REVIEW ARTICLE
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CONTINUUM (MINNEAP MINN)
2018;24(6, NEUROCRITICAL CARE):
1588–1602.
Address correspondence to
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Punchbowl St, Neuroscience
Institute QET5, Honolulu, HI
96816, mkoenig@queens.org.
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© 2018 American Academy
of Neurology.
1588
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Cerebral Edema
and Elevated Intracranial
Pressure
By Matthew A. Koenig, MD, FNCS
ABSTRACT
PURPOSE OF REVIEW: This article reviews the management of cerebral edema,
elevated intracranial pressure (ICP), and cerebral herniation syndromes
in neurocritical care.
RECENT FINDINGS: While corticosteroids may be effective in reducing vasogenic
edema around brain tumors, they are contraindicated in traumatic cerebral
edema. Mannitol and hypertonic saline use should be tailored to patient
characteristics including intravascular volume status. In patients with
traumatic brain injury who are comatose, elevated ICP should be managed
with an algorithmic, multitiered treatment protocol to maintain an ICP of
22 mm Hg or less. Third-line ICP treatments include anesthetic agents,
induced hypothermia, and decompressive craniectomy. Recent clinical
trials have demonstrated that induced hypothermia and decompressive
craniectomy are ineffective as early neuroprotective strategies and should
be reserved for third-line management of refractory ICP elevation in
severe traumatic brain injury. Monitoring for cerebral herniation should
include bedside pupillometry in supratentorial space-occupying lesions
and recognition of upward herniation in patients with posterior fossa
lesions.
SUMMARY: Although elevated ICP, cerebral edema, and cerebral herniation
are interrelated, treatments should be based on the distinct
pathophysiologic process. Focal lesions resulting in brain compression
are primarily managed with surgical decompression, whereas global or
multifocal brain injury requires a treatment protocol that includes medical
and surgical interventions.
INTRODUCTION
levated intracranial pressure (ICP), cerebral edema, and cerebral
herniation syndromes are distinct but overlapping processes in
neurocritical care. Management of elevated ICP and cerebral edema is
heavily dependent on the underlying mechanism and clinical context.
In patients with cerebral edema, determination of whether the patient
has vasogenic edema, cytotoxic edema, or hydrostatic edema is a critical first
step in identifying the most effective management strategy. Determining
whether elevated ICP is caused by global elevation in intracranial volume or focal
DECEMBER 2018
injury that results in displacement of the brain is also crucial in choosing
appropriate treatments. This article focuses on the etiology and treatment of
cerebral edema in the neurocritical care setting, current concepts in the
treatment of intracranial hypertension, and cerebral herniation syndromes.

CEREBRAL EDEMA
Cerebral edema results from the pathologic accumulation of excess water within
the brain parenchyma. Vasogenic edema results from increased permeability
of the blood-brain barrier with extravasation of proteins, electrolytes, and water
into the parenchymal extracellular compartment. Common etiologies of
vasogenic edema include intraaxial and extraaxial brain tumors and cerebral
abscess. Vasogenic edema disproportionately affects subcortical white matter
with relative sparing of the cerebral cortex and subcortical gray matter. Cytotoxic
edema is caused by disruption of cell membranes within the brain parenchyma,
resulting in water shifts from the extracellular to the intracellular compartment.
The most common cause of cytotoxic edema is ischemic stroke. Less common
etiologies include hepatic encephalopathy and Reye syndrome. Traumatic brain
injury (TBI) and intracerebral hemorrhage (ICH) result in a combination of
cytotoxic and vasogenic edema. Cytotoxic edema affects both gray matter and
white matter structures, resulting in loss of cortical-subcortical distinction on
imaging studies. Hydrostatic cerebral edema results from transependymal
displacement of CSF from the ventricular compartment into the brain parenchyma,
typically due to obstructive hydrocephalus. Cerebral edema contributes to an
increase in intracranial volume. Global cerebral edema primarily results in a
global rise in ICP, while focal cerebral edema can result in cerebral herniation
syndromes with or without ICP elevation.

Treatment of Cerebral Edema

Treatment strategies for cerebral edema are heavily contingent on the underlying
etiology and type of cerebral edema. The mainstay of treatment of hydrostatic
edema due to obstructive hydrocephalus is CSF diversion, typically by placement
of an external ventricular drain (EVD). Depending on the underlying etiology,
vasogenic cerebral edema is treated with corticosteroids, osmotic agents, and
surgical decompression. Treatment options for cytotoxic edema are much more
limited. While osmotic agents have been used as a temporizing measure, the
evidence for efficacy is poor, and surgical decompression may be considered in
the appropriate clinical context.1

CORTICOSTEROIDS. Dexamethasone has been a mainstay of treatment for

peritumoral vasogenic edema for both intraaxial and extraaxial brain tumors
since the 1960s. The role of corticosteroids in the treatment of vasogenic edema
from cerebral abscess is less clear. Despite widespread use, few clinical trials have
been conducted to determine the efficacy, optimal dose, and appropriate
duration of corticosteroids for vasogenic edema.2 Dexamethasone is typically
started at a dose of 4 mg every 6 hours, and subsequent dose adjustments are
based on the clinical course. For brain tumors that are amenable to surgical
resection and radiation, dexamethasone may be tapered off over several weeks.
For patients with untreatable brain tumors, the dose of dexamethasone may need
to be increased over time as a palliative measure. In the acute treatment of
peritumoral edema, dexamethasone use should be limited to patients who have

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CEREBRAL EDEMA AND ELEVATED INTRACRANIAL PRESSURE

significant symptoms attributable to cerebral edema rather than focal neurologic

involvement from the tumor itself.2 These symptoms include severe headache
and depressed mental status from displacement of the brain. Caution should be
applied in patients with newly discovered brain tumors awaiting tissue diagnosis
when central nervous system lymphoma is a consideration; although uncommon,
early initiation of corticosteroids can result in nondiagnostic biopsy specimens
due to tumor necrosis.3 Outside of central nervous system lymphoma treatment,
early initiation of corticosteroids has not been proven to alter the clinical
course of brain tumors.
Corticosteroids have not demonstrated efficacy in the treatment of cytotoxic
cerebral edema, and routine use of dexamethasone was not recommended in
the latest American Heart Association (AHA) guideline for the management
of cerebral and cerebellar infarction with swelling.1 Similarly, routine use of
corticosteroids is not recommended for cerebral edema related to spontaneous
ICH.4 For patients with TBI, the CRASH (Corticosteroid Randomisation After
Significant Head Injury) trial was conducted to compare mortality rates of
patients treated with 48 hours of methylprednisolone compared to placebo.
This clinical trial showed significantly increased mortality among patients with
severe TBI who were treated with corticosteroids.5 The 2017 Brain Trauma
Foundation guidelines state, “In patients with severe TBI, high-dose
methylprednisolone was associated with increased mortality and is
contraindicated.”6

OSMOTIC AGENTS. The mainstays of osmotic therapy in the treatment of cerebral

edema in neurocritical care are mannitol and hypertonic saline. Hypertonic
saline can be administered in several different concentrated solutions depending
on institutional practices, ranging from 2% to 23.4%; 3% saline is commonly
administered in 250 mL to 500 mL boluses either on an as-needed or standing
basis (eg, 250 mL every 6 hours), while 23.4% is typically administered as a
30 mL bolus over 10 to 15 minutes. Faster administration of hypertonic saline
may cause hypotension. A central line is required for administration of
hypertonic saline more concentrated than 3% to avoid peripheral vascular injury.
Hypertonic saline can also be administered as a continuous infusion, particularly
in patients who have cerebral edema in the setting of serum hyponatremia.
Most neurointensivists advise against increasing the serum sodium level above
160 mmol/L, and the safety and efficacy of iatrogenic hypernatremia beyond this
value is not well studied.7 Frequent administration of hypertonic saline may
result in hyperchloremic metabolic acidosis, which has been associated with
higher mortality in patients with ICH.8 Buffering hypertonic saline with acetate
may reduce the risk of metabolic acidosis in this circumstance.
Mannitol is a potent osmotic diuretic most commonly delivered as a 20%
concentrated solution in a dose range of 0.5 g/kg IV to 2 g/kg IV either as a scheduled
or as-needed bolus. Administration of mannitol requires use of an in-line filter
because mannitol may crystallize, especially at lower storage temperatures. For
this reason, mannitol administration is not recommended through temperature
exchange catheters. Continuous infusion of mannitol is not recommended
because mannitol may permeate across a disrupted blood-brain barrier and
cause rebound cerebral edema.9 Most neurointensivists recommend routine
monitoring of serum osmolality in patients being treated with frequent doses of
mannitol with avoidance of routinely increasing the serum osmolality to more

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than 320 mOsm/kg or an osmolar gap of more than 20 mOsm/kg. The osmolar KEY POINTS
gap is the difference between the measured and calculated osmolality, where
● Corticosteroids are
osmolality is calculated as: ineffective for the treatment
of cytotoxic edema and are
2ðNaÞ þ blood urea nitrogen=2:8 þ glucose=18
contraindicated in the
However, observational studies have shown a low incidence of deleterious treatment of patients with
severe traumatic brain
effects, including acute kidney injury, in patients with inadvertent elevation in
injury.
osmolality to 340 mOsm/kg.10
The choice of osmotic agent for a particular patient should be tailored to ● Frequent administration
volume status, serum sodium concentration, and other patient-specific factors. of hypertonic saline may
As a rule of thumb, hypertonic saline is preferred in patients who would benefit cause hyperchloremic
metabolic acidosis, which is
from volume expansion (eg, patients with the combination of hypovolemic associated with higher
shock and cerebral edema), while mannitol is preferred in patients who would mortality in neurocritical
benefit from the diuretic effect. care. Buffering hypertonic
The evidence for effectiveness of osmotic therapy in patients with cytotoxic solutions with acetate may
lower the chance of
edema from ischemic stroke is relatively weak.11 Because cytotoxic edema is developing hyperchloremic
caused by disruption of cell membrane and blood-brain barrier integrity, osmotic metabolic acidosis.
agents can permeate into infarcted brain tissue rather than remaining within the
intravascular compartment. Osmotic agents may accumulate over time, resulting ● Serum osmolality should
be monitored in patients
in rebound cerebral edema. Nevertheless, mannitol and hypertonic saline are
treated with frequent
often used as a temporizing measure in both ischemic stroke and ICH with mass doses of mannitol. Mannitol
effect as a bridge to more definitive surgical management. For patients near the should be held when serum
period of peak edema, scheduled doses of mannitol or hypertonic saline alone osmolality exceeds
320 mOsm/kg to
may provide enough time for spontaneous resolution of cytotoxic edema. In the
340 mOsm/kg or when
AHA guideline for cerebral and cerebellar infarction with swelling, there was the osmolar gap exceeds
Class IIa, Level C evidence that osmotic therapy is reasonable for patients with 20 mOsm/kg.
stroke with clinical deterioration due to cerebral edema.1 Routine use of osmotic
agents in patients with stroke or ICH without clinical deterioration due to ● Osmotic agents can be
used as a temporizing
cerebral edema is not indicated. measure to treat mass effect
from cytotoxic edema
INTRACRANIAL PRESSURE ELEVATION related to stroke and
The Monro-Kellie doctrine states that the intracranial compartment contains a intracerebral hemorrhage,
but evidence for efficacy
fixed total volume determined by the rigid skull. The intracranial volume is is weak. These lesions
determined by the relative volume of three primary compartments: blood, brain, may require surgical
and CSF. A transient increase in volume of one of these compartments results in decompression.
a transient rise in ICP that is subsequently buffered by displacement of one of
the other compartments. In normal physiology, CSF is the lowest pressure
compartment and acts as the primary buffer for expanding space-occupying
lesions. This concept is best evidenced by displacement of CSF from the
subarachnoid space and intraventricular compartment with an enlarging brain
mass. The relationship between ICP and intracranial volume is described by the
property of compliance. In conditions leading to poor brain compliance, small
changes in intracranial volume result in relatively large changes in ICP.
In normal physiology, as CSF is eluted from the choroid plexus into the
ventricle, a transient and measurable rise in ICP occurs, which is subsequently
buffered by displacement of CSF from the subarachnoid and ventricular
compartments. This transient ICP elevation and buffering results in the
characteristic ICP waveform, which is composed of the percussion wave
(P1, cardiac systole), tidal wave (P2, brain parenchymal displacement restricted
by the dura), and the dicrotic wave (P3, closure of the aortic valve).

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CEREBRAL EDEMA AND ELEVATED INTRACRANIAL PRESSURE

As demonstrated in FIGURE 1-1,

the CSF waveform can be used
as a subjective indicator of
intracranial compliance. In the
setting of global cerebral edema,
in which the CSF buffer is
displaced from the intracranial
compartment and the brain
FIGURE 1-1 parenchyma abuts the rigid dura,
Intracranial pressure waveform. Graphs shows further CSF production in the
intracranial pressure waveform contours in normal ventricle results in exaggeration
physiology (A) and poor intracranial compliance
of the P2 waveform relative to
(B). Note the relative elevation of the P2 wave in B,
representing loss of CSF buffering with diffuse P1.12 This finding indicates poor
brain edema. intracranial compliance and
suggests caution should be
exercised to ensure that even
relatively small changes in intracranial volume are avoided. In a state of poor
compliance, physiologic changes that could be expected to increase intracranial
volume include: flat head positioning, obstruction of venous return from the
external jugular veins (restrictive tape or cervical collar, internal jugular vein
catheter placement), hypercarbia, hyperemia, fever, pain and agitation, and
increased intrathoracic or intraabdominal compartment pressure.
Slower oscillations in ICP also occur during normal and pathologic states.
These Lundberg waves can be tracked by changing the time scale of physiologic
ICP monitoring in order to evaluate trends over minutes to hours.13 Lundberg C
waves can be seen in normal physiology and most likely represent interactions
between the cardiac and respiratory cycles. These oscillations occur 4 to 8 times
per minute and generally do not exceed 25 mm Hg. Lundberg B waves are an
indicator of poor intracranial compliance. These oscillations occur 0.5 to 2 times
per minute and generally do not exceed 30 mm Hg. Lundberg A waves are
also called “plateau waves.” These waves are always pathologic and may be a
harbinger of cerebral herniation. Lundberg A waves represent steep increases
in ICP and may be as high as 40 mm Hg to 50 mm Hg and last for 5 to 10 minutes.
Implicit in the discussion of Lundberg waves is that these spontaneous
oscillations in ICP are self-limited and do not necessarily require urgent
treatment. Although Lundberg A waves may be an indicator of impending
cerebral herniation, each ICP plateau does not require treatment per se.14
Well-designed ICP treatment algorithms reserve interventions for sustained
elevation of ICP that lasts more than 10 to 15 minutes. ICP treatment strategies
that require an intervention every time the ICP exceeds 20 mm Hg will likely
result in overtreatment of spontaneous ICP oscillations that would otherwise be
self-limited.

Cerebral Perfusion Pressure

Another important principle of ICP management is the relationship between
ICP and cerebral perfusion pressure (CPP). CPP is measured as the difference
between the mean arterial pressure (MAP) and the ICP (in mm Hg), which
determines the pressure gradient of cerebral perfusion as a global measure. The
normal range of CPP in adults is 50 mm Hg to 70 mm Hg, but these values can be
impacted by chronic hypertension, hydrocephalus, and other conditions. In the

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cerebral autoregulation graph KEY POINTS
depicted in FIGURE 1-2, cerebral
● In states of poor
blood flow is tightly maintained intracranial compliance due
along a wide range of CPP to global cerebral edema,
through regulation of cerebral small changes in intracranial
arterial vasoconstriction and volume related to flat head
position, hyperemia,
vasodilation. This physiologic
hypercarbia, fever, or pain
response creates a complex may result in exaggerated
relationship between ICP, increases in intracranial
cerebral perfusion, and pressure.
intravascular volume.
FIGURE 1-2 ● Spontaneous oscillations
In states of cerebral Cerebral autoregulation curve. Graph shows in intracranial pressure
hypoperfusion, the normal cerebral autoregulation curve demonstrating called Lundberg A and
physiologic response is cerebral relatively constant cerebral blood flow within a B waves may cause
wide range of systemic mean arterial pressures. At self-limited increases in
vasodilation. In patients
lower blood pressure, cerebral blood flow is intracranial pressure that
with elevated ICP and poor maintained by cerebral vasodilation, whereas last several minutes. These
intracranial compliance, cerebral cerebral vasoconstriction mitigates against high oscillations are an indicator
vasodilation increases the volume blood pressure–induced hyperperfusion. In this of poor intracranial
of intracranial blood (most of theoretical curve, constant cerebral blood flow is compliance, but they
maintained between mean arterial pressures of typically resolve
which is in the venous 50 mm Hg and 150 mm Hg. spontaneously without
compartment), further treatment.
increasing ICP, which can
paradoxically worsen cerebral ischemia by reducing CPP. In this situation, ● Augmentation of cerebral
perfusion pressure with
treatment with systemic vasopressors may be needed to augment the CPP to
systemic vasopressors may
supraphysiologic values to allow subsequent cerebral vasoconstriction with lower intracranial pressure
reduction of intracranial blood volume and ICP.15 On the other hand, in brain by causing reflex cerebral
regions with a disrupted blood-brain barrier, excessive CPP may further vasoconstriction, thereby
contribute to vasogenic edema, which will increase the parenchymal component lowering the intracranial
volume of blood. Excessive
of intracranial volume and further raise the ICP. Management of ICP in patients cerebral perfusion,
with regional hypoperfusion and cerebral edema, typical of patients with severe however, may contribute to
TBI, may require a trial-and-error process to determine whether hemodynamic vasogenic edema in regions
augmentation with vasopressors results in ICP reduction or ICP elevation. with a disrupted blood-brain
barrier.

Treatment of Elevated Intracranial Pressure

The first step in ICP treatment should be to determine whether ICP-based
treatment is actually justified based on the etiology of the neurologic injury. For
patients with focal cerebral edema or compression of brain structures from a
space-occupying lesion, ICP monitoring may not be indicated in the first place.
Current guidelines do not recommend routine ICP monitoring or ICP-based
treatment algorithms in patients with spontaneous ICH, brain tumors, meningitis,
or ischemic stroke. ICP monitoring and treatment continues to be recommended
in patients with severe TBI (initial Glasgow Coma Scale score of ≤8).6 Implicit in
this recommendation, however, is that patients with TBI who are noncomatose
do not necessarily require ICP monitoring, and ICP-based treatment may be
unhelpful or detrimental in these patients. In neurocritical care, this situation
commonly arises when patients with TBI who are initially comatose are
subsequently recovering and develop periods of intracranial hypertension
associated with pain, agitation, or other causes. In this situation, the risk of
overtreatment is high, and providers should consider removing the ICP monitor.
Current Brain Trauma Foundation guidelines recommend maintaining an ICP of

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CEREBRAL EDEMA AND ELEVATED INTRACRANIAL PRESSURE

22 mm Hg or less and a CPP of at least 50 mm Hg to 60 mm Hg.6 The recent

BEST:TRIP (Benchmark Evidence From South American Trials: Treatment of
Intracranial Pressure) clinical trial, however, failed to show improved outcomes
in patients with severe TBI treated with an ICP-based protocol compared to
patients treated with a protocol based on imaging and clinical findings without
ICP monitoring.16
Best practice for ICP-based management is the creation and institution of a
multimodality treatment algorithm that reinforces consistent, evidence-based
practices for neurocritical care nurses and physicians. Although no single
algorithm can account for every patient, ICP-based treatment algorithms
improve the consistency of care, unburden physicians and nurses from focusing
on individual treatment decisions, and improve patient outcomes.17 Institutional
treatment protocols should be formulated by a multidisciplinary team that
includes nurses, intensive care providers, neurologists, and neurosurgeons.
These protocols should be reviewed and revised annually and on an ad hoc basis.
Most ICP-based treatment protocols include first-line therapies (noninvasive
maneuvers such as repositioning, ventilator changes, sedation, analgesia),
second-line therapies (osmotic agents, hyperventilation, CSF diversion), and
third-line therapies (metabolic suppression with anesthetic agents, induced
hypothermia, surgical decompression).18 See FIGURE 1-3 for the Emergency
Neurological Life Support (ENLS) ICP treatment algorithm.

ANESTHETIC AGENTS AND METABOLIC SUPPRESSION. Although propofol and

high-dose benzodiazepine infusions can be used for metabolic suppression,
the mainstay for induction of “pharmacologic coma” in refractory intracranial
hypertension is pentobarbital. Although strong evidence indicates that
pentobarbital lowers ICP, there is a paucity of high-quality evidence for
improvement of neurologic outcomes.19 Pentobarbital is typically delivered
as a 20 mg/kg IV bolus followed by continuous infusion at 0.5 mg/kg/h to
5 mg/kg/h. Although the primary titration parameter should be targeted to ICP
control, EEG monitoring with at least a limited electrode montage should also
be undertaken to trend the suppression ratio. Pentobarbital is typically titrated
to achieve burst-suppression anesthesia with a suppression ratio of 0.8 to
0.9, where suppression ratio is the ratio of the duration of EEG suppression
to the duration of EEG bursts. Suppression ratio may be monitored with a
commercially available quantitative EEG product typically used to measure
depth of anesthesia that also displays raw EEG on bedside monitors.
Pentobarbital includes propylene glycol, which can accumulate to cause fatal
lactic acidosis with elevated osmolar gap, acute kidney failure, and circulatory
collapse, so the osmolar gap should be monitored in patients being treated with
pentobarbital.20 Other toxicities include suppression of gastrointestinal motility,
immunosuppression, bone marrow suppression, and distributive shock. The
half-life of pentobarbital ranges from 15 to 50 hours, so patients may not recover
consciousness for several days after medication discontinuation, and caution
should be exercised in brain death declaration for patients who were treated with
pentobarbital. Very high-dose pentobarbital can mimic every clinical sign of
brain death, including bilateral fixed and dilated pupils and diabetes insipidus.
After prolonged use of pentobarbital, rapid discontinuation may produce
withdrawal symptoms including seizures and rebound ICP elevation, so
phenobarbital can be administered and tapered during pentobarbital weaning.

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INDUCED HYPOTHERMIA. Ample KEY POINTS
evidence indicates induced
● Current Brain Trauma
hypothermia lowers ICP, but Foundation guidelines
the evidence that it improves recommend maintaining an
outcomes is lacking. The recent intracranial pressure of
Eurotherm3235 trial tested 22 mm Hg or less and a
cerebral perfusion pressure
whether an ICP treatment
of at least 50 mm Hg to
protocol that included early 60 mm Hg in patients with
induction of hypothermia severe traumatic brain
resulted in improved outcomes injury.
and reduced the need for other
● A recent clinical trial of an
third-line therapies in patients intracranial pressure–based
with severe TBI.21 Although treatment protocol for
fewer ICP-directed severe traumatic brain injury
interventions were required in compared to a treatment
protocol based on clinical
the hypothermia group, examination and imaging
neurologic outcomes were FIGURE 1-3 without intracranial
actually worse. This clinical trial Intracranial pressure treatment algorithm. pressure monitoring showed
Emergency Neurological Life Support (ENLS) no difference in outcomes
demonstrated that early treatment protocol for elevated intracranial between the two groups.
induced hypothermia does not pressure demonstrating an algorithmic,
improve outcomes in TBI as a multitiered approach to escalating treatment ● Pentobarbital infusion for
neuroprotective strategy, but modalities. Third-line treatments include intracranial pressure
anesthetic coma, induced hypothermia, and reduction can result in
hypothermia continues to be decompressive craniectomy. severe medication side
employed as a third-line CSF = cerebrospinal fluid; CT = computed tomography; effects such as propylene
therapy for refractory ICP ICP = intracranial pressure; MAP = mean arterial pressure;
glycol toxicity,
NaCl = sodium chloride; PaCO2 = partial pressure of
elevation. Most ICP treatment immunosuppression,
carbon dioxide, arterial.
protocols that include a
This example of an approach to treating intracranial
impaired gastrointestinal
hypothermia target a core motility, and distributive
pressure elevation includes hypertonic saline (denoted
NaCl in this figure) in tier 2 as a second-line therapy for
shock.
temperature of 32°C to 34°C
patients who were already treated with mannitol in tier 1. In
(89.6°F to 93.2°F) using either some cases, however, patients may have been treated ● A recent clinical trial of
surface cooling or intravascular with hypertonic saline instead of mannitol in tier 1. This is early induced hypothermia
cooling devices with a often the case for patients with low intravascular volume. as a neuroprotective
Modified with permission from Stevens RD, et al, Neurocrit strategy in severe traumatic
continuous automated feedback Care.18 © 2015 Springer. brain injury showed
mechanism. Successful reduction of intracranial
induction and maintenance of pressure–directed
hypothermia, especially in interventions, but
neurologic outcomes were
patients not concurrently treated with anesthetic agents, requires institution
worse in patients treated
of a multimodality shivering protocol.22 Shivering causes failure of with hypothermia.
temperature maintenance and paradoxical ICP elevation from a combination
of cerebral hypermetabolism and systemic hypercarbia. Antishivering ● Induced hypothermia
protocols typically include a combination of surface counterwarming, continues to be a useful
third-line intervention for
magnesium infusion, buspirone, meperidine, and sedative infusion.23 During refractory intracranial
the induction phase, hypothermia can produce peripheral vasoconstriction pressure elevation, but an
leading to skin ischemia, severe hypokalemia, and diuresis from shunting effective hypothermia
blood flow to the kidneys. Electrolytes should be monitored frequently during protocol that includes
multimodality treatment of
the hypothermia induction and rewarming phases.24 Rewarming should occur shivering is required.
in a tightly controlled fashion to avoid severe rebound hyperkalemia and
distributive shock from peripheral vasodilation. For this reason, rewarming
should be undertaken at a rate of 0.1°C (32.2°F) per hour or slower in patients
who have been cooled for long intervals.

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CEREBRAL EDEMA AND ELEVATED INTRACRANIAL PRESSURE

DECOMPRESSIVE SURGERY. For patients with ICP elevation due to obstructive

hydrocephalus, placement of an EVD for CSF diversion is considered a first-line
treatment. For patients with elevated ICP due to a focal compressive brain lesion,
decompressive surgery is considered a first-line treatment rather than global
ICP-directed treatments (CASE 1-1). For patients with elevated ICP due to global
or multifocal brain injuries such as severe TBI, however, decompressive
craniectomy should be considered as a third-line treatment for refractory ICP
elevation. The appropriate sequence of ICP treatment protocols has come into
better focus with the recent DECRA (Decompressive Craniectomy in Diffuse
Traumatic Brain Injury) and RESCUEicp (Randomised Evaluation of Surgery
With Craniectomy for Uncontrollable Elevation of Intracranial Pressure) clinical

CASE 1-1 A 47-year-old man presented to the neurocritical care unit because of a
gunshot wound to the left occipital lobe that was initially managed with
surgical debridement and placement of an intracranial pressure (ICP)
monitor. The patient initially had purposeful movements of the left side,
but he had aphasia and right hemiplegia.
On hospital day 3, he developed
refractory ICP elevation that was
treated with sedation and analgesia
followed by hypertonic saline boluses
according to the institutional ICP
management protocol. Despite these
interventions, he developed a
sustained ICP of more than 30 mm Hg
and a worsening neurologic
examination with extensor posturing.
Repeat head CT demonstrated an
evolving infarct of the left occipital
lobe with hemorrhagic transformation
and 8-mm midline shift. He was
treated with mannitol 1 g/kg IV as a
FIGURE 1-4 temporizing measure and then was
Head CT of the patient in CASE 1-1.
taken for decompressive
CT shows decompressive craniectomy
to allow room for the hemorrhagic craniectomy. After surgery, the ICP
infarction to swell outside of the normalized, and he began to have
skull as a treatment for refractory purposeful movements of the left side
intracranial pressure elevation and again. The postoperative head CT is
brain compression.
shown (FIGURE 1-4).

COMMENT This case illustrates the importance of tailoring interventions for ICP
elevation to the underlying pathophysiology. In this case, rather than
escalating to third-line medical management of ICP elevation with
pentobarbital coma or induced hypothermia, the team recognized that ICP
elevation was caused by an enlarging focal brain lesion that required
surgical decompression.

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trials.25,26 DECRA tested whether early bifrontal decompressive craniectomy KEY POINTS
would improve outcomes and lessen the need for other ICP-directed
● A recent clinical trial
interventions in patients with severe TBI.25 Although surgical decompression demonstrated that
lowered ICP, patients had worse neurologic outcomes in the early surgery arm. decompressive craniectomy
The RESCUEicp trial randomly selected patients with severe TBI with refractory for refractory intracranial
ICP elevation to undergo decompressive craniectomy (unilateral or bilateral) pressure elevation in severe
traumatic brain injury
as a third-line treatment or continued medical management with anesthetic
improves survival and
agents.26 This clinical trial demonstrated modest benefits to decompressive reduces the chance of
craniectomy with higher odds of survival and lower odds of severe disability, but severe disability, but more
there was no effect on the odds of good recovery, and more patients survived patients survived in a
vegetative state compared
in the vegetative state in the surgical arm. These study results clarify that
to medical management
decompressive surgery should be reserved for third-line management of alone.
refractory ICP elevation, and careful discussion of expected outcomes should be
undertaken with surrogate decision makers, including the higher chance of ● With transtentorial
survival in a vegetative state. herniation, the pupil dilation
is ipsilateral to the mass
lesion, but hemiplegia may
CEREBRAL HERNIATION SYNDROMES be contralateral because of
Cerebral herniation occurs when brain structures are displaced into an adjacent direct corticospinal tract
compartment with compression of surrounding neurologic structures. Cerebral involvement or ipsilateral
because of compression of
herniation typically occurs when enlarging space-occupying lesions result in the contralateral cerebral
displacement or expansion of brain tissue. Herniation is often but not universally peduncle against the
associated with elevated ICP. In some cases, global ICP values are normal, but tentorial edge (Kernohan
compartmentalized ICP elevation contributes to pressure gradients that displace notch phenomenon).
brain tissue. For this reason, global ICP monitoring is not always a sensitive
indicator of impending cerebral herniation. This is especially true of posterior
fossa lesions, which may result in upward herniation with little change in
ICP. Clinical monitoring for impending herniation relies on serial
neurologic examinations.

Transtentorial (Uncal) Herniation

Transtentorial herniation occurs when an expanding supratentorial mass lesion
displaces the medial temporal lobe (uncus) through the tentorial incisura with
compression of the ipsilateral oculomotor nerve followed by the midbrain. The
clinical hallmark of transtentorial herniation is ipsilateral dilation of the pupil
and, less commonly, deviation of the eye laterally and inferiorly. As herniation
progresses, patients develop extensor posturing and depressed mental status due
to dysfunction of the corticospinal tract and reticular activating system in the
midbrain. Bilateral transtentorial herniation, also known as central herniation,
typically occurs with global cerebral edema and presents with coma, extensor
posturing, and bilateral fixed and dilated pupils. With expanding extraaxial
lesions (typically subdural hematoma), a characteristic pattern of ipsilateral
pupil dilation and ipsilateral hemiplegia may develop. This so-called Kernohan
notch phenomenon occurs with lateral displacement of the midbrain such that
the contralateral cerebral peduncle is compressed against the tentorial edge at
Kernohan notch with relative sparing of the ipsilateral cerebral peduncle.27 For
patients with supratentorial space-occupying lesions, the side of the pupil
dilation is ipsilateral to the source of mass effect, while the side of hemiplegia
may be either ipsilateral or contralateral (ie, “the pupil doesn’t lie”).
Pupil dilation is the sine qua non manifestation of transtentorial herniation,
so clinical monitoring for pupillary abnormalities is the hallmark of bedside

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CEREBRAL EDEMA AND ELEVATED INTRACRANIAL PRESSURE

neuromonitoring in patients with supratentorial mass lesions at risk for herniation.

ICP elevation is often a late finding. Prior to dilation of the pupil, however,
the velocity of pupillary constriction diminishes with early compression of the
oculomotor nerve. This can be monitored with serial bedside pupillometry with
quantitative measurement of the pupillary constriction velocity using commercially
available bedside monitors.28 Observational studies have demonstrated that
the diminution of the constriction velocity may precede frank clinical signs of
transtentorial herniation by hours.29 In some cases, early recognition of
impending herniation may provide time for temporizing medical interventions
and definitive surgical decompression.
Transtentorial herniation is caused by focal displacement and compression
of brain structures rather than global elevation of ICP or cerebral edema.
For this reason, therapies directed purely at reduction of cerebral edema
(eg, corticosteroids) or global reduction in ICP (eg, anesthetic agents,
hypothermia) are ineffective in reversing clinical signs of transtentorial herniation.
Without rapid treatment to reverse clinical signs of transtentorial herniation, the
natural history is progression to central herniation, which is nearly universally
fatal. Although observational studies have demonstrated restoration of the
pupillary light reflex—and in some cases survival—after treatment with
hypertonic saline and mannitol, radiographic evidence of reversal of herniation
is lacking.30,31 For this reason, osmotic therapy and hyperventilation should be
considered temporizing measures to reverse clinical evidence of transtentorial
herniation prior to definitive surgical decompression. Decompressive surgery
requires either excision of the space-occupying lesion (extraaxial hematoma or
temporal lobectomy) or decompressive craniectomy.
Transtentorial herniation used to be considered a universally fatal event.
Depending on the etiology of herniation and availability of definitive surgical
treatment, patients with unilateral transtentorial herniation have been reported
to survive and recover independent function in some series.32 Even if clinical
signs of herniation are reversed with medical or surgical interventions, three
common sequelae of the herniation event may occur. Compression of venous
drainage from the central midbrain and pons may lead to venous congestion and
hemorrhagic infarction within the medial brainstem structures, which is termed
Duret hemorrhage. Compression of the contralateral posterior cerebral artery
against the tentorial edge may cause posterior cerebral artery territory stroke.33
Compression of the ipsilateral anterior cerebral artery against the inferior edge of
the falx cerebri due to associated subfalcine herniation may cause anterior
cerebral artery territory stroke.

Posterior Fossa Herniation Syndromes

Expanding posterior fossa lesions such as cerebellar stroke can result in
compression of the fourth ventricle with acute obstructive hydrocephalus,
compression of the brainstem and cranial nerves, and two distinct
herniation syndromes.
Cerebellar tonsillar herniation occurs with downward displacement of the
cerebellar tonsils through the foramen magnum with compression of the
cervicomedullary junction. This herniation syndrome may not be accompanied
by elevated ICP or pupillary changes until obstructive hydrocephalus develops
as a late event. For this reason, tonsillar herniation is commonly missed
with neuromonitoring that is focused on ICP and pupillary changes. Tonsillar

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herniation typically causes quadriparesis due to compression of the pyramidal KEY POINTS
decussation, respiratory insufficiency due to bulbar dysfunction and
● Serial bedside
compression of the upper cervical spinal cord, and depressed level of quantitative pupillometry
consciousness.34 As with transtentorial herniation, osmotic therapy and may detect reduction in
hyperventilation are temporizing measures, but definitive treatment requires the pupillary constriction
surgical decompression, either decompressive suboccipital craniectomy, partial velocity hours prior to
frank clinical signs of
cerebellectomy, or hematoma evacuation.1,35
transtentorial herniation,
Upward herniation occurs with upward displacement of the cerebellum which may afford time for
through the tentorial incisura with compression of the dorsal midbrain. This preemptive treatment.
uncommon herniation syndrome typically occurs in patients with expanding
posterior fossa mass lesions in combination with an EVD. Excessive CSF ● Although patients can
survive and recover from
diversion from the lateral ventricle creates a pressure gradient resulting in transtentorial herniation in
upward displacement of the cerebellum.36 Patients typically present with some cases, the sequelae of
new-onset vertical gaze palsy and depressed level of consciousness. Treatment herniation can include Duret
requires clamping the EVD in addition to treatment with osmotic agents and brainstem hemorrhage,
ipsilateral anterior cerebral
hyperventilation. As with tonsillar herniation, upward herniation is not artery stroke, and
commonly associated with pupil dilation. Because of the mechanism of contralateral posterior
herniation, the ICP is typically normal or low rather than elevated.37 For these cerebral artery stroke.
reasons, diagnosis of upward herniation is often delayed or missed (CASE 1-2).
● Posterior fossa mass
Because of the risk of upward herniation, current AHA guidelines recommend
lesions can cause cerebellar
against placement of an EVD as the primary intervention for obstructive tonsillar herniation or
hydrocephalus caused by cerebellar strokes.1 The current recommendation is to upward herniation of the
consider decompressive surgery prior to EVD insertion in this setting.38 cerebellum through the
tentorial incisura, which may
not be accompanied by
intracranial pressure
CONCLUSION elevation or pupillary
Cerebral edema, elevated ICP, and cerebral herniation syndromes are a major changes.
cause of morbidity and mortality in neurocritical care. Although these conditions
frequently overlap, they are distinct pathophysiologic entities that require
tailored neurologic monitoring and treatment. For cerebral edema, both the
mechanism and context are important to determine best practices for treatment.
While vasogenic edema surrounding brain tumors may respond to
corticosteroids, this same treatment strategy is contraindicated in treatment of
cerebral edema from TBI. Our understanding of ICP as a global measure and
treatment target is changing. Management strategies are typically directed to
global reduction of ICP, including osmotic therapies, metabolic suppression, and
hypothermia, whereas in many focal neurologic conditions, ICP can be
compartmentalized and contribute to displacement of brain structures. In these
situations, surgical decompression should be the mainstay of treatment rather
than global ICP reduction strategies.
Although many observational studies in TBI have shown that sustained ICP
elevation is associated with poor outcomes, a recent clinical trial showed that
ICP-targeted management resulted in outcomes that were no better than
management based on imaging and clinical examination, a result that could
almost be considered heretical to the last few decades of TBI management. In
addition, improved understanding of the physiology of ICP-volume relationships
and cerebral autoregulation have demonstrated that acceptable ICP thresholds
at the level of an individual patient are not as clear-cut as we imagined. ICP
thresholds may be best understood in the context of accompanying brain
perfusion and tissue oxygenation.

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CEREBRAL EDEMA AND ELEVATED INTRACRANIAL PRESSURE

CASE 1-2 A 55-year-old man presented to the emergency department after he fell
down a flight of stairs, during which he struck his head on the pavement
and experienced brief loss of consciousness. The initial head CT showed
convexity subarachnoid hemorrhage, small bifrontal cerebral contusions,
and a 20-mL contusion of the cerebellar vermis. He was admitted to the
neurocritical care unit.
On hospital day 2, he became more lethargic with new onset of
quadriparesis and acute respiratory insufficiency requiring intubation.
Repeat head CT (FIGURE 1-5) demonstrated increasing brainstem
compression, cerebellar tonsillar herniation, and acute obstructive
hydrocephalus. The
neurosurgeon placed an
external ventricular drain
(EVD), but the patient had
no significant clinical
improvement after CSF
diversion. The patient was
subsequently noted to be
obtunded with vertical
ophthalmoplegia characterized
by bilateral inferior-medial
eye deviation (“sunset eyes”).
Suspecting upward herniation,
the neurocritical care team
FIGURE 1-5 clamped the EVD, and the
Head CT of the patient in CASE 1-2. CT shows patient was taken for
compression of the brainstem and cerebellar decompressive suboccipital
tonsillar herniation in a patient with cerebellar craniectomy. He had gradual
vermis contusion and frontal subarachnoid
hemorrhage. The patient also has evidence of mild neurologic improvement,
hydrocephalus. After an external ventricular drain and the EVD was removed
placement, he developed upward herniation. during the subsequent
hospital course.

COMMENT This case demonstrates the clinical presentation and treatment of posterior
fossa herniation syndrome, which is distinct from the more commonly
recognized transtentorial herniation syndrome. Because upward herniation
is uncommon and the progression is insidious, signs are often overlooked.
Current American Heart Association guidelines recommend surgical
decompression prior to or concomitant with placement of an EVD for
posterior fossa lesions with mass effect in order to lower the chances of
upward herniation.1 This case illustrates the potential to worsen upward
herniation when CSF diversion is undertaken without surgical decompression.

1600 DECEMBER 2018

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 Monitoring for and treating cerebral herniation syndromes have also
evolved over time. What was once considered a uniformly fatal event may now
be reversible in the right clinical context. Routine bedside pupillometry in the
neurocritical care setting has demonstrated the ability to detect impending
transtentorial herniation and may buy time for definitive surgical management
in some cases.

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