increasing the yield of seizure detection. EEG has additionally been
validated as a diagnostic biomarker of covert consciousness, a predictive RELATIONSHIP DISCLOSURE:
biomarker of cerebral ischemia and impending neurologic deterioration, Dr Rosenthal serves on

scientific advisory boards for
and a prognostic biomarker of coma recovery and status epilepticus Ceribell, Inc and UCB, Inc and
resolution. A recent randomized trial concluded that patients allocated to has received personal
compensation for speaking
continuous EEG had no difference in mortality than those undergoing engagements from UCB, Inc.
intermittent EEG but could not demonstrate whether this lack of Dr Rosenthal receives
difference was because of studying heterogeneous conditions, examining research/grant support from
Moberg Analytics, Inc (DoD
a monitoring tool rather than a therapeutic approach, or examining an W81XWH-18-DMRDP-PTCRA)
outcome measure (mortality) perhaps more strongly associated with early and the National Institutes of
withdrawal of life-sustaining therapy than to a sustained response to Health/National Institute of
Neurological Diseases and
pharmacotherapy. Stroke (1R01NS117904,
1R01NS113541, 1K23NS105950,
U54NS100064, DoD
SUMMARY: Seizures and status epilepticus are events of synchronous
W81XWH-BAA-15-1).
hypermetabolic activity that are either discrete and intermittent or,
alternatively, continuous. Seizures and status epilepticus represent the far UNLABELED USE OF
end of a continuum of ictal-interictal patterns that include lateralized USE DISCLOSURE:
rhythmic delta activity and periodic discharges, which not only predict Dr Rosenthal discusses the
future seizures but may be further classified as status epilepticus on the unlabeled/investigational use of
IV injection of ketamine,
basis of intracranial EEG monitoring or a diagnostic trial of antiseizure midazolam, and propofol for the
medication therapy. In particularly challenging cases, neuroimaging or treatment of seizures.
multimodality neuromonitoring may be a useful adjunct documenting
metabolic crisis. Specialized uses of EEG as a prognostic biomarker have © 2021 American Academy
of Neurology.

SEIZURES, STATUS EPILEPTICUS, AND CONTINUOUS EEG IN THE ICU
emerged in traumatic brain injury for predicting language function and

covert consciousness, cardiac arrest for predicting coma recovery, and
subarachnoid hemorrhage for predicting neurologic deterioration due to
delayed cerebral ischemia.
INTRODUCTION
T
his article discusses how to define, diagnose, and manage seizures,
status epilepticus, and indeterminate findings on the ictal-interictal
continuum within the critical care environment. Additionally, the
recent expansion of the utility of continuous EEG as a predictive
biomarker in a variety of critical care populations is discussed, such as
in predicting secondary ischemia after subarachnoid hemorrhage, diagnosing
covert consciousness in patients who are comatose, and predicting neurologic
recovery after structural brain injury or status epilepticus.
DEFINING AND DETECTING SEIZURES AND STATUS EPILEPTICUS IN

THE INTENSIVE CARE UNIT
The detection of seizures in the critical care setting is the subject of much
attention because they are common (found in 10% to 25% of patients recorded),1,2
represent a potentially reversible cause of encephalopathy or coma,3 and are
associated with poor outcome.4-6 The American Clinical Neurophysiology
Society (ACNS) has issued consensus recommendations regarding indications
for prolonged continuous EEG monitoring7:
u Persistently abnormal mental status following generalized convulsive status epilepticus or

other clinically evident seizures
u Acute supratentorial brain injury with altered mental status
u Fluctuating mental status or unexplained alteration of mental status without known acute
brain injury
u EEG patterns along the ictal-interictal continuum such as periodic discharges and
lateralized rhythmic delta activity
u Clinical risk for seizures potentially masked by the requirement for pharmacologic
paralysis during conditions such as extracorporeal membrane oxygenation (ECMO) or
targeted temperature management for cardiac arrest
u Paroxysmal clinical events suspected to be possible seizures
These indications nearly universally include patients with altered mental

status, encephalopathy, coma, or other disorders of consciousness following
traumatic brain injury, spontaneous subdural hematoma, subarachnoid
hemorrhage, intracerebral hemorrhage, meningoencephalitis, brain tumors,
recent neurologic surgery, cardiac arrest, and sepsis, as rates of seizure
exceed 15% among these patients when referred for EEG.4-6 Other
populations with a high risk may include patients with cerebral venous
sinus thrombosis.
Of note, a provider’s suspicion for seizure is likely not a substitute for active
surveillance, as patients not referred for EEG monitoring may be having occult
seizures. For example, in a cohort of patients with subarachnoid hemorrhage
monitored solely as part of an ischemia monitoring protocol to predict delayed
1322 OCTOBER 2021

cerebral ischemia, seizures occurred with a similar rate as in those patients KEY POINTS
referred with a concern for subclinical or clinical seizures (ie, even when the
● Electrographic seizures
provider lacked suspicion for seizure and would not otherwise have ordered and status epilepticus can
an EEG).8 be diagnosed by an
The diagnosis of seizures in the critically ill population has three electroclinical response to
main challenges: antiseizure medication.
● Although most seizures

u Seizures are commonly nonconvulsive, subtle, or obscured by a primary neurologic deficit are detected in the first
or sedation 48 hours of monitoring,
u Seizures may be occult on scalp EEG and only detected by an intracranial electrode shorter-duration monitoring
may be sufficient in patients
u Seizures, as status epilepticus, may only be diagnosed in retrospect after electroclinical without any epileptiform
improvement following treatment abnormalities and
longer-duration monitoring
Current consensus definitions of electrographic and electroclinical seizures may be required in patients
have coalesced around the Salzburg Consensus Criteria9-11 and have been with subarachnoid
hemorrhage.
adopted by the ACNS.12 In the updated 2021 ACNS Standardized Critical Care
EEG Terminology, electrographic seizures are defined as either epileptiform
discharges averaging more than 2.5 Hz for at least 10 seconds or a pattern with
definite evolution and lasting at least 10 seconds. Similarly, electrographic status
epilepticus is defined as an electrographic seizure for at least 10 continuous
minutes or for at least 20% of any 60-minute period.
Other electrographic activity not meeting these criteria may qualify as
“possible” electrographic seizure or electrographic status epilepticus when the
activity consists of periodic discharges, spike-wave activity, or rhythmic delta
activity on the ictal-interictal continuum. Uncertainty about whether
ictal-interictal continuum activity in an individual patient is indeed
nonconvulsive status epilepticus can be resolved, according to the ACNS
Standardized Critical Care EEG Terminology and Salzburg Consensus Criteria,9-12
when the electroclinical activity has a time-locked clinical correlate (eg,
thumb-twitching synchronous with each discharge despite lack of electrographic
evolution) or, alternatively, has combined EEG and clinical improvement
following antiseizure medication.12
The duration of EEG necessary for exhaustive detection of seizures in a
patient remains uncertain, given inherent biases in referring patients to
short-term EEG versus longer-duration continuous EEG monitoring.
However, retrospective research has led to validated risk scores that may be
applied on initial screening EEG to predict which patients will go on to have
seizures detected by continuous EEG monitoring. One method, the 2HELPS2B
score13,14 (FIGURE 6-1) has been tested and validated in separate inpatient
populations, accurately predicting the probability of subsequent seizures
across a range of predicted risk. Overall, 93% of patients with seizures had
detected events in the first 48 hours, and an absence of epileptiform
abnormalities in the first 2 hours was associated with a 72-hour seizure risk
lower than 5%.2 Similarly, in critically ill children with encephalopathy who
were at least 1 year of age, a seizure risk lower than 5% was observed if no prior
seizures were present and no epileptiform discharges and ictal-interictal
continuum patterns were present by 6 hours of recording; 1 day of monitoring
was required if EEG risk factors or prior seizures were evident, and 2 days
were required if both EEG risk factors and prior seizures were evident.15
Specific illnesses, however, may have an increased diagnostic yield from

FIGURE 6-1
2HELPS2B risk score system for prediction of subsequent electrographic seizures during
an initial screening EEG. Predicted seizure risk using this tool is well calibrated to the actual
seizure risk observed.
a
Range across the development and validation cohorts.
Data from Struck AF, et al, JAMA Neurol.14
longer-duration monitoring. For example, the median duration until seizure

detection following subarachnoid hemorrhage has been observed to be as long
as 5.6 days, whereas 7.3 days was required to detect 75% of patients
with seizures.8
These risk estimates, however, only apply to the detection of seizures by scalp
EEG. Additional seizures may be detected when recording intracranially by
electrocorticography, using either an orthogonally inserted mini–depth electrode
or a subdural strip electrode (CASE 6-1). Experience using an orthogonal
mini–depth electrode has been reported to increase the yield of seizure detection
from 14.7% to 23.5% in patients with traumatic brain injury16 and from 8% to 38%
in patients with subarachnoid hemorrhage.17 It is not known which scalp EEG
features best predict depth seizures, although the occurrence of depth seizures is
greatest ipsilateral to the side of dominant injury in patients with traumatic
brain injury.16
TREATMENT APPROACHES TO SEIZURES, REFRACTORY STATUS

EPILEPTICUS, AND SUPER-REFRACTORY STATUS EPILEPTICUS
Although the treatment of occult nonconvulsive seizures remains controversial,
antiseizure medication is commonly administered, and clinical trials examining
optimal dosing strategies have typically been performed without a placebo. In
one study, lacosamide was found to be noninferior to fosphenytoin for
controlling nonconvulsive seizures.18 When using fosphenytoin or phenytoin,
therapeutic drug monitoring requires assessment of free phenytoin levels in
patients who are critically ill or the use of more complex correction equations to
estimate a free phenytoin level or else high-magnitude errors can occur when
applying historical correction equations in critically ill patients to estimate free
phenytoin levels.19
1324 OCTOBER 2021

For convulsive seizures, the treatment approach is more straightforward. KEY POINTS
Benzodiazepines, specifically IV lorazepam or IM midazolam, are first-line
● Seizure detection is
agents,20,21 with IV lorazepam preferred for its rapidity of seizure control if an IV significantly augmented by
catheter is already in place.22 However, benzodiazepines are commonly the implantation of a single
underdosed after status epilepticus,23 despite their use being associated with intraparenchymal or
decreased rates of endotracheal intubation.24 When seizures are refractory to subdural strip electrode.
benzodiazepines, similar rates of terminating established status epilepticus were
● Because of changes in
observed with levetiracetam, fosphenytoin, or valproate. Of note, dosing was protein binding,
robust compared to doses commonly administered, particularly for levetiracetam large-magnitude errors are
(TABLE 6-125).26,27 However, antiseizure medications did not have a high rate of common when estimating
terminating clinically apparent seizures and improving consciousness without free phenytoin applying
standard phenytoin
need for additional antiseizure medication; success rates were approximately correction equations to
52% in children, 44% in adults, and 37% in older adults with established patients who are critically
status epilepticus.26 ill; correction equations
Patients for whom these therapies fail because of continued seizures are adjusting for age, renal
function, hepatic function,
commonly treated with anesthetic seizure suppression or burst suppression; and critical illness are
however, no randomized controlled trials are available to guide drug selection or necessary to avoid
dose. Trends embracing therapies other than traditional anesthetics include significant errors if free
increasing use of IV ketamine25 and ketogenic or low-glycemic diet therapy,28 in phenytoin levels are
unavailable.
addition to rational polytherapy aimed at avoiding the complications of status
epilepticus that are independently associated with mortality at 1 year.29 In the ● High-frequency periodic
absence of comparative effectiveness studies, the selection of antiseizure discharges may be transient
medications in refractory and super-refractory status epilepticus remains when weaning patients from
anesthetic coma following
focused on rational polytherapy targeting different mechanisms of action while
status epilepticus; pausing
managing and preventing complications (TABLE 6-2). and observing the patient
and EEG, evaluating
EEG NEUROMONITORING TO GUIDE LIBERATION FROM ANESTHETIC background activity, and
COMA AFTER STATUS EPILEPTICUS examining for frank seizures
may avoid delaying
EEG is used routinely in the treatment and monitoring of status epilepticus. anesthetic liberation.
Following convulsive status epilepticus, 48% of patients demonstrated persistent
seizures, including 14% with nonconvulsive status epilepticus. Those with
nonconvulsive status epilepticus had a mortality greater than 50% compared
with less than 15% among those without ictal discharges, conferring 1.9-fold risk
of mortality even when adjusted for age and etiology.30 Rapid EEG has not been
used to date in interventional clinical trials in the emergency department; thus,
primary end points in acute status epilepticus clinical effectiveness trials have
been limited to absence of clinically apparent seizures with improved
consciousness and without additional antiseizure medication.26,27 Without an
end point that includes EEG monitoring, patients intubated for neuroimaging or
progression of a structural brain injury have been considered to have failed status
epilepticus therapy regardless of the reason for intubation, a major limitation
given that the rate of intubation has nearly doubled over the past 2 decades.31
In critical care studies of status epilepticus utilizing continuous EEG, an
aggressive approach to anesthetic weaning has demonstrated EEG normalization
and clinical improvement despite initial increases in periodic discharges.32
Although the literature suggests that metabolic crisis is associated with these
high-frequency periodic discharges,33 the emergence of ictal-interictal
continuum activity may be transient in the setting of weaning from anesthetic
coma.34 In this setting, other clinical and quantitative features may be of use to
determine which patients are likely to be liberated from anesthetic coma. For

example, in a population without cardiac arrest, unsuccessful anesthetic

liberation after refractory status epilepticus was associated with the presence of
highly epileptiform bursts (multiple discharges in the majority of bursts)35 as
well as with bursts that were monomorphic, exceeded 125 μV amplitude, or
(more often than not) demonstrated epileptiform features.36 A quantitative
approach using spectral power in frequency bands and functional connectivity
measures, including network density, yielded a testing accuracy of 75% in a
holdout cohort and in a secondary external validation cohort, with an area under
the curve of 83% for predicting successful anesthetic liberation. These features
add information about the potential success or failure of a wean up to 12 hours
before a wean is clinically terminated. Thus, many hours before anesthesia
weaning is determined to be a success or failure based on recurrence of status
epilepticus, emerging network connectivity is evident in patients who were
CASE 6-1 A 61-year-old man was admitted to the neurocritical care unit after
craniotomy for aneurysmal subarachnoid hemorrhage. He was comatose,
and continuous EEG monitoring with electrocorticography recording
activity from a 6-contact subdural strip electrode was initiated
immediately after the craniotomy. He was found to have seizures
consisting of periodic discharges with evolution on the subdural strip
electrode while on levetiracetam 500 mg every 12 hours (FIGURE 6-2A). He
had no evident seizures on the scalp EEG channels, which showed only
rhythmic delta activity. After two doses of levetiracetam 1500 mg every
12 hours (FIGURE 6-2B), his EEG improved to an alpha background without
epileptiform activity and his clinical examination had improved to
conversational.
COMMENT This case illustrates the discordant findings between scalp EEG and
intracranial electrocorticography. The scalp EEG showed rhythmic delta
activity, but the subdural strip electrode showed a mix of rhythmic delta
activity with embedded sharp waves as well as periodic discharges with
evolution. Additionally, the case demonstrates how changes over time in
the context of treatment may be interpreted clinically according to the
Salzburg Consensus Criteria.10 Both the rhythmic delta activity on the scalp
and the activity on the strip electrode with evolution resolved after
treatment, coincident with improvement of arousal, orientation, and verbal
functioning. Although this patient’s electroclinical improvement was
consistent with a post hoc diagnosis of nonconvulsive status epilepticus
according to the American Clinical Neurophysiology Society Standardized
Critical Care EEG Terminology and Salzburg Consensus Criteria, clinical
trials are necessary to determine whether antiseizure medication
escalation itself improves clinical outcomes.
1326 OCTOBER 2021

successfully liberated from anesthesia without seizure recurrence.37 Accordingly,
future efforts may be aimed at hastening anesthetic liberation and coma recovery
in patients with status epilepticus based on EEG measures.
BALANCING THE RISKS AND BENEFITS OF TREATING NONCONVULSIVE

SEIZURES AND ICTAL-INTERICTAL CONTINUUM ACTIVITY
When considering the risks of nonconvulsive seizure activity and status
epilepticus, a measure of overall burden (percent prevalence multiplied by time
observed) has been introduced as part of the ACNS Standardized Critical Care
EEG Terminology. When considering the risks of ictal-interictal activity, an
additional measure, index (burden multiplied by the frequency of periodic
discharges or lateralized rhythmic delta activity) can be used as a composite
measure combining both duration and intensity.12
FIGURE 6-2
Continuous EEG monitoring with intracranial electrocorticography from a six-electrode
subdural strip (red boxes) of the patient in CASE 6-1 after craniotomy for aneurysmal
subarachnoid hemorrhage while on levetiracetam 500 mg every 12 hours on hospital day 1 (A)
and on day 2 (B) after two doses of levetiracetam 1500 mg every 12 hours.

Nonconvulsive seizures and ictal-interictal continuum activity have

demonstrated an impact on outcome independent of potential confounders such
as disease severity, which itself may be associated with both seizure incidence
and outcome. In multivariate regression analysis, periodic discharges are
associated with an 18.8-fold risk of poor functional outcome on the modified
Rankin Scale in patients with subarachnoid hemorrhage.5 Although one study
demonstrated little difference between brief or prolonged periodic discharges on
functional outcome in a mixed population,38 more recent studies using burden
measures have demonstrated that patients with ischemic stroke with a peak daily
burden of epileptiform activity exceeding 10% have a 23-fold risk of poor
outcome and that the interaction of increasing epileptiform activity burden with
frequency reaching 1.5 Hz conferred a 1.6-fold risk of poor outcome.39 Similarly,
in subarachnoid hemorrhage, the burden of epileptiform activity on the first
day of monitoring and the peak daily burden of epileptiform activity were each
associated with poor functional and cognitive outcomes.40,41 In a cohort of
patients with traumatic brain injury in the INTREPID2566 (Study of NNZ-2566 in
Patients With Traumatic Brain Injury) study, ictal-interictal activity did not have
an association with poor outcome when patients with moderate (including
sub–1.5-Hz lateralized rhythmic delta activity or sub–1.5-Hz generalized periodic
discharges; 45% of patients) and severe ictal-interictal continuum activity (14%
of patients) were grouped together, with the latter underrepresented.42
Given these effects on outcome, antiseizure medication escalation to suppress
events on the ictal-interictal continuum other than generalized rhythmic delta
activity has been investigated, including retrospective studies examining
triphasic-appearing generalized periodic discharges, historically considered
metabolic in origin.3 Recognizing that unequivocal responses to antiseizure
medication escalation (resolution of both the abnormal EEG pattern and
improvement of EEG background or encephalopathy) are common has
encouraged a more proactive approach to treatment. The historic
characterization of triphasic waves as being synonymous with a metabolic
etiology needing treatment of the underlying condition has been updated by data
showing that intervening by treating patients with triphasic discharges with
benzodiazepines or antiseizure medication results in commensurate
electrographic and clinical improvement in a number of patients.3 However,
questions remain about the clinical benefit of routine antiseizure medication
escalation in patients with ictal-interictal continuum activity. One potential
TABLE 6-1 Dosing Administered in the Established Status Epilepticus Treatment Triala
Drug Dose Administration
Levetiracetam 60 mg/kg (maximum 4500 mg) 10-min infusion
Fosphenytoin 20 mg PE/kg (maximum 1500 mg PE) 10-min infusion
Valproate 40 mg/kg (maximum 3000 mg) 10-min infusion
PE = phenytoin sodium equivalent.

a
Data from Gaspard N, et al, Epilepsia.25 and Chamberlain JM, et al, Lancet.26
1328 OCTOBER 2021

strategy is a 48-hour trial of therapy to assess for electrographic response as well KEY POINTS
as sufficient time for a clinical response that may require recovery from a
● The quantified initial or
postictal period. peak burden of
ictal-interictal continuum
POSTACUTE ANTISEIZURE MEDICATION MANAGEMENT activity and electrographic
The negative effects of antiseizure medication on cognition have been seizures are independently
associated with outcome.
demonstrated in subarachnoid hemorrhage and intracerebral hemorrhage.43 As a
result, patients with symptomatic or reversible causes of seizures may be ● Even generalized periodic
considered for withdrawal of antiseizure medications at several weeks following discharges with a triphasic
critical care. These decisions must be balanced against the risks of recurrent morphology, historically
seizures, particularly in patients with seizures attributable to a focal lesion, associated with metabolic
disturbances, may
persistent epileptiform discharges after trauma, or status epilepticus.44,45 One commonly have an
strategy is to perform outpatient EEG after withdrawing seizure medications, electroclinical response to
although it is unclear whether this strategy optimizes the use of antiseizure escalation of antiseizure
medications or cognitive outcomes. medication.
● Electrometabolic status
EEG FOR DETECTION AND PREDICTION OF SECONDARY BRAIN INJURY epilepticus is increasingly
Whether epileptiform activity on the ictal-interictal continuum is a cause or appreciated as
effect of injury and ischemia has been of interest since the specific association of ictal-interictal continuum
activity of high frequency in
generalized or lateralized periodic epileptiform discharges with brain injury was
association with exhaustive
first noted as “paroxysmal high-voltage and rhythmic low-voltage discharges” by metabolic crisis measured
Echlin and colleagues46 following surgical isolation or partial isolation of human by cerebral hyperglycolysis
cortex; by Chatrian and colleagues47-49 beginning in 1952 as periodic lateralized during positron emission
tomography, increasing
epileptiform discharges associated with ischemia, malignancy, or infection; and
lactate to pyruvate ratio
by Alajouanine and colleagues50 in 1955 as generalized and lateralized periodic evident from cerebral
discharges associated with infectious and inflammatory maladies. microdialysis sampling, or
There are multiple potential mechanisms by which epileptiform activity is brain tissue hypoxia
independently associated with poor outcome: (1) association of epileptiform identified during brain tissue
oxygenation monitoring.
activity with exhaustive hypermetabolism and metabolic crisis, (2) association of
epileptiform activity with subsequent cortical spreading depolarization, (3)
association of epileptiform activity with inflammation, and (4) potential
medication toxicity related to escalating antiseizure medication to treat
epileptiform activity.
Numerous modalities have documented the temporal and regional association
of epileptiform activity with exhaustive hypermetabolism and metabolic crisis.
Ictal-interictal activity is associated with regional hyperglycolysis51 that is
frequency dependent33 and decreases with anesthetic burst suppression.51,52 In
patients with subarachnoid hemorrhage, periodic discharges have been shown to
have a regional and temporal frequency-dependent association with decreases in
brain tissue oxygenation53: median partial pressure of brain tissue oxygenation
was 23 mm Hg without periodic discharges, 16 mm Hg when periodic discharges
reached 2.0 Hz, and 14 mm Hg when discharges reached 2.5 Hz.53 In traumatic
brain injury, elevated lactate to pyruvate ratio is associated with either seizures or
periodic discharges16 and subsequent ipsilateral cortical atrophy.6 In
intracerebral hemorrhage, electrographic seizures have been linked to a
subsequent increase in midline shift of 2.7 mm (compared to a decrease of
2.4 mm in patients without seizure over the first 72 hours of admission).54
Patients with in-hospital nonconvulsive seizures after subarachnoid
hemorrhage have a 1.9-fold risk of a systemic inflammatory response syndrome
and higher levels of high-sensitivity C-reactive protein and tumor necrosis factor

TABLE 6-2 Antiseizure Medications Commonly Used On-label and Off-label in

Patients Who Are Critically Ill
Drug Proposed mechanism and rationale Monitoring Considerations
Brivaracetam Synaptic vesicle glycoprotein 2A Complete blood cell count, Prior authorization may be
(SV2A) binding; IV available; liver function tests required as outpatient
dependable and rapid kinetics; higher
binding affinity than levetiracetam
Carbamazepine Voltage-gated sodium channel Trough levels; complete No long-term IV option;

binding, inactivation blood cell count, liver function associated with higher risk of
tests/drug reaction with Stevens-Johnson syndrome in
eosinophilia and systemic certain Asian patients with
symptoms (DRESS); degraded HLA-B*15:02
by cytochrome P450 (CYP)
3A4; strong, broad enzyme
inducer of CYP3A4
Clobazam γ-Aminobutyric acid A (GABAA) partial Arousal, hypopnea; degraded Long elimination half-life; use
agonist selective α1β3γ2 with lower by CYP3A4 with caution in patients with
affinity for α1β2γ2 receptor; increase hepatic dysfunction
in calcium ion conduction; selective
receptor binding to reduce sedative
side effects with increased
antiseizure effects compared to other
benzodiazepines
Lacosamide Sodium channel selective ECG PR interval, bradycardia, IV; avoid in second- and
enhancement of slow inactivation, heart block third-degree heart block or sick
collapsin response mediator protein 2 sinus syndrome; prior
(CRMP-2) binding; IV available; authorization may be required
therapeutic drug monitoring not as outpatient
routinely required; minimal drug
interactions; noninferior to
fosphenytoin in patients with
nonconvulsive seizures
Levetiracetam Binding to SV2A; partial inhibition of Complete blood cell count, IV; dosing in clinical trials higher
N-type calcium ion currents; IV liver function tests; behavioral than commonly prescribed
available; therapeutic drug monitoring dysfunction
not routinely required; highly studied
in status epilepticus
Oxcarbazepine Binding to voltage-gated sodium Trough levels; complete No IV option; associated with
channels; inhibition of glutamate blood cell count, sodium; liver higher risk of Stevens-Johnson
release; easily titrated; less function tests/DRESS; weakly syndrome in Asian patients with
hyponatremia than carbamazepine; induces CYP3A4, weakly HLA-B*15:02, although lower risk
secondary use in mood disorders inhibits CYP2C19 than carbamazepine
Perampanel Noncompetitive α-Amino-3-hydroxy- DRESS, mood dysfunction;

5-methylisoxazole-4-proprionic acid degraded by CYP3A4
(AMPA) receptor antagonist; IV
available; unique mechanism
Phenobarbital GABAA receptor β-subunit binding; Complete blood cell count, May enhance beta activity,
increase in calcium ion channel liver function tests; induces sharpness of EEG
conduction; IV available; secondary CYP3A4, CYP2C9, CYP1A2;
use in treating alcohol withdrawal; degraded by CYP2C9,
historic data in status epilepticus CYP2C19, CYP2E1
1330 OCTOBER 2021

Drug Proposed mechanism and rationale Monitoring Considerations
Phenytoin/ Blockade of voltage-dependent Complete blood cell count, Zero-order kinetics can result in
fosphenytoin sodium channels; IV available; highly liver function tests, albumin; toxicity; free levels in patients in
studied in status epilepticus and strong, broad enzyme inducer the intensive care unit poorly
seizure prophylaxis studies of patients of CYP3A4, CYP2C9, CYP1A2; estimated by historic equations
with traumatic brain injury degraded by CYP2C9,
CYP2C19
Topiramate GABAA nonbenzodiazepine receptor pH, bicarbonate; weakly Alternatives preferred when
site binding; AMPA and kainate induces CP3A4, weakly possible in patients with
receptor binding/inhibition; inhibits CYP2C19 first-term pregnancies
voltage-dependent sodium channel
binding; IV available; case series in
refractory status epilepticus
Valproate GABA transaminase inhibition and Liver function tests, albumin, IV; may have effect on platelet
reduced GABA metabolism; amylase/lipase in patients at dysfunction even without
voltage-gated sodium channel high risk; blood cell counts, thrombocytopenia; free levels
suppression; IV available; may have albumin; inhibits CYP2C9; may be needed if
secondary benefit for mood degraded by CYP2A6, hypoalbuminemia or
stabilization or headache CYP2C9, CYP2C19, CYP2B6 concomitant phenytoin/
fosphenytoin therapy;
alternatives preferred when
possible in patients who are
pregnant; consider free levels in
patients with low albumin
Ketamine Noncompetitive N-methyl-D- Heart rate, respiratory Increasing use as earlier option
aspartate (NMDA); HCN1 receptor function, liver function tests, in patients with refractory
blockade and commensurate laryngospasm; postanesthetic seizures
decrease in AMPA receptor-mediated emergence reaction;
transmission; IV dissociative degraded by CYP2B6 and
anesthetic; reduced withdrawal CYP3A4
symptoms; well tolerated without
hemodynamic effects
Midazolam GABAA benzodiazepine binding site; Blood pressure, respiratory May require vasopressor
IV, IM, and intranasal routes; first-line function support
agent in prehospital setting;
anesthetic third-line agent
Pentobarbital GABAA β-subunit binding; IV Heart rate; respiratory Need for vasopressor support;
anesthetic third-line agent; silencing function; complete blood cell risk for bowel perforation
of cerebral metabolism at high doses count, liver function tests,
ileus; degraded by CYP2B6,
partially by CYP3A4
Propofol GABAA β2 and β3 receptor subunit Respiratory function; liver May require vasopressor
binding. IV anesthetic third-line agent; function tests, triglycerides, support; risk for propofol
rapid onset and offset creatine kinase, pH, potential infusion syndrome in children or
CYP3A4 inhibitor in patients with low body
weight; need for adjusting
nutrition to prevent
hypertriglyceridemia
ECG = electrocardiogram; EEG = electroencephalogram; IM = intramuscular; IV = intravenous.

receptor 1; a mediation analysis demonstrated that the association between

inflammatory markers and outcome was mediated in part through
nonconvulsive seizures.55 The emergence of new or worsening epileptiform
activity (lateralized rhythmic delta activity, generalized periodic discharges, or
lateralized periodic discharges) was also associated with inflammatory marker
soluble ST2 both in blood and CSF,56 suggesting that inflammation is associated
with ictal-interictal activity in addition to frank electrographic seizures.
EEG ISCHEMIA MONITORING AFTER SUBARACHNOID HEMORRHAGE

Because EEG demonstrates increased delta and decreased alpha activity during
ischemia, continuous EEG has been retrospectively examined for the ability to
predict delayed cerebral ischemia after subarachnoid hemorrhage using
continuous EEG spectral features,57,58 including decreases in the alpha to delta
power ratio57,59,60 or relative alpha power variability.60,61 Specifically, clinically
useful cutoffs in alpha to delta ratio were identified, including six consecutive
recordings with a greater than 10% decrease from baseline (sensitivity 100%,
specificity 76%) and any single measurement with a greater than 50% decrease
(sensitivity 89%, specificity 84%).59 A decrease in relative alpha variability was
100% sensitive but only 50% specific for vasospasm.61
Other findings historically associated with cerebral ischemia include
epileptiform discharges, rhythmic and periodic ictal-interictal continuum
patterns,49,62-64 and isolated alpha suppression.65 In subarachnoid hemorrhage,
new or worsening epileptiform activity has been associated with subsequent
delayed cerebral ischemia.66,67 Using change-point detection, the temporal onset
of brain tissue hypoxia was associated with increases of periodic discharge
frequency exceeding 2.0 Hz, supporting the hypothesis that secondary ischemia
is associated with subarachnoid hemorrhage.53
The findings of spectral frequency change and new epileptiform activity on
continuous EEG have been examined prospectively in both a feasibility study
(demonstrating that more than 90% of delayed cerebral ischemia events
occurred during the mean 6.9 days of continuous EEG monitoring68) and a
TABLE 6-3 Accuracy Results for Continuous EEG Prediction of Delayed Cerebral
Ischemia After Subarachnoid Hemorrhage (n = 103)a
Low risk Medium risk High risk

[risk score = 1] [risk score = 2.5] [risk score = 4]
Sensitivity (%) 91 [81-98] 94 [88-99] 95 [87-99]
Specificity (%) 83 [71-93] 80 [69-90] 77 [36-99]
Pretest probability of delayed cerebral ischemia (%) 37 [25-50] 58 [50-66] 79 [61-92]
Delayed cerebral ischemia risk (continuous EEG deterioration) (%) 76 [58-90] 87 [79-94] 94 [79-100]
Delayed cerebral ischemia risk (no continuous EEG deterioration) (%) 6 [1-13] 10 [2-19] 9 [3-53]
Number needed to monitor 2.6 [2.0-3.8] 3.5 [2.8-4.8] 6.7 [3.6-25.3]
a
Modified with permission from Rosenthal ES, et al, Ann Neurol.67 © 2018 American Neurological Association.
1332 OCTOBER 2021

diagnostic accuracy study (validating the high sensitivity and specificity of an KEY POINTS
EEG “alarm” in patients with low, medium, or high baseline risk) (TABLE 6-3).67
● Seizure activity is
These EEG alarms were prespecified as a change from baseline consisting of increasingly appreciated as
any of the following not explained by sedation, hydrocephalus, or other clinical associated with an
confounders: (1) 10% decrease in alpha to delta ratio persisting 6 hours or a 50% inflammatory complex
decrease persisting longer than 1 hour, (2) a one-grade decrease in relative alpha of biomarkers in blood
and CSF.
variability over an 8-hour epoch, (3) new focal slowing identified on regional
spectrograms or raw EEG, or (4) new or worsening epileptiform activity. ● A battery of continuous
Because patients with an EEG alarm as described above have a subsequent risk of EEG findings, including
delayed cerebral ischemia of 76% (patients at low risk), 87% (patients at medium decrease in alpha to delta
risk), and 94% (patients at high risk), these methods of ischemia monitoring may ratio of frequency-band
power, one-grade decrease
be useful as patient selection criteria for enrichment strategies in future clinical in relative alpha variability,
trials or as triggers for higher-risk diagnostic or treatment studies such as and new or worsening
cerebral angiography with endovascular vasodilator therapy. Of interest, a epileptiform activity, have
single-center study found that EEG delayed cerebral ischemia biomarkers of new been prospectively
validated as a method of
or worsening epileptiform activity were strongly associated with longitudinal predicting subsequent
functional outcomes following subarachnoid hemorrhage, whereas EEG ischemia in patients with
background deterioration was not.69 This discrepancy may be related to a subarachnoid hemorrhage.
differential response to clinically available interventions. A patient with a
● Cortical spreading
commensurate decrease in both alpha to delta ratio and invasively measured
depolarizations are
cerebral blood flow followed by a response to endovascular intraarterial increasingly being
administration of calcium channel blockers directly at the site of cerebral monitored in clinical
vasospasm is depicted in CASE 6-2. practice as brain activity
associated with unexplained
coma and poor neurologic
CORTICAL SPREADING DEPOLARIZATION MONITORING ACROSS outcome.
ACUTE BRAIN INJURIES
Cortical spreading depolarizations similar to those seen in migraine are present in
acute brain injury. These depolarizations spread slowly and typically have a
magnitude greater in amplitude than seizure activity; when they occur in
vulnerable parenchyma after acute brain injury, they result in severe metabolic
crisis, which is often irreversible when depolarizations occur repeatedly in
clusters. Intracranial electrocorticography has traditionally been required for the
detection of cortical spreading depolarization.70,71 However, evaluation of
examples of simultaneous scalp and subdural electrode recordings suggested that
depression of fast activity over the scalp may be a signature of underlying
spreading depolarization.72 The association of spreading depolarizations with
neurologic deterioration and poor outcome in patients with subarachnoid
hemorrhage, traumatic brain injury,73-76 and surgically managed subdural
hematoma, combined with the reduction of these events by ketamine,77-83 has led
to a trend of both increased clinical use of intracranial monitoring of
low-frequency activity in patients with acute brain injuries and increased interest
in future therapies targeted at treating these events.84
DETECTION OF DELIRIUM, ENCEPHALOPATHY, AND COVERT

CONSCIOUSNESS AND PREDICTION OF COMA RECOVERY
In addition to predicting anesthetic liberation after status epilepticus, EEG has
also gained attention for its ability to diagnose and monitor delirium and
disorders of consciousness in patients who are critically ill and to predict coma
recovery. The depth and severity of delirium is highly correlated with the
prevalence of EEG slowing. The EEG finding most strongly associated with the

presence of delirium in one study was a composite of generalized theta or delta

slowing, conferring a tenfold risk (95% confidence interval, 5.3-20.1). Slowing is
present even in patients with delirium who have preserved arousal.85 In clinical
practice, EEG in patients with delirium can be useful to trend improvement from
delirium as an intermediate biomarker of recovery after treatment of potential
underlying causes, such as infection, sedation, toxic-metabolic effects, or
organ dysfunction.
As a tool for patients with disorders of consciousness, EEG is useful to detect
covert consciousness. EEG performed in the background of various stimuli
(audio recordings alternating as a stimulus battery) at a mean of 10 days after
CASE 6-2 A 74-year-old woman presented with a Hunt and Hess Scale grade 4 and
Fisher Scale grade 4 subarachnoid hemorrhage due to a right supraclinoid
internal carotid artery aneurysm. Examination demonstrated delayed
response to commands but no overt focal symptoms of delayed cerebral
ischemia. The patient was considered uncertain to benefit from
catheter-based intraarterial vasodilator therapy. Over a 2-day period, a
depth electrode demonstrated a decline in the alpha to delta ratio that
was concordant with a decline in cerebral blood flow monitoring from
30 mL/100 g/min to 10 mL/100 g/min measured from a nearby probe
(FIGURE 6-3A). Based on these data, the patient was referred for
endovascular intraarterial calcium channel blocker therapy (FIGURE 6-3B),
which was associated with an increase in cerebral blood flow (FIGURE 6-3B)
from 10 mL/100 g/min to 15 mL/100 g/min and concordant emergence of
an EEG alpha rhythm measured from the colocated depth electrode
(FIGURE 6-3B).
COMMENT This case demonstrates that when changes in EEG spectral activity (such as
decrease of the alpha to delta ratio) are concordant with other modalities
(such as cerebral blood flow or brain tissue oxygenation), there may be
increased confidence of vasospasm as a treatable mechanism of
metabolic crisis, manifest as EEG background deterioration.
1334 OCTOBER 2021

traumatic coma was part of a multimodal assessment, also incorporating
functional MRI (fMRI), that was able to identify cognitive-motor dissociation in
four of 16 subjects and higher-order cortical processing in two additional
patients.86 Patients with EEG differences demonstrated by a machine learning
classifier comparing alternating blocks of auditory stimulation and rest were
more likely to have intact language function as measured by either the Coma
Recovery Scale-Revised or a composite that included fMRI.87 A manual method
examining EEG background had almost as good agreement with the behavioral
language examination as did the machine learning stimulus-based EEG classifier,
and a method employing both background and reactivity had significant
FIGURE 6-3
Findings for the patient in CASE 6-2. A, Depth electrode tracings demonstrate a decline in the
alpha to delta ratio that is discordant with a decline in cerebral blood flow monitoring from
30 mL/100 g/min to 10 mL/100 g/min measured from a nearby probe (sixth tracing from the
top). B, Tracings before (left image) and after (right image) catheter-based intraarterial
vasodilator therapy demonstrate an increase in cerebral blood flow (top image) of
10 mL/100 g/min to 15 mL/100 g/min, concordant with the emergence of an alpha rhythm
measured from the colocated depth electrode (B, bottom tracing).

agreement with the composite standard for detecting language function by either
fMRI or behavioral evidence of language.87 In addition to studies of patients with
traumatic brain injury, a prospective study evaluating EEG responses in patients
with a wide variety of acute brain injuries demonstrated that brain activation in
response to auditory stimulation was evident in 15% of 104 patients, conferring
nearly twice the rate (50% compared to 26%) of following commands before
discharge and 4.6-fold odds of achieving a good Glasgow Outcome
Scale-Extended score at 12 months (44% compared to 14%).88 EEG may also be
useful in differentiating patients in an unresponsive wakefulness state from those
in a locked-in state even without preserved eye movements, such that EEG may
demonstrate normal cortical rhythms and reactivity in the locked-in state.89,90
Prognostic information about coma recovery is also evident in patients with
cardiac arrest. Treatment with therapeutic hypothermia significantly affects the
prognostic significance of these findings.91 The occurrence of monomorphic
“identical” bursts has been linked with near uniformly poor outcome in studies
seeking to minimize biases from self-fulfilling prophecies by examining a cohort
in which limitation of life-sustaining therapy did not occur in the first 72 hours,
even though an unfavorable EEG pattern at 12 hours was the factor most strongly
associated with poor outcome.92 A prediction model including the presence of
status epilepticus, suppression-burst pattern alone, and lack of background
reactivity had an area under the curve of 0.92 for predicting poor functional
outcome in a cohort of 373 patients.93 Alternatively, patients with continuous
EEG activity are more likely to respond to antiseizure medication or therapeutic
hypothermia with a resolution of epileptiform activity,94 and the combination of
EEG continuity and lack of anoxic injury on MRI was associated with coma
recovery at a sensitivity of 91% and specificity of 99%. Other more quantitative
tools include a Cerebral Recovery Index (consisting of alpha to delta ratio of
power, standard deviation, coherence in delta activity, Shannon entropy, and
regularity)95-98 and time-varying models containing features of complexity,
category, and connectivity.99
Similarly, in intracerebral hemorrhage, the absence of an anteroposterior
gradient was associated with poor outcome and the presence of stage II sleep
activity was independently associated with good functional outcome.100 In
traumatic brain injury, absence of a posterior dominant rhythm, absence of N2
sleep transients, presence of predominant delta activity, and presence of a
discontinuous background were associated with poor outcome when evident in
the initial 72 hours.42
RESOURCE UTILIZATION
The use of EEG in the emergency and critical care environment has historically
required the availability of both EEG equipment and technologist resources.
The increasing availability of rapid EEG devices that can be placed by physicians
and nurses has enabled EEG placement at a median of 5 minutes, with only
25% of studies requiring greater than 10 minutes before recording could
commence.101 These techniques may also allow for screening neurotelemetry
that may enable examining the rate of seizures in the hyperacute phase as well as
assessing whether ictal-interictal activity is commonly preceded by progression
from sustained seizure activity.102
The use of continuous EEG has increased significantly over time, with critical
care neurophysiologists using quantitative aspects of EEG for seizure detection in
1336 OCTOBER 2021

over 90% of users, pharmacologic titration to burst suppression in nearly 60% of KEY POINTS
users, and a variety of other uses in 20% to 30% of users, including monitoring
● Covert consciousness is
the depth of sedation, detecting ischemia, detecting vasospasm, and prognosis frequently seen in patients
after cardiac arrest,103 with costs and resource utilization commensurate with who are critically ill with
intermittent EEG. Challenges with the availability and cost of continuous EEG acute brain injury; wider
monitoring compared to intermittent EEG monitoring have led to analyses availability of
stimulus-based EEG
examining differences in yield and outcomes. In patients with cardiac arrest
monitoring (in addition to
undergoing therapeutic hypothermia, for example, a high degree of agreement functional MRI) may not only
was reported between continuous and intermittent EEG methods, and an improve the accuracy of
observational study reported that continuous EEG did not confer a benefit over diagnosing patients with
disorders of consciousness
intermittent EEG in patients with cardiac arrest,104 although decisions to limit
but also improve the
life-sustaining therapy and physician biases may also have explained the lack of information available to
differences. A follow-up randomized controlled trial reported no difference in surrogate decision makers.
outcomes among patients undergoing continuous EEG compared to intermittent
EEG, but the conclusions were limited by a highly heterogeneous population, ● Assessment of the EEG
background rhythm,
lack of a specified treatment protocol during the monitoring, and the potential including sleep features and
for continuous monitoring to inform goals-of-care conversations and thereby continuity, provides
influence the rate of withdrawal of life-sustaining therapy.105 Other studies prognostic information in
reporting improved outcomes when continuous EEG was performed in patients addition to the presence of
activity on the
who were critically ill106 similarly lack an interventional approach to determine ictal-interictal continuum.
whether these effects are related to treatment effects.
● Although one randomized
study concluded that
continuous EEG showed no
CONCLUSION
benefit compared to
The advancement of consistent nomenclature and definitions has improved the intermittent EEG, a definitive
reliability of definitions for seizures, status epilepticus, and indeterminate study would require
patterns on the ictal-interictal continuum. A consolidated approach to diagnosis examining a specific
and management reflecting these many applications of EEG neuromonitoring in population expected to
have a homogeneous
neurocritical care is depicted in FIGURE 6-4. Management of clinically apparent pathophysiology, defining a
and convulsive status epilepticus (FIGURE 6-4A) has evidence-based literature treatment protocol that
guiding management along the continuum of prehospital, emergency, and makes use of
critical care, but continuous EEG may improve diagnostic accuracy and precision neuromonitoring findings,
and controlling for changes
of management at an early phase. Management of encephalopathy, coma, and in life-sustaining treatment
other disorders of consciousness requires a consideration of more diverse resulting from differences in
etiologies and multimodality neuromonitoring to improve diagnostic precision. available prognostic
Monitoring requires serial assessment and iterative management changes information.
(FIGURE 6-4B). Specifically, trends in using adjunctive tools to document both
scalp-negative seizures and the metabolic burden of epileptiform activity have
expanded the recognition that increasing seizure burden and increasing
burden and intensity of periodic and rhythmic patterns on the ictal-interictal
continuum are both associated with cerebral metabolic crisis related to
exhaustive cerebral hypermetabolism. When seizure activity is indeterminate,
intracranial EEG and empiric treatment trials with antiseizure medication have
been used to demonstrate clinical improvement in a substantial portion of
patients, thereby improving diagnostic precision. When seizures are continuous
and refractory in the form of status epilepticus, the current approach is to
optimize antiseizure medications during a structured course of anesthetic
management. Approaches including seizure suppression and burst suppression
with anesthetics have grown to incorporate medications including ketamine as
well as ketogenic or low-glycemic diet therapy and neuromodulation.

FIGURE 6-4
EEG monitoring guides the approach to both clinically apparent and convulsive status
epilepticus in the emergency and critical care settings (A) and to a broad differential
diagnosis considered in the evaluation of a patient with encephalopathy, coma, or other
disorder of consciousness (B). Increasing availability of EEG in the emergency setting (A) may
enable more precise management of the patient with established convulsive status
epilepticus by distinguishing pharmacologic sedation, progression to refractory
nonconvulsive seizures, and nonepileptic spells. EEG has numerous roles in patients who are
critically ill with encephalopathy, coma, and disorders of consciousness (B), including
detection of nonconvulsive seizures or nonconvulsive status epilepticus, evaluation for
ictal-interictal continuum activity consistent with possible nonconvulsive status, tissue
dysfunction due to secondary brain injury or delayed cerebral ischemia, and cognitive-motor
dissociation, in which consciousness is only evident through advanced monitoring. For all
these scenarios, complementary multimodality monitoring data can add contextual
information, which can be evaluated along with EEG monitoring for concordance and
iterative response to treatment.
EEG = electroencephalography; FDG CT-PET = fludeoxyglucose computed tomography positron emission
tomography; Rx = pharmacologic management; SAH = subarachnoid hemorrhage; SE = status epilepticus;
TBI = traumatic brain injury.
1338 OCTOBER 2021

Apart from diagnosing and monitoring seizure activity, other diagnostic roles for
EEG have been demonstrated recently in diverse patient cohorts: monitoring for
ischemia after subarachnoid hemorrhage; diagnosing covert consciousness in
patients who are apparently comatose; and predicting neurologic recovery after
cardiac arrest, primary acute brain injury, or resolution of status epilepticus.
ACKNOWLEDGMENT
This work was supported by a grant from the National Institutes of Health/
National Institute of Neurological Disorders and Stroke (1K23NS105950).
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1340 OCTOBER 2021

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REVIEW ARTICLE

Neuromuscular Disorders
ONLINE
in the Intensive Care Unit
By Torrey Boland Birch, MD
ABSTRACT
PURPOSE OF REVIEW: Thisarticle discusses the pathophysiology, presentation,
diagnosis, treatment, and prognosis of common neuromuscular disorders
seen in the intensive care unit, including Guillain-Barré syndrome,
myasthenia gravis, and intensive care unit–acquired weakness.
RECENT FINDINGS: Guillain-Barré syndrome can have an excellent prognosis if

patients are diagnosed early, appropriately treated, and monitored for
complications, including respiratory failure and dysautonomia. Intensive
care unit–acquired weakness increases overall mortality in patients who
are critically ill, and distinguishing between critical illness myopathy and
critical illness polyneuropathy may have important prognostic
implications.
SUMMARY: Neuromuscular disorders are not rare in the intensive care unit
setting, and precise identification and treatment of these conditions can
greatly impact long-term outcomes.
INTRODUCTION
P
atients with neuromuscular disorders are at high risk for respiratory
failure and other complications, including infection and
CITE AS:
dysautonomia, that require aggressive treatment in the intensive care
2021;27(5, NEUROCRITICAL CARE): unit (ICU). Myasthenia gravis (MG) and Guillain-Barré syndrome
1344–1364.
(GBS) are two of the most common causes of neuromuscular
respiratory failure seen in the ICU; in one study, MG accounted for up to 32% of
Dr Torrey Boland Birch, 1725 W patients presenting with respiratory failure and GBS accounted for just under
Harrison St, Ste 1106, Chicago, 15%.1 Early identification and awareness of potential complications can
IL 60026, Torrey_birch@rush.edu.
significantly mitigate morbidity and mortality,1 and with aggressive treatment,
RELATIONSHIP DISCLOSURE: many patients can experience a significant recovery. Neurologists should be
Dr Birch serves on an advisory familiar with the diagnosis, treatment, and prognosis of GBS and MG and can
board for Gift of Hope Organ &
Tissue Donor Network and has help the ICU team, the patient, and family members anticipate both
served as a consultant for the complications and the overall course of the disease. In addition, as improvements
legal firm Rhoades McKee PC. in critical care are leading to an increasing number of survivors of prolonged
UNLABELED USE OF hospitalizations, neurologists should be familiar with the complications of critical
PRODUCTS/INVESTIGATIONAL illness, including ICU-acquired weakness.
USE DISCLOSURE:
Dr Birch reports no disclosure.
GUILLAIN-BARRÉ SYNDROME
GBS is an acute monophasic polyradiculoneuropathy that is immune mediated
of Neurology. and characterized by ascending flaccid paralysis and areflexia accompanied by
1344 OCTOBER 2021

CSF findings of albuminocytologic dissociation, which is the finding of an KEY POINTS
elevated protein level in the absence of an elevated cell count. The eponym
● Guillain-Barré syndrome
Guillain-Barré has persisted since the description in 1916 by Guillain, Barré, and (GBS) has three
Strohl2 of patients with an ascending flaccid paralysis. Landry had previously phenotypical variants:
described a similar disease over 50 years earlier, and in recognition of this, the purely demyelinating (acute
disease is occasionally referred to as Landry-Guillain-Barré syndrome. inflammatory demyelinating
polyradiculoneuropathy),
purely axonal (acute motor
Pathophysiology axonal neuropathy), and
The term GBS has come to encompass several variants of an immune-mediated demyelinating with an
polyradiculoneuropathy. The primary phenotypical variants are a purely axonal component.
demyelinating variant, a purely axonal variant, and a variant that is
● The primary targets in the
demyelinating with an axonal component.3 The demyelinating variant is referred acute motor axonal
to as acute inflammatory demyelinating polyradiculoneuropathy (AIDP), neuropathy phenotype of
whereas the axonal variant is referred to as acute motor axonal neuropathy GBS are the neuronal
(AMAN). Patients may also have involvement of the sensory nerves in the acute membrane gangliosides,
including GM1, GD1a, and
motor-sensory axonal neuropathy (AMSAN) subtype. Although all the subtypes GQ1b.
of GBS are antibody mediated, AIDP does not have identified antigens or
antibodies. Inflammation, activation of complement, and destruction of myelin, ● GBS begins with
however, support the hypothesis that the process is immune mediated. In ascending weakness,
typically initially involving
AMAN, the primary antigen targets are neuronal membrane gangliosides,
the proximal leg muscles,
particularly GM1, GD1a, and GQ1b on the axon itself. This leads to direct damage with diminished or absent
of the axon, the regeneration of which is slow and often incomplete. In contrast, reflexes.
the process of remyelination may occur more efficiently. For this reason, the
AMAN phenotype is associated with worse outcomes and longer recovery times
than the AIDP phenotype.
Significant molecular mimicry exists between the glycan present on
lipooligosaccharides of Campylobacter jejuni and the neuronal membrane
gangliosides GM1 and GD1a, which is the reason infection with C. jejuni can
trigger GBS, particularly the AMAN variant.3 Other infections can similarly
precede the onset of GBS, including cytomegalovirus, Epstein-Barr virus,
influenza A, Mycoplasma pneumoniae, Haemophilus influenzae, severe acute
respiratory syndrome coronavirus 2 (SARS-CoV-2), and Zika virus. GBS has
been reported after administration of the Semple rabies vaccine and several types
of influenza A virus vaccines, most notably the 1976 H1N1 influenza A vaccine.
More recent studies suggest a possible minimal increase in GBS cases with
influenza A vaccination, although this risk may be offset by the possibility of
GBS developing after infection with influenza A.4 The specific neuronal
membrane ganglioside GQ1b is the target in the Miller Fisher variant of GBS. An
association also appears to exist between recent surgery and GBS, although the
mechanism is unclear.5
Presentation
The classic presentation of GBS is one of ascending weakness and areflexia, often
following an infection or other immune stimulus. More than two-thirds of
patients with GBS will report respiratory or gastrointestinal symptoms in the
4 weeks before symptom onset (CASE 7-1).6 Pain may precede the development
of weakness and is commonly described in the back, buttocks, and thighs. The
pain is often described as aching or throbbing and may also be described as a
tight, crampy sensation. Patients frequently report paresthesia, particularly in
the fingers and toes, although objectively their sensation is often preserved.

NEUROMUSCULAR DISORDERS IN THE INTENSIVE CARE UNIT
CASE 7-1 A 43-year-old previously healthy woman presented to the emergency

department for evaluation of lower extremity weakness. She reported an
acute onset of diarrhea 7 days earlier. Several days later, she developed
worsening fatigue, back pain, and painful paresthesia of the legs, which
progressed to difficulty climbing stairs. The following day, she was
unable to rise from a chair and noted mild weakness in her arms.
On arrival, the patient was afebrile, with mild tachycardia and
tachypnea. Blood pressure and oxygen saturation were within normal
limits. General medical examination was unremarkable. On neurologic
examination, mentation and cranial nerve examination were normal. The
patient was noted to have symmetric weakness of the legs, proximally
more so than distally. She had mild symmetric proximal weakness in the
arms. Sensation was normal. Reflexes were absent.
The patient was admitted to the intensive care unit (ICU) for close
monitoring of her respiratory status. Given concern for Guillain-Barré
syndrome (GBS), a lumbar puncture was performed, which revealed only
elevated protein. Bedside pulmonary function testing showed a
borderline low forced vital capacity of 45 mL/kg, maximal inspiratory
pressure of -40 cm H2O, and a maximal expiratory pressure of 50 cm H2O.
Several hours later, the patient developed a paradoxical breathing
pattern. Repeat pulmonary function testing showed a decline in values,
with a forced vital capacity of 20 mL/kg, maximal inspiratory pressure of
-25 cm H2O, and a maximal expiratory pressure of 40 cm H2O. Arterial
blood gas was normal. At that time, the patient was intubated.
Over the next 24 hours, the patient progressed to a flaccid
quadriparesis. IV immunoglobulin (IVIg) 0.4 g/kg/d was started, with a
planned 5-day course. EMG was performed, which showed diffusely
absent motor responses consistent with acute motor axonal neuropathy
(AMAN). Blood work showed the presence of GD1a antibodies, although
this test did not result until day 5 of admission.
The patient was noted to have several episodes of labile blood
pressure and heart rate, which slowly improved during her hospitalization
and were treated supportively. She continued to require full respiratory
support at 7 days, and tracheostomy was performed. She remained in the
ICU for an additional 2 weeks because of autonomic instability.
Ultimately, the patient’s blood pressure stabilized, and she was
discharged to a neurorehabilitation and ventilator weaning facility. One
year later, she returned to clinic ambulating, with her tracheostomy
decannulated. She had returned to work part-time.
COMMENT This patient presented with the AMAN variant of GBS, with positive GD1a
antibodies. Given her rapid progression, respiratory failure, and axonal
phenotype, early tracheostomy was required. Despite the severity of the
disease, many survivors of GBS can ultimately have a nearly full recovery.
1346 OCTOBER 2021

Weakness tends to start in the proximal legs and ultimately can progress to KEY POINTS
involve the arms, diaphragm, and cranial nerves. Patients often describe
● Symptoms in GBS
difficulty climbing stairs or rising from chairs. Reflexes are absent or diminished, typically reach maximal
although early on they may be preserved. The disease is monophasic, and severity within 2 weeks, and
typically the maximal weakness is reached within 2 weeks of the initial progression beyond 4 weeks
neurologic symptoms. Symptoms are unlikely to progress after 4 weeks; should raise concern for an
alternative diagnosis.
additional progression at that point should raise concern for an alternative
diagnosis, such as chronic inflammatory demyelinating polyradiculoneuropathy ● Autonomic dysfunction
(CIDP). In 20% to 30% of cases, progression of weakness leads to respiratory occurs in more than
failure requiring mechanical ventilation.7 one-third of patients with
Autonomic dysfunction is common in GBS as well, occurring in 38% of GBS and is related to
demyelination of
patients in one large study, with an increased incidence in patients requiring sympathetic nerves and
mechanical ventilation (odds ratio 6.93 [3.39-14.15]).8 This is likely caused by disruption of the baroceptor
demyelination of sympathetic nerves and disruption of the baroreceptor reflexes.
reflexes.9 The most common symptoms are ileus, hypertension, hypotension,
● The Miller Fisher variant
fever, tachycardia, and bradycardia. Patients with more severe disease, including of GBS presents with cranial
those with quadriparesis, bulbar and neck flexor weakness, and respiratory nerve dysfunction, ocular
failure, are more likely to manifest dysautonomia. motor weakness, and bulbar
Aside from the classic presentation, several clinical variants of GBS are well symptoms. It is associated
with antibodies against GQ1b
described. The most common is Miller Fisher syndrome (also referred to as
and is less likely to progress
Fisher syndrome), with cranial nerve dysfunction including facial weakness, to respiratory failure than
ocular motor weakness, and bulbar symptoms. Patients may also have ataxia, more classic forms of GBS.
sensory signs, and dysautonomia. This variant can progress to involve the limbs
as well, which can be referred to as an overlap syndrome and may have a course ● The diagnosis of GBS is
clinical, with progressive
more typical of the classic forms of GBS. Patients with pure Miller Fisher weakness and decreased
syndrome are less likely to need mechanical ventilation; however, those with the reflexes as key features.
overlap syndrome may require mechanical ventilation earlier than patients with Supportive features include
a more typical form of GBS.10 Miller Fisher syndrome is associated with albuminocytologic
dissociation in the CSF and
anti-GQ1b antibodies, which are located on the ocular motor nerves and in the electrophysiologic testing
brainstem, which accounts for the presentation of symptoms. Pharyngeal- consistent with either
brachial and paraparetic variants of GBS also exist, for which the target antigens demyelination or axonal
are not yet known. injury.
Diagnosis
The diagnosis of GBS is primarily clinical, based on the patient’s history,
clinical presentation, and physical examination. Supportive studies include
CSF analysis, electrophysiologic studies including nerve conduction studies
and EMG, and antibody testing. Standardized diagnostic criteria were
proposed by the National Institute of Neurological Disorders and Stroke
(NINDS) and have been modified since their introduction in 1978; however,
these criteria may miss variants such as Miller Fisher syndrome (TABLE 7-1).11
The two required features for diagnosis include progressive weakness of the
legs and arms (occasionally only in legs initially) and areflexia or decreased
tendon reflexes in the affected limbs. Additional supportive features include a
progressive phase lasting up to 4 weeks, relative symmetry, mild sensory
symptoms, cranial nerve involvement, autonomic dysfunction, and pain. The
Brighton Collaboration criteria are more stringent diagnostic criteria used for
research purposes that include the NINDS criteria as well as albuminocytologic
dissociation in the CSF in addition to electrophysiologic findings consistent with
GBS for diagnostic certainty.7

EMG is not required for diagnosis but can be helpful in determining the
phenotype (AIDP or AMAN), which may be helpful for prognosis. Appropriate
workup should be done to exclude alternative causes based on the clinical
examination. Other conditions that may present similarly include MG, botulism,
West Nile virus, organophosphate poisoning, tick paralysis, porphyria,
transverse myelitis and other causes of myelopathy, and vasculitic neuropathies
(TABLE 7-2). A leukocytosis in the CSF, fever at onset, sensory level, asymmetry,
persistent bowel and bladder dysfunction, respiratory failure in the absence of
limb weakness, and prolonged progression of symptoms should raise concern for
an alternative diagnosis. Spinal imaging should be done in the setting of acute
TABLE 7-1 Diagnostic Criteria for Guillain-Barré Syndromea
Features required for diagnosis

◆ Progressive bilateral weakness of arms and legs (initially only legs may be involved)
◆ Absent or decreased tendon reflexes in affected limbs (at some point in clinical course)
Features that strongly support diagnosis
◆ Progressive phase lasts from days to 4 weeks (usually <2 weeks)
◆ Relative symmetry of symptoms and signs
◆ Relative mild sensory symptoms and signs (absent in pure motor variant)
◆ Cranial nerve involvement, especially bilateral facial palsy
◆ Autonomic dysfunction
◆ Muscular or radicular back or limb pain
◆ Increased protein level in CSF; normal protein levels do not rule out the diagnosis
◆ Electrodiagnostic features of motor or sensorimotor neuropathy
Features that cast doubt on diagnosis
◆ Increased numbers of mononuclear or polymorphonuclear cells in CSF
◆ Marked persistent asymmetry of weakness
◆ Bladder or bowel dysfunction at onset or persistent during disease course
◆ Severe respiratory dysfunction with limited limb weakness at onset
◆ Sensory signs with limited weakness at onset
◆ Fever at onset
◆ Nadir <24 hours
◆ Sharp sensory level indicating spinal cord injury
◆ Hyperreflexia or clonus
◆ Extensor plantar responses
◆ Abdominal pain
◆ Slow progression with limited weakness without respiratory involvement
◆ Alteration of consciousness

a
Modified from Leonhard SE, et al, Nat Rev Neurol.11 © 2019 The Authors.
1348 OCTOBER 2021

Differential Diagnosis of Rapidly Progressive Weaknessa TABLE 7-2
Central nervous system

◆ Encephalitis
◆ Acute disseminated encephalomyelitis (ADEM)
◆ Transverse myelitis and other causes of myelopathy
◆ Brainstem compression
◆ Leptomeningeal malignancy
Motor neuron
◆ Poliomyelitis
◆ West Nile virus anterior myelitis
◆ Rabies
◆ Amyotrophic lateral sclerosis
◆ Progressive spinal muscular atrophy
Peripheral nerve
◆ Guillain-Barré syndrome
◆ Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP)
◆ Critical illness neuropathy
◆ Vasculitis
◆ Diphtheria
◆ Porphyria
◆ Tick paralysis
◆ Heavy metal toxicity
Neuromuscular junction
◆ Myasthenia gravis
◆ Lambert-Eaton myasthenic syndrome
◆ Botulism
◆ Organophosphate intoxication
Muscles
◆ Critical illness myopathy
◆ Mitochondrial disease
◆ Acute rhabdomyolysis
◆ Polymyositis
◆ Dermatomyositis
◆ Medication-induced myopathy
◆ Metabolic/electrolyte disorders
a
Data from Willison HJ, et al, Lancet4 and Leonhard SE, et al, Nat Rev Neurol.11

onset of symptoms, a sensory level, or hyperreflexia, or when the weakness is

asymmetric. In some cases, brain imaging may be helpful to exclude brainstem
pathology as the cause of the weakness. MRI of the spine with gadolinium can be
helpful but is not required in the diagnosis of GBS, as enhancement of the nerve
roots is a sensitive but nonspecific finding in GBS.11 The presence of
antiganglioside antibodies or evidence of recent infection, such as C. jejuni, may
increase the diagnostic certainty but is not required for diagnosis.
West Nile virus, which emerged in North America in 1999, can result in an
acute flaccid paralysis syndrome termed West Nile poliomyelitis that may mimic
GBS. This results from infection of the anterior horn cells of the spinal cord. This
may or may not be accompanied by an encephalitis. The weakness is typically
asymmetric and may cause weakness of one limb, although in more severe cases,
patients can develop quadriplegia and acute neuromuscular respiratory failure.
As compared to GBS, patients with West Nile poliomyelitis more often have
fever, absent sensory symptoms, and a pleocytosis along with elevated protein in
the CSF.12
Porphyric neuropathy can also mimic GBS by causing both progressive
weakness and autonomic dysfunction. The acute hepatic porphyrias are most
likely to cause neurologic manifestations and are inherited or acquired disorders
of heme synthesis. Acute intermittent porphyria, an autosomal dominant
condition with low penetrance, is the most common of the acute hepatic
porphyrias. Patients are often healthy young women presenting with fatigue,
abdominal pain, nausea, and subtle neurologic signs that could include
weakness.13 Seizures and psychosis are common. During an acute attack, a
combined sensory and motor neuropathy can develop, and the autonomic
nervous system can be affected as well. Weakness often begins in the proximal
muscles, and the severity is highly variable, ranging from mild sensory
symptoms to involvement of the cranial nerves or progression to
quadriparesis and respiratory failure. The diagnosis can be confirmed by
measuring porphobilinogen in the urine. For additional mimics of GBS,
refer to TABLE 7-2.
Treatment
Although supportive treatment of patients with GBS is critical, particularly in the
setting of acute respiratory failure, both plasma exchange and IV
immunoglobulin (IVIg) have been proven to be effective at reducing the length
of time patients require mechanical ventilation and to lead to faster recovery.14,15
The American Academy of Neurology’s quality measurement set on inpatient
and emergency care for patients with neurologic illnesses aims to improve timely
treatment of patients with GBS and states that patients admitted to an inpatient
facility with GBS who are nonambulatory should be treated with
immunosuppressive therapy using plasma exchange or IVIg and not prescribed
corticosteroids.16 Combination therapy, such as plasma exchange followed by
IVIg, is not more effective than monotherapy.17 In addition, no clear evidence
indicates that a second course of IVIg is helpful, although further study may be
needed. An observational study of 237 patients did not show better outcome with
a second course of IVIg in patients with a predicted poor prognosis; however, the
study was limited by small numbers and by the fact that the patients receiving a
second course were more disabled than those receiving only a single course.18 No
role exists for administration of corticosteroids.
1350 OCTOBER 2021

Intensive Care Unit Management KEY POINTS
Patients with GBS should be managed in the ICU when they have rapidly
● Plasma exchange and IV
progressive weakness, evidence of bulbar weakness, autonomic dysfunction, or immunoglobulin are equally
concern for impending respiratory failure. As many patients with GBS may effective in the treatment of
present to the medical ICU setting, a consulting neurologist can help guide the GBS. No evidence suggests
ICU team through the expected time course of respiratory failure and educate the that the combination of the
two treatments is more
team to anticipate autonomic dysfunction. As discussed later in this article, the
effective than monotherapy.
neurologist may also assist with goals-of-care discussions and help to advise on Steroids are not
the need for early tracheostomy in patients with severe weakness who are not recommended.
expected to regain enough strength to successfully wean from mechanical
ventilation in the short term. The Erasmus GBS Respiratory Insufficiency Score ● The 20/30/40 rule guides
intubation in GBS; forced
(EGRIS) is a tool that calculates the probability that a patient will require vital capacity less than
mechanical ventilation within 1 week of assessment (gbstools.erasmusmc. 20 mL/kg, maximal
nl/prognosis-tool). The main predictors are length of time between onset of inspiratory pressure less
weakness and hospital admission, facial and/or bulbar weakness at hospital than 30 cm H2O, or maximal
expiratory pressure less
admission, and Medical Research Council (MRC) sum score at hospital than 40 cm H2O suggests the
admission.19 If the patient is in clear respiratory failure, they should be need for mechanical
immediately intubated; however, even well-appearing patients should be ventilation.
monitored with objective respiratory measurements, including forced vital
capacity, maximal inspiratory pressure (MIP), and maximal expiratory
pressure (MEP). Alternatively, clinicians can ask patients to count during the
expiration of one full inspiratory effort breath to provide a measurement to
follow, although this value may vary from patient to patient depending on the
speed by which the individual counts. It may be more useful to track trends in
an individual patient. A forced vital capacity less than 20 mL/kg, MIP less than
30 cm H2O, or MEP less than 40 cm H2O should be used as cutoffs to guide
intubation. This is often referred to as the 20/30/40 rule. Although arterial blood
gases may be trended, hypercarbia and hypoxemia are late findings in the
respiratory failure associated with GBS. Patients may also exhibit a paradoxical
breathing pattern in which the abdominal wall moves inward on inspiration.
In typical respiration patterns, the abdomen moves outward on inspiration as
the diaphragm contracts and moves downward, displacing the abdominal
contents outward. When patients have weakness of the diaphragm, the
abdominal muscles may contract on inspiration to assist the expansion of the
chest (FIGURE 7-120). Patients who are not intubated should be carefully
screened for bulbar weakness and should have their ability to swallow assessed
before allowing them to take food or medications orally. Some early predictors of
respiratory failure include a short (<7 days) time course from symptom onset to
admission, inability to cough, inability to stand, inability to lift the elbows or
head, or elevated liver enzymes.21 Patients with these findings should be
monitored in the ICU for the development of respiratory failure.
Patients showing signs of respiratory failure should be intubated rather
than treated with noninvasive ventilation, as the respiratory failure is unlikely
to quickly reverse. Noninvasive ventilation also poses a high risk for aspiration
in those with bulbar weakness. Although the optimal timing of intubation in
GBS remains unclear, it is reasonable to intubate patients early and in a
controlled setting to avoid complications such as anoxic injury from sudden
respiratory or cardiac arrest.22 However, a randomized trial showed no
significant difference in the incidence of pneumonia, length of stay, neurologic
scores, need for tracheostomy, in-hospital death, or any serious adverse

FIGURE 7-1
Graphic illustration of paradoxical breathing pattern. A, Diaphragm at rest. B, Normal
diaphragm movement during inspiration resulting in expansion of the chest and abdomen. C,
Paradoxical breathing pattern (inward abdominal movement during inspiration) because of
diaphragmatic weakness.
Reprinted with permission from Wijdicks EFM, Oxford University Press.20 © 2012 Mayo Foundation for
Medical Education and Research.
events between patients randomly assigned to early intubation compared to

conventional care.23
Because of the prolonged nature of respiratory failure in patients with GBS,
tracheostomy is often necessary. The decision to proceed with tracheostomy in a
patient with severe GBS may occur early, particularly in patients with the AMAN
variant as they have a protracted recovery. Some predictors of prolonged
mechanical ventilation include the inability to lift the arms at 1 week and
evidence of axonal degeneration.24
Autonomic dysfunction associated with GBS often requires close attention in
the ICU. Severe hypertension can lead to cardiac complications and additional
neurologic complications, such as posterior reversible encephalopathy
syndrome (PRES).8 Patients may also develop the syndrome of inappropriate
secretion of antidiuretic hormone (SIADH), likely related to fluctuating
catecholamines.8 Although dysautonomia is common, clinicians should continue
to monitor for alternative causes of symptoms, such as fever, hypotension, and
hypertension, as secondary infection, pain, and other causes can all occur in
patients in the ICU. Clinicians should avoid long-acting blood pressure
medications and rapid fluctuations in blood pressure in patients with
dysautonomia.
Given the prolonged nature of severe GBS with respiratory failure,
high-level ICU care, including frequent turning and repositioning to prevent
skin breakdown, chemoprophylaxis for deep vein thrombosis, sequential
compression devices, adequate nutrition, stress ulcer prophylaxis, and early
mobilization with physical therapy are crucial. Patients with GBS have a 3% to
7% risk of pulmonary embolism, and prophylaxis against deep vein
1352 OCTOBER 2021

thrombosis is key to preventing this complication. The Neurocritical Care KEY POINTS
Society suggests combining pharmacologic and mechanical venous
● Patients with GBS have
thromboembolism prophylaxis in patients with neuromuscular disease and preserved consciousness
continuing venous thromboembolism prophylaxis until the ability to and should be assessed and
ambulate returns.25 For patients with prolonged immobilization, hand splints treated for pain, anxiety,
and pressure relief ankle-foot orthotics may be used to prevent contractures. and depression.
Ileus is the most common manifestation of dysautonomia8; patients should be
● Most survivors of GBS will
prophylactically treated with a bowel regimen, and their abdominal regain the ability to walk,
examination should be monitored closely. It should be emphasized that although recovery can take
patients with GBS have preserved consciousness despite their inability to more than a year.
respond to commands because of profound weakness. Appropriate pain
management for procedures should always be implemented, and patients
should be spoken to and updated regarding their condition. Most patients with
GBS do recover, and this should be emphasized to them. Antidepressant
medications may be appropriate, and, as patients are able to communicate,
they should be screened for depression as well as pain.
Prognosis
More than 80% of patients with GBS will recover to the point of regaining the
ability to ambulate at 6 months.7 Patients with axonal involvement,
dysautonomia, and respiratory failure requiring mechanical ventilation are
more likely to have a poor outcome. The rate of mortality in GBS has been
described in the range of 2% to 12%, most often from pulmonary
complications or autonomic dysfunction in the acute phase of the illness4;
however, as ICU care has improved, mortality has decreased. Recent studies
have described a mortality rate of 6% in patients with dysautonomia
compared to a 2% mortality overall,8 although an older study found a
mortality rate as high as 20% in patients requiring mechanical ventilation.26
Of the survivors, nearly 80% of patients requiring mechanical ventilation
went on to walk independently at 1 year. Recovery may be lengthy, with
progress continuing 12 months after the disease onset. Patients requiring
mechanical ventilation are more likely to have a prolonged recovery course.
Because of the significant recovery most patients see, clinicians should
treat GBS aggressively and ensure that all patients receive high-level ICU
care to avoid preventable complications that may increase morbidity
and mortality.
Future Trends
The International Guillain-Barré Syndrome Outcome Study, which was started
in 2012, should provide a valuable data set to help to further characterize
epidemiology, antecedent events, and long-term outcomes in GBS.27 As new
infections emerge across the globe, additional triggers of GBS may be identified
that require further investigation. Recent descriptions of GBS occurring after
infection with SARS-CoV-2 and the Zika virus indicate that the incidence of cases
could vary as new infection patterns emerge.28
MYASTHENIA GRAVIS
MG is an autoimmune disorder affecting the postsynaptic membrane of the
neuromuscular junction. Patients may present with fluctuating weakness of the
ocular, bulbar, limb, and respiratory muscles. In more severe cases, respiratory

function can be compromised because of weakness of either the muscles of

respiration or the bulbar muscles that work to protect the airway.
Pathophysiology
In MG, autoantibodies bind to the acetylcholine receptor (AChR) or related
proteins, which leads to weakness of skeletal muscles. Antibodies most
commonly bind directly to the AChR, although variants of MG exist in which
antibodies to muscle-specific tyrosine kinase (MuSK) or lipoprotein
receptor-related protein 4 (LRP4) are found.29 Treatment of MG is directed at
improving the availability of acetylcholine at the synapse through the use of
acetylcholinesterase inhibitors and immunosuppressive drug therapy.
MG can occur at any age; however, it appears to have a bimodal distribution.29
The age of 50 years is used as a cutoff to describe early-onset MG as compared to
late-onset MG. Early-onset MG is more likely to affect women, whereas
late-onset MG is slightly more common in men. Patients with early-onset MG are
more likely to have thymic hyperplasia, and many patients have additional
autoimmune conditions, including thyroiditis, systemic lupus erythematosus, or
rheumatoid arthritis. One-third of patients with a thymoma will develop MG. In
addition, an association exists between MG and neuromyelitis optica (NMO) as
well as between MG and amyotrophic lateral sclerosis.29
Diagnosis
For patients without a prior diagnosis of MG, a careful history may increase
suspicion for the disease. Significant delays often occur in the diagnosis of MG.
One study reported that although 57% of patients were diagnosed within 1 year of
onset of symptoms, 13% of patients had a delay of greater than 5 years.30 A detailed
neurologic examination often reveals some degree of ocular or facial weakness.
In this setting, confirmation of the diagnosis with additional testing should be
pursued. Immunologic testing for AChR, MuSK, and LRP4 should be obtained.
Of patients with MG, 10% to 15% will be antibody negative. The ice pack test can
be performed at the bedside in patients with ptosis. In this test, after ptosis is
observed, an ice pack is laid on the closed lid for 2 minutes. The patient is
reexamined immediately after removal to assess for improvement in the ptosis.
Improvement suggests a disorder of neuromuscular transmission, as the activity
of acetylcholinesterases is decreased at lower temperatures. Electrodiagnostic
testing can also aid in diagnosis. The presence of decremental responses on
repetitive nerve stimulation can provide physiologic support for the diagnosis
when moderate or greater generalized weakness is present (FIGURE 7-2). Single-
fiber EMG is more sensitive than repetitive nerve stimulation but is less specific
(can be abnormal in disorders such as botulism, amyotrophic lateral sclerosis,
and rapidly progressive polyneuropathies). It is a technically challenging
procedure and is rarely achievable in the critical care setting.
All patients with newly diagnosed MG should undergo CT examination of the
chest. MG has a strong association with thymoma, and this should be treated with
thymectomy. Guidelines for the indications for elective thymectomy in MG have
been published.31,32
The biggest threat to patients with MG is the development of a life-threatening
crisis that compromises respiratory function because of weakness of the muscles
of respiration or the bulbar muscles. A 2016 consensus statement defined the
terms impending myasthenic crisis and manifest myasthenic crisis.33 Impending
1354 OCTOBER 2021

KEY POINTS
● Myasthenia gravis is an
autoimmune disorder with
antibodies targeting the
postsynaptic membrane of
the neuromuscular junction,
including the acetylcholine
receptor, muscle-specific
tyrosine kinase, and
lipoprotein receptor-
related protein 4.
● Twenty percent of
patients present in
FIGURE 7-2
myasthenic crisis as the first
Repetitive nerve stimulation of the spinal accessory nerve in a patient with myasthenia gravis.
manifestation of their
This nerve conduction study shows a decremental compound muscle action potential
disease.
(CMAP) response of greater than 10% of the trapezius muscle while stimulating the spinal
accessory nerve on repetitive stimulation at 3 Hz, consistent with a disorder of
neuromuscular transmission such as myasthenia gravis. ● Myasthenic crisis can be
Figure courtesy of Ryan Jacobson, MD. triggered by infection;
medications such
aminoglycosides,
fluoroquinolones, and
beta-blockers; and surgery.
myasthenic crisis is defined as “rapid clinical worsening that, in the opinion of
the treating physician, could lead to crisis in the short term (days to weeks).”33 ● Immune checkpoint
Manifest myasthenic crisis is defined as “worsening of myasthenic weakness inhibitors may induce an
requiring intubation or noninvasive ventilation to avoid intubation, except when immune-related myasthenia
gravis in patients without a
these measures are employed during routine postoperative management.”33 Both history of myasthenia gravis.
conditions should be treated in the inpatient setting, typically in the ICU.
Presentation
Most patients who present with myasthenic crisis have a known diagnosis of MG,
although up to 20% of patients will present to medical attention for the first time
in crisis (CASE 7-2).34,35 Patients with a known diagnosis of MG may give a history
of worsening systemic and/or bulbar weakness, although, rarely, respiratory
failure can be the only symptom. Because of generalized weakness, patients may
not manifest typical signs of respiratory distress, including use of accessory
muscles. Of concern, the clinical picture can also be muddled by the escalation of
dosing of anticholinesterase medications, which may precipitate a cholinergic
crisis, with increased salivation, gastrointestinal symptoms, and, ultimately,
worsening muscle weakness.
Myasthenic crises can be triggered by several factors, including infection,
medications, and surgery. The most common cause is a simultaneous infection,
and a workup should be initiated to exclude an underlying infection in patients
presenting in crisis.36 Numerous medications can worsen weakness in patients
with MG (TABLE 7-3), and a comprehensive list can be found on the website of
the Myasthenia Gravis Foundation of America (myasthenia.org/what-is-mg/
MG-management/cautionary-drugs).37 Aminoglycosides, fluoroquinolones, and
beta-blockers are common offenders. The US Food and Drug Administration
(FDA) has issued boxed warnings against the use of fluoroquinolones and for the
antibiotic telithromycin (no longer available in the United States) in MG. In
addition, reports exist of immune checkpoint inhibitors triggering an
immune-related MG.38 These drugs are used in the treatment of melanoma,

non–small cell lung carcinoma, and other malignancies. They can worsen
symptoms of individuals with existing MG as well as lead to a new diagnosis of
MG in patients who did not previously have the disorder. As soon as a crisis is
identified, medication lists should be reviewed and offending agents should be
discontinued. In addition, patients with a known history of MG who are
receiving cautionary drugs should be monitored closely or switched to an
alternative agent, if possible.
Once concern exists for impending or manifest myasthenic crisis, the patient’s
respiratory status should be monitored closely. As in patients with GBS, forced
vital capacity, MIP, and MEP should be monitored closely, and it is reasonable to
use the same cutoffs as described earlier to guide intubation, although evidence
for these cutoffs is limited. However, given the fluctuating nature of the
weakness, clinicians should use caution in relying solely on those parameters to
CASE 7-2 A 54-year-old man presented to the emergency department with fever,
shortness of breath, and poor appetite. A chest x-ray showed an infiltrate
in the left lower lobe consistent with pneumonia, and the patient was
started on levofloxacin. He developed worsening respiratory failure and
was intubated and admitted to the medical intensive care unit. Despite
treatment of the pneumonia, the patient was unable to pass his
spontaneous breathing trials because of low lung volumes. The internal
medicine resident noted a left ptosis that seemed to vary in severity
throughout the day and consulted the neurology team.
A detailed history from the family revealed that the patient had been
intubated 4 times in the past 2 years in the setting of minor infections,
each time with difficulty weaning from the ventilator. The family reported
that over the past 2 years, the patient appeared fatigued throughout the
day, worse in the evening. They reported that they occasionally noted
ptosis, but it typically resolved within a day. At the bedside, the
neurology resident placed a cold ice pack on the left eye and waited for
2 minutes. After lifting the pack, the patient’s ptosis had resolved.
Repetitive nerve stimulation was performed, showing a decremental
response of greater than 10%, consistent with myasthenia gravis (MG).
Serum antibodies were sent, and the patient was positive for antibodies
against the acetylcholine receptor. He was started on plasma exchange
and steroids, and his antibiotic was changed to ceftriaxone. Ultimately,
he did well and was extubated 10 days later.
COMMENT This case demonstrates the difficulty in making a diagnosis of MG. This
patient had been intubated 4 times in the recent past, but each time the
diagnosis was missed as his symptoms improved with treatment of the
underlying infection. Only when a detailed history and examination was
performed was MG considered in the differential diagnosis. In this case,
the patient’s pulmonary infection in combination with the administration of
a fluoroquinolone triggered a myasthenic crisis.
1356 OCTOBER 2021

guide respiratory management. In addition, prominent bulbar symptoms leading
to inability to manage secretions are an indication for intubation. Noninvasive
ventilation may be used in patients with minimal bulbar symptoms who are able
to manage their secretions. This strategy may prevent intubation, particularly in
those with less severe symptoms.35,39
Treatment
In an exacerbation of myasthenic symptoms, early initiation of rapid short-acting
immunotherapy should occur with either IVIg or plasma exchange. No clear
evidence supports one treatment over the other40; however, several studies have
suggested that plasma exchange may have a more rapid effect, leading to fewer
intubations35 and earlier extubation.41 In a consensus statement, the Myasthenia
Gravis Foundation of America suggests that although the two treatments are
likely equally effective based on available evidence and should be chosen based
on clinical patient characteristics, plasma exchange may be more effective and
has a faster effect.33 This statement is based on consensus expert opinion. Patients
with high risk of a hypercoagulable state or renal failure should avoid IVIg, as
Cautionary Drugs in Myasthenia Gravisa TABLE 7-3
Drugs with US Food and Drug Administration (FDA) boxed warnings for use in myasthenia
gravis
◆ Telithromycin (no longer available in the United States)
◆ Fluoroquinolones (ciprofloxacin, moxifloxacin, levofloxacin)
Drugs to use with caution, if at all, in myasthenia gravis
◆ Botulinum toxin
◆ D-penicillamine
◆ Chloroquine
◆ Hydroxychloroquine
◆ Quinine
◆ Magnesium
◆ Macrolide antibiotics (erythromycin, azithromycin, clarithromycin)
◆ Aminoglycoside antibiotics (gentamicin, neomycin, tobramycin)
◆ Corticosteroidsb
◆ Procainamide
◆ Desferrioxamine
◆ Beta-blockers
◆ Statins
◆ Immune checkpoint inhibitors (pembrolizumab, nivolumab, atezolizumab, avelumab,
durvalumab, ipilimumab)
a
Data from Myasthenia Gravis Foundation of America.37
b
Corticosteroids may cause transient worsening of symptoms in the first 2 weeks but are part of the
standard treatment for myasthenia gravis. Close monitoring should be in place when initiating steroids.

IVIg may precipitate thromboembolic events and can lead to acute kidney injury.
Patients with a history of multiple cardiovascular risk factors have an increased
risk for thromboembolic events, as do those with malignancy, hyperviscosity,
hereditary hypercoagulable states, and prior thromboembolic events. Acute
kidney injury following IVIg is more common in patients with preexisting
chronic kidney disease. Those with high risk for hemodynamic instability, such
as sepsis, recent hemorrhage, or hypotension, should avoid plasma exchange as
the procedure could precipitate further hypotension and may lead to coagulation
factor depletion, increasing the risk of bleeding. The administration of plasma
exchange often requires placement of a central venous catheter, which may
increase the risk of the procedure as well. IVIg is administered peripherally. The
American Academy of Neurology’s quality measurement standards advocate for
the administration of immunosuppressive therapies for patients admitted with
myasthenic crisis, stating that the decision between IVIg and plasma exchange
should be made based on availability, adverse effects, costs, and the patient’s
profile.16
Corticosteroids are an important part of the treatment of a myasthenic
crisis and should be used in most patients. Although high-dose steroids may
precipitate worsening weakness, administering them concurrently or several
days following plasma exchange or IVIg likely counteracts this effect. If a
patient is already intubated, the risks of beginning high-dose steroids are
lessened and they should be started immediately. Prednisone and
prednisolone are considered equally effective, and doses of 60 mg/d to
80 mg/d are recommended. On an outpatient basis, steroids are generally
given on alternate days to minimize side effects, but while patients are in the
ICU, daily administration is preferred. Once out of the crisis, steroids should
be tapered to the lowest effective dose. Consideration for steroid-sparing
immunosuppressant therapy will be needed. If patients in myasthenic crisis
are on baseline anticholinesterase therapy, it should be discontinued once the
patient is placed on mechanical ventilation to avoid complications. Although
no guidelines exist regarding the optimal timing to restart the medication, it is
reasonable to resume anticholinesterase therapy via nasogastric tube once the
patient’s respiratory status is improving and mechanical ventilation is being
weaned for potential extubation.42
As with GBS, high-level supportive ICU care is critical to ensuring good
outcomes, including early physical therapy, frequent turning, and appropriate
prophylaxis for deep vein thrombosis and gastric ulcers.
Prognosis
The mortality among patients with myasthenic crisis is estimated at 5% to 19%.35,43
In one large study of patients requiring mechanical ventilation for a myasthenic
crisis, the primary cause of death was multiorgan failure secondary to sepsis.35 In
this study, an estimated 20% of patients requiring mechanical ventilation still
required ventilatory support at the time of discharge. Risk factors for prolonged
mechanical ventilation include age, comorbidities such as pneumonia, high
disease burden, and late-onset MG.35,41 Higher preintubation CO2 was associated
with disability and death in another study.43 Extubation success can be difficult
to predict because of fluctuating symptoms, and failure can be as high as 40%.39
However, cough strength and MEP greater than 40 cm H2O may help to predict a
good outcome.39 Noninvasive ventilation may be helpful in supporting patients
1358 OCTOBER 2021

with a preserved cough following extubation, although the role of noninvasive KEY POINTS
ventilation is not clearly defined in this patient population.39 Patients who
● Fluctuations in the degree
successfully tolerated noninvasive ventilation early in their course and had of weakness in myasthenia
early-onset MG and thymic hyperplasia were more likely to require less than gravis make respiratory
15 days of mechanical ventilation.35 Of those who survive hospitalization, up to monitoring less helpful in
80% will have a good functional outcome at 12 months.43 predicting intubation.
● Noninvasive ventilation
Future Trends may be helpful in preventing
As the use of immunomodulatory drugs such as immune checkpoint inhibitors intubation in patients with
increases in other fields, it remains to be seen what effect they may have on respiratory failure and
autoimmune diseases, which may be triggered by these medications. preserved cough and bulbar
strength.
Immune-related MG carries a high mortality rate and may be more difficult to
treat than classic MG.44 Future studies should assess whether the treatment for ● Corticosteroids should be
MG caused by immune checkpoint inhibitors should be different than the administered either with or
current protocols used for classic MG. shortly after plasma
exchange or IV
immunoglobulin to prevent
INTENSIVE CARE UNIT–ACQUIRED WEAKNESS worsening of muscle
ICU-acquired weakness is a broad term used to describe weakness in patients weakness in myasthenic
who are critically ill that is not caused by an alternative etiology other than the crisis.
critical illness itself.45 This weakness can frequently manifest as inability to wean
● Intensive care
from the ventilator, may persist for many months after the acute illness has unit–acquired weakness
resolved, and is associated with worse outcomes.46 ICU-acquired weakness is includes the diagnoses of
generally classified into three groups: critical illness polyneuropathy, critical critical illness myopathy,
illness myopathy, and a combination of the two called critical illness critical illness
polyneuropathy, and critical
neuromyopathy. This phenomenon has been described since the early 1900s but illness neuromyopathy.
came into prominence in the 1970s and 1980s.47-49
Pathophysiology
The pathophysiology of ICU-acquired weakness is multifactorial. Sepsis,
prolonged mechanical ventilation, multiorgan failure, systemic inflammatory
response syndrome, hyperglycemia, hyperosmolarity, parenteral nutrition, use
of norepinephrine, elevated lactate, and female sex are all associated with
ICU-acquired weakness.50 The role of steroids in the pathophysiology of
ICU-acquired weakness is uncertain, as data are conflicting.47 Proposed
mechanisms include microcirculatory failure, inactivation of sodium channels, a
catabolic state, mitochondrial dysfunction, oxidative stress, and disuse atrophy.
Critical illness polyneuropathy is an axonal polyneuropathy without
demyelination, possibly secondary to microcirculatory failure of the axon,
although the exact mechanism is unknown.47 Critical illness myopathy is
associated with loss of thick filaments in the muscle along with muscle necrosis.47
The two conditions may coexist, as they share risk factors and likely a common
mechanism.
Presentation
Clinically, ICU-acquired weakness may be difficult to detect and diagnose.
Patients who are critically ill are often heavily sedated, although ICU practices in
recent years have shifted toward a reduction in sedation. ICU-acquired weakness
is often first considered when patients are unable to wean from the ventilator.
Both critical illness myopathy and critical illness polyneuropathy lead to a
symmetric proximal weakness. Tone is decreased, and reflexes are frequently

reduced, although they are more likely to be preserved in critical illness

myopathy. In critical illness polyneuropathy, all cranial nerves are typically
preserved. Critical illness myopathy can occasionally lead to facial weakness but
rarely affects the extraocular muscles. Involvement of the extraocular muscles
should suggest an alternative diagnosis. Serum creatinine kinase is normal in
critical illness polyneuropathy and may be normal or increased in critical illness
myopathy. In both processes, the muscles of respiration can be involved,
particularly the diaphragm. It is difficult to distinguish critical illness
polyneuropathy from critical illness myopathy clinically without the assistance of
electrophysiologic studies. This challenge is enhanced by the frequent
coexistence of the two pathologies.
Diagnosis
When making the diagnosis of ICU-acquired weakness, the clinician must
exclude alternative causes of weakness based on clinical suspicion, including a
central process such as a cervical myelopathy or other neuromuscular disorders
such as MG, GBS, botulism, and vasculitic neuropathy. Electrodiagnostic studies
are helpful in making the diagnosis, but performing them in the inpatient ICU
setting may present logistic challenges. Electrical interference may create
artifacts, and patient conditions such as anasarca, peripheral edema, and
hypothermia can create challenges. In addition, patients with poor mentation
will not be able to participate in the examination, which may limit the
ability to perform a complete evaluation. To limit technical factors, limbs
should be kept warm during the study and unnecessary machines should be
powered off.51
In critical illness polyneuropathy, CMAP and sensory nerve action potential
(SNAP) amplitudes are reduced or absent. In critical illness myopathy, CMAP
waveforms may show reduced amplitude and increased duration. Muscle
biopsy can be performed if uncertainty exists about the diagnosis or if an
alternative myopathy is being considered, with selective loss of thick
filaments and muscle necrosis being consistent with the diagnosis of critical
illness myopathy. The primary benefit of differentiating between critical
illness polyneuropathy and critical illness myopathy is to better prognosticate
the recovery of patients, as discussed below. Patients with critical illness
myopathy have a greater chance of recovery than do patients with critical
illness polyneuropathy.
Treatment
Treatment of ICU-acquired weakness is currently focused on prevention. A
large randomized controlled trial showed that aggressive control of blood
sugar decreased the rate of ICU-acquired weakness,52 although other trials
have shown similar intensive control of blood glucose to result in an increase
in mortality.53 Based on these trials, moderate, rather than intensive, glucose
control is recommended in the ICU. Avoiding early parenteral nutrition,
minimizing sedation, and promoting early mobilization are also strategies
used to prevent the development of ICU-acquired weakness. Early physical
and occupational therapy starting at the time of respiratory failure has been
shown to be beneficial in improving outcomes from decreasing time on
mechanical ventilation to increasing the percentage of patients discharged
directly to home.46 Animal studies suggest that circulating ketones may have a
1360 OCTOBER 2021

protective effect, although further research is required before translating this KEY POINTS
into a clinical strategy.54
● Critical illness
polyneuropathy typically
Prognosis spares the cranial nerves,
The risk of death is higher in patients who are critically ill with ICU-acquired and although critical illness
weakness than in those without ICU-acquired weakness.55 One study of patients myopathy may involve facial
muscles, extraocular
in the ICU receiving more than 7 days of mechanical ventilation reported a
muscles are spared.
doubling of inpatient mortality in patients with ICU-acquired weakness as Involvement of the cranial
compared with patients who were mechanically ventilated for similar amounts of nerves should prompt
time and did not develop weakness.56 In a review of survivors of critical illness assessment for an
alternative cause of
with ICU-acquired weakness, nearly 30% had long-term disability.57 However,
weakness.
all ICU-acquired weakness types are not equal. Several studies have shown a
significantly better prognosis in critical illness myopathy than in critical illness ● Primary treatment
polyneuropathy and critical illness neuromyopathy. More than 80% of patients strategies for intensive care
with critical illness myopathy may experience a complete recovery within 6 to unit–acquired weakness
focus on prevention, with
12 months following their ICU stay.58,59 Although the treatments of critical illness minimization of sedation,
myopathy and critical illness polyneuropathy/critical illness neuromyopathy do avoidance of
not differ, differentiating between the two pathologies may have important hyperglycemia, and use of
prognostic value. early mobilization
strategies.
Future Trends ● Critical illness myopathy

Although the focus of this section is on critical illness myopathy, critical illness carries a significantly better
polyneuropathy, and critical illness neuromyopathy, an additional type of prognosis than critical
illness polyneuropathy, with
ICU-acquired weakness that clinicians should be aware of is peripheral nerve
most patients with critical
injury due to compression or traction of the nerves in the ICU setting. In illness myopathy seeing a
particular, the use of the prone position for patients with acute respiratory complete recovery.
distress syndrome (ARDS) can lead to acquired peripheral nerve injury,
particularly of the brachial plexus.60 As proning has become one of the mainstays
of treatment for COVID-19, neurologists should be aware of this condition and
work toward preventive methods in the positioning of patients in the ICU. One
study of patients with injuries following hospitalization for COVID-19 showed
injuries to the ulnar nerve, radial nerve, sciatic nerve, brachial plexus, and
median nerve.61 Although proning is likely a contributing factor to these
neuropathies, further studies will need to continue to determine whether other
factors contribute to the nerve injuries seen after this disease, including direct
inflammation from the virus, vascular involvement, or demyelination. In
addition, femoral neuropathy has been described as a complication following
extracorporeal membrane oxygenation (ECMO) and may become more
prevalent as patients are treated with ECMO for COVID-19.62
Chronic Neurologic Conditions

Patients with chronic progressive neuromuscular disorders may have weakness
that becomes unmasked during a hospitalization for another reason, leading to
neuromuscular respiratory failure. These patients require a thorough workup
with consideration for more chronic conditions. They often come to the attention
of neurologists late in their course, commonly for failure to wean from the
ventilator. In one study of 85 patients admitted for neuromuscular respiratory
failure, 55% of those patients did not have a known diagnosis of a neuromuscular
condition at the time of admission.1 Of those patients, the majority were
diagnosed with a neurologic condition. Final diagnoses included amyotrophic

lateral sclerosis, CIDP, postpolio syndrome, Kennedy disease, botulism,

amyloidosis, myopathy, myasthenia, and GBS. Other conditions such as
myotonic dystrophy, muscular dystrophy, multiple sclerosis, and mitochondrial
disease may also be considered. Keeping chronic neurologic conditions in the
differential when working up neuromuscular respiratory failure is important to
ensure accurate diagnosis and prognosis.
CONCLUSION
Neuromuscular diseases frequently lead to respiratory failure in the ICU, and
prompt and accurate recognition of distinct conditions such as GBS and MG can
lead to early targeted treatment and improved outcomes. Patients with GBS can
go on to have significant recovery if they can avoid the complications associated
with the respiratory failure and severe dysautonomia that often accompany the
disease. Patients with MG may be able to avoid intubation with the use of
noninvasive ventilation, and rapid initiation of therapy with plasma exchange or
IVIg along with steroids improves outcomes. Much is still to be learned about the
treatment of ICU-acquired weakness; however, awareness of the disease and a
focus on prevention is important until further treatment options can be elicited.
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1364 OCTOBER 2021

Acute Neurologic REVIEW ARTICLE
Manifestations of

CONTINUUM AUDIO
INTERVIEW AVAILABLE
Respiratory Viruses
ONLINE
By Michael A. Pizzi, DO, PhD
ABSTRACT
PURPOSE OF REVIEW: Understanding the pathophysiology of COVID-19 and the
severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus that
causes the disease has demonstrated the complexity of acute respiratory
viruses that can cause neurologic manifestations. This article describes the
most common respiratory viruses that have neurologic manifestations,
with a focus on SARS-CoV-2 and COVID-19.
RECENT FINDINGS:In vitro and in vivo studies have better elucidated the
neurotropism of various respiratory viruses. Understanding host cell
receptors that mediate viral binding and entry not only demonstrates how
viruses enter host cells but also provides possible mechanisms for
therapeutic interventions. Elucidation of SARS-CoV-2 binding and fusion
with host cells expressing the angiotensin-converting enzyme 2 (ACE2)
receptor may also provide greater insights into its systemic and neurologic
sequelae. Respiratory virus neurotropism and collateral injury due to
concurrent inflammatory cascades result in various neurologic
pathologies, including Guillain-Barré syndrome, encephalopathy,
encephalitis, ischemic stroke, intracerebral hemorrhage, and seizures.
SUMMARY: Numerous respiratory viruses can infect the cells of the peripheral
and central nervous systems, elicit inflammatory cascades, and directly and
CITE AS:
indirectly cause various neurologic manifestations. Patients with neurologic CONTINUUM (MINNEAP MINN)
manifestations from respiratory viruses are often critically ill and require 2021;27(5, NEUROCRITICAL CARE):
mechanical ventilation. Neurologists and neurointensivists should be 1365–1381.
familiar with the common neurologic manifestations of respiratory viruses

and the unique and still-evolving sequelae associated with COVID-19. Dr Michael A. Pizzi, University
of Florida, PO Box 100236,
Gainesville, FL 32610, michael.
pizzi@neurology.ufl.edu.
INTRODUCTION
N
umerous viruses demonstrate neurotropism for the peripheral RELATIONSHIP DISCLOSURE:
Dr Pizzi reports no disclosure.
nervous system (PNS) or the central nervous system (CNS), or
both. Viruses often initially infect the epithelial cells of the UNLABELED USE OF
respiratory or gastrointestinal tract, which are innervated by
USE DISCLOSURE:
sensory and motor neurons of the peripheral nervous system. The Dr Pizzi reports no disclosure.
most common viruses that infect sensory neurons are herpes simplex virus and
varicella-zoster virus, whereas rabies virus and poliovirus infect motor neurons. © 2021 American Academy
Other viruses, in particular respiratory viruses, can infect the PNS and CNS by of Neurology.

NEUROLOGIC MANIFESTATIONS OF RESPIRATORY VIRUSES
overlapping processes. The most common respiratory viruses that affect the PNS
and CNS are enteroviruses, human respiratory syncytial virus, influenza viruses,
human metapneumovirus, and coronaviruses. Less common but increasing
because of intentionally unvaccinated children are measles and mumps. This
article discusses the pathophysiology of respiratory viruses affecting the PNS and
CNS and the neurologic manifestations of respiratory viruses, with special focus
on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the
neurologic sequelae of COVID-19. TABLE 8-11-10 lists the respiratory viruses
discussed in this article and their most common neurologic manifestations.
VIRAL INFECTION AND PROPAGATION IN THE NERVOUS SYSTEM

Entry of viruses into the nervous system can occur by direct infection of peripheral
nerves or by crossing the blood-brain barrier by various mechanisms. Virions
(extracellular individual virus particles) can gain access into peripheral neurons by
direct fusion or through endocytosis.11 After viral replication in the cell body, spread
of the progeny viruses can undergo both anterograde and retrograde transport.12
Access of virions to the CNS can occur by various processes: retrograde
transport of viruses in peripheral neurons, anterograde transport of viruses in
olfactory neurons, hematogenous spread and infection of CNS endothelial cells,
infection of leukocytes, or macrophages subsequently undergoing transcellular
or paracellular transport across the intact or permeable blood-brain barrier.13
Viral infection of epithelial cells of the respiratory and gastrointestinal tracts
can subsequently release virion progeny into the extracellular space. Neurons
from the trigeminal, facial, glossopharyngeal, vagus, and hypoglossal cranial
nerves innervate these mucosal tissues and provide a direct connection to the
CNS.14 Anterograde transport of viruses by the olfactory nerve is thought to be
the mechanism associated with early symptoms of hyposmia and hypogeusia,
often associated with SARS-CoV-2 infection.6
Virions can infect immune cells and use a “Trojan horse” mechanism utilizing
diapedesis of these cells from the intravascular space across the blood-brain
barrier into the CNS.15 Hematogenous spread/viremia results in direct infection
of epithelial and endothelial cells as well as infection of immune cells. For
example, SARS-CoV (SARS, the coronavirus that causes severe acute respiratory
TABLE 8-1 Common Neurologic Manifestations of Acute Respiratory Viruses
Respiratory viruses Neurologic manifestations
Enterovirus (D68 and A71)1,2 Acute flaccid paralysis, encephalitis, meningitis

3
Respiratory syncytial virus Central apnea, encephalopathy, encephalitis, seizures/status epilepticus
Influenza4 Acute necrotizing encephalitis, Guillain-Barré syndrome, postencephalitic parkinsonism, Reye

syndrome, febrile seizures/seizures
Human metapneumovirus5 Encephalopathy, seizures

6-9
Coronavirus (SARS-CoV-2) Acute necrotizing encephalitis, encephalopathy, encephalitis, Guillain-Barré syndrome,
ischemic stroke, intracerebral hemorrhage, seizures
Measles10 Ataxia, encephalopathy, motor and sensory deficits, progressive dementia, seizures/status
epilepticus
1366 OCTOBER 2021

syndrome) virions infect tracheal and bronchiolar epithelial cells and alveolar KEY POINTS
pneumocytes.16
● Access of virions to the
The blood-brain barrier restricts molecules in the vasculature from crossing into central nervous system can
the brain interstitial fluid. The normally highly selective blood-brain barrier is occur by various processes:
essential for maintaining ionic and fluid homeostasis.17,18 This represents a retrograde transport of
significant interface between the intravascular space and brain parenchymal tissue, viruses in peripheral
neurons, anterograde
since the human brain has approximately 400 miles of cerebral capillaries and
transport of viruses in
approximately the same number of endothelial cells as neurons.19 The blood-brain olfactory neurons,
barrier is composed of endothelial cells joined by tight junction proteins (occludins hematogenous spread and
and claudin), astrocytes, pericytes, and basement membrane.20 The basement infection of central nervous
system endothelial cells,
membrane on the basal surface of endothelial cells is composed of various proteins,
infection of leukocytes, or
including laminin, collagen type IV, and heparan sulfate proteoglycans.21 Projecting macrophages subsequently
into the vessel lumen from endothelial cells is the endothelial glycocalyx, which also undergoing transcellular or
contributes to the blood-brain barrier by regulating water and macromolecular paracellular transport
transport.22 The main constituents of the endothelial glycocalyx are heparan sulfate across the intact or
permeable blood-brain
proteoglycans (glypicans and syndecans) and hyaluronic acid. Direct infection of barrier.
endothelial cells by West Nile virus produces increased production of a heparanase
capable of degrading heparan sulfate proteoglycans of the endothelial glycocalyx, ● The blood-brain barrier is
contributing to the permeability of the blood-brain barrier.23 composed of endothelial
cells joined by tight junction
proteins, astrocytes,
ENTEROVIRUSES pericytes, and basement
Human enteroviruses are single-stranded RNA viruses comprising 80 different membrane.
genotypes that belong to the family Picornaviridae and can cause various
● The most prevalent
neurologic pathologies.1 The most common neurologic sequelae of enteroviruses
respiratory enterovirus
are acute flaccid paralysis, encephalitis, and meningitis.2 The Centers for Disease genotypes associated with
Control and Prevention (CDC) definition of acute flaccid paralysis/acute flaccid neurologic manifestations
myelitis requires acute focal limb weakness and predominantly lesions of the are D68 and A71.
gray matter that span one or more spinal cord segments on MRI.24 Patients often
● Early administration of IV
present with rapid onset (over 2 to 4 days) of asymmetric limb weakness and immunoglobulin may reduce
pain in the weak limb, with sensory abnormalities of paresthesia and numbness the risk of autonomic
in up to 45% of cases.25 Hyporeflexia or areflexia occur in up to 81% to 88% of dysregulation associated
patients with acute flaccid paralysis/acute flaccid myelitis.25-27 The most prevalent with enterovirus A71
brainstem encephalitis.
respiratory enterovirus genotypes associated with neurologic manifestations are
D68 and A71.28 Upper extremity weakness is commonly associated with D68,
whereas A71 is more often associated with lower extremity weakness.25,28 In one
recent article, a neurologist described her 4-year-old son’s rapid progression from
viral prodrome to neck and upper extremity weakness to intubation associated with
acute flaccid myelitis.29 The neurologist also detailed some of the chronic sequelae of
enterovirus/acute flaccid myelitis, such as hypertension, pain syndromes, spasticity,
and osteoporosis of paretic limbs, requiring multiyear rehabilitation.
Enterovirus genotypes most commonly associated with encephalitis are A71,
echovirus 18, and echovirus 30, whereas in meningitis the most common
genotypes are echoviruses 6, 13, and 30.2 Histologic and polymerase chain
reaction (PCR) analysis of brain and spinal cord samples from fatal cases suggest
A71 neuroinvasion by retrograde axonal transport.30
Treatment of acute flaccid paralysis/acute flaccid myelitis is supportive. No
clinical benefit was observed when high-dose IV steroids, plasma exchange, or IV
immunoglobulin (IVIg) were used in association with the D68 outbreak in
2014.26 Early administration of IVIg may reduce the risk of autonomic
dysregulation associated with A71 brainstem encephalitis.31

HUMAN RESPIRATORY SYNCYTIAL VIRUS

Human respiratory syncytial virus is a single-stranded RNA virus of the
Paramyxoviridae family. In vitro and in vivo rodent models have demonstrated
that respiratory syncytial virus directly infects sensory neurons innervating the
lung.32-34 In addition to direct neuronal infection by respiratory syncytial virus,
the virus can infect the CNS through hematogenous spread by activating
immune cells35 and possibly by binding to endothelial cells.36
Neurologic manifestations of respiratory syncytial virus infection occur in
approximately 2% cases and include ataxia, central apnea, encephalitis,
encephalopathy, and seizures/status epilepticus.3 Central sleep apnea was present
in 21% of pediatric patients with respiratory syncytial virus infection admitted to a
single hospital, where age younger than 2 months was the most significant risk
factor for apneic events.37 Increased inflammatory cytokines IL-6, IL-8, interferon
gamma, monocyte chemoattractant protein, and tumor necrosis factor-α (TNF-α)
in the CSF have been associated with seizures in patients with respiratory syncytial
virus.38 Mice and rats infected with respiratory syncytial virus were positive for
respiratory syncytial virus RNA and proteins in the brainstem, hippocampus, and
ventromedial hypothalamus and demonstrated cognitive impairment 1 month
after infection as assessed by the Morris water maze and marble-burying assays.39
These data demonstrate that respiratory syncytial virus is present in the
mammalian brain and may affect cognition. The effect of respiratory syncytial
virus infection on cognitive and functional outcomes is currently being
investigated among the CARES (China Ageing REspiratory infections Study)
cohort of patients with laboratory-confirmed respiratory syncytial virus.40
INFLUENZA VIRUS
Influenza viruses are single-stranded RNA viruses of the Orthomyxoviridae
family. Influenza types A, B, and C infect humans, with type A often causing
more severe symptoms. Influenza A subtypes are further characterized based on
the surface proteins expressed, with 16 different hemagglutinin and nine
different neuraminidase subtypes.4 The hemagglutinin proteins appear to play a
role in neurotropism and viral replication of influenza A in the CNS.41,42
Neurologic manifestations of influenza virus include acute necrotizing
encephalitis, Guillain-Barré syndrome (GBS), mutism, postencephalitic
parkinsonism, Reye syndrome, febrile seizures, and seizures.43 Acute necrotizing
encephalitis is the most severe neurologic manifestation of influenza infection.
First described in pediatric patients with encephalitis and influenza in 1995,44
subsequent cases of adults with acute necrotizing encephalitis have been
reported.45 Patients with acute necrotizing encephalitis often present with
rapidly progressive encephalopathy, with imaging frequently showing bilateral
thalamic, caudate head, and putamen hyperintensities on MRI.46 Hyperintense
regions on MRI also frequently have hemorrhagic components seen on gradient
recalled echo (GRE) or susceptibility-weighted imaging (SWI) sequences.
Analysis of CSF typically does not have a pleocytosis and often has a normal
glucose and occasionally elevated protein with elevated opening pressure.
Elevated transaminases, hyperammonemia, and thrombocytopenia may occur in
patients with acute necrotizing encephalitis. Pathology samples of fatal cases of
acute necrotizing encephalitis demonstrate findings of diffuse cerebral edema
and areas of focal necrosis, which correlate with MRI findings in patients who
had undergone imaging before death.47 Cerebrovascular pathology shows
1368 OCTOBER 2021

perivascular inflammation but no occlusion of vessels. Empiric treatment with KEY POINTS
steroids, IVIg, plasma exchange, and anti-influenza medications have not
● Neurologic
resulted in decreased mortality (approximately 20% to 40% of cases)48 or manifestations of human
mitigation of the neurologic sequelae of acute necrotizing encephalitis.42 respiratory syncytial virus
GBS is a monophasic demyelinating polyradiculoneuropathy manifesting as infection occur in
cranial nerve deficits and flaccid quadriparesis that has occurred during (less approximately 2% cases and
include ataxia, central
frequently) and after (more frequently) resolution of influenza infection. Data
apnea, encephalitis,
from the United Kingdom General Practice Research Database between 1991 and encephalopathy, and
2001 demonstrated an 18-fold increased risk of GBS within 2 months of an seizures/status epilepticus.
influenzalike illness.49 In a single-center retrospective study between 1996 and
2004, 13.7% of patients with GBS had serologic evidence of influenza A and 5.5% ● Influenza types A, B, and
C infect humans, with type A
had serologic evidence of influenza B.50 Influenza vaccination has been associated often causing more severe
with increased risk of GBS compared to nonvaccinated individuals. According to symptoms.
CDC data from 1990 to 2009, the incidence of GBS was 0.46 cases per million
influenza vaccinations, with peak occurrence 2 weeks after vaccination.51 ● Neurologic
manifestations of influenza
In 1917, the neurologist Constantin von Economo described a constellation of virus include acute
symptoms consisting of confusion, lethargy, high fever, ophthalmoplegia, and necrotizing encephalitis,
somnolence as encephalitis lethargica. Approximately one-third to one-half of the Guillain-Barré syndrome,
patients he studied developed parkinsonian features such as resting tremor, mutism, postencephalitic
parkinsonism, Reye
bradykinesia, and masked facies.52 This postencephalitic parkinsonism differed
syndrome, febrile seizures,
from idiopathic Parkinson disease by presentation at a younger age (<60 years and seizures.
of age) with rapid progression of symptoms and oculogyric crises. Clinical features
of bradykinesia, cogwheel rigidity, and tremor approximately 2 weeks after onset ● According to Centers for
of influenza A infection have been described.53 Furthermore, patients with Disease Control and
Prevention data from 1990 to
postencephalitic parkinsonism do not present with higher cortical dysfunction 2009, the incidence of
such as apraxia and aphasia.54 One hypothesis is that influenza infection may Guillain-Barré syndrome
function as the first hit in the later development of Parkinson disease.55 Pathology was 0.46 cases per million
samples of patients with postencephalitic parkinsonism show degeneration of influenza vaccinations, with
peak occurrence 2 weeks
the substantia nigra, with lymphocytes and plasma cells around blood vessels after vaccination.
most frequently located in the brainstem.56 The exact pathophysiology of
postencephalitic parkinsonism has not been clearly defined but may be associated ● The typical Reye
with inflammatory injury to midbrain and brainstem structures based on the syndrome symptoms of
vomiting, encephalopathy,
occurrence of postencephalitic parkinsonism associated with herpes simplex virus,
and seizures occur 3 to
cytomegalovirus, Epstein-Barr virus, varicella-zoster virus, measles, coxsackie virus, 5 days after influenza
human immunodeficiency virus (HIV), and West Nile virus.57 infection.
Reye syndrome was initially described in 21 children after fatal influenza B
infection. These patients had encephalopathy and were found to have fatty
degeneration of the liver. The occurrence of Reye syndrome is approximately
tenfold greater with influenza B than with influenza A infections.58 Typical
symptoms of vomiting, encephalopathy, and seizures occur 3 to 5 days after
infection. Hyperammonemia due to liver failure plays a role in cerebral edema,
encephalopathy, and possibly lowering the seizure threshold.59 In a cohort of 12
pediatric patients with Reye syndrome, mean serum ammonia concentration
was 147 μmol/L in survivors (n = 5) and 396 μmol/L in those who died (n = 7).60
The concentration of ammonia in the brain of patients with Reye syndrome may
be up to 3 times higher than the serum concentration.61 The mechanism by
which influenza causes Reye syndrome and why Reye syndrome occurs as the
patient is recovering from influenza infection are unknown.
In a single-center retrospective study of all hospitalized pediatric patients
positive for H1N1 influenza A during a 4-month winter period, seizures were

present in 71% of patients with neurologic manifestations.62 Febrile seizures are

more common with influenza A infection than with influenza B, parainfluenza,
adenovirus, or respiratory syncytial virus infections.63
HUMAN METAPNEUMOVIRUS
Human metapneumovirus, discovered in 2001, is a paramyxovirus in the same
family as respiratory syncytial virus and parainfluenza. The usual clinical
presentation of human metapneumovirus consists of cough, fever, hypoxia, and
wheezing. Children are most commonly affected, but older adult patients
reinfected with human metapneumovirus can have severe symptoms, such as
pneumonitis.64 The most common neurologic manifestations are seizures and
encephalopathy.5,65 A multicenter retrospective study using the California
Encephalitis Project database identified samples from 63 patients positive for
human metapneumovirus out of a registry of 1474 specimens. Four out of the
63 patients with human metapneumovirus (6.3%) had seizures compared to 0.7%
of patients who were positive for respiratory syncytial virus.66 Status epilepticus
due to human metapneumovirus has also been reported in 15-month-old and
18-month-old toddlers.67 Postmortem analysis of a 14-month-old patient with
encephalitis showed human metapneumovirus RNA present in lung and brain
samples, which indicates that human metapneumovirus likely has neurotropism,
but it is currently unclear how human metapneumovirus gains access to
the CNS.68
MEASLES
Measles infection and its neurologic manifestations have seen a steady
increase since 2004, despite having a vaccine available in the United States
since 1963. The incidence of measles hospitalizations in 2002-2004 was 1.5 per
10 million people, which increased to 4.0 per 10 million people in 2014-2016.69
Part of the rise in measles infections is because of importation of cases as well
as nonvaccination and undervaccination of some children; evidence also exists
of waning immunity in young adults previously vaccinated.10,70 Measles is a
single-stranded RNA virus of the Paramyxoviridae family. After infecting
epithelial cells of the respiratory tract, the virus spreads to the lymph nodes
and infects lymphocytes and monocytes during the viremia phase. During the
viremia phase of infection, measles can infect endothelial cells and gain access
to the CNS across the blood-brain barrier by Trojan horse mechanisms.
Neurologic manifestations of measles usually present as primary measles
encephalitis, acute postinfectious measles encephalomyelitis, measles
inclusion body encephalitis, or subacute sclerosing panencephalitis. Primary
measles encephalitis occurs during active infection and presents with
altered mental status, ataxia, and seizures. Acute postinfectious measles
encephalomyelitis occurs within a week to months after infection, with
sensory and motor deficits being the most common symptoms. CSF is usually
negative for measles-specific antibodies. Measles inclusion body encephalitis
presents with altered mental status, motor deficits, and refractory seizures.
Pathology shows inclusion bodies in neurons and glia, with neuronal loss and
inflammation absent. Subacute sclerosing panencephalitis can present
3 to 20 years after measles infection with behavioral problems, myoclonus,
and progressive dementia.10,71 Of note, neurologic complications increase
with the patient’s age and are associated with chronic morbidity.
1370 OCTOBER 2021

CORONAVIRUSES KEY POINTS
Coronaviruses are single-stranded RNA viruses of the Coronaviridae family.72
● The most common
Betacoronaviruses are common pathogens causing respiratory infections in humans, neurologic manifestations of
with recent strains causing more severe manifestations. Middle East respiratory human metapneumovirus
syndrome coronavirus (MERS-CoV), SARS-CoV, and SARS-CoV-2 cause more are seizures and
severe respiratory and extrapulmonary symptoms. SARS-CoV-2 produces respiratory encephalopathy.
symptoms requiring intensive care unit admission in 25.6% of symptomatic cases.73
● Neurologic
The rate of clinical deterioration of patients who are hospitalized with COVID-19 is manifestations of measles
often rapid, ranging from dyspnea to hypoxic respiratory failure requiring intubation usually present as primary
and intensive care unit admission within 1 to 5 days.74 measles encephalitis, acute
Approximately 10% to 20% of unvaccinated patients infected with SARS- postinfectious measles
encephalomyelitis, measles
CoV-2 are admitted to the hospital, of which 20% to 30% will be admitted to the inclusion body encephalitis,
intensive care unit.75 Patients who are critically ill may require noninvasive or subacute sclerosing
respiratory support, such as a nonrebreather mask (without side vents) or high- panencephalitis.
flow nasal cannula. Identifying patients at risk for unsuccessful noninvasive
● The mechanism of
respiratory support has generated various evaluation tools to assist clinicians in coronaviruses infecting host
deciding when to intubate a patient. Two common tools are the HACOR (heart cells involves the virion’s
rate, acidosis, consciousness, oxygenation, and respiratory rate) Scale and ROX spike protein binding to host
(respiratory rate-oxygenation) Index. The HACOR Scale incorporates variables cell surface enzymes as
receptors, such as
such as acidosis, consciousness, heart rate, oxygenation, and respiratory rate
angiotensin-converting
after 1 hour of noninvasive positive pressure ventilation. Intubation when the enzyme 2 in the case of
score is greater than 5 may improve hospital mortality. The ROX Index is the ratio SARS-CoV-2.
of SpO2/FIO2 to respiratory rate in patients on high-flow nasal cannula. Indices
less than 2.85 at 2 hours, less than 3.47 at 6 hours, and less than 3.85 at 12 hours are
associated with high risk of treatment failure and likely require endotracheal
intubation.76 It is essential to be fastidious in donning personal protective
equipment and implement environmental preparation once the decision is made
to intubate. Manual ventilation with a bag valve mask should be avoided to
decrease aerosolization of oral secretions. Neuromuscular blocking medications,
such as relatively long-acting rocuronium (>1.2 mg/kg), should be used to
decrease the risk of patient coughing or gagging during endotracheal intubation
and potentially generating aerosol contamination.76 The majority of patients who
are critically ill with COVID-19 and require mechanical ventilation will develop
acute respiratory distress syndrome (ARDS) and therefore should be placed on a
low tidal volume setting of 4 mL/kg to 8 mL/kg of ideal body weight.75
Coronavirus infection of the CNS has been reported, but it remains uncertain
if there has been direct viral invasion causing CNS disease.77 Postmortem
analysis of brain samples from patients with COVID-19 who did and did not have
neurologic manifestations have demonstrated the presence of SARS-CoV-2 in
the CNS.7 The presence of SARS-CoV-2 RNA in brain tissue has been identified
in some patients despite having negative CSF using reverse transcription PCR.78
The mechanism of coronaviruses infecting host cells involves the virion’s spike
(S) protein binding to host cell surface enzymes as receptors, such as
angiotensin-converting enzyme 2 (ACE2) in the case of SARS-CoV-2. In
sequencing data of various cell types, ACE2 was present on pericytes of the
blood-brain barrier, choroid plexus, and neocortical neurons; however, the
number of neurons labeled was less than 2%.79,80 The S protein of SARS-CoV-2
consists of three S1 subunits for binding to the ACE2 receptor and one S2 subunit
for membrane fusion. Indirect evidence supports possible neuroinvasion via
olfactory neurons based on expression of ACE2 in the nasal mucosa and

hyposmia and hypogeusia as early symptoms in patients with COVID-19;

however, studies using single-cell sequencing of olfactory neurons have not
confirmed expression of ACE2.8,81
Infection of the CNS by SARS-CoV-2 may occur through crossing the
blood-brain barrier either by directly infecting endothelial cells or via a Trojan
horse mechanism by infecting immune cells. Degradation of the blood-brain
barrier with subsequent paracellular transport of infected immune cells is a likely
pathway of infecting the CNS in the context of systemic inflammation in some
patients with COVID-19. One proposed mechanism underpinning the
degradation and permeability of the blood-brain barrier is elevated inflammatory
cytokines (ie, hypercytokinemia or cytokine storm), which occurs in human
coronavirus and influenza infections.80,82 Patients with COVID-19 have elevated
serum cytokines, such as IL-1β, IL-2, IL-6, TNF-α, and interferon gamma.74
Hypercytokinemia in human coronavirus and influenza virus infections are
associated with enzymatic degradation of epithelial and endothelial cells,
basement membranes, and the extracellular matrix of the lung.82,83
Neurologic manifestations in patients with COVID-19 usually occur within the
first 17 days of systemic or respiratory symptoms and are often in proportion to
the severity of illness.84 Approximately 30% of patients who are hospitalized,
45% of patients with severe respiratory illness, and up to 85% of patients with
acute respiratory distress syndrome have neurologic manifestations.8
Hyposmia/anosmia has been reported in 85.6% and hypogeusia/dysgeusia in 88%
of patients with mild to moderate COVID-19.85 However, these symptoms were
much less frequent in a study of 214 patients with COVID-19 from three different
hospitals in Wuhan, China, where 5.1% reported hyposmia and 5.6% reported
hypogeusia.86 Less common neurologic manifestations in patients who are
hospitalized with COVID-19 are acute necrotizing encephalitis, encephalopathy,
encephalitis, GBS, ischemic stroke, intracerebral hemorrhage, and seizures.
Hospitalized COVID-19 patients in the New York metropolitan area demonstrated
13.5% with neurologic manifestations. Encephalopathy was the most common at
6.8%, followed by stroke, seizures, and hypoxic/ischemic injury.87
Acute necrotizing encephalitis in patients with COVID-19 has been reported,
with radiographic findings of medial bilateral thalamic, putaminal, brainstem,
and cerebellar lesions,88-90 which has also been noted in patients with MERS.91
However, another case report of a patient with COVID-19 with acute necrotizing
encephalitis reported no typical MRI findings of bilateral thalamic lesions or
enhancement of lesions after gadolinium contrast.92 Most of the patients in these
case series were noted to be febrile, with altered level of consciousness and gait
abnormalities. Acute necrotizing myelitis of the cervical and thoracic spinal cord
has been reported in a patient positive for SARS-CoV-2; interestingly, the CSF
was negative for SARS-CoV-2 using PCR.93
Encephalopathy in patients with COVID-19 due to neurologic etiologies (such
as encephalitis) has been difficult to distinguish from other systemic etiologies.
As mentioned above, the proportion of neurologic manifestations in patients
with COVID-19 is proportional to disease severity; therefore, many patients with
encephalopathy have concurrent hypercytokinemia, hypoxia, renal
insufficiency, and sepsis. In a cohort of 58 patients with COVID-19 in the
intensive care unit, 69% were diagnosed with encephalopathy.94 In a systematic
review of seven patients with COVID-19 with encephalitis, SARS-CoV-2 was
detected in only one patient; three patients tested negative, and three patients
1372 OCTOBER 2021

were not tested.9 Two other case reports note positive CSF for SARS-CoV-2 in KEY POINTS
patients with COVID-19 with encephalitis.95,96 In a multicenter prospective study
● One proposed
of 4491 COVID-19 patients, 606 had new onset of neurologic manifestations. Of mechanism underpinning
the 606 patients, CSF samples from 18 out of 18 were negative for SARS-CoV-2 the degradation and
by PCR.87 permeability of the
In a review of patients with COVID-19 who developed GBS, the syndrome blood-brain barrier in
COVID-19 is elevated
presented with the typical symptoms of hypoesthesia, paresthesia, and
inflammatory cytokines (ie,
progressive weakness of extremities and bulbar musculature, with an average hypercytokinemia or
onset of neurologic symptoms 8 days after systemic symptoms of fever and cytokine storm), which
cough.9 PCR was negative for SARS-CoV-2 in all 11 CSF samples obtained, and occurs in human coronavirus
and influenza infections.
neurologic improvement occurred in 59% of the reviewed cases. Axonal (in three
patients) and demyelinating (in two patients) forms of GBS were characterized ● Neurologic
in a small case series of five patients with COVID-19.97 In a review of 19 case manifestations in patients
reports (13 males), the median age was 63 years and median onset of neurologic with COVID-19 usually occur
symptoms was 7 days after systemic or respiratory symptoms.84 Among these within the first 17 days of
systemic or respiratory
19 patients, 12 underwent electrophysiologic testing, with 66% demonstrating symptoms and are often in
the demyelinating form and 33% the axonal form of GBS. proportion to the severity of
Various pathophysiologic processes have been hypothesized to contribute to illness. Approximately 30%
acute ischemic stroke in patients with COVID-19, such as systemic inflammation of patients who are
hospitalized, 45% of patients
and hypercytokinemia, degradation of the endothelial glycocalyx exposing platelets with severe respiratory
to prothrombotic factors,98 platelet activation, and stasis.99 Approximately 1% of illness, and up to 85% of
patients hospitalized with COVID-19 had acute ischemic stroke.100,101 In a review patients with acute
of 46 patients with stroke with COVID-19, four (8.7%) had hemorrhagic stroke.9 respiratory distress
syndrome have neurologic
Brain biopsies of two patients with acute ischemic stroke showed thrombotic
manifestations.
microangiopathy and damage to endothelial cells with surrounding degeneration of
neuropil, with absence of arteriolosclerosis and cerebral amyloid angiopathy.102 ● In a review of patients
These pathologic findings are consistent with systemic postmortem pathologic with COVID-19 who
findings of thrombotic microangiopathy in multiple organs.103 developed Guillain-Barré
syndrome, the syndrome
In addition to evidence for arterial thrombotic events in the cerebral vasculature, presented with the typical
cases have been reported of cerebral venous thrombosis that may be due to similar symptoms of hypoesthesia,
mechanisms.104,105 In an analysis of a New York State health care system database paresthesia, and progressive
of all discharged patients, no increased association was seen between ischemic weakness of extremities and
bulbar musculature, with an
stroke and patients with COVID-19; however, patients with COVID-19 with average onset of neurologic
ischemic stroke had a ninefold increase in mortality.106 Another contributing symptoms 8 days after
factor for cerebrovascular thrombotic events in patients with COVID-19 is the systemic symptoms of fever
activation of platelets by SARS-CoV-2. Platelets express ACE2 and transmembrane and cough.
protease, serine 2 (TMPRSS2), facilitating infection by SARS-CoV-2. Infection of
● Approximately 1% of
platelets with SARS-CoV-2 results in increased platelet aggregation, release of patients hospitalized with
coagulation factors, and secretion of inflammatory cytokines IL-1β and TNF-α.107 COVID-19 had acute
Septic emboli may also be a source of stroke in patients with COVID-19. ischemic stroke. In a review
of 46 patients with stroke
Twelve percent of patients with COVID-19 who were critically ill requiring
with COVID-19, four (8.7%)
mechanical ventilation had bacteremia in a single-center retrospective study.108 had hemorrhagic stroke.
However, no postmortem studies have been published to confirm such
a mechanism.
Patients with COVID-19 can present with various coagulopathies. The exact
mechanism(s) causing coagulopathy in COVID-19 has not been fully elucidated.
Patients with a hypercoagulable state often have elevated D-dimer levels
concerning for the presence of a deep vein thrombosis. Cerebral venous
thrombosis is a neurologic emergency that requires prompt diagnosis and
treatment with anticoagulation (CASE 8-1). A case series and review of cerebral

venous thrombosis cases in COVID-19 patients reported 14 cases of cerebral

venous thrombosis.109 The majority of patients had no significant past medical
history, but two of the 14 had a prior history of cancer. The most common
location for cerebral venous thrombosis was the transverse sinus (75%) followed
by the sigmoid sinus (50%). One-third of the patients had involvement of the
deep venous system.
CASE 8-1 A 41-year-old woman presented to the emergency department 10 hours

after the onset of confusion and aphasia, rendering her ineligible for IV
recombinant tissue plasminogen activator (rtPA). No large vessel
occlusion was identified on CT angiogram of the head. Laboratory results
on admission showed positive severe acute respiratory syndrome
coronavirus 2 (SARS-CoV-2) reverse transcriptase polymerase chain
reaction (PCR), white blood cell count of 9950 cells/mm3, platelets
239,000/mm3, and D-dimer 787 ng/mL (normal <500 ng/mL). The
patient’s D-dimer increased during the course of her admission to a peak
level of 2032 ng/mL. Shortly after admission, the patient developed
shortness of breath and decreased consciousness and was emergently
intubated. Noncontrast head CT showed hypodensity of the left basal
ganglia, left thalamus, and left temporal lobe, with intraparenchymal and
intraventricular hemorrhage (FIGURE 8-1A). Ground-glass opacities and
consolidations were noted bilaterally on the chest part of the imaging,
consistent with pneumonia and/or pneumonitis (FIGURE 8-1B). Sagittal
reconstruction of the noncontrast head CT demonstrated hyperdensity
of the left internal cerebral vein and vein of Galen (FIGURE 8-1C). Sagittal
reconstruction of CT venogram showed lack of contrast filling the
internal cerebral veins and vein of Galen (FIGURE 8-1D). A heparin infusion
was started to treat the cerebral venous thromboses. Unfortunately, the
patient eventually lost all brainstem reflexes and died 4 days after
presentation.
COMMENT This case describes a patient with COVID-19 presenting with a not-so-
common neurologic manifestation: cerebral venous thrombosis. Patients
with COVID-19 often present with sentinel neurologic symptoms of
decreased smell and taste. Respiratory symptoms of cough and shortness
of breath along with radiographic imaging concerning for pulmonary
abnormalities should prompt immediate testing for SARS-CoV-2.
Laboratory values concerning for coagulopathy and/or deep vein
thrombosis (such as elevated D-dimer), although not specific to deep
venous thrombosis, should prompt investigation into possible cerebral
venous thrombosis in a patient with bilateral thalamic hypodensities on a
noncontrast head CT.
Modified with permission from Cavalcanti DD, et al, AJNR Am J Neuroradiol.105 © 2020 American
Journal of Neuroradiology.
1374 OCTOBER 2021

Use of corticosteroids for moderate to severe COVID-19 has been reported to
increase the risk of patients developing mucormycosis. Angioinvasion of cerebral
vasculature can result in cavernous or sagittal sinus thrombosis, intracranial
hemorrhage, cerebral infarction, and intracranial aneurysm. A case series from
India of 47 patients with COVID-19 with mucormycosis demonstrated five
patients (11%) with ischemic stroke and two (4%) with cavernous sinus
FIGURE 8-1
Imaging of the patient in CASE 8-1. A, Axial noncontrast head CT shows hypodensity of the left
basal ganglia, thalamus, and frontal and temporal lobes, with intraparenchymal hemorrhage
in the left basal ganglia and thalamus and intraventricular hemorrhage. B, Axial view of chest CT
with IV contrast shows ground-glass opacities suggestive of pneumonitis/pneumonia. C, Sagittal
reconstruction of noncontrast head CT shows hyperdensity of internal cerebral vein (long
arrow) and vein of Galen (short arrow). D, Sagittal reconstruction of CT venogram shows filling
defects of the internal cerebral veins (long arrow) and vein of Galen (short arrow).
Reprinted with permission from Cavalcanti DD, et al, AJNR Am J Neuroradiol.105 © 2020 American Journal of
Neuroradiology.

KEY POINTS thrombosis.110 Clinicians should have a high index of suspicion for
mucormycosis in patients with COVID-19 with a history of diabetes and those
● Platelets express
angiotensin-converting
receiving corticosteroids, with poor glycemic control, and displaying fever with
enzyme 2 and nasal congestion and purulent discharge.
transmembrane protease, Reversible cerebral vasoconstriction syndrome (RCVS) has been reported
serine 2, facilitating in a patient with COVID-19 with no known risk factors.111 A possible
infection by SARS-CoV-2.
mechanism for developing RCVS in patients with COVID-19 could be
Infection of platelets with
SARS-CoV-2 results in increased levels of angiotensin II contributing to cerebral vasoconstriction.112
increased platelet Seizures associated with COVID-19 occurring between 3 and 7 days from
aggregation, release of initial symptom onset have been described.9 In a case series of 100
coagulation factors, and
non-post–cardiac arrest patients with COVID-19 monitored with EEG, 7% were
secretion of inflammatory
cytokines IL-1β and tumor positive for seizures, of which 14.3% were nonconvulsive seizures and 14.3%
necrosis factor-α. were nonconvulsive status epilepticus.113 Of the 7% found to have seizures, 15%
had no prior history of seizures. This case series had an incidence of nonconvulsive
● In a study of patients with seizures/nonconvulsive status epilepticus of 2%, which is much lower than the
cerebral venous thrombosis
associated with COVID-19,
10% to 13% reported in patients with intracerebral hemorrhage, subarachnoid
the most common location hemorrhage, subdural hematoma, traumatic brain injury, and sepsis who were
for cerebral venous monitored with EEG.114 In another case series of patients with COVID-19, five of
thrombosis was the the six patients with seizures had MRI scans of the brain.9 The brain imaging in
transverse sinus (75%)
followed by the sigmoid
these patients did not correlate with the focal onset of electrographic seizures,
sinus (50%). One-third of the and therefore no structural etiology for these patients’ seizures was identified.
patients had involvement of Lymphocytic pleocytosis was noted in the CSF of four of the six patients, and
the deep venous system. SARS-CoV-2 was detected by PCR in the CSF of one of the four patients.
Systemic hypoxia can result in anoxic/hypoxic brain injury, which was
● Seizures have been
described in association described in a series of autopsies from 18 consecutive patients with COVID-19
with COVID-19 occurring positive for SARS-CoV-2.115 All brains were sampled from 10 standard brain
between 3 and 7 days from areas. All of the 18 brains analyzed showed acute hypoxic injury in the cerebellum
initial symptom onset. and cerebral cortex.115
● Systemic hypoxia can
Adverse events of the three US Food and Drug Administration (FDA)–
result in anoxic/hypoxic approved COVID-19 vaccines in the United States are reported to the Vaccine
brain injury, which was Adverse Events Reporting System (VAERS).116 The US Centers for Disease
described in a series of Control and Prevention and the FDA temporarily paused the administration of
autopsies from 18
consecutive patients with
the Ad.26.COV2.S vaccine April 13-23, 2021, because of reports of six cases of
COVID-19 positive for cerebral venous sinus thrombosis.117 On July 13, 2021, the FDA revised the
SARS-CoV-2. Johnson & Johnson (Janssen) vaccine provider fact sheet to include the risk
of GBS after 100 preliminary reports of GBS were reported to VAERS after
patients received the Johnson & Johnson vaccine. Of these 100 reports, 95 were
described as serious and required hospitalization.
Some of these patients developed thrombosis with thrombocytopenia
syndrome, defined as the presence of arterial or venous thrombosis (often
cerebral or abdominal) after COVID-19 vaccination with thrombocytopenia
and positive antiplatelet factor 4 (heparin-induced platelet antibody). This
syndrome is also known as vaccine-induced thrombotic thrombocytopenia.
Initial symptoms typically peak 6 to 14 days after vaccination. Patients
fulfilling the above criteria for thrombosis with thrombocytopenia syndrome
should undergo prompt treatment with IVIg 1 g/kg/d for 2 days with
nonheparin anticoagulation. Current guidelines for the treatment of
thrombosis with thrombocytopenia syndrome can be found at the American
Society of Hematology website (hematology.org/covid-19/vaccine-induced-
immune-thrombotic-thrombocytopenia).118
1376 OCTOBER 2021

CONCLUSION
Various respiratory viruses can gain access to the nervous system by direct
infection of neurons or by breaching the blood-brain barrier. Once viruses have
infected the nervous system, the manifestations are variable depending on
whether peripheral nerves are infected or cells within the CNS are infected.
Neurologic syndromes may also occur in the context of systemic viral infection.
The time from systemic infection by the virus to neurologic symptoms also
varies. Treatment is often supportive and centered on mitigating neurologic
symptoms.
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hospitalized patients with COVID-19 in New York
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Barbella-Aponte RA, et al. Cerebrovascular and COVID-19: an epidemic within a pandemic in
disease in patients with COVID-19: India. Mycoses 2021. doi:10.1111/myc.13353
neuroimaging, histological and clinical
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10.1093/brain/awaa239
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critically ill ICU patients with COVID-19. Thromb
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venous thrombosis associated with COVID-19
113 Pellinen J, Carroll E, Friedman D, et al.
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hematology.org/covid-19/vaccine-induced-
immune-thrombotic-thrombocytopenia

REVIEW ARTICLE
Neurologic Complications
in the Postoperative

INTERVIEW AVAILABLE
Neurosurgery Patient
ONLINE
By Aarti Sarwal, MD, FNCS, FAAN, FCCM, RPNI
ABSTRACT
PURPOSE OF REVIEW: This article discusses neurologic complications
encountered in the postoperative care of neurosurgical patients that are
CITE AS:
common or key to recognize in the immediate postoperative period. The major
2021;27(5, NEUROCRITICAL CARE): neurosurgical subspecialty procedures (cerebrovascular neurosurgery,
1382–1404. neuro-oncology, epilepsy neurosurgery, functional neurosurgery, CSF
diversion, endovascular neurosurgery, and spinal surgery) are broadly
Dr Aarti Sarwal, Neurology, Wake included under craniotomy procedures, endovascular/vascular procedures,
Forest Baptist Medical Center, and spinal procedures. This article focuses on the range of complications
Medical Center Blvd, Winston- inherent in these approaches with specific scenarios addressed as applicable.
Salem, NC 27157,
asarwal@wakehealth.edu.
RECENT FINDINGS: Themorbidity and mortality related to neurosurgical
Dr Sarwal has served as a
procedures remains high, necessitating ongoing research and quality
consultant for Lungpacer improvement efforts in perioperative screening, intraoperative
Medical Inc; has received management, surgical approaches, and postoperative care of these
personal compensation for
speaking engagements for the
patients. Emerging research continues to investigate safer and newer
American Physical Therapy options for routine neurosurgical approaches, such as coiling over clipping
Association, the Neurocritical for amenable aneurysms, endoscopic techniques for transsphenoidal
Care Society, and the Society of
Critical Care Medicine; and has hypophysectomy, and minimally invasive spinal procedures; postoperative
received research/grant support monitoring and care of patients after these procedures continues to be a
from the Clinical Translational
key component in the continuum of care for improving outcomes.
Science Institute (supported by
the National Center for
Advancing Translational SUMMARY: Postoperative care of patients undergoing major neurosurgical
Sciences) and the National
procedures is an integral part of many neurocritical care practices.
(UL1TR001420). Neurosurgeons often enlist help from neurologists to assist with
evaluation, interpretation, and management of complications in routine
UNLABELED USE OF
inpatient settings. Awareness of the common neurologic complications of
USE DISCLOSURE: various neurosurgical procedures can help guide appropriate clinical
Dr Sarwal discusses the monitoring algorithms and quality improvement processes for timely
unlabeled/investigational
use of dexmedetomidine, evaluation and management of these patients.
gabapentinoids, muscle
relaxants, and nerve blocks for
postoperative headaches;
steroids for retraction edema; INTRODUCTION
N
and intraarterial verapamil,
eurosurgical procedures have, in general, a higher morbidity and
nicardipine, and nimodipine for
catheter-induced vasospasm. mortality than many other surgical procedures. A database
maintained by the American College of Surgeons National Surgical
Quality Improvement Program querying elective neurosurgical
of Neurology. procedures from 2006 to 2011 reported the incidence of
1382 OCTOBER 2021

postoperative complications to be as high as 14.3%, with smaller studies reporting KEY POINT
a range of 5% to 15%.1-3 Cranial cases have 2.6 times the rate of complications of
● Patients who have had
spinal cases.1 Among the most common complications are bleeding requiring emergent cranial
transfusion and reoperation within 1 month of initial surgery.1 Common neurosurgical procedures,
neurologic complications include alterations in the level of consciousness, high-risk elective
postoperative seizures, and headaches and other pain syndromes. craniotomies, or multilevel
spinal surgeries, especially
Intensive care monitoring has traditionally been requested during the
those involving the cervical
postoperative period for most patients after neurosurgery, but escalating health spine, and patients with
care utilization costs, limitations in intensive care unit (ICU) capacity, and a significant cardiopulmonary
lower rate of observed complications in selected procedures have ignited comorbidities are typically
admitted for overnight
investigations into the cost-effectiveness of such systematic monitoring.4-7
monitoring in a step-down or
Elective low-risk craniotomies or limited-level spinal surgeries in patients neurocritical care unit for
without significant cardiopulmonary comorbidities can be monitored in the their postoperative care.
postoperative anesthesia unit after extubation before transfer to routine
inpatient settings. The rate of unexpected complications after initial floor
admission requiring subsequent transfer to the ICU in these patients has been
reported to be 1% to 2%.6 Patients who have had emergent cranial neurosurgical
procedures, high-risk elective craniotomies, or multilevel spinal surgeries,
especially those involving the cervical spine, and patients with significant
cardiopulmonary comorbidities are typically admitted for overnight monitoring
in a step-down or neurocritical care unit for their postoperative care. Attempts
have been made to stratify the risk of complications related to specific
procedures to allow appropriate triage of such patients for selective versus
routine admission to a high level of care or neurocritical care monitoring, but a
discrete scalable scoring system has not yet emerged.3,8,9 More research is needed
into developing scores that take into account local resources, demographic health
risk factors, and surgical practices.
This article reviews the major neurosurgical procedures and neurologic
complications that require careful monitoring and evaluation in the postoperative
period. The major neurosurgical procedures are broadly included under craniotomy
procedures, endovascular/vascular procedures, and spinal procedures.
CRANIOTOMY PROCEDURES
Craniotomies can be supratentorial or infratentorial and are most commonly
performed for tumor resection or aneurysm surgery. Supratentorial craniotomies
include pterional craniotomy (for all anterior circulation or basilar tip aneurysms
and resection of suprasellar tumors), temporal craniotomies (usually done for
temporal lobe biopsy or resection of temporal lobe hematomas or tumors),
frontal craniotomies (which provide an approach to frontal tumors and
hematomas and access to the third ventricle), and petrosal craniotomies
(reserved for lesions of the petrous apex and clivus, usually meningiomas and
chordomas). Skull base surgeries involve a pterional craniotomy with extradural
removal of the anterior clinoid; they are the preferred approach for resection of
skull base tumors or for access to cavernous sinus lesions and carotid-ophthalmic
artery aneurysms.
Preoperative Planning
Preoperative screening and advances in neuroanesthesiology, such as
preferential selection of nondepolarizing neuromuscular blockers in patients
with preexisting neurologic deficits and avoidance of inhalational anesthetics

COMPLICATIONS IN THE POSTOPERATIVE NEUROSURGERY PATIENT
with adverse impact on cerebral hypoperfusion, have significantly minimized

anesthesia-related complications. In general, propofol decreases cerebral blood
flow but maintains neurovascular coupling and is the preferred agent for most
surgeries. Inhalational anesthetics have a dose-dependent effect on cerebral
vasodilatation, causing an increase in cerebral blood flow, and may result in
cerebral edema in predisposed patients. Selection of appropriate anesthetics and
intraoperative strategies can minimize their adverse effects. Perioperative
planning also extends to ensuring patients take their antiseizure medications on
the day of surgery and supplying any anticipated missed doses judiciously and
intravenously, if necessary and possible. Awareness of the expected neurologic
deficits in a given neurosurgical procedure and comparison of the patient's
postoperative neurologic examination to the preoperative neurologic status are
important components of the postoperative evaluation of patients. Cerebral
edema, intracranial bleeding, and status epilepticus are commonly recognized
complications of elective and emergent neurosurgical procedures.
Cerebral Edema
Many patients in need of a craniotomy may have underlying cytotoxic or
vasogenic edema related to the intracranial pathology necessitating surgery and
may already be undergoing medical therapy for intracranial hypertension. In
addition, a large craniotomy access exposes the intracranial compartment to
atmospheric pressure for the duration of surgery, which may require further
osmotic therapy to reduce the resulting increase in intracranial pressure before
closure. Surgical approaches that minimize the extent of the craniotomy while
ensuring appropriate access and anesthesia techniques that decrease the adverse
effect of exposure on cerebral hemodynamics have reduced the incidence of
cerebral edema. Patients who have elective craniotomies may receive mannitol
intraoperatively before closure. Focal edema from small craniotomies often
persists, especially around resection tracts or cavities, and may present with
focal motor deficits corresponding to the operated area. Direct brain retraction
itself may be associated with local vasogenic and cytotoxic edema that may
require perioperative steroids. Prolonged retraction of the cingulate gyrus may
produce a state of akinetic mutism that is usually temporary. CASE 9-1 highlights
a patient with cerebral edema resulting from multiple pathologies, with
contribution from underlying tumor, retraction-related edema, and cytotoxic
edema from postoperative stroke. Direct injury affecting cranial nerves may
also occur. Posterior fossa or suboccipital craniectomy may cause fifth or
seventh cranial nerve injuries. Transient motor weakness can be seen, in
particular with tumor resection adjacent to the motor cortex, with some
degree of this coming from cerebral edema and some degree related to the
actual resection. This has been termed the supplementary motor area syndrome
with hemiparesis and neglect; it usually resolves with resolution of edema.
Supportive care and reevaluation in a few days may often elucidate the
underlying permanent deficit versus the transient effects of cerebral edema.
Rarely, global cerebral edema may persist after closure and can manifest with
decreased consciousness. Cerebral edema can progress to cerebral herniation
and should be managed according to current guidelines appropriate to the
underlying cerebral pathology.10
Postoperative neurologic deficits may occur in the first 24 hours after surgery
in up to 37% of patients with craniotomies performed for brain tumor surgeries,
1384 OCTOBER 2021

and the majority of these are related to edema.11 Any unexpected focal deficit or KEY POINTS
impairment of consciousness not explicable by other factors, such as late
● Awareness of the
emergence, sedation, or pain medications, should be evaluated with emergent expected neurologic
neuroimaging. CT continues to be the imaging modality of choice for emergent deficits in a given
evaluation of cerebral edema, but focal edema or noncontributory CT scans may neurosurgical procedure
need follow-up with MRI to elucidate pathology. and comparison of the
patient's postoperative
neurologic examination to
Intracranial Hemorrhage the preoperative neurologic
Intraoperative or postoperative hemorrhage may be extraaxial, intraparenchymal, status are important
or subarachnoid and may occur at the surgical site or in a remote location. components of the
Systemic factors such as coagulopathy and thrombocytopenia are usually postoperative evaluation of
patients.
evaluated and managed perioperatively against the risk-benefit assessment
of neurosurgical procedures. Inadequate hemostasis; vascular injury during ● Surgical approaches that
exposure, retraction, or resection; or bleeding from a highly vascular lesion minimize the extent of the
during manipulation may be responsible for intracranial hemorrhage. The craniotomy while ensuring
effects of inhalational anesthetics such as isoflurane causing increased appropriate access and
anesthesia techniques that
cerebral blood flow and blood pressure surges during surgery have also decrease the adverse effect
been proposed as contributory factors and can be mitigated by optimal of exposure on cerebral
anesthetic management. The increasing use of newer anticoagulation agents, hemodynamics have
inadequate markers of adequate reversal of such agents, and, sometimes, reduced the incidence of
cerebral edema.
unknown use because of lack of medication history in an unresponsive
patient needing an emergent neurosurgical procedure may also contribute ● Any unexpected focal
to the risk of bleeding. The definitive incidence of postoperative hemorrhage deficit or impairment of
on a large scale is difficult to discern because of the variability of surgical consciousness not
explicable by other factors,
details contributing to the risk. The overall incidence of major unexpected
such as late emergence,
bleeding requiring repeat cranial procedures for evacuation continues to be sedation, or pain
low and may be impacted by underreporting in the literature.12,13 CASE 9-2 medications, should be
highlights an example of aneurysm clipping leading to vessel perforation, evaluated with emergent
neuroimaging.
resulting in cerebral hemorrhage and cerebral infarction despite further
intervention. ● Intraoperative or
Remote site hemorrhage may occur because of sudden decompression of postoperative hemorrhage
the intracranial compartment in patients with raised intracranial pressure and may be extraaxial,
can be seen after cranial and, more often, spinal surgeries. This may occur intraparenchymal, or
subarachnoid and may occur
because of accidental excessive CSF drainage, especially in patients with global at the surgical site or in a
cerebral atrophy or sudden compartmental shifts with release of intracranial remote location.
pressure. Such bleeds may be venous or arterial in origin, depending on the
mechanical shifts that trigger them. Both supratentorial and infratentorial bleeds ● Remote site hemorrhage
may occur because of
have been reported. Overall, remote site hemorrhages are ominous and tend to
sudden decompression of
have poor outcomes.14 the intracranial
compartment in patients
Cerebral Infarction with raised intracranial
Postoperative neurologic deficits after nonvascular neurosurgical procedures pressure and can be seen
after cranial and, more
may be related to patients’ underlying risk of prothrombotic events and
often, spinal surgeries.
cessation of antithrombotic agents or anticoagulation preoperatively. These
may occur independent of neurosurgical and anesthetic factors.15 Other
mechanisms of stroke pertinent to neurosurgical procedures include the
following:
u Direct vessel injury to arteries or veins

u Air embolism with right-to-left shunt

u Cauterization-related direct tissue damage

u Coil dislodgement causing arterial occlusion
u Vasospasm from vessel traction or exposure of circle of Willis to cisternal blood
Cerebral infarction can occur because of direct vascular injury, especially if the
surgical site is close to major cerebral veins and venous sinuses or if the lesion is
encasing the vasculature. Arterial strokes related to possible air embolism may
occur in patients with right-to-left shunt during craniotomies done in a sitting
position with the head elevated above the level of the heart. Intraoperative
air embolism can be diagnosed by a fall in end-tidal CO2 seen on monitoring but
CASE 9-1 A 62-year-old woman with no significant past medical history presented
with new-onset speech difficulties and was found to have significant
cerebral edema with suspicion for an underlying brain mass on
noncontrast CT scan. MRI of the brain showed an avidly enhancing mass
in the left middle cranial fossa suggestive of a sphenoid wing meningioma
with extension into the left suprasellar cistern, associated mass effect
and effacement of the left lateral ventricle, rightward midline shift, and
effacement of the left perimesencephalic cistern (FIGURE 9-1). High-dose
dexamethasone was initiated for vasogenic edema.
The patient underwent an uneventful left skull base frontotemporal
craniotomy with extradural clinoidectomy. Her postoperative course was
complicated by generalized
tonic-clonic seizures during
evaluation for extubation.
Initiation of propofol and
levetiracetam resulted in
resolution of seizures with
recovery of consciousness.
Postoperatively, she was
found to have right hemiparesis
but intact comprehension.
Follow-up MRI showed
expected postoperative
changes and a significant
amount of retraction edema
extending to the left cerebral
hemisphere as well as
restricted diffusion changes
concerning for acute left
middle cerebral artery
territory infarct (FIGURE 9-2). FIGURE 9-1
Postoperative vascular Imaging of the patient in CASE 9-1. A, Axial
postcontrast T1-weighted MRI shows enhancing
imaging did not reveal a large sphenoid wing meningioma encasing the left middle
vessel occlusion. Cerebral cerebral artery. B, Postoperative axial postcontrast
edema was presumed to be T1-weighted MRI shows total resection of the tumor.
1386 OCTOBER 2021

may be difficult to distinguish postoperatively from other causes of ischemic
stroke until air is visualized on follow-up neuroimaging.
Aneurysm coiling surgeries are particularly prone to vessel occlusion.
Placement of a clip across the neck of the aneurysm, which disconnects the
aneurysm from the circulation, has been long considered the gold standard
surgery for aneurysm. A clip placed too low can cause large vessel occlusion of
the parent vessel, resulting in acute ischemic stroke. A clip placed distally,
leaving a portion of nonoccluded neck (called aneurysmal rest) can increase the
risk of rebleeding complications. Coil dislodgment can occur despite all
intraoperative precautions.
the combination of cytotoxic

edema from the acute
ischemic stroke and
vasogenic edema from the
meningioma resection and
retraction; this was managed
with osmotic therapy,
and she received high-dose
dexamethasone for
retraction edema. Surgical
decompression with
hemicraniectomy was
considered, but the patient
regained right motor
function and remained
clinically stable on medical
therapy. She was extubated
FIGURE 9-2 to nasal cannula and
Imaging of the patient in CASE 9-1. A, Axial diffusion- eventually discharged to
weighted and apparent diffusion coefficient MRIs acute inpatient rehabilitation;
showing acute left middle cerebral artery ischemic
infarct. B, Axial T2-weighted images showing left she had minimal motor and
hemispheric edema (left image) as well as vasogenic speech deficits 6 months
edema in the tumor resection bed (right image). after discharge.
This case demonstrates several complications. The patient had COMMENT

postoperative seizures after a frontotemporal craniotomy. This patient had a
complex sphenoid meningioma encasing the critical vascular supply of her
left cerebral hemisphere. Surgical manipulation possibly resulted in
vasospasm and cerebral infarction of the left middle cerebral artery territory.
In addition, this patient had both vasogenic edema from the underlying
meningioma and retraction edema.

CASE 9-1 and CASE 9-2 both describe complications of cerebral infarction
occurring because of various mechanisms, one from direct vessel
manipulation and the other due to direct vessel injury from clipping. Venous
infarctions may occur during parietal craniotomy for approach to the third
ventricle for a colloid cyst or thalamic glioma because of sacrifice of a critical
cortical draining vein or superior sagittal sinus thrombosis from retractor
injury, overretraction of the dural sinus flap, or bipolar coagulation–related
injury. In most cases, the superior sagittal sinus tolerates loss in its anterior
one-third without engendering venous infarction. Venous infarction,
however, occurs with a high likelihood after more posterior injuries involving
the superior sagittal sinus.
CASE 9-2 A 43-year-old woman presented with new-onset severe headaches and
was found to have a suprasellar anterior cerebral artery aneurysm on
vascular imaging. Her examination was unremarkable for any focal
neurologic deficits, but further history corroborated by family members
revealed bouts of confusion and several falls. CT angiogram of the head
and neck confirmed an abnormal circle of Willis with an absent A1
segment of the left anterior cerebral artery and a 12.5-mm aneurysm of
the anterior communicating artery with irregular morphology and two
daughter sacs coming out of the aneurysm. A dominant right anterior
cerebral artery bifurcated and supplied both left and right distal anterior
cerebral segments. Her headaches responded to symptomatic
management and were felt unlikely to be related to the aneurysm, but
because of the aneurysmal morphology and her gait changes, the
decision to resect the aneurysm was made.
The patient underwent a right pterional craniotomy for aneurysm
clipping, which was complicated by anterior cerebral artery
thromboembolic occlusion. Attempted endovascular thrombectomy
resulted in anterior cerebral artery perforation. Postoperatively, the
patient did not have any new neurologic deficits. Induced hypertension
was maintained to augment collateralization to feed the bilateral anterior
cerebral artery territory frontal lobes and was gradually weaned to allow
the patient to be normotensive by day 3. Head CT on postoperative day 1
confirmed adequate placement of clips on the anterior communicating
artery aneurysm, right frontal intraparenchymal hemorrhage with
surrounding cerebral edema, right convexity subdural hemorrhage
adjacent to the craniotomy site, left inferior frontal hypodensity
concerning for acute infarct, and bifrontal pneumocephalus (FIGURE 9-3).
Head CT on postoperative day 3 showed a stable right inferior frontal
intracranial hemorrhage, resolving pneumocephalus, and convexity
subdural hemorrhage adjacent to the craniotomy site. A new hypodensity
in the left frontal lobe was seen as suspicious for involving infarct rather
than postoperative edema. The patient had an uneventful postoperative
course and was discharged home with recommendations for fall
precautions and outpatient occupational therapy.
1388 OCTOBER 2021

Vasospasm of the intracranial vessels may also occur because of mechanical
manipulation of vessels and is short-lasting in many instances. Patients who
have significant basal cistern bleeding intraoperatively may get intraoperative
washouts with saline or even thrombolytics to clear and minimize exposure to
blood. Delayed cerebral ischemia may be seen as a delayed complication after
exposure to basal cistern blood from intraoperative subarachnoid hemorrhage
similar to that seen in aneurysmal subarachnoid hemorrhage.16,17 Symptoms
of such vasospasm may range from mild oligemia causing encephalopathy to
florid focal vascular symptoms of large vessel ischemia. Unless a high index of
suspicion is maintained in surgeries involving intraoperative blood loss or
proximity to major cerebral blood vessels, vasospasm of the intracranial
FIGURE 9-3
Imaging of the patient in CASE 9-2. Axial noncontrast head CT at three different levels on
postoperative day 1 (A) and postoperative day 3 (B) show artifact produced by clipping
of the anterior communicating artery aneurysm (A, arrow, left image), right frontal
intraparenchymal hemorrhage with surrounding cerebral edema (A, arrow, middle image),
right convexity subdural hemorrhage adjacent to the craniotomy site (A, arrow, right image),
left inferior frontal hypodensity concerning for acute infarct (B, arrow, left image), and
bifrontal pneumocephalus (A, right image).
This case demonstrates a typical presentation with several classic COMMENT

complications of open and endovascular procedures for aneurysm:
pneumocephalus related to craniotomy, arterial injury resulting in thrombosis
from clipping, arterial perforation related to angiogram, and cerebral
infarction from vascular injury.

vessels may go undetected and present with delayed ischemic neurologic

deficits. Patients who are postoperative with persistent unexplained
encephalopathy and EEG inconsistent with possible ictal etiology should be
assessed for vasospasm.
Seizures
The overall incidence of seizures after elective craniotomies and the
symptomatology of the seizures corresponds to the underlying pathology and
resection territory. A 2020 Cochrane Review on postcraniotomy seizures
reported a 15% to 20% incidence of seizures following supratentorial craniotomy
for nontraumatic pathology, with most seizures occurring within 1 month of
surgery.18,19 Reports using surveillance with continuous EEG report a higher
incidence (up to 30%), attributed to detection of nonconvulsive seizures.20
Cortical irritation caused by surgical manipulation, retraction edema,
intracranial bleeding, ischemic injury related to cautery, and pneumocephalus
are the usual mechanisms of seizures in the perioperative period. Certain surgical
approaches may have a high risk of seizures, for example, the superior temporal
gyrus approach for middle cerebral artery aneurysm clipping or subdural
hematoma evacuation. Patients with a history of seizures preoperatively may be
predisposed to postoperative seizures. Neurologists may need to emphasize
compliance in use of antiseizure medications before scheduled surgeries.
Hyponatremia following cranial surgeries due to cerebral salt wasting or the
syndrome of inappropriate secretion of antidiuretic hormone (SIADH), often
triggered by pain, can lower the seizure threshold as well. Patients who are
postoperative may have nonconvulsive seizures that can manifest as subtle
involuntary movements, fluctuating encephalopathy, aphasia, or altered
behavior, and diagnosis requires a high degree of clinical suspicion.20,21 Rapid
and around-the-clock availability of continuous EEG aids in both surveillance of
nonconvulsive seizures in this population and avoidance of unnecessary
antiepileptic therapies. Any encephalopathy or involuntary movement not
explained by the patient’s neuroimaging and expected structural deficits should
be investigated with continuous EEG to assess for the possibility of
nonconvulsive seizures. Clinical algorithms that incorporate surgical details,
lesional pathology, clinical examination, and continuous EEG monitoring should
be investigated in the evaluation of patients with new-onset unexpected
encephalopathy after craniotomy. Such algorithms should be used with a goal to
maximize the detection of nonclinical seizures and minimize empiric
antiepileptic therapy.22
Traditional algorithms recommended perioperative prophylactic antiseizure
medications for all patients having a craniotomy. Despite a lack of robust
randomized trials, the traditional use of antiseizure medications for all
craniotomies has fallen out of favor because of the adverse impact of antiseizure
medications on cognitive outcomes.18,23 Seizure prophylaxis is usually indicated
for the underlying indication requiring a craniotomy rather than for the
craniotomy itself. Levetiracetam has been more commonly used as an
prophylactic antiseizure medication than fosphenytoin because of fewer
cardiovascular side effects and fewer drug interactions, but it may have
neuropsychiatric adverse effects.
The incidence of seizures in acute and chronic subdural hemorrhages (SDHs)
and their evacuation needs a special mention. The occurrence of early and late
1390 OCTOBER 2021

posttraumatic seizures ranges from 28% to 43% in acute SDH and from 5.3% to KEY POINTS
10% in chronic SDH. The need for craniotomy and low preoperative and
● Unless a high index of
postoperative Glasgow Coma Scale scores (<8) have been shown to be risk suspicion is maintained in
factors for seizures. These factors are surrogate markers of the severity of the surgeries involving
brain injury itself, explaining the association with higher incidence of seizures. intraoperative blood loss or
Patients with SDH who undergo craniotomy for evacuation have a 6% to 25% proximity to major cerebral
blood vessels, vasospasm of
incidence of postoperative seizures, with the highest risk in the initial 48- to
the intracranial vessels may
72-hour period despite evacuation and lack of recurrence of SDH or ischemic go undetected and present
complications on neuroimaging.20,24-26 Different surgical approaches have with delayed ischemic
reported varied incidence of postoperative seizures in acute and chronic SDH neurologic deficits. Patients
who are postoperative with
evacuations. Burr hole treatment reportedly has lower seizure incidence than
persistent unexplained
craniotomy and capsulotomy.27 Large-scale studies evaluating the incidence of encephalopathy and EEG
postcraniotomy nonconvulsive seizures in SDH are scarce, but smaller studies inconsistent with possible
using routine and continuous EEG show a high incidence of epileptiform ictal etiology should be
discharges in patients with SDH. EEG may help evaluate nonconvulsive seizures assessed for vasospasm.
in patients with persistent encephalopathy or focal symptoms. Although clinical ● Certain surgical
seizures are more common than nonconvulsive seizures with SDH, the approaches may have a high
occurrence of subsequent nonconvulsive seizures may be observed in a small risk of seizures, for example,
subset of patients, with exclusively nonconvulsive seizures occurring in 2.6% of the superior temporal gyrus
approach for middle
patients.25,28 Smaller studies have shown benefit from prophylactic antiseizure cerebral artery aneurysm
medications in acute SDH, but the role of prophylactic antiseizure medications is clipping or subdural
unclear in chronic SDH, especially when it is treated nonsurgically. hematoma evacuation.
Levetiracetam has shown similar efficacy to phenytoin, with significantly lower
● Any encephalopathy or
complication rates and better long-term outcomes.29 Recurrent seizures or status
involuntary movement not
epilepticus refractory to medical therapy in patients with SDH warrant repeat explained by the patient’s
neuroimaging and, when associated with reaccumulation or acute bleeding, may neuroimaging and expected
necessitate repeat evacuation.30 structural deficits should be
Emerging data suggest that patients with SDH may have intermittent investigated with continuous
EEG to assess for the
nonepileptic stereotypical symptoms. The term nonepileptic, stereotypical, and possibility of nonconvulsive
intermittent symptoms (NESIS) has been proposed to investigate the existence of seizures.
this nonseizure syndrome in patients with SDH.31
Most neurosurgical procedures require general anesthesia, but more and more ● The traditional use of
antiseizure medications for
practices are incorporating awake craniotomies for at least part of the procedure, all craniotomies has fallen
for example, for mapping in epilepsy surgery and tumor resection of lesions out of favor because of the
involving speech and motor areas in selected patients. Drugs such as propofol, adverse impact of
dexmedetomidine, and remifentanil may be used for analgesia and anxiolysis in antiseizure medications on
cognitive outcomes.
these cases. In carefully selected patients, awake craniotomy may lead to
decreased need for intraoperative vasopressors and use of fewer narcotics for ● Proper dural closure is
pain, and it is associated with fewer neurologic deficits.32 Such patients may have necessary to prevent CSF
a 3% to 6% incidence of intraoperative seizures during stimulation mapping, leaks, which seem to be
which responds to cortical washout with cold saline and rarely requires more common in posterior
fossa decompression than in
antiseizure medications.33 supratentorial craniotomies.
If local drainage at surgical
CSF Leak and Postoperative Meningitis sites goes undetected,
Direct leakage of serous material from the surgical wound site or unexpected patients may present with
signs and symptoms of CSF
serous drainage in the surgical drain may be early signs of CSF leak. Proper dural hypotension, such as
closure is necessary to prevent CSF leaks, which seem to be more common in postural headaches,
posterior fossa decompression than in supratentorial craniotomies. If local meningismus, and
drainage at surgical sites goes undetected, patients may present with signs photophobia.
and symptoms of CSF hypotension, such as postural headaches, meningismus,

and photophobia. Most cases of CSF leaks of cranial origin respond to

conservative maneuvers, such as elevating the head of the bed and fluid
resuscitation, but leaks refractory to conservative therapy may require lumbar
subarachnoid drainage to reduce the intracranial pressure around the draining
site and allow the defect to heal. Rarely, patients may require a repeat procedure
to repair the defect, particularly if a pseudomeningocele has formed.
Persistent drainage, especially if undetected, may predispose the patient
to meningitis.
The presence of a drain increases the risk of infection, and many clinical
algorithms suggest perioperative antibiotic prophylaxis for drains with CSF
access. The routine use of prophylactic antibiotics in craniotomies or in patients
with subgaleal or subdural drains is falling out of favor, with increasing evidence
of no benefit but more harm because of the increased risk of nosocomial
infections and growth of antibiotic-resistant bacteria.34 Rarely, CSF leaks may
present with postoperative infection, including ventriculitis and meningitis, that
may require targeted treatment with antimicrobials at that point. The Joint
Commission monitors the use of prophylactic antibiotics and rates of
discontinuation after 24 hours for a number of surgical procedures to promote
antibiotic stewardship, but neurosurgical procedures are not among those
tracked at this time.35
Transsphenoidal hypophysectomy via an open approach is associated with a
5% to 15% incidence of CSF leak because of the inherent nature of the surgical
approach.36,37 The incidence of this complication has remarkably decreased, with
most hypophysectomies now done via an endoscopic approach. Another surgical
approach that has a risk of CSF leak is suboccipital craniectomy performed for
posterior fossa tumor resection or cerebellar decompression in ischemic stroke.
This may be accompanied by herniation of subarachnoid space to the cranial
defect creating a pseudomeningocele; careful attention to duraplasty may reduce
the incidence of this complication.
Pneumocephalus
Intracranial air can be seen on imaging after craniotomy, most commonly in the
subdural space along the frontal lobes, and may take up to 3 weeks to reabsorb
completely. Small amounts of intracranial air may be asymptomatic or may cause
transient headaches. Pneumocephalus, if persistent or large in volume, can cause
neurologic symptoms of encephalopathy, confusion, headaches, and seizures.38
Tension pneumocephalus may occur because of a one-way entry of air through
the craniectomy defect and can cause acute neurologic decline, with coma,
seizures, and cerebral herniation. The classic radiologic sign of bifrontal lobe
compression by air is called the Mount Fuji sign. CASE 9-3 highlights a patient with
tension pneumocephalus that necessitated external ventricular drain placement
and antibiotics because of CSF leak.
Postoperative Headache
Postcraniotomy headaches are one of the most common neurologic
complications of craniotomy, occurring in more than two-thirds of patients,
and have a multifactorial etiology.39 Pain and muscle spasms at the incision site
can be seen in both supratentorial and posterior fossa craniotomies. Some
surgical features, such as dural traction due to tight closure, temporalis or nuchal
muscle dissection, nerve entrapment during closure, meningismus caused by
1392 OCTOBER 2021

blood breakdown products, or longer duration of surgery, can also contribute to KEY POINTS
postoperative headaches. Suboccipital approach or skull base surgeries may
● Pneumocephalus, if
have a higher incidence of pain because of the considerable dissection of major persistent or large in
muscles involved compared to anterior approaches, although studies have not volume, can cause
reproducibly shown this association. Postcraniotomy headaches may be remote neurologic symptoms of
to the incision location and correlate more to amount of tissue damage.40 encephalopathy, confusion,
headaches, and seizures.
Attention to intraoperative anesthesia and local analgesia is the mainstay
Tension pneumocephalus
of prophylaxis. The International Classification of Headache Disorders, Third may occur because of a one-
Edition (ICHD-3) defines postcraniotomy headaches as those that occur within way entry of air through the
7 days of surgical craniotomy; postcraniotomy headaches may be persistent craniectomy defect and can
cause acute neurologic
for longer than 3 months in one-third of patients.41 Analgesic control strategies
decline, with coma,
have centered on narcotics because of the inherent risk of bleeding with seizures, and cerebral
nonsteroidal anti-inflammatory drugs. Nerve blocks, gabapentinoids, herniation.
dexmedetomidine, cold packs, muscle relaxants, massage, and biobehavioral
interventions have all been tried with various degrees of success. Refractory ● Postcraniotomy
headaches are one of the
headaches, especially if associated with focal local signs, should be investigated most common neurologic
for CSF leak, cerebral edema, meningitis, and postoperative hemorrhage. complications of
Medication-overuse headache should be considered in patients with craniotomy, occurring in
persistent headaches. more than two-thirds of
patients, and have a
multifactorial etiology.
Compressive Neuropathies Related to Patient Positioning
Compressive neuropathies may develop in patients related to the specific patient ● Compressive
positioning used to enhance anatomic access for the surgical approach. The four neuropathies may develop in
patients related to the
primary patient positions employed in neurosurgical procedures are supine,
specific patient positioning
lateral, prone, and sitting. Prolonged positioning may cause compressive used to enhance anatomic
neuropathies, including brachial plexus neuropathies from arm abduction access for the surgical
exceeding 90 degrees, ulnar neuropathies from pronation, radial neuropathy approach.
from prolonged contact against the spiral groove of the humerus, median
neuropathy from overextension of the elbow, sciatic neuropathy from hip
flexion, and fibular (peroneal) neuropathy from fibular head compression
against a hard surface. Practice parameters for positioning during neurosurgical
procedures are published and updated periodically by the American Society of
Anesthesiologists Task Force on Prevention of Perioperative Peripheral
Neuropathies.42 This evidence-based advisory takes into account expert opinions
to make recommendations to address positioning strategies, protective padding,
and proper placement of equipment as useful preventive strategies. These
strategies have decreased the incidence of various upper and lower limb
compressive neuropathies.
Decompressive Craniectomy and Cranioplasty

Patients undergoing decompressive craniectomy for malignant cerebral edema
may have persistent elevated intracranial pressure despite surgical
decompression. Detailed inspection of the fullness, pulsatility, and softness of the
skull flap and invasive intracranial pressure monitoring, when available, can
guide efforts to maximize medical therapy despite surgical decompression. In
some cases, the craniectomy defect is small and the brain parenchyma may
herniate through the defect and cause further parenchymal injury. Preoperative
planning for an adequately sized craniectomy can prevent this complication.
Sinking skin flap syndrome, also called the syndrome of the trephined, has been
described in patients with large bone defects.43 This syndrome can present with a

large spectrum of symptoms, including headache, dizziness, impaired cognition,

and seizures. Atmospheric pressure exerted on the brain through the
craniectomy site causes direct brain compression, which impairs venous return
and decreases blood flow. Patients may have initial clinical improvement from
decompression but may experience progressive neurologic deterioration. If left
untreated, sinking skin flap syndrome may progress to paradoxical herniation,
with brain herniation away from the craniectomy defect. Cranioplasty usually
results in significant improvement in neurologic symptoms.38
Cranioplasty after decompressive craniectomy is necessary for optimal
neurologic recovery but has a relatively high rate of complications, ranging from
12% to 50%.44 The timing of the surgery, patient comorbidities, and technical
aspects of the cranioplasty affect the rate of complications. Minor complications
after cranioplasty include subgaleal collections and seizures. Major
complications, such as hydrocephalus and bone flap infection, may require
repeat surgeries.44,45 Cerebral edema and hemorrhage after cranioplasty are rare
but recognized complications that may affect outcomes. Exposure of the brain
to atmospheric pressure reduces cerebral vascular resistance and increases
cerebral perfusion pressure. Replacement of the bone flap leads to overperfusion
that outpaces the brain’s capacity for elastic response, leading to cerebral edema.
Patients with preexisting CSF flow disturbances have recently been shown to
have a high risk of postoperative hemorrhage after cranioplasty.46 Seizures are
CASE 9-3 A 54-year-old woman had open transsphenoidal hypophysectomy for

craniopharyngioma resection. This was complicated by a CSF leak
requiring lumbar drainage. The leak symptoms resolved, and the patient
was eventually discharged home but returned in an acute confusional
state with a rapidly deteriorating examination. A noncontrast head CT
showed pneumocephalus in the lateral ventricles and third ventricle;
within the sella, suprasellar cisterns, and prepontine cisterns; and in the
posterior fossa that had communication with the nasal cavity through the
sphenoid sinus and sella (FIGURE 9-4A). The brain parenchyma showed
significant diffuse sulcal effacement consistent with cerebral edema. An
external ventricular drain was placed for tension pneumocephalus
resulting in improvement in imaging (FIGURE 9-4B) and symptoms. After an
appropriate course of antibiotics, the patient was discharged to an acute
brain injury rehabilitation center for functional mobility deficits and
impaired memory. She eventually was able to return to home,
functionally independent.
COMMENT The patient in this case had an open transsphenoidal hypophysectomy for
craniopharyngioma resection complicated by CSF leak and delayed onset
of tension pneumocephalus. She received an external ventricular drain,
and her symptoms resolved. Tension pneumocephalus is a rare occurrence
but key to recognize for timely decompression via external ventricular drain
in a patient with encephalopathy and air on imaging.
1394 OCTOBER 2021

the most common complication, occurring in 3% to 30% of patients.47 A longer
interval between craniectomy and cranioplasty, use of artificial duraplasty
material,48 and presence of postcraniectomy seizures are known risk factors
predictive of early postcranioplasty seizures occurring within 7 days of the
procedure. The presence of neurologic deficits has shown correlation with late
postcranioplasty seizures. Some practices use 7 days of prophylactic antiseizure
medications to reduce the risk of early seizures, although underlying conditions
necessitating decompressive hemicraniectomy likely influence the decision of
whether long-term antiseizure medications are needed.49
CSF Diversion Procedures

Ventriculoperitoneal shunt placement is one of the most commonly performed
neurosurgical procedures. Immediate postoperative complications of shunt
placement include issues related to surgical access. Shunt obstruction most often
occurs in the proximal catheter and is often delayed. This complication has been
greatly reduced by the use of programmable shunt valves. Shunt obstruction
in the immediate postoperative period may rarely occur because of brain
parenchyma clogging the catheter during placement or by obstruction from
ingrowth of pieces of choroid plexus into the catheter lumen. Patients with shunt
obstruction have persistent headache, lethargy, nausea, and vomiting because of
persistent hydrocephalus. Such obstruction usually requires shunt revision.
FIGURE 9-4
Imaging of the patient in CASE 9-3. A, Axial noncontrast head CT shows pneumocephalus
(arrows) in the lateral ventricles, third ventricle, and various cisterns causing mass effect
and global cerebral edema concerning for tension pneumocephalus. B, Axial noncontrast
head CT shows resolving pneumocephalus (arrows) with insertion of an external
ventricular drain catheter.

Overdraining of the shunt causing subdural hematoma formation is a formidable

neurologic complication that occurs more often in patients with normal pressure
hydrocephalus. Shunt infection may occur in 8% to 15% of patients and can be
seen more often in younger patients, patients with a postoperative CSF leak, and
patients receiving a shunt for intraventricular hemorrhage.50
ENDOVASCULAR/VASCULAR PROCEDURES
This section of the article discusses the complications associated with diagnostic
and interventional cerebral angiograms and carotid revascularization procedures
(carotid stenting and endarterectomy) relevant to postoperative care.
Diagnostic Cerebral Angiograms

Catheter-based cerebral angiography usually involves a transfemoral or transradial
approach to inject a contrast medium into one of the common carotid arteries or
vertebral arteries under direct fluoroscopic guidance to allow a high-resolution
three-dimensional view of the cerebrovascular anatomy. Digital subtraction
angiography typically provides two-dimensional snapshots of the cerebral vessels
filled with contrast in different time periods of arterial and venous phases. The
overall rate of permanent neurologic complications has significantly decreased
with improvement in catheters and angiographic techniques. Vessel occlusion,
ischemic stroke, or intracranial hemorrhage has been reported in less than 1% of
cases; transient ischemic attacks occur in up to 2.5% of cases.51 TABLE 9-1
summarizes common complications encountered in cerebral angiograms.
Angiography typically uses nonionic and isoosmolar iodinated contrast media.
In rare cases, contrast-induced encephalopathy and cerebral edema directly
attributed to contrast exposure in cerebral and coronary angiograms have been
reported.52 Contrast-induced encephalopathy may present with new-onset focal
deficits, confusion, coma, or seizures; it may also manifest as worsening of
underlying neurologic deficits if the angiogram was done for large vessel
occlusion–related thrombectomy and may be challenging to distinguish from
reperfusion injury, hemorrhagic conversion, or recurrent ischemic stroke. A higher
incidence of contrast-induced kidney injury also seems to exist in these patients.
Neuroimaging will show cortical or subcortical contrast enhancement and vasogenic
edema, likely related to direct neurotoxicity causing disruption of the blood-brain
barrier. The few reported cases resolved slowly with supportive care.
Vessel dissection is rare, with incidence of less than 0.4% of patients who have
had a diagnostic cerebral angiogram. Vertebral artery dissection may be more
TABLE 9-1 Neurologic Complications Associated With Cerebral Angiogramsa
◆ Direct vessel injury by dissection or perforation

◆ Dislodgment of a known thrombus or atherosclerotic plaque or device fragmentation
causing thromboembolism
◆ Asymptomatic restricted-diffusion lesions on MRI
◆ Silent microembolic events detected by transcranial Doppler
MRI = magnetic resonance imaging.

a
Data from Pereira VA, Anthony C, Pract Neurol.51
1396 OCTOBER 2021

common than carotid dissection because of the vertebral artery’s small caliber KEY POINTS
and tortuous anatomy. Interventional cerebral angiograms may have a higher
● Patients with shunt
incidence of dissection compared to diagnostic studies because of the higher obstruction have persistent
number of microcatheter passes and a greater degree of vessel manipulation headache, lethargy, nausea,
during stenting, angioplasty, and thrombectomy. Catheter-induced vasospasm and vomiting because of
can also cause ischemia and may respond to intraarterial verapamil, nicardipine, persistent hydrocephalus.
Such obstruction usually
or nimodipine. It usually lasts only a few hours and does not cause permanent
requires shunt revision.
ischemia. Cerebral air embolism is a very rare but recognized phenomenon that
can be actively prevented by using air filters and appropriate catheter priming. ● Although postprocedural
Although postprocedural headaches are common after angiograms (occurring in headaches are common
more than one-third to one-half of patients), severe headaches or headaches after cerebral angiograms
(occurring in more than
accompanied by focal deficits are not typically seen after cerebral angiography.53 one-third to one-half of
New-onset severe headaches after cerebral angiography should trigger patients), severe headaches
investigations via neuroimaging. Rarely, heparin-induced thrombocytopenia or headaches accompanied
may cause thromboembolic events related to heparin given during angiograms. by focal deficits are not
typically seen after cerebral
Persistently low activated coagulation time levels should raise the suspicion of angiography. New-onset
heparin-induced thrombocytopenia. Closer monitoring suggests that the rate of severe headaches after
asymptomatic cerebrovascular events following cerebral angiogram may be cerebral angiography should
higher than anticipated, with reports of up to 26% incidence of asymptomatic trigger investigations via
neuroimaging.
restricted diffusion lesions on MRI and significant embolic events seen on
transcranial Doppler monitoring. ● Most intraprocedural
aneurysm ruptures can be
Interventional Angiograms managed with achieving
hemostasis with further
Therapeutic cerebral angiograms (ie, interventional neuroangiography) is
coiling or balloon-assisted
usually performed for coiling of aneurysms, embolization of arteriovenous embolization.
malformations, thrombectomy, and stenting.
The International Subarachnoid Aneurysm Trial (ISAT) demonstrated
benefits of coiling over clipping, making this the favored approach for protection
of aneurysms.54 Although coiling was initially reserved for narrow-necked
aneurysms, the introduction of flow diverters has provided an important tool for
management of large, wide-necked, or anatomically challenging aneurysms.55 In
addition, stent-assisted coiling has reduced the rate of recanalization after coil
embolization, making coiling the procedure of choice for many additional
aneurysms. The major complications related to coiling of aneurysms include
thromboembolic events and intraprocedural perforation of the aneurysm.
Intraprocedural rupture of aneurysms has been reported with an estimated
incidence of 1% to 5% and is independently associated with a high risk of
mortality. The clinical consequences of rupture may be variable, from a slight
leakage of contrast material into the subarachnoid space to a massive
hemorrhage causing malignant cerebral edema. Most intraprocedural
ruptures can be managed with achieving hemostasis with further coiling or
balloon-assisted embolization. The increasing use of flow-diverter devices,
mainly for unruptured aneurysms with complex anatomy (eg, pipeline
embolization devices for managing delayed complications or primary treatment
of giant and posterior circulation aneurysms), has produced a higher incidence of
posttreatment aneurysmal rupture than other procedures. This may possibly be
caused by mechanical stretching of the vessel or inflammatory neurologic
destabilization triggered by the device.
Thromboembolic complications can occur in 2% to 15% of aneurysm coiling
procedures and are usually caused by clot formation in the guiding catheter,

propagation of clot from the coil mass, or malpositioning of coil in the parent
vessel. The empiric use of antiplatelet agents has reduced the reported high rate
of thromboembolic complications associated with stent-assisted coiling.55 In
general, rescue therapy with glycoprotein IIb/IIIa inhibitors with or without
mechanical thrombectomy has been shown to be superior to intraarterial
fibrinolytic therapy in procedural thromboembolic events.56 Perianeurysmal
edema occurring de novo after aneurysm coiling has been rarely described in
both ruptured and unruptured aneurysms when the aneurysms are embedded in
the brain parenchyma.52 Carotid termination aneurysms invariably project into
the brain and hence have the highest risk of this complication. The edema is
restricted to the area around the coil and may occur within days to months of the
endovascular procedure. Brain-embedded aneurysms with early postprocedural
wall enhancement have been shown to be significantly associated with
perianeurysmal edema. Neurologic symptoms may occur when the aneurysms
are in eloquent locations. Some cases have spontaneous gradual resolution, but
others may respond to steroids.
Endovascular treatment for acute ischemic stroke with mechanical
thrombectomy has a reported incidence of complications of 15% in recent
randomized control trials that used newer-generation devices such as stent
retrievers and aspiration thrombectomy.57 Arterial perforation was reported in
up to 5% of patients and may require reduction of blood pressure and reversal of
anticoagulation, both counterintuitive to the management of the underlying
ischemic stroke. Arterial dissection may occur in 0.6% to 3.9% of cases and may
lead to further occlusive and thromboembolic complications, such as ischemic
stroke. Asymptomatic cases may respond to antithrombotic therapy or
anticoagulation. Severe cases of flow-limiting dissections may require balloon
angioplasty or stenting. Preceding thrombolysis may increase the risk of
intracerebral hemorrhage, with a reported incidence of 3.6% to 9.3%, which may
be underreported because of variable definitions in different published clinical
trials. A larger ischemic core, higher baseline stroke scale score, diabetes, and
prolonged procedure time increase the risk of symptomatic intracerebral
hemorrhage. Unexpected stent detachment during mechanical thrombectomy is
known to occur in detachable first-generation thrombectomy devices in 0.6% to
3.9% of cases and is associated with higher rates of intracerebral hemorrhage and
poor clinical outcomes because of potential vascular injury, particularly if
retrieval of the detached stent is attempted.57,58 Three or more thrombectomy
passes have been reported as predictive of stent detachment during mechanical
thrombectomy for acute ischemic stroke. Most stent manufacturers now provide
instructions on the maximum number of passes for their specific device to reduce
the frequency of this complication.
A 2019 systematic review assessing the embolization of brain arteriovenous
malformations with an intent to cure reported a 13.6% rate of procedural
complications, such as vessel perforations, embolic agent extravasation,
catheter disconnection, and trapped/glued/retained catheter tip.59 The overall
clinical complication rate of hemorrhage, ischemia, seizures, focal neurologic
deficits, or procedure-related death was 24.1%. Hemorrhage or vessel
perforation, embolic agent extravasation, and venous compromise were the
most common complications. A large randomized controlled trial reported the
rate of procedural complications with endovascular embolization higher than
the short-term natural history risk; hence, careful patient selection for
1398 OCTOBER 2021

embolization with an intent to cure and a conservative approach is KEY POINTS
recommended.60
● Perianeurysmal edema
occurring de novo after
Carotid Stenting and Endarterectomy aneurysm coiling has been
Carotid revascularization techniques, whether done via endarterectomy or rarely described in both
stenting, have been associated with cerebral hyperperfusion syndrome and ruptured and unruptured
aneurysms when the
intracranial hemorrhage. Carotid artery stenting is the preferred treatment for
aneurysms are embedded in
patients for whom carotid endarterectomy is not suitable because of high surgical the brain parenchyma.
risk or unfavorable anatomy for carotid endarterectomy.61 Revascularization of
the brain of a patient with a chronically stenosed carotid is the proposed ● Revascularization of the
mechanism of hyperperfusion injury after carotid endarterectomy and carotid brain of a patient with a
chronically stenosed carotid
artery stenting; hyperperfusion syndrome can be avoided by careful control of is the proposed mechanism
hypertension in the postoperative period for both of these procedures. Carotid of hyperperfusion injury
endarterectomy seems to be associated with a higher risk of hyperperfusion after carotid
compared to carotid stenting, although patient selection and postoperative care endarterectomy and carotid
artery stenting;
paradigms may have negated this difference.62 hyperperfusion syndrome
The clinical equipoise for carotid artery stenting and carotid endarterectomy can be avoided by careful
has been demonstrated by several trials, including SAPPHIRE (Stenting and control of hypertension in
Angioplasty with Protection in Patients at High Risk for Endarterectomy), the postoperative period for
both these procedures.
CREST (Carotid Revascularization Endarterectomy versus Stenting Trial), ICSS
(International Carotid Stenting Study), and ACT-1 (Carotid Angioplasty and ● Local surgical
Stenting Versus Endarterectomy in Asymptomatic Subjects Who Are at Standard complications unique to
Risk for Carotid Endarterectomy With Significant Extracranial Carotid Stenotic carotid endarterectomy
include direct cranial nerve
Disease) with regard to the long-term complications of stroke.62,63 A recent
palsies, which may occur in
review of a nationwide readmissions database evaluated trends for treating up to 5% of patients and
carotid stenosis in 378,354 patients who had undergone carotid endarterectomy usually involve the
and 57,273 patients who had undergone carotid artery stenting.63 It found a high hypoglossal and facial
rate of perioperative stroke in patients undergoing carotid endarterectomy and nerve.
more so in symptomatic patients, in contrast to the findings of CREST. More

research is needed into individualizing procedural choice in patients with unique
anatomic or cerebrovascular factors.
Local surgical complications unique to carotid endarterectomy include direct
cranial nerve palsies, which may occur in up to 5% of patients and usually involve
the hypoglossal and facial nerve. The nerves commonly involved include
the following:
u Facial nerve, mandibular branch

u Hypoglossal nerve
u Vagus nerve, recurrent laryngeal branch
u Glossopharyngeal nerve
Postoperative facial weakness can occur from local muscle spasm, anesthesia,
or injury to the marginal mandibular branch of the facial nerve. Careful
examination must be done to differentiate this from upper motor neuron facial
palsy that could be a sign of a small postoperative stroke.
SPINAL PROCEDURES
Posterior cervical spinal procedures, in general, have a higher incidence of
complications than anterior cervical procedures,64 although posterior approaches

may be preferred in the frail and in older adults. Postoperative hematoma can
occur in spinal surgeries in patients predisposed to coagulopathy, whereas CSF
leak can occur with repeat surgeries and in patients undergoing multilevel
surgeries. Upper posterior cervical spine surgeries have higher risk of vertebral
artery injuries than anterior cervical spine procedures. Each of these
complications has a reported incidence of less than 1% with careful patient
selection and advancements in surgical approaches.
Dysphagia may be seen after anterior cervical procedures because of local
edema or incidental nerve injuries.65 Recurrent laryngeal nerve injury can occur
in high cervical spine procedures done via the anterior approach as well and
result in vocal cord paralysis causing dysphonia. Both of these complications are
usually reversible.
Emerging literature reports an incidence of 6.7% to 8.5% of new postoperative
neurologic deficits after posterior cervical procedures, with the most notable
syndrome being C5 palsy.64 The most likely attributed mechanisms are iatrogenic
injury, spinal cord ischemia, reperfusion injury, and spinal cord shifts tethering
the nerve. The majority of these patients eventually recover fully, although
weakness of the upper extremities and variable recovery times impact quality of
life in the postoperative period and lead to higher health care utilization. One
study reported a significant impact of C5 palsy on postoperative morbidity and
mortality.66
Prone positioning, in particular, is associated with a rare incidence of
postoperative visual loss that may be caused by ischemic optic neuropathy,
central retinal artery occlusion, or external ocular injury.67 The National Surgical
Quality Improvement Program reported a 10% incidence from 2005 to 2010.
Certain frames used to position patients, a longer anesthetic duration, higher
blood loss, obesity, and male sex predispose to this complication. This
complication is more commonly reported in spinal procedures.68 The American
Society of Anesthesiologists has a multispecialty practice advisory on prevention
and management strategies, including positioning practices to keep the head
above the level of the rest of the body to avoid direct pressure on the eye,
management of hypotension, and staging of long-duration spinal procedures.67
Anecdotal reports of improvement with high-dose steroids, antiplatelet agents,
and induced hypertension have been reported in the otherwise typically
irreversible ischemic optic neuropathy that causes postoperative visual loss.
CSF leaks are also a known complication of lumbar spinal procedures and
occur in up to 9% of primary surgeries but may be as common as 21% in revision
surgeries.69 Durotomies in cervical spine procedures have a lower incidence of
CSF leak of 0.5% to 3% than lumbar spine surgeries because of differences in
anatomy and surgical approaches.70 In addition to causing prolonged health
care utilization, CSF leaks lead to prolonged bed rest, predisposing patients to
deep venous thrombosis and increased risk of infection, which may be
ominous, especially in the presence of hardware. Incidental durotomies can
occur in 1% to 17% of spinal surgeries.
CONCLUSION
Postoperative neurologic deficits in a patient who has undergone a neurosurgical
procedure often require comanagement, collaboration, and communication
between the neurosurgeon, the neurologist, and other providers participating in
1400 OCTOBER 2021

the patient’s care. Careful assessment of known or expected complications of the KEY POINT
procedure and perioperative strategies to reduce these complications are key to
● Prone positioning is
providing a smooth postoperative course for patients. Thorough communication associated with a rare
between providers that focuses on procedural details and expected neurologic incidence of postoperative
deficits can lead to timely evaluation and management of postoperative visual loss that may be
complications when they do occur. Neurocritical care practitioners should be caused by ischemic optic
neuropathy, central retinal
aware of routine surgical details pertinent to postoperative complications to
artery occlusion, or external
facilitate their early detection and management and can be an asset to improving ocular injury.
postoperative care of patients who undergo neurosurgery.
USEFUL WEBSITES
AMERICAN ASSOCIATION OF NEUROLOGICAL SURGEONS NEUROCRITICAL CARE SOCIETY EMERGENCY
This American Association of Neurological Surgeons NEUROLOGICAL LIFE SUPPORT
website has continuing medical education The Emergency Neurological Life Support (ENLS)
resources, journal articles, and webinars relevant to course is designed to help healthcare professionals
postoperative complications in neurosurgery. The improve patient care and outcomes during the
“Front Row” series allows physicians to submit critical first hours of a patient’s neurologic
complex cases and review with experts. emergency. This course has a self-directed option,
aans.org a live lecture series, and instructor-led in-person
courses.
CONGRESS OF NEUROLOGICAL SURGEONS enls.neurocriticalcare.org
This Congress of Neurological Surgeons website is
a good repository of clinical practice guidelines,
podcasts, case of the month, and other continuing
medical education resources relevant to this article.
cns.org
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1404 OCTOBER 2021

Neurologic Outcome REVIEW ARTICLE

Prediction in the C O N T I N U UM A U D I O
I NT E R V I E W A V A I L AB L E
ONLINE
Intensive Care Unit 

VIDEO CONTENT
By Carolina B. Maciel, MD, MSCR A V AI L A B L E O N L I N E
ABSTRACT
PURPOSE OF REVIEW: The burden of severe and disabling neurologic injury
on survivors, families, and society can be profound. Neurologic outcome
prediction, or neuroprognostication, is a complex undertaking with
many important ramifications. It allows patients with good prognoses
to be supported aggressively, survive, and recover; conversely, it
avoids inappropriate prolonged and costly care in those with devastating
injuries.
RECENT FINDINGS:Striving to maintain a high prediction performance during

prognostic assessments encompasses acknowledging the shortcomings of
this task and the challenges created by advances in medicine, which
constantly shift the natural history of neurologic conditions. Embracing the
unknowns of outcome prediction and the boundaries of knowledge
surrounding neurologic recovery and plasticity is a necessary step toward
refining neuroprognostication practices and improving the accuracy of
prognostic impressions. The pillars of modern neuroprognostication
include comprehensive characterization of neurologic injury burden
(primary and secondary injuries), gauging cerebral resilience and estimated
CITE AS:
neurologic reserve, and tying it all together with individual values
surrounding the acceptable extent of disability and the difficulties of an 2021;27(5, NEUROCRITICAL CARE):
arduous convalescence journey. 1405–1429.
SUMMARY: Comprehensive multimodal frameworks of neuroprognostication Dr Carolina Maciel, McKnight
using different prognostic tools to portray the burden of neurologic injury Brain Institute, 1149 Newell Dr,
coupled with the characterization of individual values and the degree of L3-100, Gainesville, FL 32610,
carolina.maciel@neurology.ufl.
cerebral reserve and resilience are the cornerstone of modern outcome edu.
prediction.
Dr Maciel serves on the editorial
boards of Critical Care
Explorations, eNeurologicalSci,
INTRODUCTION
and Neurocritical Care ON CALL.
N
eurologic outcome prediction is perhaps the most traditional
undertaking neurologists have been tasked with, besides lesion UNLABELED USE OF
localization. It is also arguably the most difficult one, as accurate USE DISCLOSURE:
outcome prediction is an art that is fluid. Inherently a moving Dr Maciel reports no disclosure.
target, neuroprognostication should shift constantly with the
advent of new diagnostic and therapeutic tools, which, in turn, change the © 2021 American Academy
natural history of disease processes and humble even seasoned neurologists. of Neurology.

NEUROLOGIC OUTCOME PREDICTION
Surviving a severe acute illness to intensive care unit admission is the

beginning of an arduous journey, during which efforts to sustain life with
aggressive organ support are often the main priority. Not uncommonly, comfort
and dignity are sacrificed to some extent during the daily battle against death. On
a day-to-day basis (or multiple times per day in unstable patients) critical care
providers and families ponder the benefit of aggressive interventions and life
support against their tolls; neuroprognostic impressions are within the core of
this reasoning, and guide end-of-life decision making. Deciding whether or not to
continue aggressive treatment relies on the assessment of the severity of
neurologic injury, the potential for neurologic recovery, and how the expected
deficits fit within individual perspectives of a tolerable level of disability.
IMPACT OF NEUROPROGNOSTICATION
The impact of outcome predictions in the clinical course of devastating brain
injuries cannot be overstated. The burden of disabling neurologic injury on
survivors, families, and society can be profound. Accurate neuroprognostication
allows patients with good prognoses to be supported aggressively, survive, and
recover; conversely, it avoids inappropriate prolonged care that may not be
aligned with the goals of care in those with devastating injuries.
Neuroprognostication also guides termination of efforts in cardiac arrest and
resuscitation and helps provide closure for families.
However, the positive impact of outcome prediction hinges upon its accuracy.
Inappropriately pessimistic prognostic impressions may claim the lives of one in
four cardiac arrest survivors, of whom one in six might have survived to an
ambulatory state by hospital discharge if given a chance to recover.1 On the other
end of this spectrum, delivering maximal therapy targeting survival to patients
with devastating spontaneous intracranial hemorrhages may prevent in-hospital
deaths in 65% of cases, although enduring such a journey may be regarded as a
torment if nearly all survivors would ultimately die in the subsequent 12 months
or be rendered severely disabled.2 This is so important that multiple societies
have put forth position statements defining futile and potentially inappropriate
interventions for patients who are critically ill,3 providing guidance on how to
manage intractable treatment conflicts4 and centering on the outcome prediction
and psychosocial and ethical management of devastating brain injuries.5-7
THREATS TO ACCURATE NEUROPROGNOSTICATION

A multitude of factors may ultimately decrease the accuracy of final prognostic
impressions. Advances in diagnostic methods and neurotherapeutics may
challenge the prediction performance of previously studied prognostic tools, and
various cognitive biases may affect the interpretation of prognostic impressions.
Imprecision of Diagnostic Methods and Uncertainties in Clinical

Trajectories
Precision in detecting degrees of impairment in consciousness is contingent on
the diagnostic yield of evaluation methods, which are ever evolving.8 The
sensitivity of an examiner in detecting awareness of a patient’s response to motor
commands during a bedside neurologic evaluation fades in comparison to
advanced signal processing and analyses of ancillary tests, such as EEG and MRI.
More than one in seven patients who are unresponsive on examination may
display electrical responses reflecting activation of areas of the brain
1406 OCTOBER 2021

corresponding to spoken motor commands in the early phase following acute KEY POINTS
brain injury,9 a condition termed cognitive-motor dissociation (ie, a disconnection
● Neurologic outcome
between the activation of the region of the brain correlating to the task and the prediction, or
actual demonstration of the behavior). Recognizing this subset of patients is neuroprognostication, may
important, as their recovery trajectories may diverge significantly. Nearly half of directly impact outcomes,
unresponsive patients who exhibit signs of brain activation in the acute period health care costs, and
surrogates of patients via its
may attain at least partial independence at the 1-year mark, whereas only 14% of
mediation effect on
those who do not exhibit such signs of brain activation can achieve this goals-of-care decision
milestone.9 making.
The length of follow-up and timing of clinical and outcome evaluations also
play a pivotal role in the accuracy of neuroprognostic assessments. Early ● Devastating brain injuries
represent conditions that
evaluations may be heavily influenced by common confounders in the acute pose an immediate threat to
phase, such as the effect of sedating medications and of the postictal state life from a severe neurologic
following acute symptomatic seizures (CASE 10-1), and serial evaluations are insult in which limitation of
needed following a trial of neuroresuscitation (eg, CSF diversion and osmotic disease-targeted
interventions is being
therapy) (CASE 10-2). In addition, delayed assessments allow for a better considered in conjunction
evaluation of the overall effect of rehabilitation following acute neurologic with implementation of
injuries. For example, more than 80% of patients with moderate to severe comfort measures.
traumatic brain injury (TBI) who were unconscious upon hospital discharge
● Potentially inappropriate
recovered consciousness during rehabilitation in a 31-year sample of patients
treatments are different from
enrolled in the Traumatic Brain Injury Model System program; of these, 40% futile interventions. In the
achieved at least partial independence.10 Another example is the recovery former, a reasonable chance
trajectory following traumatic spinal cord injury (also dependent on length of exists of accomplishing an
effect sought by the patient,
follow-up), which led to the recommendation of 12-month follow-up
but the treatment team
assessments of patients with incomplete injuries (ie, American Spinal Injury may recognize competing
Association [ASIA] Impairment Scale grades B through D [TABLE 10-111-14]).15 ethical considerations that
Although the recovery in the initial 3 months following the spinal injury is warrant their withholding.
steepest, in a 2019 meta-regression analysis, studies with longer follow-up were The latter refers to the rare
event that the desired
associated with the highest conversion rate between injury grades, thus physiologic effect is not
representing neurologic improvement, except in patients with complete injuries attainable with the treatment.
(ie, ASIA grade A). Similar longitudinal improvement can be seen in many other
acute brain injuries, including hypoxic-ischemic brain injury, in which gains in ● It is essential to consider
each context when
function may occur beyond the first year.16 However, even individuals who interpreting clinical and
recover consciousness (defined as Glasgow Coma Scale scores ≥12) during index outcome evaluations in
hospitalization after cardiac arrest face high odds of unfavorable outcomes; more individual patients,
than one in three of those discharged ultimately die or experience at least particularly their timing in
relation to the injury,
moderate to severe disabilities in the subsequent 18 months.16
medications, and seizures
Furthermore, the impact of novel therapeutics (including surgical treatment) and the progress or lack
and their timing from the injury onset may vary considerably depending on thereof following
the disease process, particularly with reperfusion strategies in acute ischemic therapeutic and
rehabilitation trials.
stroke and decompressive surgeries in space-occupying lesions.
● Many factors modulate
Cognitive Biases the clinical course of severe
Increasingly recognized by the scientific community17 and patient advocacy neurologic injuries, yielding
groups, one of the main threats to accurate neuroprognostication is a type of heterogeneous longitudinal
trajectories; some patients
confirmation bias known as the self-fulfilling prophecy, in which the tool being may experience worsening
investigated in outcome prediction studies is also used in clinical decision of functional status after
making; the result is an inappropriately inflated prediction performance. This discharge, some will
exaggerated prediction performance mediated by the self-fulfilling prophecy improve, and some will
remain unchanged.
bias leads to a portentous vicious cycle in which the liberal use of tools and

extrapolation of evidence from flawed studies coupled with false security and
overly confident assessments compound in an untold toll of lives lost when it
does not need to be this way. Embracing the unknowns of outcome prediction
and the boundaries of knowledge surrounding neurologic recovery and its
plasticity is a commitment we neurologists ought to have to our patients and
colleagues, who rely so heavily on our prognostic impressions. Furthermore, this
vicious cycle blocks advancement of the field by contributing to knowledge gaps
shielded by dogmas in neurocritical care and exponentially impacts future steps
in research and clinical care.
CASE 10-1 A 23-year-old woman was brought to the emergency department after
being hit by a truck in a parking lot. She was intubated in the field and,
upon arrival to the emergency department, experienced a 90-second
generalized tonic-clonic seizure. The examination performed by the
neurosurgery resident was remarkable for 4/4 twitches on train-of-four
(suggesting no or minimal residual effect from neuromuscular blockade),
unreactive anisocoria (right eye 6 mm, left eye 4 mm), absent corneal
reflexes bilaterally, preserved cough and gag reflexes, and absent motor
responses to central and appendicular noxious stimuli. She was found to
have an acute right subdural hematoma with 11-mm right-to-left midline
shift and effacement of suprasellar cisterns (VIDEO 10-1); she was deemed
an unsuitable candidate for hematoma evacuation based on the poor
examination (owing to absent ocular reflexes and motor responses).
Upon admission to the neurocritical care unit, she was noted to have
spontaneous bilateral extensor posturing coupled with rigors and marked
tachycardia with hypertension, suggesting paroxysmal sympathetic
hyperactivity. Following a trial of osmotic therapy with 23.4% sodium
chloride, she started to localize bilaterally to noxious stimuli and
regained, albeit sluggish, pupillary reactivity to light. Prompt
communication with the neurosurgical team led to the decision to offer
decompressive craniectomy in an otherwise nonsurvivable injury even
with optimized medical management. She regained consciousness on
postoperative day 20 and was discharged to an acute rehabilitation
facility on postoperative day 47 after early cranioplasty for sunken flap
syndrome and CSF leak repair.
COMMENT This case illustrates the importance of placing the neurologic examination
findings into the context of potential confounders, particularly seizures
(eg, ongoing seizures, postictal state, and residual effect of
benzodiazepines) and the residual effect of drugs used in rapid-sequence
intubation, such as sedatives and neuromuscular blockade (which can be
evaluated at bedside with train-of-four or reversed with sugammadex, for
example). Furthermore, in acute brain injuries, it is imperative to consider
the examination findings following neuroresuscitation (eg, a trial of osmotic
therapy) when deciding on suitability for lifesaving interventions, as
therapeutic nihilism is associated with nearly 100% mortality.
1408 OCTOBER 2021

Therefore, this conventional approach to neuroprognostication (including
research) that ignores the effect of the self-fulfilling prophecy bias is no longer
acceptable. However, the alternative of avoiding or delaying definitive
prognostic impressions, or abolishing the possibility of withdrawing life support,
is not viable from humanistic and administrative standpoints. This renders the
self-fulfilling prophecy bias inherent to any neuroprognostic research, hence the
need for critically appraising the potential impact this bias may have imparted
when new evidence arises. The TRIPOD (transparent reporting of a
multivariable prediction model for individual prognosis or diagnosis) guidelines,
curated by the EQUATOR (Enhancing the QUAlity and Transparency Of health
Research) Network international initiative, provide great guidance on
transparent reporting of multivariable prediction models for individualized
prognosis18; however, these guidelines are not specific for neurologic outcome
prediction studies and fail to account for factors that reflect the influence of
self-fulfilling prophecy bias. Future scientific efforts must employ a standardized
and transparent approach in reporting data elements that allow readers to gauge
the impact of self-fulfilling prophecy bias in the prediction performance of the
neuroprognostic tools being investigated, for example, whether the institution
where the study was conducted used a standardized neuroprognostication
algorithm, and if so, whether the tool being investigated is part of routine
assessments or if the treatment team was blinded from the results of such testing.
Additionally, studies should report a breakdown of mortality: brain death, death
due to refractory cardiac arrest despite resuscitation attempts and aggressive
care, death due to withdrawal of life support because of perceived poor
A 94-year-old woman with hypertension presented to the emergency CASE 10-2

department with lethargy, projectile vomiting, and thunderclap
headache. She lost consciousness while being evaluated and was
intubated for airway protection without the need for sedatives or
neuromuscular blockade. Head CT demonstrated marked intraventricular
hemorrhage casting the entire ventricular system and leading to
hydrocephalus, as well as diffuse subarachnoid hemorrhage, on the
background of significant global atrophy (VIDEO 10-2). Following
ventriculostomy and gentle CSF drainage for 24 hours, she regained the
ability to localize central noxious stimuli and underwent coiling of an
anterior communicating artery aneurysm.
Her hospital course was complicated by dysphagia requiring
gastrostomy and dependence on CSF diversion requiring a
ventriculoperitoneal shunt. She was discharged to acute rehabilitation on
postbleed day 17 and returned home 8 weeks later, no longer relying on
artificial nutrition.
This case demonstrates another example of the important effect of COMMENT

neuroresuscitation techniques when deciding whether or not to offer
neurosurgical treatment. In this case, neuroresuscitation centered on
treating critical mass effect in midline structures and hydrocephalus.

neurologic prognosis, or death due to withdrawal of life support because of

medical condition. Reporting the timing of final neuroprognostic assessments
and withdrawal of life-sustaining therapies in relation to when the injury
occurred is important, as the evolution of the patient’s trajectory over time
is a key aspect in neuroprognostication for many reasons, from gauging
cerebral resilience and capacity for recovery to accounting for the potential
confounding effect of drugs and seizures and to evaluate for the burden of
TABLE 10-1 Commonly Used Disability Outcome Scales in Acute Neurologic Injuries
Scale/grade Description
American Spinal Injury Association Impairment Scale (AIS)11,a
A Complete. No sensory or motor function is preserved in the sacral segments S4-5.
B Sensory incomplete. Sensory but not motor function is preserved below the neurologic level and includes
the sacral segments S4-5 (light touch or pinprick at S4-5 or deep anal pressure) AND no motor function is
preserved more than three levels below the motor level on either side of the body.
C Motor incomplete. Motor function is preserved at the most caudal sacral segments for voluntary anal
contraction (VAC) OR the patient meets the criteria for sensory incomplete status (sensory function
preserved at the most caudal sacral segments S4-5 by light touch, pinprick, or deep anal pressure), and has
some sparing of motor function more than three levels below the ipsilateral motor level on either side of
the body. (This includes key or non-key muscle functions to determine motor incomplete status.) For AIS
grade C – less than half of key muscle functions below the single neurologic level of injury have a muscle
grade ≥3.
D Motor incomplete. Motor incomplete status as defined above, with at least half (half or more) of key
muscle functions below the single neurologic level of injury having a muscle grade ≥3.
E Normal. If sensation and motor function as tested with the International Standards for Neurological
Classification of Spinal Cord Injury are graded as normal in all segments, and the patient had prior deficits,
then the AIS grade is E. Someone without an initial spinal cord injury does not receive an AIS grade.
Modified Rankin Scale12,b
0 No symptoms at all.
1 No significant disability: despite symptoms, able to carry out all usual duties and activities.
2 Slight disability: unable to perform all previous activities but able to look after own affairs without
assistance.
3 Moderate disability: requiring some help but able to walk without assistance.
4 Moderately severe disability: unable to walk without assistance and unable to attend to own bodily needs
without assistance.
5 Severe disability: bedridden, incontinent, and requiring constant nursing care and attention.
6 Death.
1410 OCTOBER 2021

secondary injury. Many other important cognitive biases that pose a threat to
accurate neuroprognostication in severe brain injuries can be found in a
2017 editorial.19
Limitations of Outcome Assessments and Prognostic Models

The selection of meaningful outcomes in neuroprognostic studies involves an
important trade-off: balancing feasibility with the need for the delineation of
Scale/grade Description
Glasgow Outcome Scale – Extended13,c
1 Death.
2 Vegetative state: condition of unawareness with only reflex responses but with periods of spontaneous
eye opening.
3 Low severe disability: patient fully dependent for all activities of daily living. Requires assistance to be
available constantly. Unable to be left alone at night.
4 Upper severe disability: can be left alone at home for up to eight hours but remains dependent. Unable to
use public transport or shop by themselves.
5 Lower moderate disability: able to return to work in sheltered workshop or noncompetitive job. Rarely
participates in social and leisure activities. Ongoing daily psychological problems (quick temper, anxiety,
mood swings, depression).
6 Upper moderate disability: able to return to work but at a reduced capacity. Participates in social and
leisure activities less than half as often. Weekly psychological problems.
7 Lower good recovery: return to work. Participates in social and leisure activities a little less and has
occasional psychological problems.
8 Upper good recovery: full recovery with no current problems relating to the injury.
Glasgow-Pittsburgh Cerebral Performance Category Scale14,d
1 Good cerebral performance: conscious, alert, able to work; might have mild neurologic or psychological
deficit.
2 Moderate cerebral disability: conscious, sufficient cerebral function for independent activities of daily life.
Able to work in sheltered environment.
3 Severe cerebral disability: conscious, dependent on others for daily support because of impaired brain
function. Ranges from ambulatory state to severe dementia or paralysis.
4 Coma or vegetative state: any degree of coma without the presence of all brain death criteria.
Unawareness, even if appears awake (vegetative state) without interaction with the environment; may have
spontaneous eye opening and sleep/awake cycles. Cerebral unresponsiveness.
5 Brain death: apnea, areflexia, EEG silence, etc.
EEG = electroencephalogram.
a
Note that this classification can be applied to injury at any level of the spinal cord; thus, the same grade may have markedly different levels of
disability depending on the level of injury.
b
Cutoffs commonly used for favorable outcome: 0 to 2 or 0 to 3.
c
Highly variable cutoffs for favorable outcome, usually 4 to 8, 5 to 8, or 6 to 8.
d
Cutoffs commonly used for favorable outcome: 1 to 2 or 1 to 3.

functional states, ideally with a granularity that allows for a projection of the
threat imparted to quality of life. The relevance of patient-oriented outcomes is
increasing, now trumping traditionally used end points that can be hard to
interpret in the context of severe brain injuries, such as mortality. For example,
a therapy that only increases survival without improving the degree of disability
is not as valuable as one that has a positive impact on disability-free survival.
Many validated functional outcome scales are used in clinical trials and
neuroprognostic studies, with ordinal scores lumped into favorable and
unfavorable categories (TABLE 10-1). Lack of understanding of the instrument
used to evaluate outcomes and the definitions used to dichotomize outcomes into
good or poor and failure to account for individual perspectives regarding the
acceptable level of disability compound as major threats to accurate
neuroprognostication.
NEUROPROGNOSTICATION FRAMEWORK
Neurologic outcome prediction is a longitudinal process that begins on the very
first encounter. Information pertaining to the burden of accrued neurologic
injury (both primary and secondary) should be assessed in the context of
individual factors pertaining to the potential for recovery and accepted level of
disability. The elements of this proposed neuroprognostication framework are
depicted in FIGURE 10-1. FIGURE 10-2,20-22 FIGURE 10-3,23-31 and FIGURE 10-432-38
summarize factors relevant to outcome prediction specific to hypoxic-ischemic
brain injury, TBI, and subarachnoid hemorrhage, respectively. Similar factors
also impact prognosis in acute ischemic stroke and intracerebral hemorrhage,
along with the overall volume and anatomic location of injured tissue. In
ischemic stroke, additional prognostic factors include details of reperfusion,
involved vessel and collateral status, and occurrence of hemorrhagic
transformation, among others.
Multimodal Characterization of Injury Burden Using Prognostic Tools

The most important characteristic
of a useful neuroprognostic tool is
to carry a virtually zero false-
positive rate when predicting a
poor outcome. This ensures a low
likelihood to contribute toward a
falsely pessimistic prognostic
impression that could, in turn,
lead to withdrawal of life-
sustaining therapies and deprive
individuals with potential for
recovery of a chance to regain
function. Additionally, the ideal
tool would carry a high sensitivity
to avoid missing individuals
destined to a poor outcome, FIGURE 10-1
which, in practical terms, could The neuroprognostication pyramid. Key
supporting elements of neuroprognostication
ultimately commit them to a include the perceived individual values and
potentially inappropriate estimates of burden of neurologic injury, cerebral
long-term journey depending on resilience, and reserve.
1412 OCTOBER 2021

KEY POINTS
● The neuroprognostication
literature has been blighted
by the self-fulfilling
prophecy bias, which
overinflates the prediction
performance of
neuroprognostic tools and
leads to overly confident,
and often inaccurate,
prognostic impressions.
● Modern
neuroprognostication
studies must attempt to
mitigate self-fulfilling
prophecy bias by reporting a
breakdown of deaths,
blinding the treatment team
to the studied tool
whenever possible, and
accounting for the timing of
prognostication in relation
to injury.
FIGURE 10-2
Summary of relevant factors when prognosticating hypoxic-ischemic brain injury. Several
demographic factors impact prognosis. Obesity and comorbidities can impact outcomes, but
this effect is heterogeneous across studies. Details of the injury mechanism and offered
therapies are very important. Better outcomes are generally seen in shockable versus
nonshockable rhythms, cardiac versus noncardiac etiology, in-hospital cardiac arrest versus
out-of-hospital cardiac arrest, witnessed versus unwitnessed events, and when bystander
cardiopulmonary resuscitation (CPR) is performed. Patients who have been offered prompt
coronary reperfusion therapies (if ischemic etiology) and targeted temperature management
(TTM) also have higher odds of achieving a favorable outcome. The presence of gasping during
arrest and relative bradycardia during TTM carry a favorable prognostic significance. The
thermoregulatory status also matters, as the occurrence of shivering during TTM and early
rebound hyperthermia reflect relative sparing of hypothalamic injuries; however, a higher
burden of hyperthermia is associated with secondary brain injuries. Additionally, exposure to
glycemic dysregulations, hypotension, and ventilatory derangements compound on other
factors that increase cerebral metabolism (eg, seizures) to exacerbate secondary injury.
Neuroprognostic tools should be used in combination and employed at optimal times to
mitigate the effect of confounders and maximize yield of prognostic impressions.20,21 Note
that no single factor has been consistently demonstrated to have 0% false-positive rates (FPR)
for predicting outcomes.22
↑ = increased; ADC = apparent diffusion coefficient; e-CPR = extracorporeal membrane oxygenation–
assisted cardiopulmonary resuscitation; NSE = neuron-specific enolase; ROSC = return of spontaneous
circulation; SSEP = somatosensory evoked potentials.

FIGURE 10-3
Summary of relevant factors when prognosticating traumatic neurologic injury. Several
demographic factors may impact outcome, but their prognostic impact has varied across
studies.23 Details of the injury mechanism and offered therapies are very important. In
penetrating injuries, outlining the areas of the nervous system that are affected, the caliber of
bullet, and whether retained fragments are present can be helpful. Every traumatic brain
injury harbors potential for associated systemic, neurovascular, and spinal injuries,24 which
also impact recovery trajectories. Even in isolated brain injuries, patterns of injury portend
different trajectories: patients with associated intraventricular hemorrhage and mass effect
are less likely to regain consciousness during rehabilitation.10 In spinal cord injuries, the
extent of neurologic recovery is lowest in thoracic and penetrating injuries and lowest in
American Spinal Injury Association (ASIA) Impairment Scale A and D grades.15 The occurrence
of hypotension and paroxysmal sympathetic hyperactivity, despite being treatable, carries a
negative impact on prognosis.25 Several prognostic biomarkers have been proposed in
traumatic brain injury.26 Coagulopathy has been associated with expansion of hemorrhagic
contusions in traumatic brain injuries; specific cutoffs vary across studies, and the displayed
values reflect the ones with a strong association with outcomes in the pooled analysis.27
Derived from peripheral white blood cell analysis, the neutrophil to lymphocyte ratio adds
prognostic information in traumatic neurologic injuries.28,29 Diffuse axonal injury is associated
with poor outcomes, but the strength of this association depends on grades of severity and
predominant location of injury; high burden of injury in specific areas in the brainstem30 and in
the corpus callosum appear to reflect the most severe end of this spectrum.31
↑ = elevated; INR = international normalized ratio.
1414 OCTOBER 2021

KEY POINTS
● Most helpful
neuroprognostic tools yield
objective information linking
injury burden with outcomes
with very low false-positive
rates.
● Bilaterally absent corneal

and pupillary light reflexes
carry significant prognostic
value with very low
false-positive rates when
predicting poor outcome
but are sensitive to the
effect of confounders.
FIGURE 10-4
Summary of relevant factors when prognosticating subarachnoid hemorrhage. Several
demographic factors and premorbid conditions are associated with outcomes.32 Higher
scores on radiologic and clinical scales are associated with poor outcome, but approximately
one-third of patients with poor-grade subarachnoid hemorrhage regain functional status.33,34
Endovascular treatment modalities are associated with better neuropsychiatric and
functional outcomes when compared to clipping.35 Many prognostic tools center on the
prediction of vasospasm and delayed cerebral ischemia because of their role in secondary
brain injury development.32 The most employed monitoring modality is transcranial Doppler;
however, its prediction performance varies widely because of technical factors and limited
temporal resolution. EEG has emerged as an attractive tool with high temporal and spatial
resolution; however, no consensus exists on thresholds for predicting delayed cerebral
ischemia and significant expertise is required for the interpretation of findings.36 Laboratory
abnormalities such as leukocytosis,37 hypokalemia, and hyponatremia are also predictors of
vasospasm.32 Important prevalent systemic complications that carry prognostic meaning for
poor outcome include paroxysmal sympathetic hyperactivity and stress-induced
cardiomyopathy.38
↓ = decreased.
the level of disability that is perceived as unacceptable. But no neuroprognostic

tool is infallible, and false-positive predictions of poor outcome have been
reported widely in neurocritical care. The use of multimodal approaches to
characterize injury burden is a promising tactic to circumvent the individual
shortcomings of prediction tools.39
The search for the holy grail of neuroprognostication has led to a growing
number of prediction models, scores, nomograms, and algorithms of varying
complexity, prediction performance, and applicability to specific disease states in
the neurocritically ill.40-43 Neuroprognostication practices vary widely, even for

patients who are comatose after cardiac arrest,44 for whom multiple guidelines
are available20,21 and recommended multimodal prognostic algorithms perform
relatively well.45,46 Scores grading the severity of injury can provide prognostic
information based on probabilities of death and disability and are most useful in
research for balancing groups and comparing cohorts. However, adopting
population-based scores to individual cases can be misleading and is
not recommended.
CLINICAL EXAMINATION. The clinical examination can provide critical prognostic

information, but it is the prognostic tool most susceptible to the effect of
confounders. Employing a meticulous technique when assessing brainstem
reflexes and motor responses is imperative to maximize the yield of findings. The
examination features most studied for their prognostic utility, particularly
following hypoxic-ischemic brain injury, include corneal and pupillary light
reflexes and motor responses to noxious stimulation.22 The evaluation of gag and
cough reflexes, particularly in patients who are intubated, can be helpful in
predicting the need for tracheostomy and gastrostomy; patients who tolerate the
endotracheal tube with minimal or no sedation likely will experience some
difficulty managing their own secretions upon extubation. Other components of
the clinical examination that carry prognostic significance are the occurrence of
paroxysmal sympathetic hyperactivity, or storming, in most acute brain injuries
and myoclonus after cardiac arrest. Paroxysmal sympathetic hyperactivity is
highly prevalent in the neurocritical care unit, affecting up to 10% of patients
with severe acute brain injuries, and is characterized by episodic and transient
paroxysms of dysautonomia with simultaneous increases in sympathetic and
motor activity. Usually triggered by any stimuli, the exaggerated response
includes marked elevation of blood pressure, tachycardia, tachypnea,
hyperthermia, sweating, rigors, and posturing (often extensor). The diagnosis
can be made using the Paroxysmal Sympathetic Hyperactivity Assessment
Measure.25 Recognizing this complication is important; patients with paroxysmal
sympathetic hyperactivity frequently require high doses of sedating medications
and prolonged hospitalizations and have worse morbidity and mortality.25
Postanoxic myoclonus, previously considered an agonal phenomenon, can have
distinct prognostic implications based on the timing of occurrence, clinical
manifestation at presentation, and associated EEG and MRI findings.22,47 In
traumatic spinal cord injuries, ASIA scores (TABLE 10-1) outlining the severity of
neurologic impairment below the level of injury carry major prognostic significance.
Neurologic improvement markedly differs across grades of spinal cord injury
severity; patients with ASIA grade C have the highest odds for the steepest
neurologic recovery, followed by patients with ASIA grade B, grade D, and, finally,
grade A. Although patients with ASIA grade D may achieve the best functional
status, their recovery trajectories tend to be less steep given lower burden of deficits,
illustrating a ceiling effect in the recovery from spinal cord injuries.15
NEUROPHYSIOLOGIC TESTS. Neurophysiologic tests yield diagnostic and prognostic

information, but their utility in the intensive care unit may be hindered by
limited availability and technical difficulties decreasing the signal to noise ratio in
this setting. EEG is the most widely used neurophysiologic prognostic tool in
critical care as it provides neuroprognostic information while patients are being
evaluated for nonconvulsive seizures and status epilepticus, which may also
1416 OCTOBER 2021

exacerbate brain injury burden. Many features of cerebral background activity
and of rhythmic and periodic patterns have prognostic utility, particularly in
hypoxic-ischemic brain injury.22 Of these, greater than 50% suppression of
background activity in the absence of sedation and loss of reactivity when a
standardized approach is used seem to be the most valuable features.20,21
The conjured electrophysiologic responses of the central and peripheral nervous
systems from applied sensory or motor stimuli (termed evoked potentials) carry
significant diagnostic and prognostic value in a myriad of neurologic conditions.
Bilateral absence of cortical peaks (N20 potentials, shown in FIGURE 10-5)
following stimulation of median nerves is helpful in predicting poor outcome in
hypoxic-ischemic brain injury, although the accuracy of this study hinges upon
technical factors and false-positive rates may reach 25%.22
Technical limitations also curb the potential for the widespread use of nerve
conduction studies and EMG in the evaluation of patients who are critically ill;
however, these tests can provide valuable prognostic information in autoimmune
neuromuscular disorders and in patients with suspected critical illness
neuropathy and myopathy (CASE 10-3).
NEUROIMAGING. Many scales exist to classify head CT findings and their

prognostic implications, such as the Marshall and Rotterdam CT scores in TBI
FIGURE 10-5
Schematic representation of median nerve somatosensory evoked potentials. Following
electrical stimulation of the median nerve, signals travel across the neuraxis, and the
generated potentials are captured by electrodes placed in the key positions to assess for
pathway integrity (lower left, magnified view). By convention, a peak reflects a negative
potential (N), and a nadir reflects a positive potential (P), which are followed by their
expected latencies in milliseconds: Erb point (N9), cervical cord (N13), thalamic ventral
posterolateral nucleus (VPL) (P18), primary sensory cortex (N20).

CASE 10-3 A 52-year-old woman with end-stage lung disease following severe acute
respiratory distress syndrome (ARDS) from severe acute respiratory
syndrome coronavirus 2 (SARS-CoV-2) infection underwent evaluation
for lung transplantation. Her intensive care unit course was complicated
by severe refractory hypoxia, requiring prolonged neuromuscular
blockade, deep sedation, 4 weeks of venovenous extracorporeal
membrane oxygenation (ECMO), and prolonged dependence on artificial
life support requiring tracheostomy, gastrostomy, and renal replacement
therapy. She remained minimally responsive despite being off sedatives
for nearly a week, prompting a neurocritical care consultation for
neuroprognostication.
On examination, she opened her eyes to voice, tracked the examiner,
and followed simple axial commands with her eyes but was unable to lift
her head from the pillow. She had flaccid quadriplegia with absent deep
tendon reflexes and mute plantar reflexes, but grimacing was noted with
deep nailbed pressure. EEG demonstrated an organized alpha-theta
background with mild slowing of the posterior dominant rhythm at 8 Hz,
absent epileptiform findings, and preserved sleep architecture. Brain
MRI was unremarkable, and cervical spine MRI showed diffuse signal
abnormality in paraspinal muscles on short tau inversion recovery (STIR)
sequences, suggestive of postinfectious myositis. Nerve conduction
studies demonstrated diffusely reduced or absent sensory and motor
potentials, with preservation of conduction velocities and F waves when
potentials were identified; this suggested a severe sensorimotor axonal
polyneuropathy. Needle EMG revealed extensive insertional activity,
fibrillations and positive sharp waves, absent fasciculations, mildly
reduced amplitude and duration of motor unit action potentials, and
discrete recruitment in the upper extremity muscles with no voluntary
units in the lower extremity muscles; this was concerning for denervation
but can also be seen in myositis. CSF analysis was unremarkable, and
creatine kinase was less than 20 U/L.
COMMENT In this case, the degree of encephalopathy was initially perceived as a

barrier to offering lung transplantation and prompted a neurocritical care
consultation; however, in the absence of structural abnormalities on MRI
and in the setting of mild dysfunction on EEG, expected improvement is
likely. Far more concerning is the degree of neuromuscular weakness with
flaccid quadriplegia, profound axonal sensorimotor polyneuropathy, and
evidence of denervation with absent recruitment; this could represent a
significant barrier for liberation from mechanical ventilation even in the
setting of normal lungs. Nonetheless, abnormal STIR signal in muscle can be
seen in the setting of denervation and severe deconditioning, and in
noncontrast studies, this finding is nonspecific. This patient made strides in
her recovery journey; within the subsequent 2 weeks, she was able to be
weaned off renal replacement therapy and mechanical ventilation and no
longer needed lung transplantation.
1418 OCTOBER 2021

and modified Fisher Scale grade in subarachnoid hemorrhage. For more KEY POINT
information on the Marshall and Rotterdam CT classification scores, refer to the
● Neuroimaging is helpful in
article “Moderate and Severe Traumatic Brain Injury” by Christopher P. quantifying acute and
Robinson, DO, MS,48 in this issue of Continuum, and for more information on the chronic structural damage
modified Fisher Scale, refer to the article “Subarachnoid Hemorrhage” by Sherry and assisting in the
Hsiang-Yi Chou, MD, MSc, FNCS, FCCM,49 in this issue of Continuum. estimation of predicted
deficits and recovery
However, no single scale is universally accepted, and prospective head-to-head
trajectories.
comparison studies are lacking. MRI of the neuraxis is perhaps one of the most
useful tools in the evaluation of structural damage following severe neurologic
injuries. The risk associated with the required supine positioning of patients with
a flat head of bed and the decreased monitoring during imaging acquisition must
be carefully assessed, particularly for long studies. Another important caveat is
the variability in the quality of radiology reports in the real world as well as their
interpretation within the clinical context, often omitting key findings of
prognostic importance; this is why neurologists, who are best equipped to
perform clinical correlation according to patient-specific scenarios, must master
the interpretation of neuroimaging. Furthermore, most useful MRI methods
quantifying injury burden and the integrity of structural connectivity used in
prognostic studies, such as diffusion tensor imaging and quantitative
diffusion-weighted imaging analysis, are not widely available in clinical practice.
Nevertheless, MRI provides essential information on what regions of the brain
are affected, which is useful in outlining expected deficits and gauging the need
for long-term support (CASE 10-4). Additionally, MRI can provide key
information on factors that help estimate the individual’s cerebral reserve, such
as the burden of microvascular injury or white matter changes, degree of
atrophy, and areas of encephalomalacia. In TBI, diffuse axonal injury, which is
commonly diagnosed through susceptibility-weighted imaging (SWI) as
scattered microbleeds in the cerebrum and brainstem, has been traditionally
associated with unfavorable outcomes, although cumulative research has shown
that the relationship between diffuse axonal injury and outcomes is far from
linear. In a meta-analysis comprising 32 studies, 62% of patients with diffuse
axonal injury achieved favorable outcomes despite being 3 times more likely to
have poor outcome than patients without diffuse axonal injury.31 This
heterogeneity in the prognostic significance of diffuse axonal injury is owed, in
part, to different severity grades in the Adams Diffuse Axonal Injury Severity
Grade50; however, even the presence of grade 3 (the highest grade) does not
preclude a chance at regaining function. A 2021 MRI study scrutinized
neuroanatomic characteristics of diffuse axonal injury of patients with TBI who
were comatose at presentation but later regained consciousness.30 Subcortical
microbleed patterns were highly variable across the brainstem, thalami, and
hypothalamus, and despite consistent involvement of the so-called coma-causing
hot spot (ie, mesopontine tegmentum), patients were able to recover
consciousness, suggesting a relative resilience of arousal mechanisms.30 Refined
classifications accounting for age and involvement of the substantia nigra and
mesencephalic tegmentum have been proposed but have not been
widely adopted.51
CHEMICAL BIOMARKERS. The quest for the identification of biomarkers that carry
high prognostic significance in acute brain injuries has led to the recognition of
several promising candidates, and the list grows at a steady pace. However, many

CASE 10-4 A 53-year-old man was admitted to the burn intensive care unit following
an inhalational injury. His hospital course was complicated by failed
extubation, severe hypoxia, and cardiac arrest with pulseless electrical
activity; return of spontaneous circulation occurred after 27 minutes of
resuscitation efforts. He underwent targeted temperature management
to 33 °C (91.4 °F) and failed to regain consciousness upon discontinuation
of sedatives and rewarming.
On examination, he had absent corneal reflexes to saline squirt,
sluggish pupillary light reflexes, and absent motor responses to central
and appendicular deep noxious stimuli. His EEG evolution is shown in
FIGURE 10-6. Postanoxic status epilepticus resolved with benzodiazepine
and fosphenytoin. Noncontrast brain MRI obtained on day 4 post–cardiac
arrest showed minimal ischemic injury (VIDEO 10-3).
Somatosensory evoked potentials obtained on day 5 post–cardiac
arrest demonstrated attenuated but present N20 peaks. Given the
severity of his inhalation injury, he required high mechanical ventilation
support; however, renal and hepatic functions had normalized, and he
was liberated from vasopressor infusions. The prolonged need for
mechanical ventilation was anticipated, and his family asked about his
neurologic prognosis before considering early tracheostomy.
COMMENT This case illustrates the dilemma commonly faced by families and
providers in cases of indeterminate prognosis. Postanoxic status
epilepticus and absent corneal reflexes and motor responses point toward
a poor prognosis; however, resolution of status epilepticus with first- and
second-line therapies yielding to a nearly continuous and reactive
background and minimal injury burden on MRI are reassuring. Furthermore,
the residual effect of sedatives and likely lower sensitivity of the technique
employed to elicit corneal reflexes may have confounded the examination.
Here, the best approach is to center the discussion on the journey toward
recovery, which will include need for at least tracheostomy, continued
antiseizure medication, and possibly gastrostomy. The uncertainty
regarding the ultimate long-term neurologic outcome should be
acknowledged while maintaining cautious reassurance on the expected
high likelihood of longitudinal recovery given the patient’s young age and
preserved cerebral reserve.
1420 OCTOBER 2021

FIGURE 10-6
Evolution of EEG changes of the patient in CASE 10-4. All epochs represent 11-second,
60-Hz filtered recordings captured on longitudinal bipolar montage with high-pass filter at
1 Hz, low-pass filter at 70 Hz, and paper speed of 30 mm/s with sensitivity at 7 μV/mm. A,
Theta-delta background during hypothermia captured in the initial 12 hours following arrest.
B, Reactivity preserved with transient attenuation of theta frequencies (fourth second) and
increased delta power captured at 24 hours postarrest. C, Sharply contoured generalized
rhythmic delta activity at 2 Hz captured at 36 hours postarrest. D, Generalized periodic
discharges with associated rhythmicity averaging 25 discharges per 10 seconds meeting
criteria for electrographic status epilepticus captured at 48 hours postarrest. E, Reemergence
of theta background following 4 mg IV lorazepam reflecting therapeutic response.

limitations hinder their widespread use, including a lack of broad availability

outside research settings, inadequate turnaround times for being relevant in the
clinical realm, and intraassay and interassay variability that challenges the
interpretation of results and acceptance of universal cutoffs. The specificity of
serum biomarkers in predicting poor outcome can be jeopardized by the
occurrence of common confounders, such as hemolysis, which may be avoided
by using CSF instead of blood specimens. Balancing this improved specificity to
neuronal injury with the practical aspects of care for patients with severe injuries
can be quite challenging; obtaining a CSF sample in patients who are comatose
and do not have ventriculostomy can be difficult, particularly in those prone to
increased intracranial pressure. Many neuronal-specific biomarkers have been
studied in acute brain injuries, particularly in stroke,52 TBI,26 and
hypoxic-ischemic injuries in which serial measurements of neuron-specific
enolase,53 glial fibrillary acidic protein (GFAP),54 neurofilament light chain,26
and S100B26 may provide useful prognostic information.
Cerebral Reserve and Resilience

Although cerebral reserve and resilience are not adequately defined in the
literature and thus remain subjective concepts, they collectively convey the
notion of the brain’s ability to “bounce back” after injury. Despite some overlap,
they each express distinct nuanced information.
Cerebral reserve is akin to renal functional reserve, in which estimates
of the population of viable nephrons capable of increasing glomerular
filtration rates reflect the ability to be liberated from long-term renal
replacement therapy. Cerebral reserve encompasses more than just the cognitive
domain and reflects how much viable neural tissue is left. It is a concept that
helps us try to answer the question of whether the brain has the capacity to regain
a functional state.
Cerebral resilience reflects the brain’s ability to dodge an insult and can be
constructed by attempting to determine how well the brain has handled the
insult and how much more it can take. It is likely the reason some patients
recover from a prolonged cardiac arrest and others may experience a devastating
injury despite short and high-quality resuscitation.
Surrogate markers can be used to delineate cerebral reserve and resilience,
often based on neuroimaging. For example, a patient recovering
consciousness during the first week following a 60-minute refractory cardiac
arrest requiring mechanical support demonstrates high cerebral resilience
(particularly if with minimal ischemic injury burden on MRI). A stroke
survivor with advanced dementia and severe sepsis may present with coma
despite absence of acute structural injury on neuroimaging, reflecting a very
limited cerebral reserve.
Individual Values
Before conveying definitive prognostic impressions, clinicians should take a step
back and deconstruct the vague terms that are dichotomized in studies into
favorable/unfavorable outcomes. This necessary step will later allow for applying
the meaning of outcomes to an individual, which may be different than the
original connotation adopted by a study. Functional states with a moderate
degree of disability may be considered acceptable to some individuals even if
they fall into what a study considered poor outcome. The effort should center on
1422 OCTOBER 2021

employing a humanizing lens through which the patient’s personal values come KEY POINTS
into focus, thus answering the overarching question: “Who is this person?”
● The burden of white
Observing preinjury pictures and videos can be quite helpful during this process. matter disease and
Exploring past rehabilitation experiences can also be insightful. Asking the encephalomalacia and
following questions facilitates accruing this information; however, a true degree of atrophy
delineation of personal values can take time, often requiring multiple encounters compound on acute
structural damage,
with surrogates.
contributing substantially to
a poor cerebral reserve;
u What kind of routine activities does the patient find most pleasurable? estimates of cerebral
reserve help project
u When faced with a challenging task, does the patient tend to be more motivated or individualized expectations
withdrawn? How frustrated is the patient when significant assistance is required from of recovery trajectories.
others?
u What is the first word that comes to mind when describing the patient’s attitude toward ● The characterization of
life? individual values
surrounding the acceptable
extent of disability and of
the difficulties of an arduous
Communicating Final Prognostic Impressions convalescence journey is
Many surrogate-specific factors have an independent impact on decision making crucial in the process of
following goals-of-care discussions in severe acute brain injury, including neuroprognostication.
sociodemographic factors.55,56 Key differences exist between surrogates and
● When communicating
physicians in their preferences surrounding the communication of outcome prognostic impressions with
predictions. Surrogates welcome numeric estimates describing prognosis, thus surrogates, clinicians should
limiting the uncertainty that is perceived as frustrating, whereas physicians be compassionate but
assertive, focus on what is
refrain from this approach, fearing erroneous interpretation of probabilities by
known, avoid medical
surrogates.57 So how can one reconcile a surrogate’s preference for numeric jargon, and give concrete
estimates that may not necessarily apply to the patient in question with the need examples of expected
for admitting that uncertainties exist? Although this remains an important deficits and their potential
knowledge gap, as a start, physicians should honestly acknowledge uncertainties impact on daily activities.
as much as possible; failure to do so may be perceived as frustrating to families.58

Furthermore, it is helpful to be explicit when conveying what the expected deficits
are and how they may impact activities of daily living, while also contrasting the
patient’s preinjury status with both best and worst possible functional outcomes.
Destigmatizing common support measures may be necessary, as approximately
one-third of patients with severe acute brain injury who have received a
tracheostomy regain independence and nearly 80% are successfully decannulated
by 6 to 12 months.59 It is also important to discuss openly the anticipated hurdles
even in best-case scenarios, as such hurdles directly impact what may be
considered an acceptable journey for certain individuals. For example, regaining
consciousness and surviving a months-long intensive care unit journey with
super-refractory status epilepticus from limbic encephalitis may be considered a
miraculous recovery; however, disabling cognitive impairment coupled with the
compounded side effects of a complex antiseizure regimen may be considered
intolerable for many (CASE 10-5).
TRENDS
Exciting times lie ahead for the neurocritical care community. Building on the
remarkable progress in methods of detection, promotion, and prediction of
disorders of consciousness,60 the Curing Coma campaign,61 launched in 2019,
represents a concerted effort between the Neurocritical Care Society and the
National Institute of Neurological Disorders and Stroke. The task at hand is to fill

in key knowledge gaps, from developing novel therapies and identifying

endotypes of injury to refining neuroprognostication. Future efforts in
expanding follow-up times beyond the initial injury following acute neurologic
injury, including neurocognitive and neuropsychiatric assessments as well as
health-related quality of life, will be instrumental to further our understanding of
the natural history of disease states in the setting of modern medicine. Refining
methods of quantification of brain injury burden, including the validation of
objective thresholds associated with a high prediction performance and the use of
other modalities such as neurosonology and proteomics, will help expand our
prognostic arsenal. The use of artificial intelligence in the identification of
brain injury phenotypes is becoming a reality after promising pilot data in
hypoxic-ischemic brain injury.62 The field is also rapidly evolving in the area of
optimized communication between physicians and surrogates,63 and novel and
CASE 10-5 A 22-year-old previously healthy man was admitted with generalized
convulsive status epilepticus nearly 1 week after a viral illness. His clinical
course was complicated by super-refractory status epilepticus despite
ketamine 7.5 mg/kg/h, midazolam 2 mg/kg/h, propofol 50 mcg/kg/min,
pentobarbital 1.5 mg/kg/h, and six antiseizure medications at maximally
optimized doses. He had brainstem areflexia and absent motor responses
to central and appendicular noxious stimuli in the setting of therapeutic
coma. Workup was remarkable for nonenhancing T2 hyperintensities in
the limbic regions on brain MRI (VIDEO 10-4), moderate lymphocytic
pleocytosis with elevated protein on CSF analysis, and elevated serum
interleukins. No response to empiric plasma exchange, IV
immunoglobulin (IVIg), anakinra, and electroconvulsive therapy was seen.
He was started on rituximab when anti–glutamic acid decarboxylase
(GAD) antibodies were noted to be markedly elevated, and he tolerated
complete wean of anesthetics during the second week of hospitalization.
Recalcitrant seizures prevented down-titration of the antiseizure
regimen, and he remained deeply comatose. Prolonged need for life
support was anticipated, and his family asked about his neurologic
prognosis before considering tracheostomy and gastrostomy.
COMMENT In cases of new-onset refractory status epilepticus (NORSE), the

identification of seizure etiology is key when ascertaining neurologic
prognosis. When a clear cause is established, antiseizure therapies can be
tailored more effectively and estimations of predicted course are a bit less
challenging. Seizures from autoimmune etiologies can be monophasic
(such as often occurring in acute disseminated encephalomyelitis [ADEM]
or in anti–N-methyl-D-aspartate [NMDA] receptor encephalitis when a
provoking antigen is identified and removed) or remain refractory, leading
to highly debilitating drug-resistant epilepsy syndromes (such as
Rasmussen encephalitis and GAD encephalitis).
1424 OCTOBER 2021

feasible goals-of-care decision aid resources are currently being investigated with
promising results.64,65
PEDIATRIC CONSIDERATIONS
This general approach to neuroprognostication can be applied to the pediatric
population with a few caveats. Individual values may not be crystallized by the
time of injury, which creates difficulty in ascertaining acceptable levels of
disability. Additionally, one could argue that younger patients are more likely to
adapt to deficits and the magnitude of the effect from recalibration shifts
(ie, changing what is considered as an acceptable level of disability) may be much
higher. Younger patients have less atrophy and burden of white matter disease in
general, which renders their cerebral reserve and potential for neuroplasticity
higher than older adults. Developing brains are also notoriously resilient, and
dramatic recovery trajectories can be seen.
CONCLUSION
Neuroprognostication is a complex undertaking that not only impacts the
injured individual but also has broad ramifications relevant to public health
and society. Striving to maintain a high prediction performance during
prognostic assessments encompasses acknowledging the shortcomings of this
task and the challenges created by advances in medicine, which constantly shift
the natural history of neurologic conditions. The pillars of modern
neuroprognostication include a comprehensive characterization of injury
burden, estimation of cerebral resilience and reserve, and the patient’s
perception of acceptable degree of disability and attitude toward an arduous
convalescence journey.
ACKNOWLEDGMENT
The author thanks Megan Centrella for her skilled artwork contribution to this
article.
VIDEO LEGENDS
VIDEO 10-1 VIDEO 10-2
Admission head CT in a patient with severe Admission head CT in a patient with subarachnoid
traumatic brain injury. Video shows axial head CT hemorrhage. Video shows axial head CT, with the
demonstrating extensive skull base fractures with cursor demonstrating hyperdensities consistent
pneumocephalus (predominantly anterior to with acute blood completely filling the ventricular
pontomedullary junction and prepontine cistern), system, including the foramen of Luschka bilaterally
diffuse cerebral edema with effacement of (lateral apertures linking fourth ventricle to the
suprasellar cistern and loss of sulci diffusely, cerebellopontine cistern) and cerebral aqueduct.
compression of lateral ventricles, diffuse Subarachnoid hemorrhage fills the quadrigeminal
subarachnoid hemorrhage (most evident on the plate, and a predominance of blood is noted in the
right sylvian fissure), and acute right subdural interhemispheric fissure, suggestive of ruptured
hematoma with mass effect causing right-to-left anterior communicating artery aneurysm. Marked
midline shift. ventriculomegaly, particularly of temporal horns of
the lateral ventricle, and diffuse atrophy are also
© 2021 American Academy of Neurology. noted.
© 2021 American Academy of Neurology.

VIDEO 10-3 VIDEO 10-4

Brain MRI in a patient with postanoxic status Brain MRI in a patient with new-onset
epilepticus. Video shows (from left to right and top super-refractory status epilepticus. Video shows
to bottom) axial diffusion-weighted imaging (DWI), (from left to right and top to bottom) axial diffusion
apparent diffusion coefficient (ADC), weighted imaging (DWI), apparent diffusion
fluid-attenuated inversion recovery (FLAIR), and coefficient (ADC), fluid-attenuated inversion
susceptibility-weighted imaging MRI sequences. recovery (FLAIR), precontrast T1-weighted, and
Diffuse sulcal FLAIR hyperintensities are seen, postcontrast T1-weighted MRI sequences.
without corresponding restriction on DWI and ADC Multifocal restricted diffusion is seen,
sequences, which could reflect reversible changes predominantly in limbic structures (yellow arrows),
in the setting of hyperoxia or even a result of status including cortical insula, mesial frontal regions, and
epilepticus and no significant hypoxic-ischemic hippocampi as well as splenium (dashed orange
injury burden; the incidental small acute stroke in arrow). No corresponding changes are seen on the
the right corona radiata is not expected to lead to T1-weighted sequence (bottom left), and
significant disability. inadequate contrast administration suggested by
lack of physiologic uptake on postcontrast
© 2021 American Academy of Neurology. T1-weighted sequence (bottom middle) limits
evaluation for enhancement.
USEFUL WEBSITES
EQUATOR NETWORK BRAIN TRAUMA FOUNDATION
The Equator Network website provides a The Brain Trauma Foundation website provides a
compilation of guidelines for conducting and compilation of guidelines for the care of patients
reporting results in prognostic studies, including with traumatic brain injury.
checklists for quick reference.
braintrauma.org
equator-network.org/reporting-guidelines/tripod-
statement AMERICAN SPINAL INJURY ASSOCIATION (ASIA)
The American Spinal Injury Association website
CURING COMA provides a reference for administration of the ASIA
The Curing Coma campaign website provides scale.
resources for patients, families and caregivers,
asia-spinalinjury.org/international-standards-
researchers, and health care providers to promote
neurological-classification-sci-isncsci-worksheet
engagement in this important public health effort.
curingcoma.org/home
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55 Garg A, Soto AL, Knies AK, et al. Predictors of 61 Curing Coma. Accessed August 10, 2021.
surrogate decision makers selecting curingcoma.org/home
life-sustaining therapy for severe acute brain
62 Elmer J, Coppler PJ, May TL, et al. Unsupervised
injury patients: an analysis of US population
learning of early post-arrest brain injury
survey data. Neurocrit Care 2021. doi:10.1007/
phenotypes. Resuscitation 2020;153:154-160.
s12028-021-01200-9
doi:10.1016/j.resuscitation.2020.05.051
56 Williamson T, Ryser MD, Ubel PA, et al.
63 Wendler D. A call for a patient preference
Withdrawal of life-supporting treatment in
predictor. Crit Care Med 2021;49(6):877-880.
severe traumatic brain injury. JAMA Surg 2020;
doi:10.1097/CCM.0000000000004949
155(8):723-731. doi:10.1001/jamasurg.2020.1790
64 Goostrey KJ, Lee C, Jones K, et al. Adapting a
57 Quinn T, Moskowitz J, Khan MW, et al. What
traumatic brain injury goals-of-care decision aid
families need and physicians deliver: contrasting
for critically ill patients to intracerebral
communication preferences between surrogate
hemorrhage and hemispheric acute ischemic
decision-makers and physicians during outcome
stroke. Crit Care Explor 2021;3(3):e0357.
prognostication in critically ill TBI patients.
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s12028-017-0427-2 65 Muehlschlegel S, Hwang DY, Flahive J, et al.
Goals-of-care decision aid for critically ill
58 Jones K, Quinn T, Mazor KM, Muehlschlegel S.
patients with TBI: development and feasibility
Prognostic uncertainty in critically ill patients
testing. Neurology 2020;95(2):e179-e193.
with traumatic brain injury: a multicenter
doi:10.1212/WNL.0000000000009770
qualitative study. Neurocrit Care 2021.
doi:10.1007/s12028-021-01230-3

REVIEW ARTICLE

Palliative Care and
CONTINUUM AUDIO
INTERVIEW AVAILABLE
ONLINE
Shared Decision Making
in the Neurocritical
Care Unit
By Claire J. Creutzfeldt, MD
ABSTRACT
PURPOSE OF REVIEW: Thisarticle reviews the evidence on integrating palliative
care into the care of patients with various types of serious neurologic
illness, emphasizes the importance of palliative care in the neurocritical
care unit, and suggests tools for clinicians to improve their communication
skills and decision making.
RECENT FINDINGS: Palliative care is a holistic approach to medical care that

aims to relieve physical, psychological, social, and spiritual suffering. It is
both a medical specialty as young as neurocritical care itself and an
approach to patient care by all clinicians who manage patients with serious
CITE AS:
illness. Patients presenting to the neurocritical care unit and their families
2021;27(5, NEUROCRITICAL CARE): have unique palliative care needs that challenge communication and
1430–1443. shared decision making.
Dr Claire J. Creutzfeldt, SUMMARY: Palliative care, effective communication, and shared decision
Department of Neurology, making require a set of core skills that all neurology clinicians
University of Washington
Harborview Medical Center; 325
should master.
Ninth Ave, Box 359775, Seattle,
WA 98104, clairejc@uw.edu.
INTRODUCTION
T
Dr Creutzfeldt serves on the he neurocritical care unit admits patients with a unique disease
board of directors of the trajectory that presents with sudden severe neurologic deficits that
International Neuropalliative
Care Society and on the threaten not only a patient’s life but also their personhood and quality
editorial board of Neurology of life. Treatment decisions rely on accurate prognostication of likely
and receives research/grant outcomes and treatment options, efficient and compassionate
support from the National
Institute of Neurological prognosis communication that allows a mutual understanding among clinicians
Disorders and Stroke and family members, and careful deliberation of how the patient’s values and
(K23 NS099421).
priorities might align with these treatment options. To add to this complexity,
UNLABELED USE OF brain injury renders patients unable to participate in these treatment decisions,
PRODUCTS/INVESTIGATIONAL leaving their clinicians and family members to make decisions on their behalf.
USE DISCLOSURE:
Dr Creutzfeldt reports no
The challenges in caring for these patients and their families are evident.
disclosure. This article reviews the evidence currently available regarding the overall
benefits of palliative care and discusses different methods to integrate palliative
© 2021 American Academy of care into daily practice by improving communication, shared decision making,
Neurology. and a team approach to neurocritical care.
1430 OCTOBER 2021

THE CONCEPT OF PALLIATIVE CARE
Palliative care is an integral part of medicine that focuses on communication
about goals of care and on maximizing quality of life for anyone affected by any
serious illness, regardless of their age, the stage of their disease, or their chances
of survival. Serious illness is often defined as a “health condition that carries a
high risk of mortality and either negatively impacts a person’s daily function or
quality of life or excessively strains their caregiver,”1 therefore encompassing all
patients presenting to the neurocritical care unit.
When people hear the words “palliative care,” they often think of cancer and
hospice. However, from its conception, the intent of palliative care was to
improve the quality of life of all patients and families facing serious illness by
treating patients as whole persons who have needs that go beyond the direct
management of their disease, including pain and other physical symptoms,
difficult emotions, social isolation, spiritual distress, and life goals or priorities.
The National Consensus Project for Quality Palliative Care defines eight domains
as the framework for palliative care (TABLE 11-1).2 As with other medical
subspecialties, palliative care can be provided in a variety of formats. Some
distinguish between primary palliative care (care provided by all clinicians caring
for patients with serious illness) and specialist palliative care (provided by
palliative care specialists).3 Primary palliative care involves early recognition of
palliative care needs, the basic management of pain and other distressing
symptoms, and conversations about prognosis and goals of care. Primary palliative
Domains of Palliative Care as Described by the National Consensus Project TABLE 11-1
for Quality Palliative Carea
Domain Description
Structure and processes of care Working as an interdisciplinary team, clinicians develop a plan of care by assessing
patient/family needs and goals of care, emphasizing engagement, communication, care
coordination, and continuity of care
Physical aspects of care Assessment and management of physical symptoms encompasses pharmacologic and
nonpharmacologic treatment to relieve/address pain, dyspnea, nausea/vomiting,
fatigue, constipation, performance status, medical diagnoses, medication hygiene
Psychological and psychiatric Mental health assessments include anxiety, depression, delirium, cognitive impairment;
aspects of care stress, anticipatory grief, coping strategies; grief/bereavement
Social aspects of care Social and environmental factors affecting functioning and quality of life, including
needs of family, caregiver, friends
Spiritual aspects of care Spiritual and religious aspects of care include existential questions, exploring hopes and
fears, forgiveness
Cultural aspects of care Practicing cultural humility and exploring aspects around language, rituals, diet, other
Care of the imminently dying Presence; recognize and communicate with patient/family signs of imminent death, time
frame/prognosis (eg, hours to days, very few days)
Ethical and legal aspects of care Determine decision maker; review regulatory and local, state, federal laws with the goal
of respecting patient needs/goals; advance directives
a
Data from Dahlin C.2

PALLIATIVE CARE AND SHARED DECISION MAKING
care skills also include timely identification of more complex palliative care needs
and referral to hospice or palliative care specialists. Specialist palliative care is
the multidisciplinary approach to refractory pain or other symptoms, complex
depression, anxiety, grief, or existential distress; palliative care specialists may also
assist with conflict resolution, especially regarding goals or methods of treatment.3
This article discusses palliative care as an approach to care, thereby focusing
less on the clinicians providing the care and more on the type of care the patient
and family receive. The approach is applicable to various settings, including the
neurocritical care unit, and can be adapted to the available skills and resources.
The past decade has seen an impressive development of palliative care around
the world; in the United States, for example, more than 90% of all large hospitals
have palliative care services, with a higher rate in teaching and nonprofit
hospitals.4 This growth is based on evidence that palliative care is effective in
improving outcomes for people with serious illness. Two recent meta-analyses
examined the evidence for the benefits of palliative care for patients with serious
illness.5,6 Three observations from these studies are important to consider for
how best to integrate palliative care with neurocritical care. First, the definition
of a palliative care intervention was deliberately broad and included a variety of
interventions that were consistent with the philosophy or components
(TABLE 11-1) of palliative care (the palliative care approach) without a necessary
prescription of specialist palliative care involvement. In other words, when
people use the term palliative care, they may think of a certain type of patient or
disease, a certain type of provider or provider team, or a certain type of medical
care. What they all have in common is a holistic approach to relieving suffering
and a goal to improve quality of life not only for patients but also for the patients’
whole ecosystem: their caregivers, families, friends, and clinicians. Second, the
meta-analyses suggested that palliative care interventions overall provided
benefits such as lower symptom burden, although improvements in other
outcomes, such as quality of life or survival, were mixed. In other words, the
common goal of palliative care is probably beneficial, but we still need to find
optimal interventions and better understand the outcomes we are seeking to
improve. Third, the studies included patients in a variety of settings but none with
critical or neurologic illness. This article focuses on those patients.
PALLIATIVE CARE IN THE INTENSIVE CARE UNIT

Nearly one in five Americans dies in an intensive care unit (ICU),7 and patients
who are critically ill and their families experience high rates of psychological
distress, including symptoms of depression, anxiety, and posttraumatic stress.8
Palliative care is already considered a core component of comprehensive
TABLE 11-2 SuPPOrTT Checklist for Daily Rounds in the Neurocritical Care Unit
◆ Su: Does the patient or family need social or spiritual Support or help with coping?
◆ P: Does the patient have Pain or other distressing symptoms?
◆ PO: Does the family have concerns about Prognosis or treatment Options?
◆ rTT: Do we need to readdress goals of care or Target Treatment toward patient-centered
goals?
1432 OCTOBER 2021

high-quality critical care, regardless of prognosis or treatment goals.9 Different KEY POINTS
models of palliative care integration in the ICU setting have been described: (1) a
● Patients in the
consultative model, in which palliative care consultants are called upon to neurocritical care unit face
provide a specific aspect of care to the patient without being part of the critical challenging treatment
care team; (2) an integrative model, in which palliative care is provided by the decisions but are
critical care team; or (3) a mixed model, in which consultative and integrative themselves typically unable
to participate, leaving
approaches are used in parallel.10 Several promising ICU interventions using an
families and clinicians to
interprofessional team to enhance clinician-family communication may improve make life-and-death
patient and family outcomes.11 However, a randomized trial of palliative care–led decisions on their behalf.
family meetings designed to discuss prognosis of patients requiring prolonged
mechanical ventilation was associated with increased posttraumatic stress in ● Palliative care is an
approach to medical care
family members.12 The palliative care team in this study met only once or that aims to relieve physical,
twice with the family, and the primary critical care team was present in a social, psychological, and
minority of these meetings. This study affirms the importance of a team spiritual suffering and
approach to family meetings. A randomized trial of a nurse-driven support improve communication
about end of life and quality
intervention for families of patients who were critically ill designed to promote of life for patients and their
family meetings with the primary ICU team and to provide family members families.
with emotional support showed improved family ratings of the quality of
communication and the patient- and family-centeredness of care.13 ● Most of the evidence
showing benefits of
palliative care intervention
NEUROPALLIATIVE CARE IN THE NEUROCRITICAL CARE UNIT comes from the cancer
The growing subspecialty of neuropalliative care suggests not only a growing literature, although some
recognition of the need for palliative care integration into neurology but also an nurse-led support
interventions in the general
understanding that the palliative care needs of patients with neurologic illness
intensive care unit literature
may differ from those of patients with non-neurologic disease.14,15 A study are promising.
comparing characteristics of inpatients with neurologic disease receiving a palliative
care specialist consultation to inpatients with cancer found that those with ● Progress in neurocritical
neurologic disease were older than those with cancer, more likely to be in the ICU, care with reduction in
morbidity and mortality has
and less likely to be able to communicate. They also had worse functional status brought with it a
and were more likely to die in the hospital, and the reason for their palliative care proliferation of choices that
consultation was more likely to assist with deescalation of life-sustaining treatment.16 require a compassionate
Neurocritical illness represents a major and sudden life-altering event for effective team approach to
decision making.
patients and their families and is marked by multiple iterative conversations and
serious treatment decisions that must be made along the trajectory. A study
comparing the rate of depression and anxiety among patients in the neurocritical
care unit and their family members to those with cancer found that patients in
the neurocritical care unit had greater anxiety than those with cancer, and family
members of patients in the neurocritical care unit had worse depressive
symptoms than family members of patients with cancer.17 To help target care in
the neurocritical care unit to individual patient and family needs, the author’s
institution developed and implemented a daily palliative care needs checklist that
is completed by clinicians during daily work rounds in the neurocritical care unit.
Its first iteration demonstrated that clinician-identified palliative care needs
were common (with 62% of patients showing such needs) and that most of these
needs revolved around social support needs and goals of care.18 The current
iteration of this checklist is shown in TABLE 11-2.
Most neurointensivists identify distinct palliative care needs for their patients
compared to other patients who are critically ill, in particular the complexity
and uncertainty of prognosis; however, the use of palliative care specialty
consultants in the neurocritical care unit varies widely.19 Qualitative analysis of

palliative care consultation notes in a single-center neurocritical care unit

identified four key themes in the consultations: discussing prognosis, eliciting
patient and family values, interpreting medical information, and addressing
conflict.20 The most common reason for consulting palliative care specialists for
neurocritically ill patients is assistance with clarifying goals of care and treatment
decisions, followed by providing family support.16,19,20
SURROGATE DECISION MAKERS

Given their brain injury, most patients in the neurocritical care unit are unable to
participate in treatment decisions, leaving their family members or surrogate
decision makers to make decisions on the patient’s behalf. The challenges here
are multiple. First, family members or surrogate decision makers may not know
what their loved one would want. In studies of patients and family surrogates
who were given hypothetical scenarios, the two parties agreed on standard acute
stroke treatments such as thrombolysis, but when asked about the use of
life-sustaining treatment for coma with predicted neurologic damage, agreement
between patients and surrogates was low.21,22 Second, the majority of patients in
the neurocritical care unit have not previously documented their treatment
preferences in the form of advance directives or advance care planning; even if
they have previously expressed their views, the views expressed are frequently
inadequate to the situation or limited to terminal or irreversible conditions.23 In
addition, advance care planning and surrogate decision making tend to consider
a patient’s past values while underestimating a person’s ability to adapt and their
future values.24 Third, family members are asked to make life-or-death
treatment decisions about their loved one, whom they are simultaneously
grieving and whose outcome will dramatically influence their own future. The
complexity of such decision making is evident. Clinicians must be aware of the
burden on surrogate decision makers and tailor their communication to each
individual’s needs.25
SHARED DECISION MAKING IN THE NEUROCRITICAL CARE UNIT

The majority of deaths in the neurocritical care unit are preceded by a decision to
withhold or withdraw life-sustaining treatment, and family members of patients
who die in the ICU experience high rates of psychological distress.26,27
High-quality shared decision making is therefore key to high-quality clinical
practice; this requires a deep knowledge of brain injury and brain recovery and of
technologically advanced life-sustaining treatments as well as good
communication and collaboration between clinicians and family and among
interdisciplinary team members.
Decision making in critical care is often conceptualized on a spectrum of the
physician’s role in decision making. On one end of this spectrum is parentalism,
in which the physician’s role is to direct treatment decisions with little input
from the patient or family. On the other end of this spectrum is autonomy or
“informed choice,” in which the physician provides only the medical facts
without opinion or recommendation, leaving the decision up to the family.
Between these two ends, the physician’s role can be facilitative or collaborative
(FIGURE 11-1).25,28 Clinicians adjust their role by two main factors: (1) the
patient’s diagnosis, prognosis, and treatment options and (2) the patient’s or
family’s preferred role. In some situations, the physician should be willing to
offer the family a recommendation and take on some of the burden of decision
1434 OCTOBER 2021

KEY POINT
● Neurocritical care unit

providers should engage in a
shared decision-making
process with grieving family
members who are also
surrogate decision makers
and integrate medical and
prognostic information with
their loved one’s presumed
goals of care.
FIGURE 11-1
Adaptive shared decision making. The physician’s role in shared decision making ranges from
a directing role to an informing role and is modified by clinical acuity, level of prognostic
certainty, and family role preference.
Data from Curtis JR, White DB, Chest25 and Bogetz J, et al, J Pain Symptom Manage.28
making (ie, be directive). These include settings of high acuity that do not allow
time for deliberation (eg, an acute large vessel occlusion ischemic stroke in the
emergency setting in which thrombectomy is time critical) or settings of high
prognostic certainty when offering the patient or family a choice where no
reasonable choice exists may give them a false sense of control or responsibility
for this decision. An example is a choice of whether to perform cardiopulmonary
resuscitation when a patient has a cardiac arrest in the setting of cerebral
herniation; offering cardiopulmonary resuscitation would not be a reasonable
option. Another example for a high prognostic certainty setting is the decision of
whether to perform a ventriculostomy in a patient with acute hydrocephalus in
whom prognosis with the intervention is clearly good and without it clearly not;
a more directive approach could relieve the decision maker of the decision
burden. Shared decision making also should be calibrated to the family’s
preferred role. This includes explicitly asking them what type of information
they want and what role they want to play and being sensitive to these
preferences changing over time. Although the majority of surrogate decision
makers prefer some type of shared decision-making process, a wide range of
preferences exists, from wanting to leave all decisions to the physician to wanting
to make the treatment decision on their own.29
COMMUNICATION IN THE NEUROCRITICAL CARE UNIT

Effective and compassionate communication is the key to a trusting
clinician-family relationship and a successful shared decision-making process.
Effective communication is also fundamental to cross-disciplinary teamwork, as
the care and decisions typically involve multiple providers (neurologists,
intensivists, neurosurgeons, physical medicine and rehabilitation specialists,
therapists, nurses, and palliative care providers) across multiple settings. Use of
effective communication techniques is a core competency for neurointensivists.
Although bedside updates may feel less threatening to families and can provide
an opportunity to keep one another informed, regular and proactive family
conferences are important. Ideally, the first meeting should occur early and focus

on information exchange and building a partnership between clinicians and

family rather than on decision making. Basic verbal and nonverbal skills for
clinicians are listed in TABLE 11-330 and illustrated in CASE 11-1. Anticipatory
guidance is the transparent communication of what might occur over the next
days or weeks and is a way to help family members prepare for anticipated
developments (eg, the ability to wean off the ventilator), expect complications
(eg, infections or thrombotic events), and plan for potential decisions that may
have to be made in due time (eg, extubation or percutaneous endoscopic
gastrostomy tube placement).
One specific tool to assist clinicians in their family conferences is a seven-step
clinicians’ guide to family conferences for serious illness produced by VitalTalk
(vitaltalk.org/topics/conduct-a-family-conference).31,32 The process begins
with a premeeting with all clinicians to discuss everyone’s opinion to avoid mixed
messages and agree on the goals for the family conference. The family conference
itself should start with all participants introducing themselves. The facilitator
should thank everyone for attending and explain the purpose of the meeting. The
next step follows the “Ask-Tell-Ask” strategy, beginning with asking the family
what they have already heard (eg, “What did you take away from your last
conversation with the doctors?”). Listening to the family describe their
experience often helps gauge their understanding, emotional state, and coping
mechanisms and helps determine where to start the medical update. The “tell”
aspect should focus only on the one or two key points the family should take
away from the conversation as too much information can be overwhelming. This
update will lead to an emotional reaction in the family, whether visible or not,
that needs to be acknowledged with an empathetic response (eg, “this is difficult
news”). Asking “Was I clear?” after giving new information can ensure
understanding while avoiding lecturing. An empathetic response reveals
empathy (the ability to recognize or sense someone’s emotion combined with the
ability to imagine what it might feel like) and is a key communication skill that
TABLE 11-3 Basic Verbal and Nonverbal Skills for Clinicians Conducting a Serious
Illness Conversationa
◆ Prepare in advance to understand the patient’s diagnosis, prognosis, and treatment options
◆ Prepare in advance to ensure the necessary members from the family and clinical teams are
present
◆ Provide a private, quiet, comfortable space where everyone can sit down
◆ Maintain eye contact
◆ Minimize medical jargon
◆ Ask open-ended questions
◆ Ask and listen to the family’s thoughts and feelings
◆ Check for understanding
◆ Use empathy to acknowledge concerns
a
Data from McFarlin JM, Barclay JS.30
1436 OCTOBER 2021

can help build the trust and rapport that are fundamental for decision making. KEY POINT
The next step is to prioritize the patient’s values by giving the patient a voice (eg,
● Neurocritical care unit
“What do we need to know about [patient name] as a person so that we can providers should master a
give them the best care possible?” or “What might [patient name] say if they primary palliative care skill
could see this?”). The final step is to present treatments or next steps that set that includes effective
align with the patient’s values and includes the offer of a recommendation, and compassionate
communication; elicitation
which some families may decline. This approach should be tailored to the
of patient values (goals of
individual family preferences, and all family members need to be offered care); disease-specific
the chance to share their concerns. The family conference should end with prognostication;
a clear plan for next steps; an assurance of continued support from the assessment and
management of pain and
medical team, including support for the family’s decision; and explicit
other distressing symptoms;
acknowledgment that it is hard to have a loved one in the ICU and to have and timely identification of
to make such decisions.25 social, spiritual, and
emotional support needs for
COMMUNICATING PROGNOSTIC UNCERTAINTY patients and their families.
A further challenge for shared decision making, especially in the neurocritical

care unit, is that prognosis is typically complex, and uncertainty tends to be the
rule. Uncertainty presents itself in two ways: the clinical uncertainty of how
much the patient might recover and the affective uncertainty of how the
patient and their family may emotionally adapt to future disability.33
Uncertainty can make clinicians feel powerless or inadequate, and adding
further tests is a common reflex in the futile hope for more certainty,
meanwhile avoiding the conversation with families. Instead, clinicians should
address the uncertainty with families. One way to acknowledge and
normalize the uncertainty is to describe a best case, worst case, and most likely
case and to recognize and attend to the emotions that accompany an uncertain
future.34 Although an overly optimistic prognosis may undermine trust,
families need a sense of hope when they are given uncertainty.35,36 Instead of
suggesting that substantial improvement is unrealistic or even impossible,
clinicians can help families reframe hope by focusing on goals that may be
more tangible.37 Tangible goals may include surviving for a certain amount of
time or allowing friends and families to gather, connect, or reconcile. Hoping
for the best at the same time as preparing for the worst can build a shared
perspective and strengthen the clinician-family relationship. In addition to
addressing the uncertainty with families, clinicians may also describe the
scenarios that are certain. For example, when the ultimate outcome (such as
eventual awakening or eventual regaining of independence) is uncertain,
some certainty often still exists in the short term, including the need for
prolonged ventilation or artificial nutrition.
Most situations in the neurocritical care unit require time for a clearer
prognosis to emerge and for families to fully grasp the illness and its implications.
Sometimes surgical procedures may be required to allow for more lasting
life-sustaining treatments, such as percutaneous endoscopic gastrostomy
tubes or tracheostomy. A time-limited trial is the judicious use of such
life-sustaining treatments over a defined period of time to see if the patient
recovers previously agreed-upon abilities. A time-limited trial can reduce
uncertainty and allow patients and families to deliberate their true or new
values.38,39 It is important that the agreement between clinicians and families
includes a plan for repeat conversations, reevaluation of the patient’s
trajectory, and review of patient- and family-centered goals; clinicians and

CASE 11-1 A 54-year-old man fell while putting up Christmas lights. Emergency
medical services noticed left hemiplegia and increasing somnolence.
Head CT in the emergency department showed a large right
intraparenchymal hemorrhage in the basal ganglia with intraventricular
extension and midline shift (FIGURE 11-2A). His family was available only by
phone; when contacted, they asked that everything be done to keep him
alive. He underwent emergent decompressive hemicraniectomy
(FIGURE 11-2B) and was admitted to the neurocritical care unit intubated and
unresponsive.
A family meeting with his wife and two children was held on day 2.
They described the patient as a very active and social man who would
never want to be dependent on anyone and tried to avoid the medical
system as much as he could. He also lived for his new grandson, and they
felt he would do anything to see him walk, talk, and grow up. The clinical
team described the significant brain injury he had incurred and the
medical care he was receiving and assured the family of the team’s
investment in his best possible outcome: “We are hopeful that he will get
better and also want you to know that he may very well get worse.”
On day 5, the patient was still unresponsive to voice or pain. Imaging
and clinical examination suggested additional left hemispheric
dysfunction. The clinicians described a best-case scenario in which he
would recover consciousness and be able to talk and interact with his
loved ones but would probably still need assistance with most activities,
such as dressing, toileting, and eating; in this best-case scenario, he
might, with a lot of help, return home eventually. The worst-case
scenario was described as him not waking up and requiring life support
for the long term. The most likely case was felt to be that he might be
awake some of the time but with limited ability to communicate verbally
and long-term dependence on artificial nutrition and hydration using a
feeding tube. The family members were asked to discuss with one
another what an “acceptable level of better” might be for the patient and
what kind of life might still be meaningful for him. They acknowledged
that the ability to think and communicate clearly were paramount for him
and that he would not want to be dependent on any medical support for a
prolonged period of time.
On day 9, the family decided that they would draw the line at a
tracheostomy. As breathing trials over the next few days were not
successful, the decision was made to extubate him to comfort measures
only. His grandson came in to say good-bye, and the spiritual counselor
made a handprint of the patient and his grandson’s hands together.
On day 12, the patient died within an hour of extubation, with his wife
and eldest son at his bedside.
1438 OCTOBER 2021

FIGURE 11-2
Imaging of a patient with an intraparenchymal hemorrhage. A, Axial head CT shows a large
right basal ganglia intraparenchymal hemorrhage with intraventricular extension and midline
shift. B, Axial head CT after decompressive hemicraniectomy shows removal of skull on the
right with placement of ventricular drain.
This case illustrates important principles of communicating with the family COMMENT
of a patient in the neurocritical care unit. The family conference starts with
the providers eliciting the patient’s values from the family (eg, “So that we
can take the best possible care of the patient, could you tell us a little bit
about him as a person?”). Then the clinicians provide an update on the
patient’s condition using a one-sentence headline. Hoping for the best
while at the same time preparing for the worst can help providers align with
the family and help the family sit with the uncertainty. One way to
communicate the uncertain prognosis is to describe a best case, worst
case, and most likely case, which may include describing possible
outcomes 6 to 12 months down the road and then coming back to describe
what the first months until then are likely to look like. When the decision has
been made to withhold or withdraw life-sustaining treatment (some
suggest using the phrase “let nature take its course” to illustrate that the
withdrawal of life-sustaining treatment is a natural way of dying), legacy
work can often help families process their grief. Legacy work is the
intentional process of building memories with or of the person they are
grieving. The involvement of spiritual counselors and child life specialists as
appropriate and available can be key.

hospitals should be prepared to provide this time. Fragmented care with

frequent transitions after hospital discharge tends to complicate clinicians’
ability to follow through, and families often ask for more support and
guidance over the long term.40
SPIRITUAL AND CROSS-CULTURAL CONSIDERATIONS

Regardless of their previous experience or practice, in situations of crisis and
despair, many people turn to religion or spirituality to find hope and support. In
the broadest sense, spiritual care can be seen as the emotionally sensitive,
empathetic care of the human spirit, which does not need to be specific to
religion in general or to any type of religion. Patients and families will often
welcome the conversation, and questions such as “What role does faith (religion,
spirituality) play in your (your loved one’s) life?” or “Would you like to talk to a
chaplain or spiritual care counselor?” can help provide comfort, relieve anxiety,
adjust management, and build trust.
Shared decision making can be challenging and emotionally charged even
between culturally and linguistically concordant families and clinicians; it is even
more complex when there are language barriers or when families have limited
health literacy or distrust the medical system. Being open to and aware of a
family’s religious or cultural preferences can help clinicians better understand
their decisions, especially when the family’s requests appear unrealistic or
non–evidence based.41 Medical and cultural interpreters can be helpful assets for
the team, and clinicians should meet with them before a family meeting.42
END-OF-LIFE CARE IN THE NEUROCRITICAL CARE UNIT

Most patients who die in the neurocritical care unit do so after the withholding or
withdrawal of life-sustaining treatment,43,44 with a wide variability of practices
across institutions, regions, and countries.45 Life-sustaining treatment may
include intubation and mechanical ventilation, artificial nutrition and hydration,
antibiotic treatment, brain surgery, or vasoactive support. The decision to
withdraw these treatments can only be made after careful consideration of
prognosis, treatment options, and patient values in a process of shared
deliberation.46 After the decision has been made, clinicians should counsel family
members about the anticipated time to death and signs and symptoms of
impending death and reaffirm continued support and nonabandonment during
the dying process. The most common type of withholding or withdrawal of
life-sustaining treatment in the neurocritical care unit is stopping mechanical
ventilation. Although most patients die within less than 24 hours after
extubation, some may continue to live for days or up to a week or two.43 Absence
of brainstem reflexes is associated with a shorter time to death after extubation.
In those who survive for days or more, signs of impending death include a change
in the breathing pattern or changes in skin color and urine output. Meticulous
assessment and treatment of pain or other distressing symptoms is key, and
medications such as morphine (IV or liquid oral) and benzodiazepines should be
available at all times. Although patients who are neurocritically ill generally have
a lower symptom burden than other patients who are seriously ill,47 they are also
less able to communicate their needs, requiring particular vigilance from
clinicians for any sign of discomfort.48 Symptoms that should be assessed and
documented when increasing sedation include tachypnea, tachycardia,
diaphoresis, grimacing, accessory muscle use, nasal flaring, and restlessness.
1440 OCTOBER 2021

Medications that do not contribute to relief of distressing symptoms should KEY POINTS
be discontinued, including antithrombotics or artificial nutrition or hydration.
● Prognostic uncertainty is
Antibiotics may occasionally be continued for pain relief (eg, in the setting of particularly common in the
meningitis or a urinary tract infection), and anticonvulsants should be continued neurocritical care unit.
for seizure prophylaxis. If a patient is unable to take medications by mouth and Helpful ways to
has neither parenteral nor IV access, benzodiazepines can be administered communicate this
uncertainty include
sublingually, intranasally, or rectally. For other distressing symptoms, such as
describing a best case,
pain, dyspnea, anxiety, or agitation, sublingual/liquid options also exist for worst case, and most likely
morphine, benzodiazepines, and haloperidol. case; supporting the family
in hoping for the best while
preparing for the worst; and
a mutual agreement on
CONCLUSION time-limited trials.
Neurocritical illness threatens the personhood and quality of life of patients and
their entire social environment. Palliative care, effective communication, and ● Most patients who die in
shared decision making require a set of core skills that all neurology clinicians the neurocritical care unit do
so after the withholding or
should master. withdrawal of life-sustaining
treatment. Providers should
provide guidance on timing
ACKNOWLEDGMENT and symptoms anticipated in
the last hours, days, or
This work was supported by a grant from the National Institute of Neurological weeks of life.
Disorders and Stroke (K23 NS099421).
USEFUL WEBSITES
CENTER TO ADVANCE PALLIATIVE CARE EPEC-N: EDUCATION IN PALLIATIVE AND END-OF-LIFE
The Center to Advance Palliative Care website CARE FOR NEUROLOGY
offers resources and online courses, including a EPEC-N educates health care professionals on
course on clinical communication skills. essential clinical competences of palliative and
capc.org/topics/communication-and- end-of-life care.
palliative-care inpcs.org/i4a/pages/index.cfm?pageid=3324
VITALTALK
VitalTalk offers resources for communicating
effectively with patients who are seriously ill,
including videos on disclosing serious news,
addressing goals of care, and conducting family
conferences.
vitaltalk.org
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REVIEW ARTICLE
Brain Death/Death by
Neurologic Criteria

Determination
ONLINE
By Ariane Lewis, MD; Matthew P. Kirschen, MD, PhD
ABSTRACT
PURPOSE OF REVIEW: This article describes the prerequisites for brain
death/death by neurologic criteria (BD/DNC), clinical evaluation for
BD/DNC (including apnea testing), use of ancillary testing, and challenges
associated with BD/DNC determination in adult and pediatric patients.
RECENT FINDINGS: Although death determination should be consistent among

physicians and across hospitals, states, and countries to ensure that
someone who is declared dead in one place would not be considered
alive elsewhere, variability exists in the prerequisites, clinical evaluation,
apnea testing, and use of ancillary testing to evaluate for BD/DNC.
Confusion also exists about performance of an evaluation for BD/DNC in
challenging clinical scenarios, such as for a patient who is on
extracorporeal membrane oxygenation or a patient who was treated with
therapeutic hypothermia. This prompted the creation of the World Brain
CITE AS: Death Project, which published an international consensus statement on
CONTINUUM (MINNEAP MINN) BD/DNC that has been endorsed by five world federations and 27 medical
1444–1464.
societies from across the globe.
Address correspondence to SUMMARY: The World Brain Death Project consensus statement is intended
Dr Ariane Lewis, Division of
to provide guidance for professional societies and countries to revise or
Neurocritical Care, Departments
of Neurology and Neurosurgery, develop their own protocols on BD/DNC, taking into consideration local
NYU Langone Medical Center, laws, culture, and resource availability; however, it does not replace local
530 First Ave, HCC-5A, New York,
NY 10016, ariane.kansas.lewis@
medical standards. To that end, pending publication of an updated
gmail.com. guideline on determination of BD/DNC across the lifespan, the currently
accepted medical standards for BD/DNC in the United States are the 2010
Dr Lewis serves as a deputy American Academy of Neurology standard for determination of BD/DNC in
editor for Neurology and adults and the 2011 Society of Critical Care Medicine/American Academy
Seminars in Neurology. of Pediatrics/Child Neurology Society standard for determination of
Dr Kirschen has received
research/grant support from BD/DNC in infants and children.
the Neurocritical Care Society.
UNLABELED USE OF
PRODUCTS/INVESTIGATIONAL INTRODUCTION
D
USE DISCLOSURE:
eath can be declared using cardiopulmonary or neurologic criteria
Drs Lewis and Kirschen report
no disclosures. (traditionally termed brain death). Brain death/death by neurologic
criteria (BD/DNC) is accepted as death throughout much of the
world.1,2 The incidence of BD/DNC declaration worldwide is
of Neurology. unknown, but epidemiologic studies have found that 2% to 12% of
1444 OCTOBER 2021

adult deaths in the United States and Europe and 20% of pediatric deaths in the KEY POINTS
United States are declared using neurologic criteria.2-4 Although BD/DNC is
● The incidence of brain
declared less frequently than death by cardiopulmonary criteria, it is imperative death/death by neurologic
(1) for neurologists to be adept at BD/DNC determination to prevent criteria declaration
false-positive declarations in which a person who is alive is declared dead and (2) worldwide is unknown, but
for the process to be consistent across hospitals, states, and countries to ensure epidemiologic studies have
found that 2% to 12% of adult
that someone who is declared dead in one place would not be considered alive
deaths in the United States
elsewhere. This article reviews the history of BD/DNC, the medical standards for and Europe and 20% of
BD/DNC determination, and some challenges associated with BD/DNC pediatric deaths in the
determination. United States are declared
using neurologic criteria.
HISTORY OF BRAIN DEATH/DEATH BY NEUROLOGIC CRITERIA ● The World Brain Death

The concept of BD/DNC was introduced in Europe in the 1950s when Mollaret Project standard is not
and Goulon5 noticed that some patients with catastrophic brain injuries who were intended to replace local
being maintained on ventilators were comatose, had no brainstem reflexes, medical standards; rather, it
aims to provide guidance for
and were unable to breathe spontaneously. In 1968, a multidisciplinary professional societies and
committee at Harvard Medical School introduced the first medical standard countries to revise or
for BD/DNC.6 The ensuing years led to the creation of additional medical develop their own protocols
standards for BD/DNC and the realization that BD/DNC needed to be on brain death/death by
neurologic criteria, taking
incorporated into law in order for society to accept it as death. In response, the into consideration local
President’s Commission for the Study of Ethical Problems in Medicine and laws, culture, and resource
Biomedical and Behavioral Research drafted a model statute on death availability.
determination, the Uniform Determination of Death Act.7 BD/DNC was
● Pending publication of an
subsequently accepted as death throughout the United States.8 The American
updated guideline on
Academy of Neurology (AAN) published a standard for BD/DNC in adults in determination of brain
1995 and updated it in 2010.9,10 The Task Force for Determination of Brain Death death/death by neurologic
in Children published a standard for BD/DNC in infants and children in 1987; criteria across all age groups
this was updated in 2011 by the Society of Critical Care Medicine (SCCM), beginning at birth, the 2010
American Academy of
American Academy of Pediatrics (AAP), and Child Neurology Society Neurology and 2011 Society
(CNS).11,12 of Critical Care Medicine/
Despite the existence of these standards and the fact that no aspects of the American Academy of
standards themselves are believed to inherently pose challenges to widespread Pediatrics/Child Neurology
Society standards remain
adoption, variability exists in the process of evaluation for BD/DNC between the current accepted
institutions within the United States13; further, determination of BD/DNC medical standards for brain
around the world is inconsistent.1 This prompted the creation of the World Brain death/death by neurologic
Death Project (WBDP), which published an international consensus statement criteria in the United States.
on BD/DNC that has been endorsed by five world federations and 27 medical
societies from across the globe.2 The WBDP standard is not intended to replace
local medical standards; rather, it aims to provide guidance for professional
societies and countries to revise or develop their own protocols on BD/DNC,
taking into consideration local laws, culture, and resource availability. Thus,
pending publication of an updated guideline on determination of BD/DNC across
all age groups beginning at birth, the 2010 AAN and 2011 SCCM/AAP/CNS
standards remain the current accepted medical standards for BD/DNC in the
United States.14,15
GENERAL PRINCIPLES
BD/DNC evaluations should only be performed by licensed practitioners who are
experienced in caring for patients with devastating brain injuries and have been
trained in determination of BD/DNC and in counseling families at the end of

BRAIN DEATH/DEATH BY NEUROLOGIC CRITERIA
life.2 Although no formal credentialing is required for determination of BD/DNC

at present, residency and fellowship programs should ensure trainees are
appropriately educated about this topic via didactics, simulations, and direct
observation of and participation in the evaluation of patients with catastrophic
brain injuries. Additional training is also available online through the Neurocritical
Care Society.16 To prevent false-positive declarations of death, practitioners must
take a conservative approach and be scrupulous and attentive to details. A
BD/DNC evaluation should never be rushed. Further, practitioners must be
familiar with local guidelines and laws regarding determination of BD/DNC.2
PREREQUISITES FOR BRAIN DEATH/DEATH BY NEUROLOGIC CRITERIA

Performance of an evaluation for BD/DNC should only be considered if a patient
is comatose, has absent brainstem reflexes, and is not breathing spontaneously
because of a known etiology that can cause catastrophic irreversible brain injury.
Examples of etiologies that can lead to BD/DNC include hypoxic-ischemic brain
injury, hemorrhagic stroke, ischemic stroke, traumatic brain injury, bacterial
meningitis, viral encephalitis, hepatic encephalopathy, and obstructive
hydrocephalus.2 Mimics of BD/DNC include fulminant Guillain-Barré
syndrome, botulism, high cervical cord injuries, snake bites, and rabies.2 Even
when a mechanism that is known to potentially lead to catastrophic irreversible
brain injury is identified, it is necessary to ensure the assessment is not
confounded by circumstances that could falsely suggest BD/DNC, such as
hypotension, hypothermia, or hypoglycemia.2,10,12
The minimum acceptable blood pressure for a BD/DNC evaluation in adults is
a systolic pressure ≥100 mm Hg or a mean arterial pressure ≥60 mm Hg.2,10
In pediatric patients, the systolic or mean arterial blood pressure should not be
less than 2 standard deviations below age-appropriate norms.2,12
TABLE 12-1 Medications That Could Lead to False-positive Declaration of Brain

Death/Death by Neurologic Criteriaa
◆ Antibiotics (aminoglycosides, ethambutol, isoniazid, tetracyclines)

◆ Antiepileptic drugs
◆ Baclofen
◆ Barbiturates
◆ Benzodiazepines
◆ Dexmedetomidine
◆ IV/inhaled anesthetics
◆ Narcotics
◆ Propofol
◆ Tricyclic antidepressants
◆ Zolpidem
IV = intravenous.
a
Practitioners must be aware of medications that could lead to false-positive declaration of brain
death/death by neurologic criteria. Examples are provided here, but this list is not exhaustive.
1446 OCTOBER 2021

The minimum acceptable temperature for a BD/DNC evaluation is ≥36 °C KEY POINTS
(≥96.8 °F) according to the 2010 AAN and WBDP standards and >35 °C (>95 °F)
● To prevent false-positive
according to the 2011 SCCM/AAP/CNS standard.2,10,12 Additional guidance declarations of death,
regarding BD/DNC evaluation after treatment with therapeutic hypothermia is practitioners must take a
discussed later in this article. conservative approach and
Although some countries provide clear guidance on the lower and upper limits be scrupulous and attentive
to details.
for electrolytes, pH, and hormones before BD/DNC evaluation, no scientific
rationale exists for the selection of values; as a result, the 2010 AAN, 2011 ● Examples of etiologies
SCCM/AAP/CNS, and WBDP standards recommend the need to exclude that can lead to brain
“severe” derangements.1,2,10,12 death/death by neurologic
Finally, it is necessary to ensure that medications or drugs that can depress criteria include
hypoxic-ischemic brain
the central nervous system or yield pharmacologic paralysis have been injury, hemorrhagic stroke,
metabolized or cleared before BD/DNC evaluation (TABLE 12-1).2,10,12 A ischemic stroke, traumatic
BD/DNC evaluation should not be performed until at least 5 half-lives have brain injury, bacterial
passed following administration of medications that depress the central meningitis, viral
encephalitis, hepatic
nervous system (CASE 12-1).2,10,12 Additional time may be warranted to ensure encephalopathy, and
clearance of medications that depress the central nervous system in the presence obstructive hydrocephalus.
of renal or hepatic dysfunction, recent hypothermia, or obesity. When
evaluating neonatal and pediatric patients, it should also be noted that ● Mimics of brain
death/death by neurologic
pharmacokinetics of medications vary by age. To evaluate for the residual
criteria include fulminant
presence of drugs, serum or urine toxicology screens can be employed, but it Guillain-Barré syndrome,
should be noted that the utility of these tests is limited as they do not evaluate for botulism, high cervical cord
all agents or provide quantified drug levels. injuries, snake bites, and
rabies.
No finite observation period before evaluation for BD/DNC has been
established.2,10,12 Rather, it is necessary for practitioners to err on the side of
caution when determining the appropriate time to perform a BD/DNC
evaluation, taking the mechanism of injury (particularly in the setting of
hypoxic-ischemic brain injury, in which recovery can be delayed), neuroimaging
findings, intracranial pressure, blood pressure, temperature, laboratory values,
medication or drug effects, social factors, and the patient’s age into
consideration. Infants with open fontanelles and unfused sutures may not have
the characteristic rise in intracranial pressure and subsequent brain herniation
due to cerebral edema as older children and adults with a rigid skull.
Additionally, the infant’s brainstem is more resistant to hypoxic-ischemic brain
injury than other brain structures. This may lead to the emergence of brainstem
reflexes or spontaneous respirations several days after the injury when the
cerebral edema subsides. Thus, longer observation periods, particularly after
hypoxic-ischemic brain injury, should be considered in infants and young
children.12 TABLE 12-2 provides a summary of the prerequisites for BD/DNC
included in the 2010 AAN, 2011 SCCM/AAP/CNS, and WBDP standards.2,10,12
CLINICAL EXAMINATION FOR BRAIN DEATH/DEATH BY

NEUROLOGIC CRITERIA
Once the prerequisites for BD/DNC have been met, a clinical evaluation is
performed to assess for coma, absence of motor response of the face and extremities,
and brainstem areflexia (TABLE 12-3). Of note, a number of conditions can
preclude completion of the clinical evaluation and necessitate ancillary testing. In
these situations, it is essential to perform all parts of the clinical examination that can
be completed, and they must be consistent with BD/DNC to declare BD/DNC
(ie, ancillary testing augments, but does not replace, the clinical evaluation). These

CASE 12-1 A 45-year-old woman with a history of hypertension was found

unresponsive on the sidewalk. She was intubated by emergency medical
services. Head CT revealed a large left basal ganglia hemorrhage with
intraventricular extension leading to moderate hydrocephalus and 1 cm
of midline shift (FIGURE 12-1). On a fentanyl drip, she had no response
to voice or pain, her pupils were 4 mm and unreactive bilaterally, and
corneal and oculovestibular reflexes were absent. However, cough and
gag reflexes were present, she was overbreathing the ventilator, and she
extended her right arm and leg but was
plegic on the left. She was given
hypertonic saline and mannitol and
started on nicardipine.
The following day, she no longer
had cough and gag reflexes, was not
overbreathing the ventilator, and did
not move any extremities in response
to pain. Fentanyl was stopped, and
no further hypertonic saline or
mannitol was administered.
Twenty-four hours later, she continued
to show no clinical evidence of
neurologic activity. Renal and hepatic
function were normal. Her blood
pressure was 130/80 mm Hg, and
FIGURE 12-1
her temperature was 36.5 °C Imaging of the patient in CASE 12-1. Axial
(97.7 °F). An evaluation for brain noncontrast head CT shows a large left
death/death by neurologic criteria basal ganglia hemorrhage extending to
(BD/DNC), including an apnea test, the bilateral thalami (as well as to the
midbrain and pons [not shown]).
was performed. She was Intraventricular extension, 1 cm of
subsequently declared dead by left-to-right midline shift, and
neurologic criteria. moderate hydrocephalus are seen.
COMMENT This patient was comatose because of a known etiology (intracerebral

hemorrhage). Although hypertonic saline and mannitol were initially
administered when they were felt to potentially provide therapeutic
benefit, they were discontinued once the injury progressed as it is not
necessary to perform interventions to decrease intracranial pressure if
they are not felt to be beneficial simply for the purpose of demonstrating
irreversibility of the clinical state. As the half-life of fentanyl is about
4 hours and the patient had no renal or hepatic dysfunction, an evaluation
for BD/DNC was delayed 24 hours (over 5 half-lives) from the time that
fentanyl was discontinued.2 Her blood pressure and temperature were
above the minimum threshold for BD/DNC evaluation. Thus, all
prerequisites were met.
1448 OCTOBER 2021

conditions include, but are not limited to, severe neuromuscular disorders/sensory KEY POINTS
neuropathies, spinal cord injuries, orbital/facial trauma/swelling/chemosis,
● Conditions that can
ophthalmic surgery, anophthalmia, and a ruptured tympanic membrane.2,10,12 preclude completion of the
To deem patients comatose with absent motor response of the face or clinical evaluation for brain
extremities, it is necessary to demonstrate that they are unresponsive to tactile, death/death by neurologic
auditory, and visual stimulation and make no cerebrally mediated movements criteria and thus necessitate
ancillary testing include, but
following application of painful tactile stimulation to the face and two locations
are not limited to, severe
on each extremity (or on the side of the body if an extremity is missing).2,10,12 neuromuscular
Numerous spinally mediated reflexes have been observed in patients who meet disorders/sensory
clinical criteria for BD/DNC, including myoclonus, spontaneous extensor neuropathies, spinal cord
injuries, orbital/facial
posturing, intermittent head turning, slow flexion then extension of the toes
trauma/swelling/chemosis,
(undulating toe), and isolated thumb extension (thumbs-up sign). These ophthalmic surgery,
responses have been confirmed to originate below the level of the brainstem via anophthalmia, and a
ancillary testing.2 If it is unclear whether a finding is cerebrally mediated, it is ruptured tympanic
necessary to consult with another practitioner or perform ancillary testing membrane.
following completion of the clinical examination and apnea test.2 ● Numerous spinally
The brainstem reflexes included in the 2010 AAN and WBDP standards are mediated reflexes have
the pupillary, corneal, oculocephalic, oculovestibular, gag, and cough reflexes.2,10 been observed in patients
The 2011 SCCM/AAP/CNS standard includes all of these reflexes except the who meet clinical criteria for
brain death/death by
oculocephalic reflex. The 2011 SCCM/AAP/CNS standard, like the WBDP neurologic criteria, including
standard, also notes the need to confirm absence of the sucking and rooting myoclonus, spontaneous
reflexes in neonates and infants.2,12 To be compatible with BD/DNC, the extensor posturing,
pupillary reflex assessment should demonstrate fixed midsize or dilated pupils intermittent head turning,
slow flexion then extension
bilaterally that are unresponsive to direct or consensual stimulation.2,10,12 A
of the toes (undulating toe),
magnifying glass can help facilitate assessment for a pupillary response. Use of and isolated thumb
a pupillometer may also be considered, but this has not been validated. The extension (thumbs-up sign).
corneal reflex is assessed by applying light pressure to the cornea at the external
border of the iris with a cotton swab on a stick to evaluate for eyelid movement,
which is absent in BD/DNC.2,10,12 The oculocephalic reflex is tested by briskly
rotating the head horizontally and evaluating for eye movements, the presence of
which is not compatible with BD/DNC.2,10,12 This should not be done if
evidence or suspicion of cervical injury exists.2,10 The oculovestibular reflex tests
the same nerves as the oculocephalic reflex and is, in fact, more sensitive. Thus,
in the setting of known or suspected cervical trauma when the oculocephalic
reflex cannot be performed, BD/DNC can still be declared clinically if the
oculovestibular reflex is absent.2 Before testing the oculovestibular reflex, the
auditory canal should be inspected to confirm it is patent and that the tympanic
membrane is intact (note that a ruptured membrane would lead to a stronger
response, if present, but could increase the risk of meningitis, which could be
harmful if the examination is not consistent with BD/DNC). With the head of
bed elevated to 30 degrees, 50 mL to 60 mL of cold water should be injected into
the ear while the eyes are monitored for movement for at least 1 minute. This
should be repeated on the other side following a 5-minute interval that facilitates
equilibration of the endolymph temperature.2,10,12 The gag and cough reflexes are
assessed by stimulating both sides of the posterior pharynx and the
tracheobronchial wall.2,10,12 In neonates and infants, the sucking reflex is assessed
by placing a gloved finger in the baby’s mouth to see if sucking occurs (ie, if the
lips close around the finger) and the rooting reflex is assessed by stroking the
cheeks bilaterally to see if the baby’s head moves (which indicates a
positive response).2,12

TABLE 12-2 Prerequisites for Brain Death/Death by Neurologic Criteria
2011 Society of Critical Care

Medicine, American
Academy of Pediatrics, and
2010 American Academy of Child Neurology Society
Neurology Medical Standards for Standards for BD/DNC in
Component BD/DNC in Adults10 Infants and Children12 World Brain Death Project2
Etiology Establish cause of coma through Establish that patient has a Establish cause of coma
history, examination, neuroimaging, known diagnosis that has
Exclude mimicking conditions
and laboratory tests resulted in irreversible coma
Exclude mimicking conditions Exclude mimicking conditions
Observation period Insufficient evidence to determine Assessment of neurologic Ensure an adequate

before the (first) the minimally acceptable function may be unreliable observation period (erring on
neurologic observation period to ensure immediately following the side of caution) before
examination irreversible loss of function of the cardiopulmonary evaluation
brain resuscitation or other severe
Minimum of 24 hours after
acute brain injuries, and
resuscitated cardiac arrest,
evaluation for brain death
rewarming after therapeutic
should be deferred for 24 to
hypothermia or birth asphyxia
48 hours or longer if concerns
or inconsistencies in the
examination exist
First examination may be
performed 24 hours after birth
Irreversibility Establish that brain injury is Establish that brain injury is Establish that brain injury is
irreversible irreversible irreversible
Neuroimaging should Suggested to ensure
demonstrate evidence of an neuroimaging evidence of
acute central nervous system intracranial hypertension is
injury consistent with the present or intracranial
profound loss of brain pressure measurements equal
function or exceed mean arterial
pressure
It is not necessary to perform
interventions to decrease
intracranial pressure simply for
the purpose of demonstrating
irreversibility of the clinical
state
Temperature >36 °C (96.8 °F) >35 °C (95 °F) ≥36 °C (96.8 °F)
Blood pressure Systolic blood pressure Systolic or mean arterial blood Systolic blood pressure
≥100 mm Hg pressure should not be less ≥100 mm Hg or mean arterial
than 2 standard deviations pressure ≥60 mm Hg in adults
below age-appropriate norms and age-appropriate in
pediatric patients
1450 OCTOBER 2021


Medicine, American
Neurology Medical Standards for Standards for BD/DNC in
Component BD/DNC in Adults10 Infants and Children12 World Brain Death Project2
Exclude intoxication Exclude intoxication by any Exclude intoxication by any Exclude intoxication by any
substance that can depress the substance that can depress substance that can depress
central nervous system by history, the central nervous system the central nervous system by
drug screen, ensuring serum level is (alcohol, antiepileptic drugs, drug screen, ensuring serum
below the therapeutic range, and barbiturates, IV/inhaled level does not exceed the
waiting at least 5 half-lives, taking anesthetics, opioids, therapeutic range, and waiting
hepatic or renal dysfunction into sedatives) by ensuring serum at least 5 half-lives, taking
consideration level is in the low to hepatic or renal dysfunction
midtherapeutic range and into consideration
Ensure blood alcohol level is below
waiting several half-lives
0.08% Ensure blood alcohol level is
Exclude alcohol intoxication ≤80 mg/dL
by checking levels
Exclude Ensure presence of four twitches Evaluate nerve function with a Exclude pharmacologic
pharmacologic with maximum ulnar stimulation nerve stimulator paralysis with a peripheral
paralysis nerve stimulator/train-of-
foura or by demonstrating
presence of deep tendon
reflexes
Laboratory Exclude severe electrolyte, acid- Identify and treat reversible Correct severe metabolic,
parameters base, and endocrine disturbance causes of coma that interfere acid-base, and endocrine
with the clinical evaluation, derangements that could
including severe electrolyte impact the examination
derangements,
hyperglycemia or
hypoglycemia, severe pH
disturbances, severe hepatic
or renal dysfunction, and
inborn errors of metabolism
BD/DNC = brain death/death by neurologic criteria.

a
A peripheral nerve stimulator/train-of-four delivers a small electric current to the ulnar nerve to evaluate for the presence of muscle twitches to
confirm absence of pharmacologic neuromuscular blockade (four twitches). This can be performed at the bedside by any clinician/nurse.

TABLE 12-3 Clinical Examination/Examiner Specifications for Brain Death/Death by

Neurologic Criteria

2010 American Academy of Medicine, American Academy of
Neurology Medical Pediatrics, and Child Neurology
Standards for BD/DNC in Society Standards for BD/DNC in
Component Adults10 Infants and Children12 World Brain Death Project2
Number of One Two One
examiners
Qualifications of Not stated Attending physicians who are Practitioners who have completed
examiners qualified and competent to training, are licensed to
perform the brain death independently practice medicine,
examination and are trained in determination of
BD/DNC, counseling families at
Specialty of pediatric critical care,
end of life, and managing
pediatric neurology, neonatology,
devastating brain injuries
pediatric anesthesiology with
critical care training, pediatric Pediatric patients should be
neurosurgery, or pediatric trauma evaluated by experienced
surgery pediatric clinicians with specialty
in neonatology, neurosurgery,
Adult specialists should have
pediatric critical care, pediatric
appropriate neurologic and critical
neurointensive care, pediatric
care training to diagnose brain
neurology, or trauma surgery
death when caring for the pediatric
patient from birth to 18 years of age
Number of One Two One in adults and two in pediatric

examinations patients
Observation Not stated 12 hours (>30 days-18 years of age) If two examinations are
period between performed, an observation period
24 hours (37 weeks estimated
examinations between examinations is
gestational age to 30 days)
unnecessary
Components of Assessment for Assessment for unresponsiveness Assessment for unresponsiveness

clinical unresponsiveness
examination
Assessment for absence of Assessment for absence of motor Assessment of absence of motor
motor response of face/ response of face/extremities response of face/extremities
extremities
Assessment for absence of Assessment for absence of Assessment for absence of
pupillary light reflex pupillary light reflex pupillary light reflex
Assessment for absence of Assessment for absence of Assessment for absence of
oculocephalic and oculovestibular reflex oculocephalic and oculovestibular
oculovestibular reflexes reflexes
Assessment for absence of Assessment for absence of corneal Assessment for absence of
corneal reflex reflex corneal reflex
Assessment for absence of Assessment for absence of gag and Assessment for absence of gag
gag and cough reflexes cough reflexes and cough reflexes
Assessment for absence of sucking Assessment for absence of
and rooting reflexes (neonates and sucking and rooting reflexes
infants) (neonates)
1452 OCTOBER 2021

Concordant with the 2010 AAN and 2011 SCCM/AAP/CNS standards,
the WBDP standard indicates that the minimum number of clinical
examinations for BD/DNC is one for adults and two for pediatric patients.2,10,12
However, around the world, the minimum number of clinical examinations
for BD/DNC varies.1 The rationale for conducting more than one
examination is that it decreases the potential for diagnostic error and may
increase familial confidence in a declaration of BD/DNC.2 However, no
physiologic reason exists for why more than one examination is needed or for
the number of examinations to differ by age. The 2011 SCCM/AAP/CNS
standard notes that the observation period between the first and second
clinical examination should be 24 hours for neonates between 37 weeks
estimated gestational age and 30 days of age and 12 hours for infants and
children older than 30 days of age to 18 years of age.12 Again, no data support
any particular length of an observation period. As a result, the WBDP
standard emphasizes that an adequate observation period should be allowed
before evaluation for BD/DNC, but that no scientific rationale exists for an
interexamination observation period if more than one examination
is performed.2
APNEA TESTING
Upon completion of the clinical evaluation, if a patient is found to be comatose
and have absent brainstem reflexes, barring a contraindication, the next
step is apnea testing (TABLE 12-4). Contraindications to apnea testing described
in the 2010 AAN, 2011 SCCM/AAP/CNS, and WBDP standards include severe
obesity or chronic obstructive pulmonary disease (2010 AAN standard), high
cervical spine injury (2011 SCCM/AAP/CNS and WBDP standards), chronic
hypoxemia due to cyanotic heart disease (WBDP standard), or any safety
concerns (2011 SCCM/AAP/CNS standard).2,10,12
The purpose of apnea testing is to determine if the medullary chemoreceptors,
which should stimulate respiration in the setting of hypercarbia and acidosis, are
functional.2,10,12,17 Following preoxygenation, the apnea test is performed by
removing intermittent mechanical ventilation and observing for spontaneous
respirations. In adults, hypoxia is avoided by placing an insufflation catheter that
is less than 70% of the endotracheal tube diameter down the endotracheal tube
and delivering up to 6 L/min of oxygen (these limits are in place to decrease the
risk of a pneumothorax); continuous positive airway pressure (CPAP) can also
be used if needed.2,10,17 In infants and children, tracheal insufflation generally is
not performed because of a heightened concern that their lower lung capacity
can put them at higher risk for washout of carbon dioxide, which can delay or
prevent completion of the test, or barotrauma to the lungs.2,17 Thus, in this age
group, oxygenation is provided via a T-piece circuit connected to the
endotracheal tube with a functioning positive end-expiratory pressure valve or
CPAP with a flow-inflating anesthesia bag or ventilator.2,12,18
Although the carbon dioxide level and pH at which the medullary
chemoreceptors would definitively stimulate respiration if they were functional
is unknown, the 2010 AAN standard indicates that the target PaCO2 is ≥60 mm
Hg or ≥20 mm Hg above baseline and the 2011 SCCM/AAP/CNS standard
indicates that the target PaCO2 is ≥60 mm Hg and ≥20 mm Hg above
baseline.10,12,17 However, the meaning of “baseline” is unclear in both of these
standards and, similar to the majority of standards for BD/DNC around the

TABLE 12-4 Apnea Testing for Brain Death/Death by Neurologic Criteria

Medicine, American
Neurology Medical Standards Standards for BD/DNC in
Component for BD/DNC in Adults10 Infants and Children12 World Brain Death Project2
Number of apnea One Two One in adults and two in pediatric

tests patients
Contraindications Prior evidence of carbon High cervical spine injury High cervical spine injury
dioxide retention (severe
Safety concerns for the Chronic hypoxemia due to
obesity or chronic obstructive
patient (eg, high oxygen cyanotic heart disease
pulmonary disease)
requirement or ventilator
settings)
Technique Preoxygenate for at least Preoxygenate for 5-10 minutes Preoxygenate for at least
10 minutes with 100% oxygen to with 100% oxygen 10 minutes with 100% oxygen
PaO2 >200 mm Hg
Ensure normalization of the Ensure PaCO2 35-45 mm Hg
Ensure PaCO2 35-45 mm Hg pH and PaCO2, measured by
Preserve oxygenation with an
arterial blood gas analysis
Reduce ventilator frequency to insufflation catheter placed
10 breaths per minute Discontinue intermittent through the endotracheal tube
mandatory ventilation (except in neonates, infants, or
Reduce positive end-expiratory
young children)
pressure to 5 cm H2O Attach a T-piece circuit or a
self-inflating bag valve Consider use of CPAP on the
Disconnect the ventilator
system such as a Mapleson ventilator or via resuscitation bag
Preserve oxygenation with an circuit to the endotracheal
insufflation catheter placed tube or use CPAP if needed
through the endotracheal tube
delivering 100% oxygen at 6 L/min
Use T-piece circuit or
continuous positive airway
pressure (CPAP), if needed
Apnea testing PaCO2 ≥60 mm Hg or ≥20 mm Hg PaCO2 ≥60 mm Hg pH <7.3 and PaCO2 ≥60 mm Hg
target above baseline and ≥20 mm Hg above unless the patient has preexisting
baseline hypercapnia, in which case target
should be ≥20 mm Hg above
baseline, if known
Reasons to abort Systolic blood Hemodynamic instability Spontaneous respirations

testing pressure <90 mm Hg witnessed
Oxygen saturation <85%
Oxygen saturation <85% for Systolic blood pressure
PaCO2 level of ≥60 mm Hg
>30 seconds <100 mm Hg or mean arterial
cannot be achieved
pressure <60 mm Hg
Sustained oxygen desaturation <85%
Unstable arrhythmia
1454 OCTOBER 2021

world, these standards do not emphasize the impact of acidosis on the medullary KEY POINTS
chemoreceptors by providing a pH target.1,2,10,12 This has been remedied in
● If the complete clinical
the WBDP standard, which indicates the target for apnea testing should assessment is performed
be pH <7.3 and PaCO2 ≥60 mm, unless the patient has preexisting hypercapnia, and found to be consistent
in which case the target should be ≥20 mm Hg above their baseline, if with brain death/death by
known.2 The rate of CO2 rise is approximately 3 mm Hg to 5 mm Hg neurologic criteria, the pH
and PaCO2 thresholds are
per minute.17
reached during the apnea
In line with the recommendations on the number of clinical evaluations test, and the patient does
needed to declare BD/DNC, the 2010 AAN and WBDP standards state that only not take any breaths, the
one apnea test is needed to declare BD/DNC in adults, whereas the 2011 patient is declared dead at
the time the arterial blood
SCCM/AAP/CNS and WBDP standards recommend performance of two apnea
gas results are reported.
tests for pediatric patients.2,10,12 Around the world, the number of apnea tests
required to declare BD/DNC ranges from one to three.1 Again, no data support ● Although EEG was
the performance of more than one apnea test. included in the 1968 Harvard
If the complete clinical assessment is performed and found to be consistent standard and is considered
an acceptable ancillary test
with BD/DNC, the pH and PaCO2 thresholds are reached during the apnea test, in the 2010 AAN and 2011
and the patient does not take any breaths, the patient is declared dead at the time SCCM/AAP/CNS standards,
the arterial blood gas results are reported.2 If two clinical examinations the World Brain Death
and apnea tests are performed and are consistent with BD/DNC, death is Project standard suggests it
only be used if mandated by
declared at the time the arterial blood gas results are reported after the second regional policy or law or if
apnea test.2 craniovascular impedance is
affected by an opening in
ANCILLARY TESTING the skull (such as a skull
fracture or open fontanelle),
If a portion of the clinical evaluation or the apnea test cannot be completed or
leading to concerns about
uncertainty exists about the interpretation of findings on the clinical the accuracy of a blood flow
evaluation, the 2010 AAN, the 2011 SCCM/AAP/CNS, and the WBDP study.
standard all note that ancillary testing is needed.2,10,12 The 2011
SCCM/AAP/CNS standard states that ancillary testing can also be used to ● Clearance of carbon
dioxide on extracorporeal
reduce the interexamination observation period. It further specifies that membrane oxygenation is
ancillary testing can be performed if medication effect may be present or if it influenced by the rate of
is felt that this would be helpful for family members to understand the sweep gas flow through the
diagnosis of BD/DNC.12 Similarly, the WBDP standard notes that ancillary oxygenator, so the sweep
gas flow rate is reduced to
testing is needed in the setting of uncertainty about drug elimination or severe 0.5 L/min to 1 L/min during
laboratory derangements that cannot be corrected and are felt to potentially apnea testing to facilitate
be contributing to loss of brain function.2 Although the 2010 AAN and 2011 accumulation of carbon
SCCM/AAP/CNS standards, like the WBDP standard, promote the dioxide in the arterial blood.
whole-brain formulation of death by neurologic criteria (as opposed to the
● When a patient is on
brainstem formulation that is used in some other parts of the world, most venoarterial extracorporeal
notably the United Kingdom), only the WBDP standard specifies that membrane oxygenation,
ancillary testing is needed in the setting of isolated brainstem pathology if the arterial blood should be
sampled simultaneously
whole-brain formulation is being followed (TABLE 12-5).1,2,10,12
from both the patient’s
The purpose of ancillary testing is to evaluate for loss of intracranial blood flow arterial catheter and the
or loss of electrical activity in the brain. A number of tests are currently used extracorporeal membrane
around the world for this purpose, including EEG, evoked potentials, four-vessel oxygenation circuit
catheter angiography, radionuclide cerebral perfusion scan, transcranial postoxygenator to ensure
the pH and carbon dioxide in
Doppler, CT, and magnetic resonance angiography (MRA).2,19 However, pitfalls the cerebral circulation
are associated with all these tests, and, as BD/DNC is first and foremost a clinical exceed the brain
evaluation, none are 100% sensitive or specific.2,19,20 The 2010 AAN, 2011 death/death by neurologic
SCCM/AAP/CNS, and WBDP standards all consider four-vessel catheter criteria thresholds.
angiography and radionuclide cerebral blood flow scan to be acceptable ancillary

tests.2,10,12 The 2010 AAN and WBDP standards consider transcranial Doppler to
be an acceptable ancillary test in adults. Given that transcranial Doppler has not
been validated as an ancillary test in pediatrics, it is not included in the 2011
SCCM/AAP/CNS standard, and the WBDP standard recommends it not be used
in pediatrics until more studies determine its utility in this population.2,10,12
Although EEG was included in the 1968 Harvard standard and is considered an
acceptable ancillary test in the 2010 AAN and 2011 SCCM/AAP/CNS standards,
the WBDP standard suggests it only be used if mandated by regional policy or
law or if craniovascular impedance is affected by an opening in the skull (such as
TABLE 12-5 Ancillary Testing for Brain Death/Death by Neurologic Criteria

2010 American Academy of Medicine, American Academy of
Neurology Medical Pediatrics, and Child Neurology
Standards for BD/DNC in Society Standards for BD/DNC in
Component Adults10 Infants and Children12 World Brain Death Project2
Indications Components of the Components of the examination Components of the examination

examination cannot be cannot be completed because of the cannot be completed because of the
completed because of the underlying medical condition underlying medical condition
underlying medical condition
Uncertainty about the reliability of Uncertainty regarding interpretation
Uncertainty about the parts of the neurologic examination of spinal-mediated motor reflexes
reliability of parts of the
Apnea test cannot be performed High cervical spine injury
neurologic examination
Medication effect may be present Uncertainty about drug elimination
Apnea test cannot be
performed Reduce interexamination observation Severe metabolic, acid-base, or
period endocrine derangements that cannot
be corrected and are judged to
May be helpful for social reasons,
potentially be contributing to loss of
allowing family members to better
brain function
comprehend the diagnosis of BD/DNC
The whole-brain death formulation is
being followed and there is isolated
brainstem pathology
Law/regional guidance mandates
ancillary testing
Acceptable Four-vessel catheter Four-vessel catheter angiography Four-vessel catheter angiography

tests angiography
EEG Radionuclide cerebral blood flow
EEG scan
Radionuclide cerebral blood flow
Radionuclide cerebral blood scan Transcranial Doppler (adults only)
flow scan
EEG only if mandated by regional law
Transcranial Doppler or policy or if craniovascular
impedance has been affected by
open skull fracture, decompressive
craniectomy, or an open fontanelle/
sutures, in which case it should be
performed in conjunction with
somatosensory and brainstem
auditory evoked potentials
BD/DNC = brain death/death by neurologic criteria; EEG = electroencephalography.
1456 OCTOBER 2021

A 5-year-old previously healthy boy with a recent viral upper respiratory CASE 12-2
infection presented to the emergency department with fever, decreased
oral intake, and altered mental status. In the emergency department, he
was tachycardic and hypotensive, so he was given crystalloid fluid. He
subsequently became pulseless and unresponsive. He was intubated and
cardiopulmonary resuscitation was initiated. Cardiopulmonary
resuscitation was performed for 75 minutes with return of circulation
after cannulation onto venoarterial extracorporeal membrane
oxygenation (ECMO). He was diagnosed with viral myocarditis. His
cardiac, renal, and hepatic function improved over the next few days.
On ECMO day 3, he was noted to be hypertensive and bradycardic and
had unreactive pupils. Head CT demonstrated severe hypoxic-ischemic
injury with loss of gray-white differentiation and extensive cerebral
edema with herniation. His family was updated about the imaging and his
clinical examination and was told that the team was concerned he may
have lost all function of the brain and may meet criteria for brain death/
death by neurologic criteria (BD/DNC). Sedatives and neuromuscular
blockade were stopped. Forty-eight hours later, he showed no evidence
of neurologic recovery. Deep tendon reflexes were present. After
ensuring confounders were excluded and the prerequisites were met, a
clinical evaluation for BD/DNC was performed. He was found to be
comatose with brainstem areflexia. Following preoxygenation through
the ventilator and the ECMO circuit, an arterial blood gas revealed pH of
7.4, PaCO2 of 40 mm Hg, and PaO2 of 210 mm Hg. The sweep gas flow was
reduced to 0.5 L/min, and the patient was placed on continuous positive
airway pressure (CPAP) with a flow-inflating anesthesia bag with a
positive end-expiratory pressure equivalent to the ventilator positive
end-expiratory pressure. Serial blood gases were sent from the patient’s
radial arterial line and the ECMO circuit postoxygenator to measure pH
and PaCO2. After 12 minutes, both blood gases showed pH <7.3 and
PaCO2 ≥60 mm Hg. The clinical examination and apnea test were repeated
the following day, and death was declared.
This patient had severe hypoxic-ischemic brain injury after a prolonged COMMENT
cardiac arrest due to myocarditis and was cannulated onto venoarterial
ECMO. BD/DNC evaluation was appropriately initiated after waiting a
sufficient time to allow for clearance of sedating medications and after
meeting all prerequisites. Following completion of the clinical examination,
the apnea test was performed on ECMO. The patient was taken off
mechanical ventilation, and the sweep gas flow was reduced to allow
carbon dioxide to accumulate in the blood. The practitioners ensured that
the PaCO2 levels from both the arterial catheter and the ECMO circuit
postoxygenator were above the BD/DNC thresholds. If the patient had
been too hemodynamically unstable to undergo apnea testing or the test
could not be completed because of hypotension or hypoxemia, ancillary
testing could have been performed.

a skull fracture or open fontanelle), leading to concerns about the accuracy of a

blood flow study.2,10,12 This is attributed to the fact that EEG primarily assesses
the cortex and can be confounded by drugs/medications, hypothermia, and
metabolic derangements.2
After performance of as much of the clinical assessment and apnea test as can
be completed, if the findings are consistent with BD/DNC and ancillary testing is
consistent with BD/DNC, the time of death is the time that the ancillary test
results are formally interpreted and documented.2
DETERMINATION OF BRAIN DEATH/DEATH BY NEUROLOGIC CRITERIA

IN PATIENTS ON EXTRACORPOREAL MEMBRANE OXYGENATION
Although adults and children who are being supported by extracorporeal
membrane oxygenation (ECMO) may require evaluation for BD/DNC, only the
WBDP standard provides guidance about how to do so.2 The prerequisites for the
BD/DNC evaluation do not change for patients on ECMO. The ECMO circuit can
be used to help control temperature and blood pressure before and during the
BD/DNC evaluation. For patients on venoarterial ECMO with limited native
cardiac output, only the mean arterial pressure threshold is targeted. Similarly,
FIGURE 12-2
Examples of what to say when talking to families about brain death/death by neurologic
criteria. Communication about brain death/death by neurologic criteria can be challenging.
These examples can help to educate families while empathizing with them about their family
member’s catastrophic brain injury.
1458 OCTOBER 2021

A 60-year-old woman was admitted to the intensive care unit with a CASE 12-3
catastrophic intracerebral hemorrhage. On hospital day 1, the neurologist
explained to the patient’s daughter that the patient had sustained a
very serious injury to her brain. The neurologist explained that the patient
still showed subtle signs of brain function but that it was possible the
injury to the brain would worsen and she would lose these functions. The
neurologist further noted that loss of all functions of the brain would
mean that the patient was legally dead, just as if her heart and lungs had
stopped working.
On hospital day 2, the neurologist explained to the patient’s daughter
that her mother was still comatose, had shown no signs of neurologic
recovery, and no longer had evidence of brain function. The neurologist
told the daughter that the next step would be to conduct a formal
evaluation to assess for brain death/death by neurologic criteria (BD/
DNC). The daughter objected to this evaluation, noting that she was not
ready to lose her mother, that her mother did not look like she was dead,
and that she wanted to give her mother more time to recover. The
neurologist explained that nothing could be done to improve her
mother’s condition and that neurologic recovery was impossible. The
neurologist showed the daughter her mother’s imaging and performed a
complete neurologic examination for her, explaining the findings as she
went. She reviewed that the purpose of a formal BD/DNC evaluation was
to follow a strict detailed protocol to determine if her mother showed
any signs of neurologic function. The neurologist noted that if even a
single brainstem reflex was present, it would mean her mother was alive.
However, if her mother were unresponsive, had no brainstem reflexes,
and could not take any breaths when she was taken off the ventilator and
the carbon dioxide level reached the appropriate threshold that should
stimulate the base of the brain leading to a breath if it were functional, it
would mean her mother was legally dead and that organ support would
be discontinued. After further discussions that included a social worker
and a spiritual counselor, the daughter and neurologist agreed that the
examination would be performed the following day. The next morning,
the evaluation was completed with the patient’s daughter at the bedside.
The patient’s daughter was tearful throughout but accepted the
declaration of death and subsequent discontinuation of organ support.
Patience and empathy are needed when discussing BD/DNC with a COMMENT
patient’s family. Education, including a review of imaging and
demonstration of the neurologic examination, helps families come to terms
with the severity and irreversibility of a patient’s catastrophic brain injury.
Although consent is not needed to conduct a BD/DNC evaluation, it is
appropriate to allow a family a brief period of time to process the situation.
Multidisciplinary support for a patient’s family from both hospital staff and
the family’s community can be beneficial.

the clinical examination is unchanged for patients on ECMO. Care should be

taken to avoid displacing ECMO cannulas during procedures such as testing for
the oculocephalic reflex.
The physiologic principles of apnea testing are the same for patients who
require extracorporeal support as for those who do not. Patients must
demonstrate absence of spontaneous respirations in the setting of hypercarbia
and acidosis. Apnea testing can often safely be conducted in patients
supported on both venoarterial and venovenous ECMO, although it must be
recognized that the potential for hemodynamic instability requiring the test to
be aborted is higher in this patient population.2,21 Patients should be
TABLE 12-6 Communication About Brain Death/Death by Neurologic Criteria

Medicine, American Academy
of Pediatrics and Child
2010 American Academy of Neurology Society Standards
Neurology Medical Standards for BD/DNC in Infants and
Component for BD/DNC in Adults10 Children12 World Brain Death Project2
Communication Inform patient’s surrogate about Physicians are obligated to Health care teams should be
before testing the intent to perform an provide support and guidance trained in cultural sensitivity and
evaluation for BD/DNC for families as they face difficult communication and treat all
end-of-life decisions and persons and families with respect
attempt to understand what has
Families should be provided with
happened to their child
support and education before
Permitting families to be present BD/DNC evaluation, during the
during the evaluation can help evaluation, and after
them understand that their child discontinuation of organ support
has died
A multidisciplinary support team
should be included in discussions
about BD/DNC
Families should be invited to
observe the evaluation
Reasonable efforts should be
made to notify the patient’s next
of kin before a BD/DNC
evaluation
Need for consent No obligation to obtain consent Not discussed No obligation to obtain consent
before the clinical evaluation,
apnea testing, or ancillary testing
1460 OCTOBER 2021

preoxygenated through both the ventilator and the ECMO circuit. As with
conventional apnea testing, patients are removed from intermittent
mechanical ventilation and provided apneic oxygenation, typically either by
tracheal insufflation or CPAP via a flow-inflating anesthesia bag or the
ventilator. Clearance of carbon dioxide on ECMO is influenced by the rate of
sweep gas flow through the oxygenator, so the sweep gas flow rate is reduced
to 0.5 L/min to 1 L/min during apnea testing to facilitate accumulation of
carbon dioxide in the arterial blood.2
Unique to apnea testing on venoarterial ECMO as compared with apnea
testing on venovenous ECMO or off ECMO, it is necessary to ensure that the

Medicine, American Academy
of Pediatrics and Child
2010 American Academy of Neurology Society Standards
Neurology Medical Standards for BD/DNC in Infants and
Component for BD/DNC in Adults10 Children12 World Brain Death Project2
Management of No ethical obligation to provide Communication with families Seek guidance from local ethical
objections to organ support to a deceased must be clear and concise using team, legal team, and
BD/DNC person simple terminology so that administration
parents and family members
No legal obligation to provide Attempt to handle requests to
understand that their child has
indefinite accommodation in the forgo a BD/DNC evaluation or
died
United States outside of New continue organ support after
Jersey It should be made clear that BD/DNC within a hospital
once death has occurred, system before turning to the legal
Involve mediators (spiritual
continuation of medical system
counselor, mental health
therapies, including ventilator
professionals, palliative care It is reasonable to continue
support, is no longer an option
specialists, ethicists) support after BD/DNC for a finite
unless organ donation is planned
period, assuming the period is
Attempt to transfer a patient to
Appropriate emotional support brief and uniform and the family is
another facility as a last resort
for the family should be informed of the time frame in
Unilateral withdrawal of organ provided, including adequate advance, but this period should
support is acceptable as a last time to grieve with the child not ordinarily exceed 48 hours
resort when supported by law after death is declared
Families should be informed that
and institutional policy and the
there will be no escalation of
patient is not pregnant
treatment, including
cardiopulmonary resuscitation
Invite a second physician to
provide a second opinion
Provide a finite time for the family
to arrange transfer to another
facility
Organ support should be
discontinued if a hospital bed is
required for a living patient and
no other bed is available

measured arterial pH and carbon dioxide represent the values in the cerebral
circulation.2 Oxygenated blood can arise from native cardiac output (after gas
exchange in the native lungs) and mix with oxygenated blood from the ECMO
circuit. Therefore, when a patient is on venoarterial ECMO, arterial blood should
be sampled simultaneously from both the patient’s arterial catheter and the
ECMO circuit postoxygenator to ensure the pH and carbon dioxide in the
cerebral circulation exceed the BD/DNC thresholds.2 CASE 12-2 illustrates apnea
testing for a patient on venoarterial ECMO. The WBDP standard does not
address ancillary testing for patients on ECMO, but a 2020 review of the
literature noted that all the ancillary tests used in patients who are not on ECMO
have been used in patients on ECMO.21
DETERMINATION OF BRAIN DEATH/DEATH BY NEUROLOGIC CRITERIA

AFTER TREATMENT WITH THERAPEUTIC HYPOTHERMIA
Hypothermia can lead to reversible brainstem areflexia and coma, particularly
when it is used in conjunction with drugs or medications that depress the central
nervous system.2 In two cases in the literature, a declaration of BD/DNC was
made prematurely following treatment with therapeutic hypothermia.22,23
Despite this, aside from denoting a minimum temperature at which it is
acceptable to perform a BD/DNC evaluation, the 2010 AAN and 2011
SCCM/AAP/CNS standards, like most standards around the world, do not
provide guidance on the length of time necessary to delay performance of a
BD/DNC evaluation in a patient who was previously treated with therapeutic
hypothermia.1,2,10,12 To prevent false-positive declarations of BD/DNC after
treatment with therapeutic hypothermia, the WBDP standard delineates the
timetable to delay evaluation for BD/DNC in this setting.2 If the clinical
examination appears consistent with BD/DNC, neuroimaging is recommended
to assess for severe cerebral edema and brainstem herniation. It is
recommended to delay the evaluation for a minimum of 24 hours after
rewarming is complete or longer, depending on when the most recent
medication that could depress the central nervous system was administered.
As with all patients undergoing evaluation for BD/DNC, it is recommended to
wait at least 5 half-lives to ensure adequate clearance of medications that
depress the central nervous system, but a longer duration may be needed as
hypothermia can affect pharmacokinetics and pharmacodynamics. Clearance
can also be reduced because of concomitant hepatic or renal dysfunction. If
uncertainty exists regarding the residual effects of medications or effects due
to hypothermia, an ancillary study should be performed to assess for absence
of intracranial blood flow in addition to the complete clinical evaluation
and apnea test.2
COMMUNICATION ABOUT BRAIN DEATH/DEATH BY

NEUROLOGIC CRITERIA
Family education about BD/DNC should begin as soon as a practitioner believes a
patient might meet criteria for BD/DNC.24 In addition to being timely,
communication must be clear and consistent. Practitioners should be empathetic,
patient, and culturally sensitive during discussions about BD/DNC and recognize
that public understanding of BD/DNC is poor because of misinformation
promulgated by the media, television, and movies.25,26 The fact that BD/DNC is
legal death, equivalent to loss of function of the heart and lungs, should be
1462 OCTOBER 2021

explained. Examples of phrases to use during these discussions are included in KEY POINTS
FIGURE 12-2. Although practitioners should make reasonable efforts to inform a
● Hypothermia can lead to
patient’s surrogate/health care proxy about the intent to perform an evaluation reversible brainstem
for BD/DNC, the WBDP standard and guidance published by the AAN in areflexia and coma,
2019 note that consent is not required to complete a BD/DNC evaluation, particularly when it is used in
including apnea testing or ancillary testing.2,15 However, practitioners should be conjunction with drugs or
medications that depress
aware that families sometimes object to performance of an evaluation for
the central nervous system.
BD/DNC or discontinuation of organ support after BD/DNC for a number of
reasons, including distrust, hope that the patient will regain neurologic function, ● Practitioners should be
grief, guilt, and religious or moral belief that death does not occur until the heart empathetic, patient, and
stops beating.24,27 Objections should be handled in a consistent manner by culturally sensitive during
discussions about brain
practitioners in conjunction with a multidisciplinary team that includes social death/death by neurologic
workers, spiritual counselors, ethicists, palliative care specialists, hospital criteria and recognize that
administrators, and hospital lawyers, as appropriate (CASE 12-3). TABLE 12-6 public understanding of
reviews recommendations on communication about BD/DNC and strategies to brain death/death by
neurologic criteria is poor
employ if families object to BD/DNC evaluation.2,10,12 because of misinformation
promulgated by the media,
television, and movies.
CONCLUSION
● Although practitioners
BD/DNC determination is a nuanced process that must be performed
should make reasonable
thoughtfully and carefully to prevent false-positive declarations of death. efforts to inform a patient’s
Neurologists in the United States should be familiar with the 2010 AAN and 2011 surrogate/health care proxy
SCCM/AAP/CNS standards, which are the currently accepted standards for about the intent to perform
an evaluation for brain
BD/DNC determination pending publication of a uniform standard for the entire
death/death by neurologic
lifespan. They should also be aware of the content of the WBDP standard, criteria, the World Brain
which provides updated consensus-based guidance endorsed by five world Death Project standard and
federations and 27 medical societies from across the globe on numerous facets of guidance published by the
BD/DNC, including the science behind BD/DNC, the minimum accepted criteria American Academy of
Neurology in 2019 note that
for BD/DNC, BD/DNC evaluation for a patient on ECMO, BD/DNC evaluation consent is not required to
after treatment with therapeutic hypothermia, and management of requests to complete a brain
forgo a BD/DNC evaluation or continue organ support after BD/DNC.2 death/death by neurologic
criteria evaluation, including
apnea testing or ancillary
testing.
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of brain death/death by neurologic criteria: the School to examine the definition of brain
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4 Kirschen MP, Francoeur C, Murphy M, et al.
Office, 1981.
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jamapediatrics.2019.0249 death. J Law Med Ethics 2017;45(1):112-128.
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9 Wijdicks EF. Determining brain death in 18 Puccetti DF, Morrison W, Francoeur C, et al.
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DM, American Academy of Neurology.
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1464 OCTOBER 2021

LIST OF ABBREVIATIONS
Neurocritical Care GFAP Glial fibrillary acidic protein

GRE Gradient recalled echo
HIV Human immunodeficiency virus
ICD-10 International Classification of Diseases, Tenth Revision
AAN American Academy of Neurology
ICH Intracerebral hemorrhage

AAP American Academy of Pediatrics
ICHD-3 International Classification of Headache Disorders,
ACA Anterior cerebral artery Third Edition
ACE2 Angiotensin-converting enzyme 2 ICP Intracranial pressure
AChR Acetylcholine receptor ICU Intensive care unit
ACNS American Clinical Neurophysiology Society IM Intramuscular
ADC Apparent diffusion coefficient INR International normalized ratio
ADEM Acute disseminated encephalomyelitis ISAT International Subarachnoid Aneurysm Trial
AHA American Heart Association IV Intravenous
AIDP Acute inflammatory demyelinating polyradiculoneuropathy IVH Intraventricular hemorrhage
AIDS Acquired immunodeficiency syndrome IVIg Intravenous immunoglobulin
AQP4 Aquaporin-4 LRP4 Lipoprotein receptor-related protein 4
AMAN Acute motor axonal neuropathy MAP Mean arterial pressure
AMSAN Acute motor-sensory axonal neuropathy MCA Middle cerebral artery
ARDS Acute respiratory distress syndrome MEP Maximal expiratory pressure
ASA American Stroke Association MG Myasthenia gravis
ASIA American Spinal Injury Association MIP Maximal inspiratory pressure
AVM Arteriovenous malformation MRA Magnetic resonance angiography
BD/DNC Brain death/death by neurologic criteria MRI Magnetic resonance imaging
CAA Cerebral amyloid angiopathy mRNA Messenger ribonucleic acid
CBF Cerebral blood flow mRS Modified Rankin Scale
CDC Centers for Disease Control and Prevention MuSK Muscle-specific tyrosine kinase
CIDP Chronic inflammatory demyelinating NIHSS National Institutes of Health Stroke Scale
polyradiculoneuropathy
NINDS National Institute of Neurological Disorders and Stroke
CMAP Compound muscle action potential
NMDA N-methyl-
-methyl-D-aspartate
CMRO2 Cerebral metabolic rate of oxygen consumption
NMO Neuromyelitis optica
CNS Central nervous system; Child Neurology Society
NORSE New-onset refractory status epilepticus
CPAP Continuous positive airway pressure
PbtO2 Brain tissue oxygen tension
CPP Cerebral perfusion pressure
PCR Polymerase chain reaction
CSF Cerebrospinal fluid
PNS Peripheral nervous system
CT Computed tomography
PRES Posterior reversible encephalopathy syndrome
CTA CT angiography
RCVS Reversible cerebral vasoconstriction syndrome
CVST Cerebral venous sinus thrombosis
RNA Ribonucleic acid
DAMP Damage-associated molecular pattern
rtPA Recombinant tissue plasminogen activator
DCI Delayed cerebral ischemia
SAH Subarachnoid hemorrhage
DSA Digital subtraction angiography
SARS Severe acute respiratory syndrome
DVT Deep venous thrombosis
SARS-CoV Severe acute respiratory syndrome coronavirus
DWI Diffusion-weighted imaging
SARS-CoV-2 Severe acute respiratory syndrome coronavirus 2
ECG Electrocardiogram
SCCM Society of Critical Care Medicine
ECMO Extracorporeal membrane oxygenation
SDH Subdural hemorrhage
EEG Electroencephalography
SIADH Syndrome of inappropriate secretion of antidiuretic
EGRIS Erasmus GBS Respiratory Insufficiency Score hormone
EMG Electromyography STIR Short tau inversion recovery
EVD External ventricular drain SWI Susceptibility-weighted imaging
FDA US Food and Drug Administration TBI Traumatic brain injury
FLAIR Fluid-attenuated inversion recovery TCD Transcranial Doppler
fMRI Functional magnetic resonance imaging TNF-a Tumor necrosis factor-a
GAD Glutamic acid decarboxylase VEGF Vascular endothelial growth factor
GBS Guillain-Barré syndrome WBDP World Brain Death Project
GCS Glasgow Coma Scale WFNSS World Federation of Neurological Surgeons Scale

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OCTOBER 2021

Guest Editor: Katharina M. Busl, MD, MS, FAAN

1170 Editor’s Preface

1172 Management of Cerebral Edema, Brain Compression,

1201 Subarachnoid Hemorrhage

1246 Intracerebral Hemorrhage

1278 Moderate and Severe Traumatic Brain Injury

1301 Posterior Reversible Encephalopathy Syndrome and Reversible

1321 Seizures, Status Epilepticus, and Continuous EEG in the Intensive

1344 Neuromuscular Disorders in the Intensive Care Unit

DENOTES VIDEO 1365 Acute Neurologic Manifestations of Respiratory Viruses

1382 Neurologic Complications in the Postoperative Neurosurgery

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

1430 Palliative Care and Shared Decision Making in the Neurocritical

1444 Brain Death/Death by Neurologic Criteria Determination

SELF-ASSESSMENT AND CME

1164 Learning Objectives and Core Competencies

1465 Instructions for Completing Postreading Self-Assessment and CME

1467 Postreading Self-Assessment and CME Test

1479 Postreading Self-Assessment and CME Test—Preferred Responses

List of Abbreviations (Back Cover)

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

Katharina M. Busl, MD, MS, Sherry Hsiang-Yi Chou, MD,

Associate Professor, Neurology Division of Neurocritical Care,

Torrey Boland Birch, MD

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Relationship Disclosure: Dr Liotta serves on Unlabeled Use of Products/Investigational

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Christopher P. Robinson, Aarti Sarwal, MD, FNCS, FAAN,

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Unlabeled Use of Products/Investigational

Self-Assessment and CME Test Writers

Nuri Jacoby, MD Allyson R. Zazulia, MD

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of patients with neurologic disorders in the intensive care unit

1170 OCTOBER 2021

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By Eric M. Liotta, MD, MS

RECENT FINDINGS: Cerebral edema and brain compression should be treated

1172 OCTOBER 2021

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CASE 1-1 A 58-year-old woman presented to the emergency department comatose

1174 OCTOBER 2021

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and macromolecules generate an osmotic pressure, which, combined with

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space is then exposed to a fluid source,

1176 OCTOBER 2021

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1178 OCTOBER 2021

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1180 OCTOBER 2021

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● CSF functions as the

● Lundberg A waves reflect

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occur from cycles of cerebral vasodilation precipitated by episodes of reduced

1182 OCTOBER 2021