neuro_oncologic_emergencies.14

Neuro-oncologic REVIEW ARTICLE
Emergencies

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
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By Carolina B. Maciel, MD, MSCR, FAAN; Katharina M. Busl, MD, MS, FAAN
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ABSTRACT
OBJECTIVE: Neuro-oncologic emergencies have become more frequent as
cancer remains one of the leading causes of death in the United States,
second only to heart disease. This article highlights key aspects of
epidemiology, diagnosis, and management of acute neurologic
complications in primary central nervous system malignancies and
BVPl9PByeVedA on 07/12/2024
systemic cancer, following three thematic classifications: (1) complications

that are anatomically or intrinsically tumor-related, (2) complications that
are tumor-mediated, and (3) complications that are treatment-related.
LATEST DEVELOPMENTS: The main driver of mortality in patients with brain

metastasis is systemic disease progression; however, intracranial
hypertension, treatment-resistant seizures, and overall decline due to
increased intracranial burden of disease are the main factors underlying
neurologic-related deaths. Advances in the understanding of tumor-
specific characteristics can better inform risk stratification of neurologic
complications. Following standardized grading and management
algorithms for neurotoxic syndromes related to newer immunologic
therapies is paramount to achieving favorable outcomes.
ESSENTIAL POINTS:Neuro-oncologic emergencies span the boundaries of

subspecialties in neurology and require a broad understanding of
neuroimmunology, neuronal hyperexcitability, CSF flow dynamics, CITE AS:
CONTINUUM (MINNEAP MINN)
intracranial compliance, and neuroanatomy. 2024;30(3, NEUROCRITICAL CARE):
845–877.
Address correspondence to
INTRODUCTION Dr Carolina B. Maciel, McKnight
B
Brain Institute, 1149 Newell Dr,
y 2030, more than 20 million patients will be diagnosed with cancer L3-100, Gainesville, FL 32610,
each year across the globe, increased from the 14 million patients carolina.maciel@neurology.ufl.
diagnosed per year in 2014.1 According to the 2015 to 2019 updated edu.
report from the Central Brain Tumor Registry of the United States, the RELATIONSHIP DISCLOSURE:
average annual age-adjusted incidence of all malignant and Drs Maciel and Busl report no
disclosures.
nonmalignant central nervous system (CNS) tumors is 24.71 per 100,000
people (7.02 per 100,000 and 17.69 per 100,000 people for malignant and UNLABELED USE OF
nonmalignant tumors, respectively).2 These rates are higher in women PRODUCTS/INVESTIGATIONAL
USE DISCLOSURE:
(27.62 versus 21.60 per 100,000 people) and non-Hispanic people (25.09 Drs Maciel and Busl report no
versus 22.95 per 100,000 people). The average annual mortality related to disclosures.
CNS malignancies is 4.41 per 100,000 people, representing more than 15,000
deaths per year in the United States alone. Importantly, disparities exist with © 2024 American Academy
inadequate access to care, inability to receive optimal treatment, higher of Neurology.
CONTINUUMJOURNAL.COM 845
Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

NEURO-ONCOLOGIC EMERGENCIES
complication rates, and shorter life expectancy for adults and children with
CNS tumors.3-6
As cancer remains one of the leading causes of death in the United States,
second only to heart disease, neuro-oncologic emergencies have become more
frequent. Neurologic complications of primary neurologic malignancies and
systemic cancer frequently constitute the presenting symptoms for many

patients and often require hospital admission. Increases in life expectancy
coupled with a growing prevalence of many types of cancer in older adults

and advances in oncologic treatment, resulting in longer survival7 despite
potential neurotoxicity, make the management of neurologic complications of
cancer a growing part of neurology practice. These complications commonly
span the boundaries of subspecialties in neurology and require a broad under-
standing of neuroimmunology, neuronal hyperexcitability, CSF flow dynamics,
intracranial compliance, and neuroanatomy.
Neuro-oncologic emergencies encompass a variety of pathologic processes
indirectly linked to cancer and its targeted therapy and intrinsically related
to the tumor itself. This article highlights key aspects of epidemiology,

diagnosis, and management of acute neurologic complications in primary
CNS malignancies and systemic cancer, following three thematic classifications:
(1) complications that are directly tumor-mediated (ie, occurring because
of the anatomic location of the lesion and the directly affected neurovascular
structures), (2) complications that are indirectly tumor-mediated (ie,
complications that are indirectly related to the presence and location of a
tumor, such as seizures, cerebrogenic arrhythmias, paraneoplastic syndromes,
ischemic stroke, cerebral venous thrombosis, and intracranial hemorrhage) and
(3) complications that are treatment-related (FIGURE 11-1).
DIRECT TUMOR-MEDIATED COMPLICATIONS

The annual incidence of malignant primary CNS tumors is estimated at 6.6
per 100,000 people.8 The most common malignant primary CNS tumor is
World Health Organization grade 4 (ie, glioblastoma), comprising 14.2%
of all brain tumors and over one-half of all newly diagnosed malignant
brain tumors2; these tumors are more prevalent in men and older adults.
Glioblastomas are responsible for the most mean number of years of potential
life lost among all cancers, estimated at 20 years. Meningiomas are the most
common nonmalignant CNS tumors, comprising nearly 40% of all tumors and
55.4% of all nonmalignant tumors2; meningiomas are more prevalent in
women.
Brain metastases have a higher annual incidence than malignant primary CNS
tumors at 8.3 per 100,000 people8; however, a continued decrease in the
incidence of metastasis to the brain is predicted for solid tumors according to
more recent epidemiologic assessments.7 The most common solid organ
cancers with a predilection for brain metastasis are lung, breast, and renal
carcinomas, and melanoma. Approximately 2% of patients with primary
solid tumors and a little more than 12% of those who already have metastatic
disease present with synchronous brain metastasis (ie, those diagnosed during
primary cancer staging workup) (TABLE 11-1).9-11 Approximately 75% of
metastatic lesions to the brain are in the cerebral hemispheres; a little more
than 20% are in the cerebellum; and less than 5% are in the brainstem. Fewer
than 50% are solitary brain lesions.12 The prognosis of patients with brain
846 J U N E 2 0 24

metastasis varies based on histopathologic and molecular diagnosis as well as KEY POINTS
exposure to specific targeted therapy.13
● Women and non-
Complications intrinsically related to CNS tumors initially affect the brain and Hispanic people have a
spine region in which they originate and subsequently can cause additional higher annual age-adjusted
complications due to edema, hydrocephalus, and mass effect (eg, herniation or incidence of central nervous
cord compression) (TABLE 11-2).
system (CNS) tumors.

● Neurologic emergencies
Pathophysiology from cancer comprise many
The nervous system can accommodate considerable tumoral growth, if it occurs pathologic processes
over long periods, with few and subtle or no signs and symptoms of elevated intrinsically related to the
tumor itself and indirectly
linked to the cancer and its
targeted therapy.
● Glioblastomas are the

most common malignant
CNS tumors and are more
prevalent in men and older

adults, whereas
meningiomas, the most
common nonmalignant
tumors of the CNS, are
more prevalent in women.
● Lung, breast, and

renal carcinomas, and
melanomas are the most
common primary cancer
sites for brain metastasis.
● Intrinsic complications
from CNS tumors depend
on the anatomic location of
the lesion and of the
neurovascular structures
affected.
● A combination of factors
can coexist leading to
intracranial hypertension in
the setting of neoplastic
CNS involvement, such as
mass effect by the tumor
itself, tumor-associated
vasogenic edema,
hydrocephalus, a
cerebrovascular
complication such as
intratumoral hemorrhage,
or congestive cerebral
edema due to venous
outflow obstruction.
FIGURE 11-1
Neurologic emergencies intrinsically related or indirectly mediated by tumors.
A.1 = transcalvarial; A.2 = upward; A.3 = uncal; A.4 = downward; E.1 = extradural; E.2 = intradural
extramedullary; E.3 = intradural intramedullary.

TABLE 11-1 Systemic Malignancies With High Proclivity for Brain Metastasisa
Incidenceb
Brain metastasis
Lung 16.3%
Kidney 9.8%
Skin (melanoma) 7.4%
Breast 5.0%
Synchronous metastasis (diagnosis during primary cancer staging)
Lung 10%
Small cell 15.8%

Adenocarcinoma 14.4%
Non–small cell not otherwise specified 12.8%
Squamous cell 5.2%
Bronchioloalveolar 2.3%
Esophageal 1.6%
Kidney 1.5%
Breast 0.4%
Nonsynchronous metastasis (diagnosis after primary cancer staging)
Lung
Adenocarcinoma 26.8%
Non–small cell not otherwise specified 25.6%
Small cell 23.5%
Squamous cell 15.9%
Bronchioloalveolar 15.5%
Kidney 10.8%
Breast 7.6%
Thyroid 5.8%
Esophageal 5.3%
a
Data from Cagney DN, et al, Neuro Oncol9; and Komer C, et al, J Neurooncol.11
b
Five-year cumulative incidence for brain metastasis and annual incidence for synchronous and
asynchronous metastasis.
848 J U N E 2 0 24

intracranial pressure. Once a critical threshold in intracranial compliance is
crossed, patients may experience a spiraling, life-threatening acute
decompensation. In patients with brain tumors, intracranial hypertension can
occur due to mass effect by the tumor itself, tumor-associated vasogenic edema,
hydrocephalus due to obstruction of the ventricular system or a cerebrovascular
complication such as intratumoral hemorrhage, or congestive cerebral edema

due to venous outflow obstruction. At times, many of these processes occur
concurrently and culminate with brain herniation (FIGURE 11-1), posing a

management challenge.
Edema
Vasogenic edema is the most common underlying etiology of cerebral edema in
malignancy, resulting from the disruption of the blood-brain barrier and
subsequent egress of plasma and protein into the interstitium, with consequent
increase in the interstitial fluid pressure. The loss of integrity in the blood-brain
barrier caused by tumors is multifactorial, with histologic evidence of tight
junction dysfunction, increased pinocytotic activity, presence of fenestrations,

and thickening and lack of homogeneity in the basement membrane with
reduced interactions between pericytes and astrocytes. The disturbance in the
Mechanistic Underpinnings and Management of Intrinsic Tumor-related TABLE 11-2

Complications
Complication Mechanisms Management
Edema Blood-brain barrier disruption Corticosteroids, surgical decompression, osmotic

agents, bevacizumab in selected patients
Tight junction dysfunction
Increased pinocytotic activity
Fenestrations
Dysfunctional interaction between
pericytes and astrocytes
Increased vascular endothelial growth
factor (VEGF)
Increase in interstitial fluid pressure
Herniation Direct displacement of brain tissue and Corticosteroids, surgical decompression,

compression of parenchyma and vascular osmotic agents
or ventricular structures
Hydrocephalus Obstructive CSF diversion, surgical decompression,

endoscopic third ventriculostomy
Compression in ventricular system
Communicating
Decreased CSF absorption
Decreased venous outflow from
compression of venous sinuses
Spinal cord Direct mass effect with impingement Corticosteroids, surgical decompression,
compression or compression of nervous structures radiotherapy

blood-brain barrier is partly related to increased activity in the vascular

endothelial growth factor (VEGF), a proangiogenic peptide that is upregulated
by benign and malignant tumors, as well as increased prostaglandin and
leukotriene activity. VEGF is the target for bevacizumab, a widely used
antiangiogenic therapy in many primary CNS and systemic cancers, in addition
to treating edema related to radiation necrosis.

Hydrocephalus
Tumors can lead to obstructive or communicating hydrocephalus. Compression
at a variety of points in the ventricular system may lead to obstructive
hydrocephalus. Posterior fossa tumors exerting mass effect on the fourth
ventricle, supratentorial tumors with significant midline shift effacing the lateral
and third ventricles, and intrinsic obstruction from intraventricular tumors are
the most common examples. Impaired CSF absorption in the absence of visible
tumors, such as in leptomeningeal carcinomatosis, or persistently impaired
venous outflow from mass effect in the sinuses can lead to communicating
hydrocephalus.
Posterior fossa tumors are associated with an increased risk for obstructive
hydrocephalus,12 including postoperatively, and are 7 times as likely to
require readmission for CSF diversion14; hence, intraoperative external
ventricular drain placement with cautious CSF perioperative diversion is
common. Extrapolating from the pediatric population, in whom posterior
fossa tumors represent the most common CNS neoplasm, intraventricular
location, high grade of tumor, solid consistency of tumor, presence of
metastasis, and postoperative imaging with intraventricular blood are
independent risk factors for postoperative hydrocephalus.15,16 More recently,
endoscopic third ventriculostomy, performed before or concurrently with
tumor resection in lieu of external ventricular drain and shunt placement, has
been gaining traction because of the potential for avoiding shunt-related
complications, particularly in patients with guarded prognoses and in
pediatric patients.17 Nonetheless, endoscopic third ventriculostomy is known
to have higher early failure rates in both pediatric and adult populations.18
Over two-thirds of patients with leptomeningeal carcinomatosis, or
neoplastic meningitis, develop disturbance in CSF circulation and intracranial
compliance, presumably due to obstruction of pathways and malabsorption of
CSF.19 Pressure wave symptoms may occur even in the absence of radiographic
evidence of hydrocephalus,20 and they may manifest as intolerance to quick
change in head position, pulsatile tinnitus, headache, blurry vision, papilledema,
nausea, projectile vomiting, lethargy, or acute loss of consciousness.
Leptomeningeal carcinomatosis is a highly morbid neurologic complication of
solid and hematologic malignancies, occurring in approximately 5% of patients
with solid tumors21 and up to 15% of patients with hematologic malignancies.20
Postmortem evidence of leptomeningeal spread has been detected in up to
20% of patients presenting with neurologic manifestations of cancer.20
Leptomeningeal disease carries a poor prognosis, with median overall survival
of 8 to 16 weeks.20 Clinically, symptoms can be focal, localizing to hemispheres,
and involve cranial nerves and nerve roots. Often, predominant symptoms of
hydrocephalus and pressure waves cloud focal neurologic deficits. Patients with
leptomeningeal seeding may not have radiographically evident disease, even
with MRI of the entire neuroaxis with thin cuts, and require high-volume serial
850 J U N E 2 0 24

CSF sampling with at least 10 mL (or higher in cases of low cellular count) with KEY POINTS
timely evaluation by an experienced pathologist.20,22 Palliative long-term CSF
● Hydrocephalus in the
diversion with ventriculoperitoneal shunt alleviates symptoms and improves setting of a CNS neoplasm
quality of life in most patients.19 is often obstructive due to
mass effect in the
Herniation ventricular system;

however, superimposed
Herniation represents the most common cause of death secondary to CNS tumor
communicating
progression.23 FIGURE 11-1 is a schematic diagram of herniation syndromes. In the hydrocephalus due to
setting of supratentorial mass lesions, subfalcine herniation of the cingulate gyrus impaired CSF absorption
and uncal herniation, in which the mesial temporal region projects mass effect may occur, particularly in
the setting of
over the tentorial edge and midbrain, are the most common types of herniation.
leptomeningeal tumor
Both are associated with neurovascular consequences depending on the seeding.
magnitude and pace of mass effect, with subfalcine herniation impinging the
anterior cerebral artery over the free edge of the falx and uncal herniation ● CSF diversion may
causing compression of the posterior cerebral artery between the uncus and exacerbate some
herniation syndromes,
midbrain. The clinical hallmark of uncal herniation is ipsilateral mydriasis with
hence the need for cautious

loss of the pupillary light reflex due to compression of the oculomotor nerve and sampling of CSF and the
contralateral hemiparesis from mass effect on the corticospinal tract, in addition ability to monitor patients
to decreased level of consciousness. Kernohan-Woltman notch phenomenon and promptly administer
rescue therapies.
may occur and results in ipsilateral hemiparesis, in which massive uncal
herniation leads to displacement of the midbrain and contralateral cerebral
peduncle compression against the free edge of the tentorium; concurrent
mydriasis is frequent and may be ipsilateral, contralateral, or bilateral.24
In cases of global cerebral edema or severe cerebral hypotension (eg, due to
high intraoperative loss of CSF), central or downward herniation may ensue, in
which the midbrain herniates downward through the tentorium; the clinical
hallmark is the loss of upgaze, or forced downgaze in severe cases, along with
abnormal breathing and decreased consciousness. Upward and tonsillar
herniation are complications of infratentorial lesions, in which a compartmental
syndrome in the posterior fossa caused by expansion of its contents forces the
cerebellum through the path of least resistance: upward through the tentorium or
downward through the foramen magnum, respectively (CASE 11-1).
CSF diversion with ventriculostomy or drainage via lumbar puncture can lead
to exacerbation of herniation syndromes for patients with posterior fossa lesions.
When used, CSF diversion should be cautious (ie, the drain should be kept at
15 to 20 cm H2O when leveled at the tragus) to minimize drainage and prevent
ascension of the midbrain through the tentorial incisura as a gradient of pressure
develops between the supratentorial and infratentorial compartments, with
drainage of CSF. In patients with space-occupying lesions in whom a lumbar
puncture is deemed necessary, the amount of CSF sampled should be limited to
the minimum amount sufficient for diagnostic yield. In high-risk cases, it is
prudent to have 1 g/kg 20% mannitol ready to be infused while performing a
lumbar puncture, and in very high-risk cases, CSF drainage should be deferred.
Cord Compression
Metastatic tumors represent the majority of spinal tumors. Tumors arising from
the spinal cord are much less common. The spine’s susceptibility to cancer
seeding is due to its high vascularity and close relationship with regional
lymphatic and venous drainage systems (eg, Batson plexus), hence the high
predilection of metastasis to the thoracolumbar spine (the site of 70% of spinal

CASE 11-1 A 21-year-old man presented to the emergency department with a

6-month history of blurry vision and positional headaches precipitated by
being in a supine position. Symptoms had been worsening and were
associated with morning vomiting. His neurologic examination was
notable for limited upgaze and lateral gaze, along with mild dysarthria and
slight lethargy. MRI demonstrated a cerebellar tumor with upward
herniation leading to hydrocephalus (FIGURE 11-2). He was started on

steroids and underwent tumor resection.
FIGURE 11-2
Upward herniation and obstructive hydrocephalus with cerebellar tumor in the patient in
CASE 11-1. Fluid-attenuated inversion recovery (FLAIR) MRI sequences with an axial image
(A) demonstrating diffusely increased transependymal flow associated with enlargement
of lateral ventricles (A, thick arrows) and complete obliteration of the cerebral aqueduct
(A, thin arrow) and a sagittal image (B) showing mass effect on the aqueduct with
obliteration of the fourth ventricle (B, thin arrow) causing obstructive hydrocephalus,
precipitated by the cerebellar mass. Upward herniation is noted by the steep angle of the
tentorium in the sagittal image (B, star).
COMMENT The central nervous system is able to compensate temporarily for

significant mass effect caused by slow-growing tumors. CSF diversion
should be employed judiciously in the setting of posterior fossa
compartmental syndromes such as in this case. There is a high risk for
neurologic decline, which can be triggered by worsening hydrocephalus
overcoming the tipping point of intracranial compliance accommodation as
well as by worsened upward herniation in the setting of initiation of CSF
diversion with ventriculostomy. CSF diversion from lumbar drain is
contraindicated because of the high risk for downward herniation of
cerebellar tonsils. The upward herniation must be managed via tumor
resection.
852 J U N E 2 0 24

metastases), although multilevel disease is also common. Tumors arising from KEY POINTS
the lung, breast, prostate, kidney, gastrointestinal tract, and thyroid as well as
● Spinal level and
non-Hodgkin lymphoma and multiple myeloma have a tendency for spinal ambulatory status
metastasis; tumors from the first four comprise more than 60% of cases of spinal preceding surgery are the
metastases.25 Oncologic complications of the spine stem from tumor growth or main determinants of
collapsed vertebra, commonly in the setting of osteolytic metastases, causing postoperative functional
outcomes in patients with
impingement on the nervous system structures within the spinal column. These
malignant cord
can be extradural (60% of all spinal tumors, predominantly metastasis), compression.
intradural extramedullary (30%; commonly meningiomas, nerve sheath tumors,
and drop metastasis), or, much less frequently, intradural intramedullary tumors ● Prompt identification of
the tipping point leading to
(10%; commonly ependymomas and astrocytomas predominantly in the cervical
exhaustion of adaptive
region) (FIGURE 11-1). Malignant spinal cord compression occurs in mechanisms to maintain
approximately 5% to 14% of all patients with solid tumors and may be the initial intracranial compliance is
manifestation at diagnosis in up to 20% of these patients. key in the management of
Clinically significant mass effect in the spinal cord or cauda equina is patients with brain tumor
who acutely decompensate.
considered a neurologic emergency because of the extremely high potential for
permanent disability, including loss of sphincter control and paraplegia. ● Multimodal ICP-targeted
Diagnosis centers on prompt neuroimaging with gadolinium-enhanced total- therapy with corticosteroids,
spine MRI, which is the most sensitive modality and guides surgical treatment. osmotic therapy,
consideration for CSF
Postcontrast fat-suppressed images help differentiate metastases from bone diversion, surgical
marrow. From a clinical perspective, compression and mass effect may be resection or evacuation,
insidious, often with motor symptoms following pain onset by several weeks. and supportive care are
Recovery hinges upon decompression before compression leads to ischemic often required to manage
patients with brain tumor
damage of the spinal cord. Pain, due to periosteal stretching, is ubiquitous,
who acutely decompensate.
often nocturnal, with a mechanical component (ie, exacerbated by transitional
movements from changing position) that suggests impending or established
spinal instability. Physical examination must be thorough, including
assessment for a sensory level, strength, muscle stretch reflexes, and sphincter
function. Preserved ambulation preceding surgery is the most important
prognostic factor for functional outcomes, and the preoperative spinal level is
one of the main determinants of postoperative gait function.25 Intramedullary
tumor location is a poor prognostic factor.26 Depending on individual factors,
treatment includes urgent IV corticosteroids aiming at pain control and
stabilization of edema while definitive decisions on candidacy for surgical
decompression with or without radiation therapy or radiation therapy
alone take place. The New England Spinal Metastasis Score (TABLE 11-3) is the
most rigorously studied and validated score agnostic to therapeutic measures
available. It is able to successfully predict mortality at 1 year without false
positives27 and to inform 3- and 6-month independent ambulatory function
(TABLE 11-4).28
Management of Direct Tumor-Mediated Complications

The identification of the predominant factor prompting acute decompensation
facilitates the selection of targeted interventions; however, a multipronged
approach is often required. For example, it is sometimes difficult to know
whether symptoms are due to a tumor itself or due to cerebral edema or both. As
with any neurologic emergency, general measures should be applied promptly,
including optimal patient positioning with head of bed elevation greater than
30 degrees and the head in a neutral position, ensuring normal ventilation and
oxygenation and supporting hemodynamics.

OSMOTHERAPY. The role of osmotherapy in the management of edema and mass

effect centers on leveraging the blood-brain barrier to pull water from the
parenchyma and interstitium into the intravascular space, particularly water
content from healthy tissue. The impermeability of an osmotic agent to the
blood-brain barrier (ie, its ability to remain in the intravascular space and not
be transferred into parenchyma) is indicated by its reflection coefficient, in

which a value of zero suggests that the molecule has free permeability crossing
the blood-brain barrier and a value of 1 corresponds to complete impermeability.

The high reflection coefficient for mannitol (at 0.9) and hypertonic sodium
solutions (at 1) renders them effective as osmotherapeutic agents; however, this
impermeability is contingent on an intact blood-brain barrier, which is not the
case in most acute brain injury settings, including most neuro-oncologic
emergencies. These agents are still effective in this setting because the osmotic
effectiveness, or tonicity, depends on the osmotic gradient created by the
solution. However, the osmotic gradient can worsen over time as the brain tissue
becomes hyperosmolar because of accumulation of idiogenic osmoles and with
the repeated administration of osmotic agents, mannitol in particular.

Osmotic therapies in neuro-oncologic emergencies should be used as rescue
medications or intraoperatively to facilitate resection29 because their effect is
inherently transient, and repeated use can lead to rebound exacerbation of mass
effect and elevated intracranial pressure. Dosing, risks, and benefits are relatively
similar compared with other brain injury settings30; for more information, refer
to the article “Neurocritical Care for Patients With Ischemic Stroke” by T. M.
Leslie-Mazwi, MD,31 in this issue of Continuum. Osmotic agents can also facilitate
penetration of other tumor-targeted therapies through the blood-brain barrier by
reducing the volume of the endothelial cells and widening interendothelial
tight junctions.
TABLE 11-3 The New England Spinal Metastasis Scorea
Characteristic Points assigned

b
1 Modified Bauer Score
Modified Bauer Score ≤ 2 0
Modified Bauer Score ≥ 3 2
2 Ambulatory function
Dependent ambulator or nonambulatory 0
Independent ambulator 1
3 Serum albumin
<3.5 g/dL 0
≥3.5 g/dL 1
a
Modified with permission from Schoenfeld AJ, et al, Spine J.27 © 2021 Elsevier B.V.
b
The Bauer score is calculated from the following: no visceral metastases (1 point); primary tumor is not lung
cancer (1 point); primary tumor is breast, renal, lymphoma, or myeloma (1 point); single skeletal metastasis
(1 point).
854 J U N E 2 0 24

CORTICOSTEROIDS. Corticosteroids are particularly effective in the management
of extensive vasogenic edema, mass effect, and acute neurologic manifestations
of space-occupying tumors. Their effect is attributed to suppression of tumor-
associated vascular permeability and support of the integrity of the blood-brain
barrier, but this mechanism is incompletely understood. Because of the potential
for side effects, the lowest effective steroid dose should be used for the shortest
time possible.12 Dexamethasone is the standard therapy for peritumoral edema
because of its long half-life, low mineralocorticoid activity, high bioavailability,

and lower tendency to induce psychosis. It is administered intravenously with a
10-mg loading dose, followed by a maintenance dose of up to 16 mg daily in two
or four doses.30 If patients exhibit severe symptoms consistent with increased
intracranial pressure, initial higher doses (16 mg/d or more) should be
considered.32 Significant clinical response is expected 24 to 72 hours following the
first dose of corticosteroids; clinical improvement may precede
radiographic improvement.
In the setting of malignant spinal cord compression, prompt initiation of
high-dose dexamethasone is intended to facilitate pain control and prevent

further neurologic decline. Small studies have failed to demonstrate additional
benefit of administration of massive doses of dexamethasone (eg, a 100-mg IV
bolus followed by 24 mg every 6 hours compared with a 10-mg bolus followed by
4 mg to 6 mg every 6 hours); furthermore, there were fewer side effects in the
lower-dose group.33 Corticosteroids are most effective within 12 hours of
symptom onset. Rapid improvement of motor function following initiation of
corticosteroids is a positive prognostic sign. Although 7- to 14-day regimens are
commonly used, the optimal duration of steroid therapy remains unknown.33
A caveat of the empiric use of corticosteroids in patients presenting with
severe mass effect from tumoral lesions without a formal pathology diagnosis of
the tumor is the potential lower yield of histopathologic diagnosis in biopsy
specimens with prior recent exposure to corticosteroids for some steroid-
responsive tumors (eg, primary CNS and systemic lymphoma with CNS
involvement).34 Corticosteroids are also bound to serum albumin, and increased
toxicity can be seen in the setting of hypoalbuminemia, which can lead to a high
concentration of free steroid molecules. Furthermore, corticosteroid use may
have a negative impact on the effect of checkpoint inhibitors in patients with
The New England Spinal Metastasis Score Association With 1-year Mortality TABLE 11-4
After Adjustment for Clinical and Sociodemographic Confoundersa
New England Spinal Metastasis Score Odds ratio 95% confidence interval
b
0 Perfect prediction Perfect prediction
1 31.30 8.82-111.04
2 7.04 2.47-20.08
3 Referent Referent
a
Modified with permission from Schoenfeld AJ, et al, Spine J.27 © 2021 Elsevier B.V.
b
A NESMS of 0 reliably predicts mortality at 1 year without false positives.

metastatic brain disease.35 Thus, empiric use of steroids is reserved for patients
who exhibit signs of significant clinical deterioration or life-threatening mass
effect.
SURGICAL TREATMENT. Urgent or emergent surgical resection is frequently

necessary for patients presenting with space-occupying CNS tumors. The

surgical goal is generally gross total resection, which may be followed by

radiotherapy, chemotherapy, or both, but achieving gross total resection
can be challenging because of the infiltrating nature of many tumors, particularly
glioblastoma, along the vessels and into white matter with no distinct
macroscopic brain-tumor interface. En block surgical resection of tumors has a
well-established role in the alleviation of acute neurologic complications from
solitary or limited metastases exerting significant mass effect (3 cm or greater) in
patients with adequate functional status (ie, a Karnofsky scale score of 70% or
greater) and in patients expected to improve significantly after resection (eg,
elevated intracranial pressure or lesions in the posterior fossa) whose systemic
burden of cancer is relatively stable.12,36,37 Urgent resection also has a role in

recurring space-occupying lesions with significant mass effect following
radiation, with the reasoning being manifold. Radiation necrosis is an important
consideration, the degree of vasogenic edema may be refractory to high doses of
corticosteroids, the profound breakdown in the blood-brain barrier limits the
clinical effect of osmotic therapy, and rescue bevacizumab may not be an option
in the acute setting.
Considering frailty status (TABLE 11-538) when selecting surgical candidates is
important. Patients with brain metastasis and modified frailty index of ≥2 are
nearly 3 times as likely to have higher mortality after hospital discharge than
patients with lower frailty indices.14 Furthermore, predicted solid tumor
response to chemotherapy and radiation as well as propensity for systemic
dissemination should be considered when considering surgical candidacy;
surgery is often deferred in chemotherapy- and radiation-sensitive tumors prone
to seeding. Endoscopic third ventriculostomy or concurrent CSF diversion,
either temporary through external ventricular drain placement or as a bridge to
ventriculoperitoneal shunt, is often used in the presence of CSF flow obstruction,
TABLE 11-5 The Modified Frailty Index With Five Covariatesa
Covariates assessed Points assigned if presentb

Congestive heart failure 1
Chronic obstructive pulmonary disease 1
Diabetes mellitus 1
Hypertension 1
Nonindependent functional status 1
a
Data from Subramaniam S, et al, J Am Coll Surg.38
b
Level of frailty is based on the total of points scored: 0 = nonfrail; 1 = prefrail; 2 or more = frail.
856 J U N E 2 0 24

particularly in patients with infratentorial tumors.14 Planned surgeries (ie, urgent KEY POINTS
elective versus emergent) in the setting of neurologic emergencies should occur
● The effectiveness of
with optimal use of surgical adjuncts (eg, intraoperative neuronavigation, osmotic agents to manage
fluorescence-guided resection, cortical mapping)12 because those procedures intracranial hypertension
may be more likely to achieve the best longitudinal outcomes39 given the direct depends on their reflection
association of maximal tumor resection with symptom control and progression- coefficient and the osmotic
gradient. The tendency for
free and overall survival. Postoperative imaging with MRI should be performed
rebound cerebral edema

within 48 hours from resection in patients who are clinically able to tolerate lying from gradual increase in the
flat to determine the extent of resection.12 This timeframe is based on optimal osmolarity of the brain,
reliability of imaging in the determination for residual tumor while circumventing particularly in the setting of
disrupted blood-brain
contrast enhancement from the surgical procedure.40
barrier, favors the use of this
Surgical candidacy for decompression in malignant cord compression hinges therapy as isolated
upon overall prognosis for survival and is generally recommended for patients occurrences, as a rescue, or
with expected survival greater than at least 3 months and a higher Karnofsky to facilitate brain tumor
resection.
performance score. In the POST (Prospective Observational study of Spinal
metastasis Treatment) cohort, one in five patients died by 3 months, ● Corticosteroids are
approximately one-half of the patients died at 1 year, and more than two-thirds helpful in patients with life-
of the patients did not survive after 2 years.41 Favorable outcomes in older adult threatening CNS tumor mass
patients are possible,42,43 and traditional scoring systems (eg, Tokuhashi score) effect. A dexamethasone
10-mg loading dose should
can greatly underestimate life expectancy in this setting. However, a study be promptly given to
assessing characteristics of patients who survived less than 3 months or longer patients with acute
than 2 years after surgical treatment for spine metastases showed that those who herniation.
did not survive to 3 months had a mean Karnofsky performance score of 47.6.44
● Urgent, planned
Spinal stabilization with reconstruction in addition to laminectomy may
resection of space-
contribute to better surgical results. Regardless of the surgical approach, occupying tumors with
postoperative external beam radiation is often used. Impaired wound healing acute manifestations from
and dehiscence are the most frequently reported complications of radiation. mass effect is reasonable in
patients with primary brain
Surgeries lasting longer than 4 hours and blood loss greater than 3000 mL have
tumors and with solitary or
a threefold and twofold increase in the risk of infection, respectively.25 limited metastases of 3 cm
Embolization of highly vascularized tumors before surgery may significantly or greater, in patients
reduce perioperative blood loss.45 expected to improve
significantly after resection,
and as a steroid-sparing
INDIRECT TUMOR-MEDIATED COMPLICATIONS measure.
There are a number of indirect tumor-mediated complications, including
seizures, cerebrogenic arrhythmias, paraneoplastic syndromes, ischemic stroke,
cerebral venous thrombosis (CVT), and intracranial hemorrhage. TABLE 11-6
summarizes the mechanistic underpinnings and management of these
complications.
Seizures
Seizures and status epilepticus are highly morbid complications of CNS tumors
and can be related to cortical irritation from the tumor, intratumoral
hemorrhage, paraneoplastic syndromes, or treatment effects. More than 10% of
neurologic causes of death in patients with brain metastasis are related to
refractory seizures.23 Overall, one-third of patients with malignant primary or
secondary CNS tumors develop tumor-associated epilepsy46,47; this risk is much
lower in patients with meningiomas, with a cumulative risk of epilepsy of
approximately 10% to 20%.48,49 Seizure risk varies widely depending on the
histopathologic type of tumor, particularly primary brain tumors. For example,
nearly all patients with neurogliomas (dysembryoplastic neuroepithelial tumors

and gangliogliomas) experience seizures, in contrast to 60% to 85% of patients

with low-grade gliomas and approximately one-half of patients with
glioblastoma. One in five patients with tumor-associated epilepsy experience
status epilepticus, and approximately 3% to 12% of adult patients who experience
status epilepticus have CNS tumors. Mechanisms underpinning the pathogenesis
of tumor-related seizures are multifactorial, including histology, World Health

Organization grade, size, growth speed, location of tumor, and genetic
variations.47,50,51 Seizure risk in patients with glioma varies drastically depending

on IDH1/2 variation status52 because D-2-hydroxyglutarate, which is released by
tumor cells and accumulated in brain tissue in the setting of IDH1/2 variation,53 is
structurally similar to glutamate, mimicking its excitatory activity on N-methyl-
D-aspartate (NMDA) receptors. Preoperative seizures occur in less than
TABLE 11-6 Mechanistic Underpinnings and Management of Indirect Tumor-related

Complications
Complication Mechanism Management

Acute ischemic Compression of artery Consideration for targeted recanalization therapies (systemic
stroke thrombolysis is contraindicated in patients with intracranial
Systemic hypercoagulability
intraaxial tumors)
Abnormal angiogenesis
Abnormal endothelial function
Abnormal platelet function
Cerebrogenic Imbalances in sympathetic and Characterization of event with EEG and ECG to define
arrhythmias parasympathetic tone appropriate therapy
Limbic circuitry Consideration of pacemaker
Cranial nerves IX and X
Cerebral venous Compression of venous system Anticoagulation plan is individualized on a case-by-case basis
thrombosis
Systemic hypercoagulability
Intracranial Intratumoral hemorrhage Supportive care, reversal of coagulopathy when indicated,

hemorrhage surgical evacuation
Intraparenchymal hemorrhage
Extraaxial hemorrhage
Paraneoplastic Antibody or T cell mediated Tumor targeted therapy, immunomodulation

syndromes
Seizures Cortical irritation from the tumor or Preferred agents: levetiracetam, valproic acid, oxcarbazepine,
intratumoral hemorrhage perampanel
Genetic variations In selected patients: surgical resection and corticosteroids,
immunomodulation
Histology
Size
Growth speed
Location
Paraneoplastic syndromes
Treatment effects
858 J U N E 2 0 24

one-third of patients with IDH1 wildtype tumors and over two-thirds of patients KEY POINTS
with IDH1/2 variant tumors.53
● Tumor-related seizures
Cortical hyperexcitability in cancer patients may occur in many different arise from a complex
stages: as the presenting symptom of CNS tumors, in the perioperative period, interplay of factors that
during chemotherapy and radiation therapy, upon recurrence, and in late ultimately lead to imbalances
stages of terminal disease. Seizure refractoriness has been associated with between excitation and
inhibition. Neurogliomas;
prolonged histories of seizures and insular or eloquent cortex location of
gliomas with IDH1/2 variation;

tumors.54 Early postoperative seizures have been reported in 1% to 12% of fast-growing tumors; tumors
patients with intracranial tumors, with the greatest risk in the first 48 hours with cortical, insular, frontal,
after surgery.48 Perioperative primary seizure prophylaxis has failed to and temporal involvement;
and tumors prone to
prevent postoperative seizures.55 Nevertheless, seizure prophylaxis is routinely
intratumoral hemorrhage are
used in the perioperative period in clinical practice. Whenever it is used, a most associated with
limited duration of antiseizure therapy should be explicitly established to hyperexcitability.
avoid the side effects that can be quite detrimental in patients with cancer,
such as myelosuppression, liver and cardiotoxicity, hyponatremia, and drug ● The 2021 updated
diagnostic criteria for
interactions.55
paraneoplastic syndromes
Because of its safety profile, lack of drug-drug interactions, and effectiveness stratify the likelihood of
in reducing tumor-related seizures, levetiracetam is the most common diagnosis into definite,
antiseizure medication used in patients with brain tumors.56 In fact, large cohort probable, and possible
based on clinical phenotype,
data from patients with gliomas support levetiracetam and valproate presence or absence of
monotherapy, or in combination, over other antiseizure drugs,57,58 particularly tumor, antibody type, and
over enzyme-inducing options.59 Data from preclinical and small cohort studies time of follow-up.
suggest that some antiseizure medications (eg, valproate, levetiracetam,
● In contrast to intracranial
oxcarbazepine, perampanel) may also have antiproliferative effects; however,
extraaxial tumors, stroke
there are no large clinical trials demonstrating these properties to be clinically patients with intracranial
significant.47,60,61 Patients with refractory seizures and tumor-related status intraaxial tumors are not
epilepticus may benefit from optimization of corticosteroids and consideration eligible for systemic
thrombolysis. Patients
for surgical resection, particularly in the setting of an identifiable seizure focus.
with active malignancy
and large vessel occlusion
Cerebrogenic Arrhythmias may benefit from
Neurocardiogenic arrhythmias in the setting of cancer arise from disturbances in thrombectomy, although their
the brain-heart axis, resulting in imbalances in sympathetic and parasympathetic functional outcomes at
3 months are worse than
tone. The limbic circuit and the insula, which is an important part of this axis patients without cancer.
modulating the autonomic nervous system, can be affected by paraneoplastic
encephalitis or direct tumor growth and lead to malignant cardiac arrhythmias,
which can also occur in the setting of a seizure. Moreover, cerebrogenic
arrhythmias and syncope may occur with parapharyngeal and neck tumors as
reflex-induced syncope akin to carotid sinus syndrome or overactivation of
vagus or glossopharyngeal nerves. A thorough investigation in these patients is
warranted, ideally capturing episodes of syncope with hemodynamic and
telemetry monitoring and EEG monitoring in cases of brain tumor involvement
(CASE 11-2). Appropriate therapy hinges on the identification of the main factors
driving symptoms. Pacemaker implantation can address cardiac pauses in
patients with insular tumors and bradyarrhythmia from cardioinhibitory reflex
in neck tumors, but they will be ineffective in hypotensive episodes from
vasodepressor reflex from persistent carotid sinus irritation.
Paraneoplastic Syndromes
Over the past several decades, advances in the overlapping fields of
neuro-oncology and neuro-immunology have yielded the identification of

myriad autoantibodies associated with neurologic manifestations in the setting of

malignancies. The resulting high complexity of the contemporary diagnosis of
these conditions requires the use of standardized terminology and an algorithmic
approach. The 2021 updated consensus for the diagnostic criteria of
paraneoplastic syndromes includes a scoring system based on clinical
phenotypes, antibody type, and presence of tumor (TABLE 11-7).62 These criteria
have good diagnostic performance (ie, sensitivity 88%, specificity 80%) and
excellent interrater reliability.63 Paraneoplastic syndromes are more prevalent in

patients with tumors that express neuroendocrine proteins (eg, small cell lung
cancer),64 those that affect organs with immunoregulatory functions (eg,
thymoma),65 or those that contain nervous tissue (eg, teratoma); however, many
other solid organ tumors and hematologic malignancies have been associated
with paraneoplastic syndromes. Most syndromes have a relatively insidious
onset, but patients with advanced disease can become critically ill, particularly in
the setting of severe encephalitis, dysautonomia, and neurogenic respiratory
failure. High-risk antibodies, specifically antineuronal nuclear antibody type 1
CASE 11-2 A 69-year-old woman was admitted to the hospital with recurrent
episodes of transient loss of consciousness and headache. Her
neurologic examination was remarkable for mild inattention and impaired
delayed recall. Workup revealed sinus bradycardia but no epileptiform
findings on 24 hours of continuous EEG monitoring; however, no spells
were captured. Neuroimaging demonstrated an infiltrating tumor
involving the right insula and superior temporal region with mass effect
(FIGURE 11-3A). Craniotomy with resection was performed. Postoperatively,
her examination was unchanged; however, her course was complicated
by several episodes of syncope associated with asystolic pauses of up to
8 seconds, most of which were triggered by trivial parasympathetic
stimulation, such as the arrival of her food tray in the room and
swallowing of medications.
Postoperative head CT demonstrated partial resection of tumor with
expected postoperative findings of blood products in the resection
cavity and pneumocephalus (FIGURE 11-3B). An empiric increase in
dexamethasone dose and a trial of osmotherapy had no impact on the
severity or frequency of the events, which were also captured on EEG and
were associated with diffuse attenuation of faster frequencies and
increased slowing. A minimally invasive, transcatheter cardiac pacing
system was placed with resolution of asystolic events, allowing for
hospital discharge without the need for mobility restrictions and
mitigation of pocket-related complications (eg, impaired healing and
infection, which are both highly relevant in a patient required to continue
corticosteroid therapy during radiotherapy for brain tumor).
860 J U N E 2 0 24

(ANNA-1, also known as anti-Hu), anti–collapsin response mediator protein-5
(CRMP-5), as well as anti-NMDA receptor and anti-acetylcholine receptor
autoantibodies are known to be associated with paraneoplastic syndromes
involving the autonomic nervous system. Clinically, patients may exhibit marked
swings in hemodynamics, particularly when orthostatic. Paraneoplastic limbic
encephalitis such as the syndrome associated with anti–γ-aminobutyric acid B

(GABAB) antibodies can present with refractory status epilepticus and profound
dysautonomia. Some paraneoplastic syndromes have a significant

neuromuscular component (eg, myasthenia gravis and Lambert-Eaton
myasthenic syndrome) that may manifest as impending neurogenic respiratory
failure. Although supportive treatment is similar regardless of the etiology,
distinguishing between neurotoxicity from antineoplastic agents (eg, checkpoint
inhibitors) and antibody-mediated conditions is key for appropriately choosing
targeted therapies, which often comprise tumor-related treatment and
immunosuppression. A comprehensive overview of paraneoplastic syndromes is
beyond the scope of this review and can be found in other Continuum issues.66,67
FIGURE 11-3
Infiltrative high-grade glioma involving the right insula in the patient in CASE 11-2. A,
Preoperative axial postcontrast T1-weighted MRI demonstrating an infiltrating tumor and
vasogenic edema involving the right insula and superior temporal region. B, Postoperative
axial head CT images showing ongoing mass effect on the insula and effacement of the lateral
ventricles from residual tumor as well as postsurgical changes, with blood products in the
surgical cavity and pneumocephalus.
This case illustrates how cardiac function can be affected in a patient with a COMMENT
brain tumor infiltrating the right insula. Lack of clinical improvement despite
treatment with corticosteroids and no electrographic findings to suggest an
epileptiform mechanism for the events led to selection of a cardiac
pacemaker as the appropriate treatment in this case.

Ischemic Stroke
A new cancer diagnosis is associated with a sixfold increase in the risk of stroke
(ischemic or hemorrhagic) or transient ischemic attack during the first month
after diagnosis.68 The overall stroke incidence in the first year after a cancer
diagnosis is 1.4%, with ischemic stroke being more common than hemorrhagic
stroke.69 For patients with brain tumors, the risk of both ischemic and
hemorrhagic stroke, and the risk of poststroke mortality, are higher than for
patients with other malignancies. Nearly 1 in 10 patients with a brain tumor will
experience an ischemic stroke.70 Although cerebrovascular events may occur
because of direct tumor effects via compression of vascular structures, with acute
arterial and venous ischemia, they are more likely to occur because of cancer-
mediated hypercoagulability and indirect effect on angiogenesis, platelet and
endothelial functions,71 or treatment effect. Advanced lung, pancreatic, and
colorectal cancers seem to be associated with the highest stroke risk,72 but strokes
are also frequent in patients with breast and prostate cancer.73 Among patients
with primary brain tumors, the risk of ischemic stroke is highest for those with
gliomas, meningiomas, and primary CNS lymphoma. Patients on bevacizumab

are at higher risk of any arterial thromboembolic events (neurologic and
cardiovascular).
Efficacy and safety data for systemic thrombolysis in patients with active
cancer are limited to case series and nonrandomized studies, and they are likely
affected by publication bias; the dearth of data is acknowledged in current acute
TABLE 11-7 Paraneoplastic Neurologic Syndrome Care Scorea
Pointsb
Clinical level
High-risk phenotypes 3
Intermediate-risk phenotypes 2
Defined phenotype epidemiologically not associated with cancer 0
Laboratory level
High-risk antibody (>70% cancer association) 3
Intermediate-risk antibody (30-70%) 2
Lower-risk antibody (<30%) or negative 0
Cancer
Found, consistent with phenotype, and (if present) antibody, or not consistent 4
but antigen expression demonstrated
Not found (or not consistent) but follow-up <2 years 1
Not found and follow-up ≥2 years 0
a
Data from Graus F, et al, Neurol Neuroimmunol Neuroinflamm.62
b
Diagnostic level based on the total of points scored: definite = 8 or more; probable = 6-7; possible 4-5; not
paraneoplastic syndrome = 3 or fewer.
862 J U N E 2 0 24

stroke guidelines. Intracranial intraaxial neoplasms with coexisting
coagulopathy, including thrombocytopenia, constitute a contraindication for
systemic thrombolysis because of higher risk for intracranial hemorrhage;
however, intracranial extraaxial neoplasms should not impact thrombolysis
decision-making. A 2020 meta-analysis assessing efficacy and safety of
thrombolysis in patients with cancer found comparable outcomes to patients

without cancer, regarding neurologic function, symptomatic intracranial
hemorrhage, major hemorrhage, and 3-month mortality74; however, patients

with primary brain tumors and metastases were not analyzed separately. By
contrast, a 2021 meta-analysis evaluating reperfusion therapy, including both
systemic thrombolysis (n = 1012) and endovascular treatment (n = 2496) in
patients with active cancer showed a nearly 10-fold higher risk of symptomatic
intracranial hemorrhage in patients who received thrombolysis75; this study also
did not specify presence or absence of intracranial lesions.
Data on endovascular thrombectomy for patients with malignancies are also
derived from retrospective studies and case reports because patients in these
studies have been excluded from most randomized trials. Recanalization rates
may be similar between patients with and without active cancer76; however, the
thrombus composition is different in patients with cancer, with higher fibrin and
platelet content, which may make clot retrieval more challenging.77 Functional
outcomes 3 months after thrombectomy are worse in patients with cancer, with a
little more than one-third reaching functional independence.76 Nonetheless,
there is therapeutic benefit from thrombectomy, therefore patients with active
cancer and a large vessel occlusion should not be automatically excluded from
endovascular therapy if they are otherwise eligible and have a reasonable life
expectancy.78
Cerebral Venous Thrombosis

Although CVT is a rare cause of hemorrhagic stroke, patients with cancer are at
disproportionally higher risk of this diagnosis. Overall, nearly 1 in 10 patients
with CVT have a malignancy, and among patients older than 55 years, this ratio
increases to one in four.79 Patients with hematologic, lung, gastrointestinal, and
breast malignancies have the highest risk of CVT, especially in the first year after
cancer diagnosis.
Patients with cancer-associated CVT were excluded from anticoagulation
trials for CVT in general; thus, data on management are scarce, and current
guidelines provide no specific recommendation on anticoagulation of patients
with cancer-associated CVT.80,81 In general, low-molecular-weight heparin has
been the treatment of choice for patients with cancer-associated venous
thromboembolism (VTE).81 Direct oral anticoagulants have been shown to have
similar, and in some studies better, efficacy and safety profile for VTE in patients
with cancer and are now favored over low-molecular-weight heparin for
cancer-associated VTE in patients whose cancer is not gastrointestinal or
urogenital and in the absence of contraindications to direct oral anticoagulants.82
The primary malignancy site is an important driver of the risk of both recurrent
thrombosis and hemorrhagic events.83 Extrapolation of any of those data and
recommendations to CVT is tricky, especially because approximately 40% of
these patients present with intracranial hemorrhage.80 Hence, in practice,
anticoagulation often commences with continuous heparin infusion, because of
the shorter half-life and ability to reverse, if needed.

Spontaneous Intracranial Hemorrhage

The etiology of intracranial hemorrhage in patients with oncologic diseases
hinges on their type of tumor and differs from those in the general population,
in whom hypertension and trauma predominate as risk factors. Intracranial
hemorrhages can be intraaxial or extraaxial. When intraparenchymal, they tend
to occur later in the course of a malignancy, but they may also present as a first
manifestation and should be considered in the differential diagnosis of
spontaneous intracranial hemorrhage. Approximately 1% to 2% of spontaneous

intracranial hemorrhages are due to cancer. These hemorrhages may occur in the
setting of coagulopathy, thrombocytopenia, or hemorrhage in the tumor bed.84
Intratumoral hemorrhages in patients with solid tumors represent the largest
subgroup of cancer-related intracranial hemorrhage,84 followed by hemorrhages
in the setting of a disturbed coagulation cascade. Coagulopathy may be
intentional and therapeutic for the treatment of VTE, which is highly prevalent
in patients with active cancer, or the result of platelet abnormalities, with
thrombocytopenia secondary to bone marrow suppression being a common
reason.85 Primary CNS tumors with a predilection for intratumoral hemorrhage

are glioblastomas, oligodendrogliomas, and meningiomas. Their increased
propensity to hemorrhage is rooted in their structural composition, with fragility
of the tissue types involved. Lung and breast adenocarcinomas, renal cell
carcinomas, and melanomas carry a high risk of intracranial hemorrhage because
of both their high prevalence in the general population (eg, lung cancer, breast
cancer, and melanoma, in particular) and propensity for CNS metastasis, in
addition to histologic composition with high cell turnover and tissue fragility. In
contrast, papillary thyroid cancer, hepatocellular carcinoma, and choriocarcinoma
are much more rare, but they are predisposed to hemorrhage when metastatic to
the brain. Tumor size and combination therapy with tyrosine kinase inhibitor
and intracranial radiation therapy are strong predictors for hemorrhagic brain
metastasis in patients with lung adenocarcinoma.86 Patients on bevacizumab are
approximately 3 times as likely to develop intracranial hemorrhage.
Pituitary apoplexy occurs in 2% to 12% of patients with pituitary adenomas
and is characterized by sudden headache, abnormal vision, encephalopathy, and
ophthalmoparesis from third, fourth, and sixth cranial nerve palsies. It is
considered a life-threatening complication due to acute panhypopituitarism
caused by hemorrhage and accompanying infarction of the pituitary gland.
Management is centered on supportive care, including hormone replacement
with prompt administration of corticosteroids with both glucocorticoid and
mineralocorticoid effects and surgical evaluation for possible evacuation
of hemorrhage.
Hematologic malignancies usually cause intracranial hemorrhage through
coagulopathy from thrombocytopenia or dysfunction of the coagulation cascade.
Mean platelet counts in patients with hematologic malignancies and intracranial
hemorrhage are well below 50,000/mm3; guidelines do not recommend
prophylactic transfusions in nonbleeding critically ill patients unless counts are
less than 10,000/mm3.87 Extraaxial location of the hemorrhage is more typical for
hematologic malignancies; however, subdural hematoma is also common in
patients with other malignancies, particularly those with prostate cancer and
gliomas.88 Of note, subdural hematoma may coexist with dural metastases in 15%
to 40% of cases.89 Although trivial trauma, such as bumping the head on a shelf,
can often be elicited in the history, cancer-related subdural hematomas tend to
864 J U N E 2 0 24

present with gradually progressive confusion and lethargy. A high level of KEY POINTS
suspicion may be necessary, particularly if there are other reasons for confusion
● Approximately 10% of
such as medications and septic encephalopathy. patients with cerebral
In general, the approach in these patients is to correct any underlying venous thrombosis have an
coagulopathy and consider surgical evaluation if mass effect is present. Reversal active malignancy, and this
of coagulopathies follows accepted standards.90 Platelet goals in the setting of
number increases to 26%

among patients older than
intracranial hemorrhage, regardless of whether surgery is planned, are
55 years.
conventionally greater than 100,000/mm3, although there are only low-quality
data supporting this threshold.91 In some cases, patients have refractory ● Cancer-related
thrombocytopenia from splenic or hepatic sequestration or bone marrow spontaneous intracranial
hemorrhage is often
suppression, and achieving and sustaining platelet targets greater than
intraparenchymal, it may be
75,000/mm3 may not be realistic or definitively necessary (CASE 11-3). In these a presenting sign or occur
situations, it is imperative to balance the risks and benefits of continued later in the course of
transfusions and adjust to individual circumstances on a case-by-case basis. malignancies, and it may be
Middle meningeal artery embolization has been gaining traction in the intratumoral or secondary
to coagulopathy.
management of chronic subdural hematoma, particularly in the setting of
refractory thrombocytopenia,92 but whereas this intervention decreases the risk ● Glioblastomas,
of further bleeding, it does not address existing hemorrhage or mass effect.92,93 oligodendrogliomas,
The complication rate of middle meningeal artery embolization is 1.2%. meningiomas, lung and
breast adenocarcinomas,
Complications are predominantly related to arterial access or nontargeted renal cell carcinomas,
embolization in the setting of anastomoses between further branches of the melanoma, papillary
middle meningeal artery and the ophthalmic or the posterior auricular artery.93 thyroid cancer, and
Long-term outcomes in these patients are driven largely by underlying choriocarcinoma are
associated with highest
pathology. Prognosis is worse for intracranial hemorrhage caused by
intratumoral
coagulopathy than for intratumoral hemorrhage if consciousness is impaired and hemorrhage risk.
multiple hemorrhagic foci, hydrocephalus, and increased intracranial pressure
are present.84,85 Among patients with brain metastases, preoperative ● Intratumoral hemorrhage
intratumoral hemorrhage is an independent predictor for poor outcomes.94 is an independent predictor
of poor outcomes in
Patients with systemic cancer, particularly those with metastatic disease, fare patients with primary or
worse regarding both mortality and discharge outcome.70 secondary CNS malignancy.
TREATMENT-RELATED COMPLICATIONS
Neurotoxicity of cancer therapies is widely recognized. Common syndromes
include neuropathy and cognitive dysfunction, but interventions to treat cancer
can also lead to life-threatening complications, such as encephalitis, cerebral
edema, posterior reversible encephalopathy syndrome (PRES), fulminant
demyelinating processes, cortical hyperexcitability and status epilepticus, and
cerebrovascular complications. Neurotoxicity, akin to myelosuppression, is one
of the main dose-limiting factors of oncologic treatment. The diagnosis can be
challenging, as typically there are no specific, confirmatory tests available;
however, prompt identification of severe neurotoxicity is key to adjusting
treatment and preventing further injury. This section focuses on severe
neurotoxicity from cancer therapy that presents as a neurologic emergency or
can be encountered in the critically ill patient population. A thorough review of
neurologic complications of cancer treatment can be found in the June 2023 issue
of Continuum on the neurology of systemic disease.95
Immune Checkpoint Inhibitor–related Complications

Monoclonal antibodies targeting immune checkpoint molecules have changed both
the landscape of oncologic care and the spectrum of neurotoxicity syndromes.

CASE 11-3 A 69-year-old man with acute myeloid leukemia and myelodysplastic
syndrome who was taking azacitidine and enasidenib was admitted to the
hospital for the evaluation of severe headache in the setting of severe
thrombocytopenia (ie, platelet count 2 103/μL). Initial neuroimaging
demonstrated a large mixed-density extraaxial fluid collection over the
right hemisphere with effacement of the right lateral ventricle and mass
effect onto the right hemispheric parenchyma (FIGURE 11-4A). He was given
serial platelet transfusions targeting a platelet goal of 100 103/μL or
greater, but his platelet count increased to only 72 to 81 103/μL and he
developed worsening oxygen requirements despite diuresis. He was
closely monitored with surveillance imaging and given transfusions as
needed for a more liberal platelet goal (ie, 40 to 50 103/μL) for 2 weeks,
then platelets were allowed to drift to 20 to 30 103/μL. A follow-up CT of
his head 3 weeks later showed evolution of the subdural hematoma with
decreased mass effect and no new acute areas of hemorrhage (FIGURE 11-4B).
FIGURE 11-4
Evolution of a loculated acute on chronic subdural hematoma in the setting of refractory
thrombocytopenia with conservative management of the patient in CASE 11-3. A, Initial axial
CT image demonstrating multiple complex, loculated, right-sided extraaxial collections of
mixed density reflecting acute hemorrhage superimposed on chronic fluid collection, in the
setting of a platelet count less than 10 103/μL. B, Surveillance axial CT imaging 3 weeks
after initial CT showing resolution of the acute component and overall improvement in
the mass effect from collections while maintaining platelets 20-50 103/μL.
COMMENT This case illustrates the challenge of maintaining a conventional platelet

goal in the setting of severe thrombocytopenia and hematologic cancer.
Such challenges are often encountered in practice and may require
individual adjustment of the goal to maximize the benefit (reducing the risk
of further intracranial hemorrhage) and reduce the risk (transfusion-related
complications, including lung injury or hypoxic respiratory failure).
866 J U N E 2 0 24

Immune checkpoint inhibitors include biological agents targeting programmed KEY POINTS
cell death protein-1 (PD-1) (eg, pembrolizumab, nivolumab, cemiplimab) or
● Up to one in 10 patients on
ligand of PD-1 (PD-L1) (eg, atezolizumab, avelumab, durvalumab), cytotoxic immune checkpoint
T-lymphocyte–associated protein-4 (CTLA4) (eg, ipilimumab, tremelimumab), inhibitors have neurotoxicity,
and lymphocyte activating gene-3 (LAG-3) (eg, relatlimab). Checkpoint inhibitors which can involve the CNS
are immune inducers, and whereas the goal is to enhance the antitumor activity and peripheral nervous
system and often overlap
of T cells, immune-related adverse effects can affect any organ system.
with concurrent systemic

Neurologic immune-related toxicity includes hypophysitis and inflammatory involvement.
hypopituitarism, myasthenia gravis, myositis, vasculitis, neuropathies including Patients on dual therapy
acute inflammatory demyelinating polyradiculoneuropathy, meningocephalitis (eg, anti–cytotoxic
T-lymphocyte–associated
and encephalitis, and other demyelinating disorders, and they often overlap.
antigen-4 [CTLA4] plus
CNS involvement may be concurrent with peripheral nervous system anti–programmed cell
manifestations in approximately 20% of cases.96,97 Distinct encephalitic death protein-1 [PD-1]/ligand
phenotypes related to immune checkpoint inhibitors have been identified: focal of PD-1 [PD-L1]) are
at higher risk.
with limbic involvement (and more prevalent association with neuronal
autoantibodies) or extralimbic meningoencephalitis.98 Patients with extralimbic ● Management of
meningoencephalitis or with focal limbic involvement with either no neurotoxicity from immune
autoantibody or positive anti–glutamic acid decarboxylase or anti–cell-surface checkpoint inhibitors
antibodies are more likely to respond to therapy and achieve a favorable includes removal of the
agent, supportive therapy,
outcome.98 The neuromuscular phenotype of immune checkpoint inhibitor and prompt initiation of
toxicity may be more prevalent with anti-PD-1/PD-L1 therapy.99 Moreover, corticosteroids. Patients
the overlap of myositis with myasthenia is more commonly seen in this who do not improve in
population,96,99 which can contribute to higher fatality rates seen with this 48 hours should be
considered for escalation of
presentation, attributed to refractory neuromuscular respiratory failure. immunotherapy (eg,
Overall, neurologic complications occur in less than 10% of patients on infliximab).
immune checkpoint inhibitors,100 with severe neurotoxicity experienced by
1% to 3% of patients.96 Concurrent inflammatory toxicity involving other organ ● Among patients receiving
CAR T-cell therapy, immune
systems (eg, myocarditis, thyroiditis, pneumonitis, enterocolitis, vitiligo) occurs
effector cell-associated
in more than two-thirds of patients.96 Dual immune checkpoint inhibitor therapy neurotoxicity syndrome is
(eg, anti-CTLA4 plus anti–PD-1/PD-L1 therapy) incurs higher risk for any, and highly prevalent and
fatal, neurologic complications100; among all agents, anti-CTLA4 drugs have the comprises aphasia,
highest risk for severe neurotoxicity.96 The majority of immune checkpoint encephalopathy, cortical
hyperexcitability, and
inhibitor-related neurologic complications occur within the first six cycles of cerebral edema of varying
therapy, but they may also occur when another immune checkpoint inhibitor is degrees; risk factors include
added to the regimen or when therapy is extended.96 Interestingly, patients with younger age, preexisting
neurologic immune-related adverse events from immune checkpoint inhibitors neurologic conditions, high
tumor burden, cytopenia,
have a higher prevalence of autoantibodies than patients with cancer who are not and early or severe cytokine
exposed to immune checkpoint inhibitors as well as those on immune release syndrome.
checkpoint inhibitor therapy but without neurotoxicity.97 Antibodies
may develop de novo on initiation of immune checkpoint inhibitor therapy.97
The cornerstone of managing immune checkpoint inhibitor toxicity is
supportive therapy with removal of the offending agent in patients with grade
3-4 toxicity101 and most who have grade 2 toxicity. Empiric immunosuppressive
treatment is often used in severe cases, including corticosteroids (eg, pulse dose
of 3 g to 5 g of methylprednisolone followed by 1 mg/kg/d of prednisone for 1 to
2 weeks and taper over 4 to 6 weeks), IV immunoglobulin, plasma exchange,
rituximab, or infliximab. Guidelines favor infliximab for severe toxicity without
improvement within 48 hours of initiation of corticosteroids.101 Patients who
receive systemic corticosteroids are more likely to achieve a favorable clinical
outcome (76% versus 24%)96 and tend to improve within the first few days of its

initiation. Prompt identification of patients refractory to corticosteroid therapy

facilitates decision-making on escalation of immunotherapy. Relapse rates are
markedly higher in patients with concurrent CNS and peripheral nervous system
involvement, those treated with anti-CTLA4 monotherapy or dual therapy, and
those in whom checkpoint inhibitors were restarted.96
Chimeric Antigen Receptor T-cell Therapy–related Complications

Another form of immunotherapy, genetically engineered autologous or

allogeneic T cells with chimeric antigen receptors (CARs) (eg, idecabtagene
vicleucel, lisocabtagene maraleucel, tisagenlecleucel, brexucabtagene autoleucel,
and axicabtagene ciloleucel), was approved in 2017 and has revolutionized
cancer care for patients with hematologic malignancies and certain solid tumors.
CAR agents have an extracellular domain that binds to a specific target molecule
expressed by tumor cells. Upon binding, T cells are activated via their
intracellular domain. Although each CAR T-cell therapy may have different
cellular targets, this class of drug has a very specific systemic toxidrome termed
cytokine release storm, during which a massive release of interleukin (IL)-1, IL-6,
IL-10, interferon gamma, and tumor necrosis factor alpha leads to high fever,
hypotension, shock, and hypoxia. Neurotoxicity is typically characterized by
toxic encephalopathy, aphasia, cortical hyperexcitability with seizures, and
cerebral edema; nonconvulsive status epilepticus occurs in approximately 10% of
these patients.102 The mechanisms underpinning neurotoxicity are not entirely
clear, but they are thought to be related to passive diffusion of cytokines into the
brain, trafficking of T cells into the CNS, and disruption of the blood-brain
barrier. Risk factors for development of neurotoxicity include younger age,
preexisting neurologic conditions, high tumor burden, cytopenia, and early or
severe cytokine release storm.103 In severe cases, disseminated intravascular
coagulation and other thrombotic events have been described, and rarely,
cytokine release storm can evolve into fulminant hemophagocytic
lymphohistiocytosis (or macrophage-activation syndrome).
Overall, cytokine release storm occurs in half of patients who receive CAR
T-cell therapy, and immune effector cell–associated neurotoxicity syndrome
(ICANS; ie, neurotoxicity from CAR T-cell therapy, also referred to CAR T-cell–
related encephalopathy syndrome) in 15% of these patients. These syndromes
can be fatal in approximately 4% of patients according to the US Food and
Drug Administration (FDA) Adverse Event Reporting System database as of
December 2022. Among survivors, more than two-thirds of patients report
persistent neurocognitive deficits 1 year later.104 The magnitude of cytokine
release storm and immune effector cell–associated neurotoxicity syndrome
varies widely and can be described using the 2019 American Society for
Transplantation and Cellular Therapy consensus standardized grading system for
both toxic syndromes (TABLE 11-8).105
In high-grade neurotoxicity (eg, grades 3-4), in which there is a concern for
intracranial hypertension, monitoring in the intensive care setting is
recommended, with consideration for osmotic therapy and surveillance imaging.
Neuroimaging is often unrevealing104; however, rare cases of subarachnoid
hemorrhage, infarction, and reversible T2 hyperintensity in the thalami, dorsal
pons, and medulla have been reported in addition to cerebral edema.102 EEG
monitoring is recommended for any level of toxicity because of high prevalence
of cortical hyperexcitability; antiseizure regimens are γ-aminobutyric
868 J U N E 2 0 24

acid–mediated (GABA-ergic) centered (eg, benzodiazepines and phenobarbital)
coupled with levetiracetam. High-dose corticosteroid therapy is added in patients
who have cytokine release storm and immune effector cell–associated
neurotoxicity syndrome refractory to anti-IL-6 therapy (IV tocilizumab 8 mg/kg
or IV siltuximab 11 mg/kg); in these patients methylprednisolone (1 mg/kg every
12 hours) or dexamethasone (10 mg every 6 hours) is often used.102,103 More
recently, centers have been using anakinra, an IL-1 receptor antagonist, for
management of corticosteroid-refractory cytokine release storm and immune

effector cell–associated neurotoxicity syndrome with some success in mitigating
cytokine release storm symptoms but less impact on severity of neurologic
symptoms.106
The American Society for Transplantation and Cellular Therapy Consensus TABLE 11-8
for Grading Neurotoxicity From Immune Effector Cellsa
Toxicity domainb Grade 1 Grade 2 Grade 3 Grade 4
Neurologic assessment score 7-9 3-6 0-2 Untestable

(Immune Effector Cell–Associated
Encephalopathy scorec)
Level of consciousness Awake Arousable to Arousable to tactile Stupor or coma

voice stimulus
Seizure Not NA Clinical seizures (focal or Clinical status epilepticus

applicable generalized)
Convulsive seizure
(NA)
Nonconvulsive seizures longer than 5 min
Repetitive seizures
without return to
baseline
Motor function NA NA NA Hemiparesis or

paraparesis
Intracranial NA NA Focal mass effect on Diffuse cerebral edema on

hypertension/ neuroimaging (excluding neuroimaging
cerebral edema from hemorrhage)
Clinical findings
suggestive of clinically
significant cerebral
edema
Extensor or flexor
posture
Abducens nerve palsy
Papilledema
Cushing triad
a
Modified with permission from Lee DW, et al, Bio Blood Marrow Transplant.105 © 2019 Elsevier B.V.
b
The most concerning finding drives the grading of neurotoxicity. Symptoms and findings must be
attributable to immune effector cells and no other cause (eg, medication).
c
The Immune Effector Cell–Associated Encephalopathy score is a 10-point scale for neurologic
assessment, with lower scores representing more severe impairment. One point is given for each task
that is correctly answered or performed: orientation (four points total) to year, month, city, hospital;
naming of three objects (one point each), ability to follow simple commands (one point), sentence writing
(one point), counting backward from 100 by 10s (one point).

Hematopoietic Stem Cell Transplantation–associated Thrombotic

Microangiopathy
The diagnostic criteria for thrombotic microangiopathy include blood markers of
multiorgan dysfunction, particularly renal, hepatic, and tissue injuries, as well as
presence of neurologic symptoms, need for transfusions, and hypertension. CNS
involvement in hematopoietic stem cell transplantation-associated thrombotic

microangiopathy may manifest as encephalopathy (9% to 33% of patients),
seizures (11% to 19% of patients), intracranial hemorrhage (2% to 15% of patients),

posterior reversible encephalopathy syndrome (9% to 17% of patients), and
ischemic stroke (11% of patients), according to a 2023 meta-analysis of 15
studies.107 In clinical practice, establishing the diagnosis can be challenging, and
transdisciplinary collaboration with hematology is paramount. Treatment may
include immunomodulation, particularly in patients with neurologic involvement.
Radiation Neurotoxicity
Radiation neurotoxicity can be classified as acute (ie, occurring immediately
after or during therapy), early delayed (ie, within 12 weeks of treatment), and
delayed long-term (ie, 3 months to years after treatment). The main driving
mechanism in acute toxicity is increased edema from leaky capillaries. Although
exacerbation of neurologic deficits from mass effect can be pronounced in acute
radiation neurotoxicity, this is usually responsive to corticosteroids, and the
prognosis is favorable. In subacute neurotoxicity, pathobiology is caused by a
temporary delay in myelin synthesis. Patients may experience somnolence,
headaches, and cognitive impairment. No definite treatment exists, although
corticosteroids may be helpful, and symptoms can resolve spontaneously. In
contrast, delayed neurotoxicity can progress relentlessly from direct injury to
oligodendrocytes and the endothelium, triggering an inflammatory cascade and
ongoing progressive syndrome comprising focal deficits or nonspecific neurologic
decline; the prognosis is guarded, even with treatment. Radiation necrosis, a type
of delayed neurotoxicity, is highly prevalent, with risks following a single-session
stereotactic irradiation reaching 12% to 20%, depending on the radiation dose
and volume of irradiated tissue.34 It is usually a delayed complication, more
prevalent 10 to 36 months after therapy.
Teasing apart radionecrosis from progression of disease can be challenging,
and it is often only possible with histopathologic evaluation. MRI perfusion
and spectroscopy demonstrating high plasma volumes and choline peaks,
respectively, suggest tumor recurrence, and positron emission tomography
(PET) with amino acid tracers can aid in the diagnosis.12 However, these
neuroimaging modalities are often not possible during acute decompensation
and in the neurocritical care setting. Significant radiation necrosis leading to
acute neurologic manifestations can be treated with corticosteroids, with
consideration of the use of bevacizumab (an inhibitor of VEGF) whenever
feasible because of its superior effect and lack of interference with future efficacy
of immunotherapy in patients with metastatic disease.12
Radiation-induced myelopathy is a chronic, debilitating process that
progresses over weeks to months and carries a mortality risk of more than 50%,
largely attributable to infectious complications. The risk of radiation-induced
myelopathy increases with the radiation dose, estimated at less than 1% for total
doses 50 Gy to 55 Gy and 5% for 55 Gy to 60 Gy. This risk exponentially increases
with reirradiation, particularly with a cumulative dose of 120 Gy.108
870 J U N E 2 0 24

Postsurgical Complications KEY POINTS
Acute postsurgical complications include hematoma into the surgical bed, dural
● Supportive and
closure–related complications, postoperative peritumoral edema, early symptomatic care, centered
postoperative seizure, perioperative stroke, syndrome of inappropriate on antiseizure and
antidiuretic hormone secretion, systemic complications, VTE, and sepsis.14 Five intracranial pressure
percent of patients may require reoperations, which are as likely to occur during targeted therapies, are the
mainstay of care for high-
index hospitalization as after discharge.14 Postsurgical hematoma occurs in
grade neurotoxicity from

1.1% to 4.4% of patients, manifesting in the majority of patients within 6 hours CAR T-cell therapies.
after surgery but also reported up to 30 days later, with a median occurrence circa Concurrently,
postoperative day 2.14 Infratentorial location of tumor is associated with immunosuppression with
anti-interleukin (IL)-6
increased postoperative length of stay, pneumonia, reintubation, and superficial
therapy and consideration
site infection.14 Perisurgical morbidity of ventriculoperitoneal shunt placement is for high-dose
slightly higher in patients with CNS malignancy, with rates of complications at corticosteroids in refractory
4% to 10%; peritoneal seeding of tumor has not been demonstrated. Outcomes cases targets the etiology of
the syndrome, addressing
are better if surgery can be performed electively as opposed to emergently.39
the cytokine storm.
Additionally, early transition to radiosurgery to accelerate adjuvant therapy
appears promising and safe.109 Impaired wound healing and infection and ● Radiation necrosis is a
perioperative hemorrhagic complications are more common in patients with frequent type of delayed
long-term exposure to corticosteroids and in those with recent exposure to toxicity from radiation
therapy, manifested as
antiangiogenic agents (eg, bevacizumab).34 increased edema,
hemorrhage, and mass
PEDIATRIC CONSIDERATIONS effect. Distinguishing
Cancer in the pediatric, adolescent, and young adult populations should be radiation necrosis from
progression of oncologic
recognized as a distinct disease entity because of specific features in each disease can be challenging
of these age subgroups different from each other and from older adults. Cancer is but is critical to the correct
the fourth leading cause of death and the tenth leading cause of disability- implementation of
adjusted life-years in adolescents and young adults.110 CNS tumors are associated appropriate therapy.
with the highest mortality among pediatric patients with malignancies and are
the second most common malignancy after hematologic malignancies, which
may, in itself, present with CNS emergencies. In general, most children with
solid brain tumors will require surgical treatment. The approach to seizures,
hydrocephalus and herniation, and spinal cord compression is similar to that in
adults, adjusting medication dosing to pediatric requirements. Hydrocephalus is
present in nearly 60% of children with solid brain tumors, often presenting with
the typical yet nonspecific symptoms of headache, nausea and vomiting, and gait
disturbance, whereas seizures occur in about one-third of these patients (more
commonly in patients with benign brain tumors), and focal findings are less
common. In children with infratentorial brain tumors, which comprise
approximately two-thirds of brain tumors in children, hydrocephalus is even
more common. Of note, there are differences in pathophysiology. In children
with obstructive hydrocephalus due to posterior fossa lesions, there is commonly
secondary compression of venous outflow in addition to the primary
compressive mass, rendering the etiology of postoperative hydrocephalus
slightly different. The specific tumor characteristics and presence of
intraventricular blood affect the rate of postoperative hydrocephalus.14 Further,
CNS infection is more frequent with the placement of an external ventricular
drain in addition to tumor resection.111 For posterior fossa-related
hydrocephalus, endoscopic third ventriculostomy is similarly successful to
ventriculoperitoneal shunting.17 Cancer-related stroke occurs in only 1% of
children with cancer, more commonly in patients with brain tumors and

leukemia. Malignant spinal cord compression occurs in approximately 3% to 5%

of patients with pediatric cancers and is the presenting finding in three in four
cases.112 Survivors of childhood cancers, even when successfully treated, often
continue to experience a significant chronic burden of major surgical
interventions.113
CONCLUSION
Neuro-oncologic emergencies span the boundaries of subspecialties in neurology
and require a broad understanding of neuroimmunology, neuronal
hyperexcitability, CSF flow dynamics, intracranial compliance, neuroanatomy,
and general principles of neurocritical care.
ACKNOWLEDGEMENT
The authors thank Bakhtawar Ahmad, MD, Daniela Pomar MD, and Maryam
Rahman, MD, for their contributions to this article.
USEFUL WEBSITES
The Graded Prognostic Assessment Tool FDA Adverse Event Reporting System
This tool provides an updated diagnosis-specific This FDA webpage contains the FDA Adverse Event
graded prognostic assessment to estimate survival Reporting System for the epidemiologic data on
of patients with brain metastasis. adverse events from treatment modalities, and it is
brainmetgpa.com updated quarterly.
open.fda.gov/data/faers/
NYUMets
This website contains the dataset available from the
NYU Mets-Brain project.
nyumets.org
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Neuro-oncologic REVIEW ARTICLE

systemic cancer, following three thematic classifications: (1) complications

LATEST DEVELOPMENTS: The main driver of mortality in patients with brain

ESSENTIAL POINTS:Neuro-oncologic emergencies span the boundaries of

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

systemic cancer frequently constitute the presenting symptoms for many

coupled with a growing prevalence of many types of cancer in older adults

to the tumor itself. This article highlights key aspects of epidemiology,

DIRECT TUMOR-MEDIATED COMPLICATIONS

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

system (CNS) tumors.

● Glioblastomas are the

prevalent in men and older

● Lung, breast, and

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Skin (melanoma) 7.4%

Synchronous metastasis (diagnosis during primary cancer staging)

Small cell 15.8%

Non–small cell not otherwise specified 12.8%

Squamous cell 5.2%

Skin (melanoma) 0.7%

Nonsynchronous metastasis (diagnosis after primary cancer staging)

Skin (melanoma) 28.2%

Non–small cell not otherwise specified 25.6%

Small cell 23.5%

Squamous cell 15.9%

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

complication such as intratumoral hemorrhage, or congestive cerebral edema

concurrently and culminate with brain herniation (FIGURE 11-1), posing a

junction dysfunction, increased pinocytotic activity, presence of fenestrations,

Mechanistic Underpinnings and Management of Intrinsic Tumor-related TABLE 11-2

Complication Mechanisms Management

Edema Blood-brain barrier disruption Corticosteroids, surgical decompression, osmotic

Herniation Direct displacement of brain tissue and Corticosteroids, surgical decompression,

Hydrocephalus Obstructive CSF diversion, surgical decompression,

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blood-brain barrier is partly related to increased activity in the vascular

to treating edema related to radiation necrosis.

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Herniation ventricular system;

hence the need for cautious

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CASE 11-1 A 21-year-old man presented to the emergency department with a

herniation leading to hydrocephalus (FIGURE 11-2). He was started on

COMMENT The central nervous system is able to compensate temporarily for

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Management of Direct Tumor-Mediated Complications

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OSMOTHERAPY. The role of osmotherapy in the management of edema and mass

be transferred into parenchyma) is indicated by its reflection coefficient, in

the blood-brain barrier and a value of 1 corresponds to complete impermeability.

the repeated administration of osmotic agents, mannitol in particular.

TABLE 11-3 The New England Spinal Metastasis Scorea

Characteristic Points assigned

Modified Bauer Score ≤ 2 0

Modified Bauer Score ≥ 3 2

Dependent ambulator or nonambulatory 0

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because of its long half-life, low mineralocorticoid activity, high bioavailability,

high-dose dexamethasone is intended to facilitate pain control and prevent

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SURGICAL TREATMENT. Urgent or emergent surgical resection is frequently

necessary for patients presenting with space-occupying CNS tumors. The

surgical goal is generally gross total resection, which may be followed by